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Diabetes in pregnancy: management from preconception to the postnatal period
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Diabetes in pregnancy: management from preconception to the postnatal period
This guideline covers managing diabetes and its complications in women who are planning pregnancy or are already pregnant. It aims to improve the diagnosis of gestational diabetes and help women with diabetes to self-manage their blood glucose levels before and during pregnancy.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Blood glucose and plasma glucose
'Blood glucose' is the more commonly used term. However, a lot of the evidence this guideline is based on uses 'plasma' rather than 'blood' glucose, and patient‑held glucose meters and monitoring systems are calibrated to plasma glucose equivalents. Because of this, in this guideline we use the term 'blood glucose', except when referring to specific concentration values.
# Preconception planning and care
## Information about outcomes and risks for mother and baby
Provide information, advice and support, to empower women to have a positive experience of pregnancy and to reduce the risks of adverse pregnancy outcomes for mother and baby.
Explain to women with diabetes who are planning a pregnancy that:
if they have good blood glucose control before conception and throughout their pregnancy, this will reduce the risk of miscarriage, congenital malformation, stillbirth and neonatal death but
the risks can be reduced but not eliminated.
When women with diabetes are planning a pregnancy, provide them and their families with information about how diabetes affects pregnancy and how pregnancy affects diabetes. The information should cover:
the role of diet, body weight and exercise
the risks of hypoglycaemia and impaired awareness of hypoglycaemia during pregnancy
how nausea and vomiting in pregnancy can affect blood glucose control
the increased risk of having a baby who is large for gestational age, which increases the likelihood of birth trauma, induction of labour, and instrumental and caesarean section deliveries
the need for diabetic retinopathy assessment before and during pregnancy
the need for diabetic nephropathy assessment before pregnancy
the importance of maternal blood glucose control during labour and birth, and the need for early feeding of the baby, in order to reduce the risk of neonatal hypoglycaemia
the possibility of that the baby may have health problems in the first 28 days, and may need admitting to a neonatal unit
the risk of the baby developing obesity, diabetes and/or other health problems in later life.
## The importance of planning pregnancy and the role of contraception
Emphasise the importance of planning for pregnancy, as part of diabetes education from adolescence for women with diabetes.
Explain to women with diabetes that their choice of contraception should be based on their own preferences and any risk factors (covered in the Faculty of Sexual and Reproductive Healthcare UK medical eligibility criteria for contraceptive use).
Advise women with diabetes that they can use oral contraceptives.
Advise women with diabetes who are planning to become pregnant:
that the risks associated with diabetes in pregnancy will increase the longer they have had diabetes
to use contraception until they have good blood glucose control (assessed by HbA1c levels – see recommendation 1.1.18)
that blood glucose targets, glucose monitoring, medicines for treating diabetes (including insulin regimens) and medicines for complications of diabetes will need to be reviewed before and during pregnancy
that extra time and effort is needed to manage diabetes during pregnancy, and that more frequent contact is needed with healthcare professionals.
For women with diabetes who are planning a pregnancy, provide information about the local arrangements for support, including emergency contact numbers.
## Diet, dietary supplements and body weight
Offer individualised dietary advice to women with diabetes who are planning a pregnancy.
For women with diabetes who are planning a pregnancy and who have a body mass index (BMI) above 27 kg/m2, offer advice on how to lose weight, in line with the NICE guideline on identifying, assessing and managing obesity. See the NICE guideline on BMI for guidance on using variations on the BMI cut-off, based on the risk for different ethnic groups.
Advise women with diabetes who are planning a pregnancy to take folic acid (5 mg/day) until 12 weeks of gestation to reduce the risk of having a baby with a neural tube defect.
## Monitoring blood glucose and ketones before pregnancy
Offer up to monthly measurement of HbA1c levels for women with diabetes who are planning a pregnancy.
Offer blood glucose meters for self-monitoring to women with diabetes who are planning a pregnancy.
If a woman with diabetes who is planning a pregnancy needs to intensify blood glucose‑lowering therapy, advise her to monitor her blood glucose more often, to include fasting levels and a mixture of pre‑meal and post‑meal levels.
Offer blood ketone testing strips and a meter to women with type 1 diabetes who are planning a pregnancy, and advise them to test for ketonaemia if they become hyperglycaemic or unwell.
## Target blood glucose and HbA1c levels before pregnancy
Agree individualised targets for self‑monitoring of blood glucose with women who have diabetes and are planning a pregnancy, taking into account the risk of hypoglycaemia.
Advise women with type 1 diabetes who are planning a pregnancy to aim for the normal capillary plasma glucose target ranges:
a fasting plasma glucose level of 5 mmol/litre to 7 mmol/litre on waking and
a plasma glucose level of 4 mmol/litre to 7 mmol/litre before meals at other times of the day.For more information, see the section on blood glucose targets in the NICE guideline on type 1 diabetes in adults.
Advise women with diabetes who are planning a pregnancy to aim to keep their HbA1c level below 48 mmol/mol (6.5%), if this is achievable without causing problematic hypoglycaemia.
Reassure women that any reduction in HbA1c level towards the target is likely to reduce the risk of congenital malformations in the baby.
Strongly advise women with diabetes whose HbA1c level is above 86 mmol/mol (10%) not to get pregnant until their HbA1c level is lower, because of the associated risks (see recommendation 1.1.2).
## Safety of medicines for diabetes before and during pregnancy
Women with diabetes may be advised to use metformin as an adjunct or alternative to insulin in the preconception period and during pregnancy, when the likely benefits from improved blood glucose control outweigh the potential for harm. Stop all other oral blood glucose‑lowering agents before pregnancy, and use insulin instead.
Be aware that the available evidence on rapid‑acting insulin analogues (aspart and lispro) does not show an adverse effect on the pregnancy or the health of baby.
Use isophane insulin (also known as NPH insulin) as the first choice for long‑acting insulin during pregnancy. Consider continuing treatment with long‑acting insulin analogues (insulin detemir or insulin glargine) for women with diabetes who have established good blood glucose control before pregnancy.Note that this is an off-label use of long-acting insulin analogues. See NICE's information on prescribing medicines.
## Safety of medicines for complications of diabetes before and during pregnancy
Stop angiotensin‑converting enzyme inhibitors and angiotensin‑II receptor antagonists before conception, or as soon as pregnancy is confirmed. Use alternative antihypertensive agents that are suitable for pregnant women.
Stop statins before pregnancy, or as soon as pregnancy is confirmed.
## Making it easier for women to access preconception care
From adolescence onwards, at every contact with women with diabetes:
healthcare professionals (including the diabetes care team) should explain the benefits of preconception blood glucose control
the diabetes care team should record the plans women have for pregnancy and conception.
Provide preconception care for women with diabetes in a supportive environment, and encourage partners or other family members to attend.
## Education and advice
As early as possible, offer a structured education programme to women with diabetes who are planning a pregnancy (if they have not already attended one). For more guidance, see the education and information section in the NICE guideline on type 1 diabetes in adults, and the patient education section in the NICE guideline on type 2 diabetes in adults.
Offer preconception care and advice before stopping contraception for women with diabetes who are planning a pregnancy.
## Retinal assessment before pregnancy
For women with diabetes who are seeking preconception care, offer a retinal assessment at their first appointment (unless they have had a retinal assessment in the last 6 months).
Advise women with diabetes who are planning a pregnancy to defer rapid optimisation of blood glucose control until after they have had retinal assessment and treatment.
## Renal assessment before pregnancy
Offer women with diabetes a renal assessment (including a measure of albuminuria) before stopping contraception.
Consider referring women with diabetes to a nephrologist before stopping contraception if:
serum creatinine is 120 micromol/litre or more or
the urinary albumin:creatinine ratio is greater than 30 mg/mmol or
the estimated glomerular filtration rate (eGFR) is less than 45 ml/minute/1.73 m2.
# Gestational diabetes
## Risk assessment, testing and diagnosis
To help women make an informed decision about risk assessment and testing for gestational diabetes, explain that:
some women find that gestational diabetes can be controlled with changes in diet and exercise
most women with gestational diabetes will need oral blood glucose‑lowering agents or insulin
if gestational diabetes is not detected and controlled, there is a small increase in the risk of serious adverse birth complications such as shoulder dystocia
women with gestational diabetes will need more monitoring, and may need more interventions during pregnancy and labour.
Assess the risk of gestational diabetes using risk factors in a healthy population. At the booking appointment, check for the following risk factors:
BMI above 30 kg/m2
previous macrosomic baby weighing 4.5 kg or more
previous gestational diabetes
family history of diabetes (first‑degree relative with diabetes)
an ethnicity with a high prevalence of diabetes.Offer women with any of these risk factors testing for gestational diabetes (see recommendations 1.2.5 to 1.2.7).
Do not use fasting plasma glucose, random blood glucose, HbA1c, glucose challenge test or urinalysis for glucose to assess the risk of developing gestational diabetes.
Consider further testing to exclude gestational diabetes in women who have the following reagent strip test results during routine antenatal care:
glycosuria of 2+ or above on 1 occasion
glycosuria of 1+ or above on 2 or more occasions.
Use the 75-g 2-hour oral glucose tolerance test (OGTT) to test for gestational diabetes in women with risk factors (see recommendation 1.2.2).
For women who have had gestational diabetes in a previous pregnancy, offer:
early self‑monitoring of blood glucose or
a 75-g 2‑hour OGTT as soon as possible after booking (whether in the first or second trimester), and a further 75-g 2‑hour OGTT at 24 to 28 weeks if the results of the first OGTT are normal.
Offer women with any of the other risk factors for gestational diabetes (see recommendation 1.2.2) a 75-g 2‑hour OGTT at 24 to 28 weeks.
Diagnose gestational diabetes if the woman has either:
a fasting plasma glucose level of 5.6 mmol/litre or above or
a 2‑hour plasma glucose level of 7.8 mmol/litre or above.
When women are diagnosed with gestational diabetes:
-ffer a review with the joint diabetes and antenatal clinic within 1 week.
tell their primary healthcare team (see also the section on continuity of care in the NICE guideline on patient experience in adult NHS services).
## Interventions
Explain to women with gestational diabetes:
the implications (both short and long term) of the diagnosis for her and her baby (including UK government advice on driving with diabetes)
that good blood glucose control throughout pregnancy will reduce the risk of fetal macrosomia, trauma during birth (for her and her baby), induction of labour and/or caesarean section, neonatal hypoglycaemia, and perinatal death
that treatment includes changes in diet and exercise, and could involve medicines.
Teach women with gestational diabetes how to self‑monitor their blood glucose.
Use the same capillary plasma glucose target levels for women with gestational diabetes as for women with pre‑existing diabetes (see recommendations 1.3.5 and 1.3.6).
Tailor blood glucose‑lowering therapy to the blood glucose profile and personal preferences of the woman with gestational diabetes.
When women are diagnosed with gestational diabetes, offer advice about changes in diet and exercise.
Advise women with gestational diabetes to eat a healthy diet during pregnancy, and to switch from high to low glycaemic index food.
Refer all women with gestational diabetes to a dietitian.
Advise women with gestational diabetes to exercise regularly (for example, walking for 30 minutes after a meal).
For women with gestational diabetes who have a fasting plasma glucose level below 7 mmol/litre at diagnosis, offer a trial of diet and exercise changes.
If blood glucose targets are not met with diet and exercise changes within 1 to 2 weeks, offer metformin.
If metformin is contraindicated or unacceptable to the woman, offer insulin.
If blood glucose targets are not met with diet and exercise changes plus metformin, offer insulin as well.
For women with gestational diabetes who have a fasting plasma glucose level of 7.0 mmol/litre or above at diagnosis, offer:
immediate treatment with insulin, with or without metformin and
diet and exercise changes.
For women with gestational diabetes who have a fasting plasma glucose level of between 6.0 and 6.9 mmol/litre and complications such as macrosomia or hydramnios, consider:
immediate treatment with insulin, with or without metformin and
diet and exercise changes.
# Antenatal care for women with diabetes
See also the NICE guideline on antenatal care for uncomplicated pregnancies.
## Monitoring blood glucose
Advise pregnant women with type 1 diabetes to test their fasting, pre‑meal, 1‑hour post‑meal and bedtime blood glucose levels daily.
Advise pregnant women with type 2 diabetes or gestational diabetes who are on a multiple daily insulin injection regimen to test their fasting, pre‑meal, 1‑hour post‑meal and bedtime blood glucose levels daily.
Advise pregnant women with type 2 diabetes or gestational diabetes to test their fasting and 1‑hour post‑meal blood glucose levels daily if they are:
managing their diabetes with diet and exercise changes alone or
taking oral therapy (with or without diet and exercise changes) or single‑dose intermediate‑acting or long‑acting insulin.
## Target blood glucose levels
Agree individualised targets for self‑monitoring of blood glucose with pregnant women with diabetes, taking into account the risk of hypoglycaemia.
Advise pregnant women with any form of diabetes to maintain their capillary plasma glucose below the following target levels, if these are achievable without causing problematic hypoglycaemia:
fasting: 5.3 mmol/litreand
hour after meals: 7.8 mmol/litre or
hours after meals: 6.4 mmol/litre.
Advise pregnant women with diabetes who are taking insulin to maintain their capillary plasma glucose level above 4 mmol/litre.
## Monitoring HbA1c
Measure HbA1c levels at the booking appointment for all pregnant women with pre‑existing diabetes, to determine the level of risk for the pregnancy.
Consider measuring HbA1c levels in the second and third trimesters of pregnancy for women with pre‑existing diabetes, to assess the level of risk for the pregnancy.
Be aware that the level of risk for the pregnancy for women with pre‑existing diabetes increases with an HbA1c level above 48 mmol/mol (6.5%).
Measure HbA1c levels when women are diagnosed with gestational diabetes, to identify women who may have pre‑existing type 2 diabetes.
Do not routinely use HbA1c levels to assess a woman's blood glucose control in the second and third trimesters of pregnancy.
## Managing diabetes during pregnancy
A 2020 Medicines and Healthcare products Regulatory Agency drug safety update highlights the need to rotate insulin injection sites within the same body area to avoid cutaneous amyloidosis.
Consider rapid‑acting insulin analogues (aspart and lispro) for pregnant women with diabetes. Be aware that these insulin analogues have advantages over soluble human insulin during pregnancy.
Advise women with insulin‑treated diabetes of the risks of hypoglycaemia and impaired awareness of hypoglycaemia in pregnancy, particularly in the first trimester.
Advise pregnant women with insulin‑treated diabetes to always have a fast‑acting form of glucose available (for example, dextrose tablets or glucose‑containing drinks).
Provide glucagon to pregnant women with type 1 diabetes, for use if needed. Explain to the woman and her partner or other family members how to use it.
Offer continuous subcutaneous insulin infusion (CSII; also known as insulin pump therapy) to pregnant women with insulin-treated diabetes who:
are using multiple daily injections of insulin and
do not achieve blood glucose control without significant disabling hypoglycaemia.
Offer real-time continuous glucose monitoring (rtCGM) to all pregnant women with type 1 diabetes to help them meet their pregnancy blood glucose targets and improve neonatal outcomes.
Offer intermittently scanned continuous glucose monitoring (isCGM, commonly referred to as 'flash') to pregnant women with type 1 diabetes who are unable to use rtCGM or express a clear preference for isCGM.
Consider rtCGM for pregnant women who are on insulin therapy but do not have type 1 diabetes, if:
they have problematic severe hypoglycaemia (with or without impaired awareness of hypoglycaemia) or
they have unstable blood glucose levels that are causing concern despite efforts to optimise glycaemic control.
For pregnant women who are using continuous glucose monitoring (CGM), a member of the joint diabetes and antenatal care team with expertise in these systems should provide education and support (including advising women about sources of out-of-hours support).
For a short explanation of why the committee made the 2020 recommendations and how they might affect practice, see the rationale and impact section on continuous glucose monitoring .
Full details of the evidence and the committee's discussion are in evidence review A: continuous glucose monitoring.
Loading. Please wait.
Offer blood ketone testing strips and a meter to pregnant women with type 1 diabetes. Advise them to test for ketonaemia and to seek urgent medical advice if they become hyperglycaemic or unwell.
Advise pregnant women with type 2 diabetes or gestational diabetes to seek urgent medical advice if they become hyperglycaemic or unwell.
Test urgently for ketonaemia if a pregnant woman with any form of diabetes presents with hyperglycaemia or is unwell.
Immediately admit pregnant women with suspected diabetic ketoacidosis for level 2 critical care, where they can receive both medical and obstetric care.
## Retinal assessment during pregnancy
After pregnant women with pre‑existing diabetes have had their first antenatal clinic appointment:
-ffer retinal assessment by digital imaging with mydriasis using tropicamide (unless they have had a retinal assessment in the last 3 months)
if they have diabetic retinopathy, offer an additional retinal assessment at 16 to 20 weeks
-ffer another retinal assessment at 28 weeks.
Diabetic retinopathy should not be considered a contraindication to rapid optimisation of blood glucose control in women who present with a high HbA1c in early pregnancy.
Diabetic retinopathy should not be considered a contraindication to vaginal birth.
## Renal assessment during pregnancy
Arrange a renal assessment at first contact during the pregnancy for women with pre‑existing diabetes, if they have not had 1 in the last 3 months.
Consider referring pregnant women with diabetes to a nephrologist if:
their serum creatinine is 120 micromol/litre or more or
the urinary albumin:creatinine ratio is greater than 30 mg/mmol or
total protein excretion exceeds 0.5 g/day.
Do not use eGFR to measure kidney function in pregnant women.
Consider thromboprophylaxis for pregnant women with nephrotic range proteinuria above 5 g/day (albumin:creatinine ratio greater than 220 mg/mmol).
## Preventing pre‑eclampsia
For guidance on using antiplatelet agents to reduce the risk of pre‑eclampsia in pregnant women with diabetes, see the section on antiplatelet agents in the NICE guideline on hypertension in pregnancy.
## Detecting congenital malformations
Offer women with diabetes an ultrasound scan at 20 weeks to detect fetal structural abnormalities, including examination of the fetal heart (4 chambers, outflow tracts and 3 vessels).
## Monitoring fetal growth and wellbeing
Offer pregnant women with diabetes ultrasound monitoring of fetal growth and amniotic fluid volume every 4 weeks from 28 to 36 weeks.
Routine monitoring of fetal wellbeing before 38 weeks is not recommended in pregnant women with diabetes, unless there is a risk of fetal growth restriction. This includes methods such as fetal umbilical artery doppler recording, fetal heart rate recording and biophysical profile testing.
Provide an individualised approach to monitoring fetal growth and wellbeing for women with diabetes and a risk of fetal growth restriction (macrovascular disease or nephropathy).
## Organisation of antenatal care
Offer immediate contact with a joint diabetes and antenatal clinic to pregnant women with diabetes.
Joint diabetes and antenatal clinics should be in contact with women with diabetes every 1 to 2 weeks throughout pregnancy, for blood glucose control assessment.
At antenatal appointments, provide care specifically for women with diabetes, in addition to routine care for healthy pregnant women (see the NICE guideline on antenatal care for uncomplicated pregnancies). Table 1 describes how care for women with diabetes differs from routine antenatal care.
At each appointment, offer pregnant women with diabetes ongoing opportunities for information and education.
Appointment
Care for women with diabetes during pregnancy
Booking appointment (joint diabetes and antenatal care) – ideally by 10 weeks
Discuss how diabetes will affect the pregnancy, birth and early parenting (such as breastfeeding and initial care of the baby).
If the woman has not had preconception care:
give information, education and advice
take a clinical history to establish the extent of diabetes‑related complications (including neuropathy and vascular disease), and review medicines for diabetes and its complications.
If the woman has had preconception care, continue to provide information, education and advice on achieving optimal blood glucose control (including dietary advice).
Offer retinal assessment for women with pre‑existing diabetes unless the woman has been assessed in the last 3 months.
Offer a renal assessment for women with pre‑existing diabetes, if they have not had 1 in the last 3 months.
Arrange contact with the joint diabetes and antenatal clinic every 1 to 2 weeks throughout pregnancy for all women with diabetes.
Measure HbA1c levels for women with pre‑existing diabetes to determine the level of risk for the pregnancy.
Offer self‑monitoring of blood glucose or a 75-g 2‑hour oral glucose tolerance test (OGTT) as soon as possible for women with previous gestational diabetes who book in the first trimester.
Confirm the viability of the pregnancy and gestational age at 7 to 9 weeks.
weeks
Offer retinal assessment at 16 to 20 weeks to women with pre‑existing diabetes who had diabetic retinopathy at their first antenatal clinic visit.
Offer self‑monitoring of blood glucose or a 75-g 2‑hour OGTT as soon as possible for women with previous gestational diabetes who book in the second trimester.
weeks
Offer an ultrasound scan to detect fetal structural abnormalities, including examination of the fetal heart (4 chambers, outflow tracts and 3 vessels).
weeks
Offer ultrasound monitoring of fetal growth and amniotic fluid volume.
Offer retinal assessment to all women with pre‑existing diabetes.
Women diagnosed with gestational diabetes as a result of routine antenatal testing at 24 to 28 weeks enter the care pathway.
weeks
Offer ultrasound monitoring of fetal growth and amniotic fluid volume.
Offer nulliparous women all routine investigations normally scheduled for 31 weeks in routine antenatal care.
weeks
No differences in care for women with diabetes.
weeks
Offer ultrasound monitoring of fetal growth and amniotic fluid volume.
Provide information and advice about:
timing, mode and management of birth
analgesia and anaesthesia
changes to blood glucose‑lowering therapy during and after birth
care of the baby after birth
starting to breastfeed and the effect of breastfeeding on blood glucose control
contraception and follow‑up.
weeks to 38 weeks plus 6 days
Offer induction of labour or (if indicated) caesarean section to women with type 1 or type 2 diabetes. Await spontaneous labour for other women.
weeks
Offer tests of fetal wellbeing.
weeks
Offer tests of fetal wellbeing.
Advise women with uncomplicated gestational diabetes to give birth no later than 40 weeks plus 6 days.
## Preterm labour in women with diabetes
Diabetes should not be considered a contraindication to tocolysis or to antenatal steroids for fetal lung maturation.
For women with insulin‑treated diabetes who are taking steroids for fetal lung maturation, give additional insulin according to an agreed protocol and monitor the woman closely.
Do not use betamimetic medicines for tocolysis in women with diabetes.
# Intrapartum care
## Timing and mode of birth
Discuss the timing and mode of birth with pregnant women with diabetes during antenatal appointments, especially during the third trimester.
Advise pregnant women with type 1 or type 2 diabetes and no other complications to have an elective birth by induced labour or (if indicated) caesarean section, between 37 weeks and 38 weeks plus 6 days of pregnancy.
Consider elective birth before 37 weeks for women with type 1 or type 2 diabetes who have metabolic or other maternal or fetal complications.
Advise women with gestational diabetes to give birth no later than 40 weeks plus 6 days. Offer elective birth by induced labour or (if indicated) by caesarean section to women who have not given birth by this time.
Consider elective birth before 40 weeks plus 6 days for women with gestational diabetes who have maternal or fetal complications.
Diabetes should not be considered a contraindication to vaginal birth after a previous caesarean section.
For pregnant women with diabetes who have an ultrasound‑diagnosed macrosomic fetus, explain the risks and benefits of vaginal birth, induction of labour and caesarean section.
## Anaesthesia
For women with diabetes and comorbidities such as obesity or autonomic neuropathy, offer an anaesthetic assessment in the third trimester of pregnancy.
If the woman has general anaesthesia for the birth, monitor blood glucose every 30 minutes from induction of general anaesthesia until after the baby is born and the woman is fully conscious.
## Blood glucose control during labour and birth
Monitor capillary plasma glucose every hour during labour and birth for women with diabetes, and maintain it between 4 mmol/litre and 7 mmol/litre.
Consider intravenous dextrose and insulin infusion from the onset of established labour for women with type 1 diabetes.
Use intravenous dextrose and insulin infusion during labour and birth for women with diabetes whose capillary plasma glucose is not maintained between 4 mmol/litre and 7 mmol/litre.
# Neonatal care
## Initial assessment and criteria for admission to intensive or special care
Advise women with diabetes to give birth in hospitals where advanced neonatal resuscitation skills are available 24 hours a day.
Babies of women with diabetes should stay with their mothers, unless there are complications or abnormal clinical signs that mean the baby needs to be admitted to intensive or special care.
Carry out blood glucose testing routinely at 2 to 4 hours after birth in babies of women with diabetes. Carry out blood tests for babies with clinical signs of polycythaemia, hyperbilirubinaemia, hypocalcaemia or hypomagnesaemia.
Perform an echocardiogram for babies of women with diabetes if they show clinical signs associated with congenital heart disease or cardiomyopathy, including heart murmur. Base the timing of the examination on the clinical circumstances.
Admit babies of women with diabetes to the neonatal unit if they have:
hypoglycaemia associated with abnormal clinical signs
respiratory distress
signs of cardiac decompensation from congenital heart disease or cardiomyopathy
signs of neonatal encephalopathy
signs of polycythaemia, and are likely to need partial exchange transfusion
need for intravenous fluids
need for tube feeding (unless adequate support is available on the postnatal ward)
jaundice requiring intense phototherapy and frequent monitoring of bilirubinaemia
been born before 34 weeks (or between 34 and 36 weeks, if the initial assessment of the baby and their feeding suggests this is clinically appropriate).
Do not transfer babies of women with diabetes to community care until:
they are at least 24 hours old and
you are satisfied that the baby is maintaining blood glucose levels and is feeding well.
## Preventing and assessing neonatal hypoglycaemia
All maternity units should have a written policy for preventing, detecting and managing hypoglycaemia in babies of women with diabetes.
Test the blood glucose of babies of women with diabetes using a quality‑assured method validated for neonatal use (ward‑based glucose electrode or laboratory analysis).
Women with diabetes should feed their babies:
as soon as possible after birth (within 30 minutes) and then
at frequent intervals (every 2 to 3 hours) until feeding maintains their pre‑feed capillary plasma glucose levels at a minimum of 2.0 mmol/litre.
Only use additional measures (such as tube feeding or intravenous dextrose) if:
capillary plasma glucose values are below 2.0 mmol/litre on 2 consecutive readings despite maximal support for feeding or
there are abnormal clinical signs or
the baby will not effectively feed orally.
For babies with clinical signs of hypoglycaemia, test blood glucose levels and provide intravenous dextrose as soon as possible.
# Postnatal care
## Blood glucose control, medicines and breastfeeding
Women with insulin‑treated pre‑existing diabetes should reduce their insulin immediately after birth and monitor their blood glucose levels to find the appropriate dose.
Explain to women with insulin‑treated pre‑existing diabetes that they are at increased risk of hypoglycaemia in the postnatal period (especially when breastfeeding), and advise them to have a meal or snack available before or during feeds.
Women who have been diagnosed with gestational diabetes should stop blood glucose‑lowering therapy immediately after birth.
Women with pre‑existing type 2 diabetes who are breastfeeding can resume or continue metformin immediately after birth, but should avoid other oral blood glucose‑lowering therapy while breastfeeding.Note that this is an off-label use of metformin. See NICE's information on prescribing medicines.
Women with diabetes who are breastfeeding should continue to avoid any medicines for their diabetes complications that were stopped for safety reasons when they started planning the pregnancy.
## Information and follow-up after birth
Refer women with pre‑existing diabetes back to their routine diabetes care arrangements.
Remind women with diabetes of the importance of contraception and the need for preconception care when planning future pregnancies.
Before women who were diagnosed with gestational diabetes are transferred to community care, test their blood glucose to exclude persisting hyperglycaemia.
Remind women who were diagnosed with gestational diabetes of the symptoms of hyperglycaemia.
Explain to women who were diagnosed with gestational diabetes about the risks of recurrence in future pregnancies, and offer them diabetes testing when planning future pregnancies.
For women who were diagnosed with gestational diabetes and whose blood glucose levels returned to normal after the birth:
-ffer lifestyle advice (including weight control, diet and exercise)
-ffer a fasting plasma glucose test 6 to 13 weeks after the birth to exclude diabetes (for practical reasons this might take place at the 6‑week postnatal check)
after 13 weeks offer a fasting plasma glucose test if this has not been done earlier, or an HbA1c test if a fasting plasma glucose test is not possible
do not routinely offer a 75-g 2‑hour OGTT
-ffer a referral into the NHS Diabetes Prevention Programme if eligible based on the results of the fasting plasma glucose test or HbA1c test.
For women having a fasting plasma glucose test as the postnatal test:
Advise women with a fasting plasma glucose level below 6.0 mmol/litre that:
they have a low probability of having diabetes at the moment
they should continue to follow the lifestyle advice (including weight control, diet and exercise) given after the birth
they will need an annual test to check that their blood glucose levels are normal
they have a moderate risk of developing type 2 diabetes, and offer them advice and guidance in line with the NICE guideline on preventing type 2 diabetes (note that this guideline uses different risk thresholds, because it covers a different population).
Advise women with a fasting plasma glucose level between 6.0 mmol/litre and 6.9 mmol/litre that they are at high risk of developing type 2 diabetes, and offer them advice, guidance and interventions in line with the NICE guideline on preventing type 2 diabetes (note that this guideline uses different risk thresholds, because it covers a different population).
Advise women with a fasting plasma glucose level of 7.0 mmol/litre or above that they are likely to have type 2 diabetes, and offer them a test to confirm this.
For women having an HbA1c test as the postnatal test:
Advise women with an HbA1c level below 39 mmol/mol (5.7%) that:
they have a low probability of having diabetes at the moment
they should continue to follow the lifestyle advice (including weight control, diet and exercise) given after the birth
they will need an annual test to check that their blood glucose levels are normal
they have a moderate risk of developing type 2 diabetes, and offer them advice and guidance in line with the NICE guideline on preventing type 2 diabetes (note that this guideline uses different risk thresholds, because it covers a different population).
Advise women with an HbA1c level between 39 mmol/mol and 47 mmol/mol (5.7% and 6.4%) that they are at high risk of developing type 2 diabetes, and offer them advice, guidance and interventions in line with the NICE guideline on preventing type 2 diabetes (note that this guideline uses different risk thresholds, because it covers a different population).
Advise women with an HbA1c level of 48 mmol/mol (6.5%) or above that they have type 2 diabetes, and refer them for further care.
Offer an annual HbA1c test to women with gestational diabetes who have a negative postnatal test for diabetes.
Offer women with gestational diabetes early self‑monitoring of blood glucose or an OGTT in future pregnancies. Offer a subsequent OGTT if the first OGTT results in early pregnancy are normal (see recommendation 1.2.6).
# Terms used in this guideline
## Continuous glucose monitoring
This covers both real-time (rtCGM) and intermittently scanned (isCGM, commonly referred to as 'flash') continuous glucose monitoring.
## Disabling hypoglycaemia
Repeated and unpredicted hypoglycaemia, requiring third‑party assistance, that results in continuing anxiety about recurrence and is associated with significant adverse effect on quality of life.
## HbA1c levels
HbA1c values are reported in mmol/mol, using the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) standardised HbA1c test. The equivalent values in %, using the Diabetes Control and Complications Trial (DCCT)‑aligned HbA1c test, are reported in parentheses.
## Level 2 critical care
Care for patients who need detailed observation or intervention, including support for a single failing organ system, postoperative care, and patients 'stepping down' from higher levels of care.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Key recommendations for research
## Preconception care for women with diabetes: insulin pump therapy and real-time continuous glucose monitoring
What are the roles of insulin pump therapy (continuous subcutaneous insulin infusion) and real-time continuous glucose monitoring (rtCGM) in helping women with diabetes to achieve blood glucose targets before pregnancy?
Babies born to women with diabetes have a high risk of having congenital malformations and this risk is greater if blood glucose control is poor around the time of conception. However, lowering the risk to that of women without diabetes would require normalisation of blood glucose levels, and this is difficult to achieve without increasing the risk of serious hypoglycaemia. Insulin pump therapy and rtCGM have been shown to reduce both blood glucose levels and rates of hypoglycaemia in the non‑pregnant population, but it is uncertain if this holds true before conception and in early pregnancy. There is therefore an urgent need to test the effectiveness and acceptability of these technologies in women with diabetes who are planning pregnancy. This would be best undertaken in a randomised controlled trial of women with diabetes who are trying to conceive. Women would be allocated to receive either conventional care (self‑monitoring of blood glucose and insulin adjustment) or insulin pump therapy and rtCGM.
## Testing for gestational diabetes
When should testing for gestational diabetes take place – in the first or second trimester?
Conventionally, testing for gestational diabetes takes place in the second trimester. Intervention has been shown to improve outcomes for women diagnosed with gestational diabetes. However, maternal age and obesity are increasing, and some women (especially those from populations with a high incidence of type 2 diabetes) enter pregnancy with undiagnosed type 2 diabetes, but may not be tested for diabetes until the second trimester. This exposes the woman and the fetus to risks resulting from early and prolonged maternal hyperglycaemia. It is presumed that this is associated with increased morbidity. UK population studies are needed to establish the incidence of glucose intolerance in women in the first trimester. Well‑designed randomised controlled trials are needed to establish if testing, diagnosis and intervention in the first rather than the second trimester improves maternal, fetal and neonatal outcomes, including fetal hyperinsulinaemia.
## Barriers to achieving blood glucose targets before and during pregnancy
What are the barriers that women experience to achieving blood glucose targets?
It is vital for normal fetal development in the first trimester that women with pre‑existing diabetes achieve good blood glucose control both before and during pregnancy. Good control also helps to prevent macrosomia and other complications in the third trimester in women with pre‑existing or gestational diabetes. Whereas many women manage to achieve blood glucose targets, a proportion of women continue to find it difficult to do so. A number of factors could be involved, such as health beliefs, a poor understanding of the importance of good blood glucose control, an inability to be able to comply with a demanding regimen of blood glucose testing up to 7 times a day, and the need to adjust insulin dosage. A better understanding of the barriers in this cohort of women is needed so that healthcare professionals can work to overcome them. Robust qualitative studies are needed to explore these barriers, with the aim of improving blood glucose control and fetal outcomes in pregnancy for women with pre‑existing diabetes and women with gestational diabetes.
## Risk of fetal death for women with diabetes
How can fetuses at risk of intrauterine death be identified in women with diabetes?
Unexpected intrauterine death remains a significant contributor to perinatal mortality in pregnant women with diabetes. Conventional tests of fetal wellbeing (umbilical artery doppler ultrasound, cardiotocography and other biophysical tests) have been shown to have poor sensitivity for predicting such events. Alternative approaches that include measurements of erythropoietin in the amniotic fluid and MRI spectroscopy may be effective, but there is currently insufficient clinical evidence to evaluate them. Well‑designed randomised controlled trials that are sufficiently powered are needed to determine whether these approaches are clinically and cost effective.
## Postnatal treatment for women diagnosed with gestational diabetes
Are there effective long‑term pharmacological interventions to prevent the onset of type 2 diabetes that can be recommended postnatally for women who have been diagnosed with gestational diabetes?
Gestational diabetes is one of the strongest risk factors for the subsequent development of type 2 diabetes: up to 50% of women diagnosed with gestational diabetes develop type 2 diabetes within 5 years of the birth. There are some data suggesting that changes in diet and exercise, with or without metformin, can prevent type 2 diabetes developing in non‑pregnant middle‑aged people with glucose intolerance, but there are no studies specifically in women with a past history of gestational diabetes. There is thus an urgent need to investigate what interventions may delay or prevent type 2 diabetes developing in this high‑risk population of women. Undertaking a formal randomised controlled trial involving long‑term outcomes is often not feasible in practice. However, it would be possible to have a quasi‑randomised study comparing 2 populations of women with similar demographic profiles who had gestational diabetes. One population would be encouraged at their annual check to follow a specific diet and exercise regime and those in the other population would not. The incidence of the development of type 2 diabetes in the 2 groups at 5 years, 10 years and 20 years would be compared.# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice.
# Continuous glucose monitoring
Recommendations 1.3.17 to 1.3.20
## Why the committee made the recommendations
There was evidence comparing real-time continuous glucose monitoring (rtCGM) with intermittently scanned CGM (isCGM) and with intermittent capillary glucose monitoring, for pregnant women with type 1 diabetes.
When compared with intermittent capillary glucose monitoring, rtCGM resulted in:
more women achieving their blood glucose targets
fewer caesarean sections
fewer neonatal intensive care unit (NICU) admissions.
One retrospective study was identified that compared isCGM with rtCGM. This study showed no clear difference between the 2 monitoring systems in maternal and neonatal outcomes.
Health economic modelling found that isCGM clearly has the lowest overall cost of the 3 options. It is much less certain that isCGM provides the most benefit (a finding that is in line with the clinical evidence). The committee were concerned by the very low quality of the evidence for isCGM, the accuracy of isCGM (particularly in the hypoglycaemic range) and the number of finger-pricks that would still be needed to use isCGM safely.
The committee agreed that all the uncertainties in the evidence would be likely to lead to the benefits of isCGM being overestimated. Therefore, they could not be confident that isCGM represents a better use of NHS resources than rtCGM, which had been shown in high-quality evidence to have better outcomes than intermittent capillary glucose monitoring and a 94% chance of being cheaper in the probabilistic sensitivity analysis.
Based on these findings, the committee recommended that rtCGM should be offered to all women with type 1 diabetes to help women meet their pregnancy blood glucose targets and improve neonatal outcomes.
The committee also noted that some women may be unable to use rtCGM or may prefer using isCGM instead. In these situations they recommended offering isCGM.
The committee amended the 2015 recommendation on considering rtCGM for pregnant women who are on insulin therapy but do not have type 1 diabetes because they wanted to identify specific scenarios in which rtCGM could be considered.
The committee believed that education and support are important for pregnant women using continuous glucose monitoring (CGM), to ensure they get the full benefit. Therefore, they updated and expanded the 2015 recommendation on providing support.
## How the recommendations might affect practice
Use of CGM varies across the country, but most centres offer isCGM and/or rtCGM to pregnant women with type 1 diabetes (in accordance with the NHS long-term plan). Because of this, the recommendations are unlikely to cause a major shift in practice.
Return to recommendations# Context
Approximately 700,000 women give birth in England and Wales each year, and up to 5% of these women have either pre‑existing diabetes or gestational diabetes. Of women who have diabetes during pregnancy, it is estimated that approximately 87.5% have gestational diabetes (which may or may not resolve after pregnancy), 7.5% have type 1 diabetes and the remaining 5% have type 2 diabetes. The prevalence of type 1 diabetes, and especially type 2 diabetes, has increased in recent years. The incidence of gestational diabetes is also increasing as a result of higher rates of obesity in the general population and more pregnancies in older women.
Diabetes in pregnancy is associated with risks to the woman and to the developing fetus. Miscarriage, pre‑eclampsia and preterm labour are more common in women with pre‑existing diabetes. In addition, diabetic retinopathy can worsen rapidly during pregnancy. Stillbirth, congenital malformations, macrosomia, birth injury, perinatal mortality and postnatal adaptation problems (such as hypoglycaemia) are more common in babies born to women with pre‑existing diabetes.
This guideline contains recommendations for managing diabetes and its complications in women who are planning pregnancy and those who are already pregnant. The guideline focuses on areas where additional or different care should be offered to women with diabetes and their newborn babies. Where the evidence supports it, the guideline makes separate recommendations for women with pre‑existing diabetes and women with gestational diabetes. The term 'women' is used in the guideline to refer to all females of childbearing age, including young women who have not yet transferred from paediatric to adult services.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines\xa0explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Blood glucose and plasma glucose\n\n'Blood glucose' is the more commonly used term. However, a lot of the evidence this guideline is based on uses 'plasma' rather than 'blood' glucose, and patient‑held glucose meters and monitoring systems are calibrated to plasma glucose equivalents. Because of this, in this guideline we use the term 'blood glucose', except when referring to specific concentration values.\n\n# Preconception planning and care\n\n## Information about outcomes and risks for mother and baby\n\nProvide information, advice and support, to empower women to have a positive experience of pregnancy and to reduce the risks of adverse pregnancy outcomes for mother and baby. \n\nExplain to women with diabetes who are planning a pregnancy that:\n\nif they have good blood glucose control before conception and throughout their pregnancy, this will reduce the risk of miscarriage, congenital malformation, stillbirth and neonatal death but\n\nthe risks can be reduced but not eliminated. \n\nWhen women with diabetes are planning a pregnancy, provide them and their families with information about how diabetes affects pregnancy and how pregnancy affects diabetes. The information should cover:\n\nthe role of diet, body weight and exercise\n\nthe risks of hypoglycaemia and impaired awareness of hypoglycaemia during pregnancy\n\nhow nausea and vomiting in pregnancy can affect blood glucose control\n\nthe increased risk of having a baby who is large for gestational age, which increases the likelihood of birth trauma, induction of labour, and instrumental and caesarean section deliveries\n\nthe need for diabetic retinopathy assessment before and during pregnancy\n\nthe need for diabetic nephropathy assessment before pregnancy\n\nthe importance of maternal blood glucose control during labour and birth, and the need for early feeding of the baby, in order to reduce the risk of neonatal hypoglycaemia\n\nthe possibility of that the baby may have health problems in the first 28 days, and may need admitting to a neonatal unit\n\nthe risk of the baby developing obesity, diabetes and/or other health problems in later life. \n\n## The importance of planning pregnancy and the role of contraception\n\nEmphasise the importance of planning for pregnancy, as part of diabetes education from adolescence for women with diabetes. [2008, amended 2015]\n\nExplain to women with diabetes that their choice of contraception should be based on their own preferences and any risk factors (covered in the Faculty of Sexual and Reproductive Healthcare UK medical eligibility criteria for contraceptive use). \n\nAdvise women with diabetes that they can use oral contraceptives. \n\nAdvise women with diabetes who are planning to become pregnant:\n\nthat the risks associated with diabetes in pregnancy will increase the longer they have had diabetes\n\nto use contraception until they have good blood glucose control (assessed by HbA1c levels – see recommendation 1.1.18)\n\nthat blood glucose targets, glucose monitoring, medicines for treating diabetes (including insulin regimens) and medicines for complications of diabetes will need to be reviewed before and during pregnancy\n\nthat extra time and effort is needed to manage diabetes during pregnancy, and that more frequent contact is needed with healthcare professionals. \n\nFor women with diabetes who are planning a pregnancy, provide information about the local arrangements for support, including emergency contact numbers. \n\n## Diet, dietary supplements and body weight\n\nOffer individualised dietary advice to women with diabetes who are planning a pregnancy. \n\nFor women with diabetes who are planning a pregnancy and who have a body mass index (BMI) above 27\xa0kg/m2, offer advice on how to lose weight, in line with the NICE guideline on identifying, assessing and managing obesity. See the NICE guideline on BMI for guidance on using variations on the BMI cut-off, based on the risk for different ethnic groups. \n\nAdvise women with diabetes who are planning a pregnancy to take folic acid (5\xa0mg/day) until 12\xa0weeks of gestation to reduce the risk of having a baby with a neural tube defect. \n\n## Monitoring blood glucose and ketones before pregnancy\n\nOffer up to monthly measurement of HbA1c levels for women with diabetes who are planning a pregnancy. [2008, amended 2020]\n\nOffer blood glucose meters for self-monitoring to women with diabetes who are planning a pregnancy. \n\nIf a woman with diabetes who is planning a pregnancy needs to intensify blood glucose‑lowering therapy, advise her to monitor her blood glucose more often, to include fasting levels and a mixture of pre‑meal and post‑meal levels. \n\nOffer blood ketone testing strips and a meter to women with type\xa01 diabetes who are planning a pregnancy, and advise them to test for ketonaemia if they become hyperglycaemic or unwell. \n\n## Target blood glucose and HbA1c levels before pregnancy\n\nAgree individualised targets for self‑monitoring of blood glucose with women who have diabetes and are planning a pregnancy, taking into account the risk of hypoglycaemia. \n\nAdvise women with type 1 diabetes who are planning a pregnancy to aim for the normal capillary plasma glucose target ranges:\n\na fasting plasma glucose level of 5\xa0mmol/litre to 7\xa0mmol/litre on waking and\n\na plasma glucose level of 4\xa0mmol/litre to 7\xa0mmol/litre before meals at other times of the day.For more information, see the section on blood glucose targets in the NICE guideline on type 1 diabetes in adults. \n\nAdvise women with diabetes who are planning a pregnancy to aim to keep their HbA1c level below 48\xa0mmol/mol (6.5%), if this is achievable without causing problematic hypoglycaemia. \n\nReassure women that any reduction in HbA1c level towards the target is likely to reduce the risk of congenital malformations in the baby. \n\nStrongly advise women with diabetes whose HbA1c level is above 86\xa0mmol/mol (10%) not to get pregnant until their HbA1c level is lower, because of the associated risks (see recommendation 1.1.2). \n\n## Safety of medicines for diabetes before and during pregnancy\n\nWomen with diabetes may be advised to use metformin as an adjunct or alternative to insulin in the preconception period and during pregnancy, when the likely benefits from improved blood glucose control outweigh the potential for harm. Stop all other oral blood glucose‑lowering agents before pregnancy, and use insulin instead. \n\nBe aware that the available evidence on rapid‑acting insulin analogues (aspart and lispro) does not show an adverse effect on the pregnancy or the health of baby. \n\nUse isophane insulin (also known as NPH insulin) as the first choice for long‑acting insulin during pregnancy. Consider continuing treatment with long‑acting insulin analogues (insulin detemir or insulin glargine) for women with diabetes who have established good blood glucose control before pregnancy.Note that this is an off-label use of long-acting insulin analogues. See NICE's information on prescribing medicines. [2008, amended 2015]\n\n## Safety of medicines for complications of diabetes before and during pregnancy\n\nStop angiotensin‑converting enzyme inhibitors and angiotensin‑II receptor antagonists before conception, or as soon as pregnancy is confirmed. Use alternative antihypertensive agents that are suitable for pregnant women. \n\nStop statins before pregnancy, or as soon as pregnancy is confirmed. \n\n## Making it easier for women to access preconception care\n\nFrom adolescence onwards, at every contact with women with diabetes:\n\nhealthcare professionals (including the diabetes care team) should explain the benefits of preconception blood glucose control\n\nthe diabetes care team should record the plans women have for pregnancy and conception. \n\nProvide preconception care for women with diabetes in a supportive environment, and encourage partners or other family members to attend. [2008, amended 2015]\n\n## Education and advice\n\nAs early as possible, offer a structured education programme to women with diabetes who are planning a pregnancy (if they have not already attended one). For more guidance, see the education and information section in the NICE guideline on type 1 diabetes in adults, and the patient education section in the NICE guideline on type 2 diabetes in adults. \n\nOffer preconception care and advice before stopping contraception for women with diabetes who are planning a pregnancy. \n\n## Retinal assessment before pregnancy\n\nFor women with diabetes who are seeking preconception care, offer a retinal assessment at their first appointment (unless they have had a retinal assessment in the last 6\xa0months). [2008, amended 2020]\n\nAdvise women with diabetes who are planning a pregnancy to defer rapid optimisation of blood glucose control until after they have had retinal assessment and treatment. \n\n## Renal assessment before pregnancy\n\nOffer women with diabetes a renal assessment (including a measure of albuminuria) before stopping contraception. [2008, amended 2015]\n\nConsider referring women with diabetes to a nephrologist before stopping contraception if:\n\nserum creatinine is 120\xa0micromol/litre or more or\n\nthe urinary albumin:creatinine ratio is greater than 30\xa0mg/mmol or\n\nthe estimated glomerular filtration rate (eGFR) is less than 45\xa0ml/minute/1.73\xa0m2. [2008, amended 2015]\n\n# Gestational diabetes\n\n## Risk assessment, testing and diagnosis\n\nTo help women make an informed decision about risk assessment and testing for gestational diabetes, explain that:\n\nsome women find that gestational diabetes can be controlled with changes in diet and exercise\n\nmost women with gestational diabetes will need oral blood glucose‑lowering agents or insulin\n\nif gestational diabetes is not detected and controlled, there is a small increase in the risk of serious adverse birth complications such as shoulder dystocia\n\nwomen with gestational diabetes will need more monitoring, and may need more interventions during pregnancy and labour. \n\nAssess the risk of gestational diabetes using risk factors in a healthy population. At the booking appointment, check for the following risk factors:\n\nBMI above 30\xa0kg/m2\n\nprevious macrosomic baby weighing 4.5\xa0kg or more\n\nprevious gestational diabetes\n\nfamily history of diabetes (first‑degree relative with diabetes)\n\nan ethnicity with a high prevalence of diabetes.Offer women with any of these risk factors testing for gestational diabetes (see recommendations 1.2.5 to 1.2.7). [2008, amended 2015]\n\nDo not use fasting plasma glucose, random blood glucose, HbA1c, glucose challenge test or urinalysis for glucose to assess the risk of developing gestational diabetes. \n\nConsider further testing to exclude gestational diabetes in women who have the following reagent strip test results during routine antenatal care:\n\nglycosuria of 2+ or above on 1 occasion\n\nglycosuria of 1+ or above on 2 or more occasions. \n\nUse the 75-g 2-hour oral glucose tolerance test (OGTT) to test for gestational diabetes in women with risk factors (see recommendation 1.2.2). \n\nFor women who have had gestational diabetes in a previous pregnancy, offer:\n\nearly self‑monitoring of blood glucose or\n\na 75-g 2‑hour OGTT as soon as possible after booking (whether in the first or second trimester), and a further 75-g 2‑hour OGTT at 24 to 28\xa0weeks if the results of the first OGTT are normal. \n\nOffer women with any of the other risk factors for gestational diabetes (see recommendation 1.2.2) a 75-g 2‑hour OGTT at 24 to 28\xa0weeks. \n\nDiagnose gestational diabetes if the woman has either:\n\na fasting plasma glucose level of 5.6\xa0mmol/litre or above or\n\na 2‑hour plasma glucose level of 7.8\xa0mmol/litre or above. \n\nWhen women are diagnosed with gestational diabetes:\n\noffer a review with the joint diabetes and antenatal clinic within 1\xa0week.\n\ntell their primary healthcare team (see also the section on continuity of care in the NICE guideline on patient experience in adult NHS services). \n\n## Interventions\n\nExplain to women with gestational diabetes:\n\nthe implications (both short and long term) of the diagnosis for her and her baby (including UK government advice on driving with diabetes)\n\nthat good blood glucose control throughout pregnancy will reduce the risk of fetal macrosomia, trauma during birth (for her and her baby), induction of labour and/or caesarean section, neonatal hypoglycaemia, and perinatal death\n\nthat treatment includes changes in diet and exercise, and could involve medicines. \n\nTeach women with gestational diabetes how to self‑monitor their blood glucose. \n\nUse the same capillary plasma glucose target levels for women with gestational diabetes as for women with pre‑existing diabetes (see recommendations 1.3.5 and 1.3.6). \n\nTailor blood glucose‑lowering therapy to the blood glucose profile and personal preferences of the woman with gestational diabetes. \n\nWhen women are diagnosed with gestational diabetes, offer advice about changes in diet and exercise. \n\nAdvise women with gestational diabetes to eat a healthy diet during pregnancy, and to switch from high to low glycaemic index food. \n\nRefer all women with gestational diabetes to a dietitian. \n\nAdvise women with gestational diabetes to exercise regularly (for example, walking for 30\xa0minutes after a meal). \n\nFor women with gestational diabetes who have a fasting plasma glucose level below 7\xa0mmol/litre at diagnosis, offer a trial of diet and exercise changes. \n\nIf blood glucose targets are not met with diet and exercise changes within 1 to 2\xa0weeks, offer metformin. \n\nIf metformin is contraindicated or unacceptable to the woman, offer insulin. \n\nIf blood glucose targets are not met with diet and exercise changes plus metformin, offer insulin as well. \n\nFor women with gestational diabetes who have a fasting plasma glucose level of 7.0\xa0mmol/litre or above at diagnosis, offer:\n\nimmediate treatment with insulin, with or without metformin and\n\ndiet and exercise changes. \n\nFor women with gestational diabetes who have a fasting plasma glucose level of between 6.0 and 6.9\xa0mmol/litre and complications such as macrosomia or hydramnios, consider:\n\nimmediate treatment with insulin, with or without metformin and\n\ndiet and exercise changes. \n\n# Antenatal care for women with diabetes\n\nSee also the NICE guideline on antenatal care for uncomplicated pregnancies.\n\n## Monitoring blood glucose\n\nAdvise pregnant women with type\xa01 diabetes to test their fasting, pre‑meal, 1‑hour post‑meal and bedtime blood glucose levels daily. \n\nAdvise pregnant women with type\xa02 diabetes or gestational diabetes who are on a multiple daily insulin injection regimen to test their fasting, pre‑meal, 1‑hour post‑meal and bedtime blood glucose levels daily. \n\nAdvise pregnant women with type\xa02 diabetes or gestational diabetes to test their fasting and 1‑hour post‑meal blood glucose levels daily if they are:\n\nmanaging their diabetes with diet and exercise changes alone or\n\ntaking oral therapy (with or without diet and exercise changes) or single‑dose intermediate‑acting or long‑acting insulin. \n\n## Target blood glucose levels\n\nAgree individualised targets for self‑monitoring of blood glucose with pregnant women with diabetes, taking into account the risk of hypoglycaemia. \n\nAdvise pregnant women with any form of diabetes to maintain their capillary plasma glucose below the following target levels, if these are achievable without causing problematic hypoglycaemia:\n\nfasting: 5.3\xa0mmol/litreand\n\nhour after meals: 7.8\xa0mmol/litre or\n\nhours after meals: 6.4\xa0mmol/litre. \n\nAdvise pregnant women with diabetes who are taking insulin to maintain their capillary plasma glucose level above 4\xa0mmol/litre. [2015, amended 2020]\n\n## Monitoring HbA1c\n\nMeasure HbA1c levels at the booking appointment for all pregnant women with pre‑existing diabetes, to determine the level of risk for the pregnancy. \n\nConsider measuring HbA1c levels in the second and third trimesters of pregnancy for women with pre‑existing diabetes, to assess the level of risk for the pregnancy. \n\nBe aware that the level of risk for the pregnancy for women with pre‑existing diabetes increases with an HbA1c level above 48\xa0mmol/mol (6.5%). \n\nMeasure HbA1c levels when women are diagnosed with gestational diabetes, to identify women who may have pre‑existing type\xa02 diabetes. \n\nDo not routinely use HbA1c levels to assess a woman's blood glucose control in the second and third trimesters of pregnancy. \n\n## Managing diabetes during pregnancy\n\nA 2020 Medicines and Healthcare products Regulatory Agency drug safety update highlights the need to rotate insulin injection sites within the same body area to avoid cutaneous amyloidosis.\n\nConsider rapid‑acting insulin analogues (aspart and lispro) for pregnant women with diabetes. Be aware that these insulin analogues have advantages over soluble human insulin during pregnancy. \n\nAdvise women with insulin‑treated diabetes of the risks of hypoglycaemia and impaired awareness of hypoglycaemia in pregnancy, particularly in the first trimester. \n\nAdvise pregnant women with insulin‑treated diabetes to always have a fast‑acting form of glucose available (for example, dextrose tablets or glucose‑containing drinks). [2008, amended 2015]\n\nProvide glucagon to pregnant women with type\xa01 diabetes, for use if needed. Explain to the woman and her partner or other family members how to use it. [2008, amended 2015]\n\nOffer continuous subcutaneous insulin infusion (CSII; also known as insulin pump therapy) to pregnant women with insulin-treated diabetes who:\n\nare using multiple daily injections of insulin and\n\ndo not achieve blood glucose control without significant disabling hypoglycaemia. \n\nOffer real-time continuous glucose monitoring (rtCGM) to all pregnant women with type 1 diabetes to help them meet their pregnancy blood glucose targets and improve neonatal outcomes. \n\nOffer intermittently scanned continuous glucose monitoring (isCGM, commonly referred to as 'flash') to pregnant women with type 1 diabetes who are unable to use rtCGM or express a clear preference for isCGM. \n\nConsider rtCGM for pregnant women who are on insulin therapy but do not have type 1 diabetes, if:\n\nthey have problematic severe hypoglycaemia (with or without impaired awareness of hypoglycaemia) or\n\nthey have unstable blood glucose levels that are causing concern despite efforts to optimise glycaemic control. [2015, amended 2020]\n\nFor pregnant women who are using continuous glucose monitoring (CGM), a member of the joint diabetes and antenatal care team with expertise in these systems should provide education and support (including advising women about sources of out-of-hours support). \n\nFor a short explanation of why the committee made the 2020 recommendations and how they might affect practice, see the rationale and impact section on continuous glucose monitoring\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: continuous glucose monitoring.\n\nLoading. Please wait.\n\nOffer blood ketone testing strips and a meter to pregnant women with type\xa01 diabetes. Advise them to test for ketonaemia and to seek urgent medical advice if they become hyperglycaemic or unwell. \n\nAdvise pregnant women with type\xa02 diabetes or gestational diabetes to seek urgent medical advice if they become hyperglycaemic or unwell. \n\nTest urgently for ketonaemia if a pregnant woman with any form of diabetes presents with hyperglycaemia or is unwell. \n\nImmediately admit pregnant women with suspected diabetic ketoacidosis for level 2 critical care, where they can receive both medical and obstetric care. \n\n## Retinal assessment during pregnancy\n\nAfter pregnant women with pre‑existing diabetes have had their first antenatal clinic appointment:\n\noffer retinal assessment by digital imaging with mydriasis using tropicamide (unless they have had a retinal assessment in the last 3\xa0months)\n\nif they have diabetic retinopathy, offer an additional retinal assessment at 16 to 20\xa0weeks\n\noffer another retinal assessment at 28\xa0weeks. [2008, amended 2015]\n\nDiabetic retinopathy should not be considered a contraindication to rapid optimisation of blood glucose control in women who present with a high HbA1c in early pregnancy. \n\nDiabetic retinopathy should not be considered a contraindication to vaginal birth. \n\n## Renal assessment during pregnancy\n\nArrange a renal assessment at first contact during the pregnancy for women with pre‑existing diabetes, if they have not had 1 in the last 3 months. [2008, amended 2015]\n\nConsider referring pregnant women with diabetes to a nephrologist if:\n\ntheir serum creatinine is 120\xa0micromol/litre or more or\n\nthe urinary albumin:creatinine ratio is greater than 30\xa0mg/mmol or\n\ntotal protein excretion exceeds 0.5\xa0g/day. [2008, amended 2015]\n\nDo not use eGFR to measure kidney function in pregnant women. [2008, amended 2015]\n\nConsider thromboprophylaxis for pregnant women with nephrotic range proteinuria above 5\xa0g/day (albumin:creatinine ratio greater than 220 mg/mmol). [2008, amended 2015]\n\n## Preventing pre‑eclampsia\n\nFor guidance on using antiplatelet agents to reduce the risk of pre‑eclampsia in pregnant women with diabetes, see the section on antiplatelet agents in the NICE guideline on hypertension in pregnancy. \n\n## Detecting congenital malformations\n\nOffer women with diabetes an ultrasound scan at 20 weeks to detect fetal structural abnormalities, including examination of the fetal heart (4\xa0chambers, outflow tracts and 3\xa0vessels). [2008, amended 2015]\n\n## Monitoring fetal growth and wellbeing\n\nOffer pregnant women with diabetes ultrasound monitoring of fetal growth and amniotic fluid volume every 4\xa0weeks from 28 to 36\xa0weeks. \n\nRoutine monitoring of fetal wellbeing before 38\xa0weeks is not recommended in pregnant women with diabetes, unless there is a risk of fetal growth restriction. This includes methods such as fetal umbilical artery doppler recording, fetal heart rate recording and biophysical profile testing. [2008, amended 2015]\n\nProvide an individualised approach to monitoring fetal growth and wellbeing for women with diabetes and a risk of fetal growth restriction (macrovascular disease or nephropathy). [2008, amended 2015]\n\n## Organisation of antenatal care\n\nOffer immediate contact with a joint diabetes and antenatal clinic to pregnant women with diabetes. \n\nJoint diabetes and antenatal clinics should be in contact with women with diabetes every 1 to 2\xa0weeks throughout pregnancy, for blood glucose control assessment. [2008, amended 2015]\n\nAt antenatal appointments, provide care specifically for women with diabetes, in addition to routine care for healthy pregnant women (see the NICE guideline on antenatal care for uncomplicated pregnancies). Table 1 describes how care for women with diabetes differs from routine antenatal care. [2008, amended 2015]\n\nAt each appointment, offer pregnant women with diabetes ongoing opportunities for information and education. [2008, amended 2015]\n\nAppointment\n\nCare for women with diabetes during pregnancy\n\nBooking appointment (joint diabetes and antenatal care) – ideally by 10\xa0weeks\n\nDiscuss how diabetes will affect the pregnancy, birth and early parenting (such as breastfeeding and initial care of the baby).\n\nIf the woman has not had preconception care:\n\ngive information, education and advice\n\ntake a clinical history to establish the extent of diabetes‑related complications (including neuropathy and vascular disease), and review medicines for diabetes and its complications.\n\nIf the woman has had preconception care, continue to provide information, education and advice on achieving optimal blood glucose control (including dietary advice).\n\nOffer retinal assessment for women with pre‑existing diabetes unless the woman has been assessed in the last 3\xa0months.\n\nOffer a renal assessment for women with pre‑existing diabetes, if they have not had 1 in the last 3\xa0months.\n\nArrange contact with the joint diabetes and antenatal clinic every 1 to 2\xa0weeks throughout pregnancy for all women with diabetes.\n\nMeasure HbA1c levels for women with pre‑existing diabetes to determine the level of risk for the pregnancy.\n\nOffer self‑monitoring of blood glucose or a 75-g 2‑hour oral glucose tolerance test (OGTT) as soon as possible for women with previous gestational diabetes who book in the first trimester.\n\nConfirm the viability of the pregnancy and gestational age at 7 to 9\xa0weeks.\n\nweeks\n\nOffer retinal assessment at 16 to 20\xa0weeks to women with pre‑existing diabetes who had diabetic retinopathy at their first antenatal clinic visit.\n\nOffer self‑monitoring of blood glucose or a 75-g 2‑hour OGTT as soon as possible for women with previous gestational diabetes who book in the second trimester.\n\nweeks\n\nOffer an ultrasound scan to detect fetal structural abnormalities, including examination of the fetal heart (4\xa0chambers, outflow tracts and 3\xa0vessels).\n\nweeks\n\nOffer ultrasound monitoring of fetal growth and amniotic fluid volume.\n\nOffer retinal assessment to all women with pre‑existing diabetes.\n\nWomen diagnosed with gestational diabetes as a result of routine antenatal testing at 24 to 28\xa0weeks enter the care pathway.\n\nweeks\n\nOffer ultrasound monitoring of fetal growth and amniotic fluid volume.\n\nOffer nulliparous women all routine investigations normally scheduled for 31\xa0weeks in routine antenatal care.\n\nweeks\n\nNo differences in care for women with diabetes.\n\nweeks\n\nOffer ultrasound monitoring of fetal growth and amniotic fluid volume.\n\nProvide information and advice about:\n\ntiming, mode and management of birth\n\nanalgesia and anaesthesia\n\nchanges to blood glucose‑lowering therapy during and after birth\n\ncare of the baby after birth\n\nstarting to breastfeed and the effect of breastfeeding on blood glucose control\n\ncontraception and follow‑up.\n\nweeks to 38 weeks plus 6 days\n\nOffer induction of labour or (if indicated) caesarean section to women with type\xa01 or type\xa02 diabetes. Await spontaneous labour for other women.\n\nweeks\n\n\n\nOffer tests of fetal wellbeing.\n\nweeks\n\n\n\nOffer tests of fetal wellbeing.\n\nAdvise women with uncomplicated gestational diabetes to give birth no later than 40 weeks plus 6 days.\n\n## Preterm labour in women with diabetes\n\nDiabetes should not be considered a contraindication to tocolysis or to antenatal steroids for fetal lung maturation. \n\nFor women with insulin‑treated diabetes who are taking steroids for fetal lung maturation, give additional insulin according to an agreed protocol and monitor the woman closely. [2008, amended 2015]\n\nDo not use betamimetic medicines for tocolysis in women with diabetes. \n\n# Intrapartum care\n\n## Timing and mode of birth\n\nDiscuss the timing and mode of birth with pregnant women with diabetes during antenatal appointments, especially during the third trimester. \n\nAdvise pregnant women with type\xa01 or type\xa02 diabetes and no other complications to have an elective birth by induced labour or (if indicated) caesarean section, between 37 weeks and 38 weeks plus 6 days of pregnancy. \n\nConsider elective birth before 37 weeks\xa0for women with type\xa01 or type\xa02 diabetes who have metabolic or other maternal or fetal complications. \n\nAdvise women with gestational diabetes to give birth no later than 40 weeks plus 6 days. Offer elective birth by induced labour or (if indicated) by caesarean section to women who have not given birth by this time. \n\nConsider elective birth before 40\xa0weeks plus 6 days for women with gestational diabetes who have maternal or fetal complications. \n\nDiabetes should not be considered a contraindication to vaginal birth after a previous caesarean section. \n\nFor pregnant women with diabetes who have an ultrasound‑diagnosed macrosomic fetus, explain the risks and benefits of vaginal birth, induction of labour and caesarean section. \n\n## Anaesthesia\n\nFor women with diabetes and comorbidities such as obesity or autonomic neuropathy, offer an anaesthetic assessment in the third trimester of pregnancy. \n\nIf the woman has general anaesthesia for the birth, monitor blood glucose every 30\xa0minutes from induction of general anaesthesia until after the baby is born and the woman is fully conscious. \n\n## Blood glucose control during labour and birth\n\nMonitor capillary plasma glucose every hour during labour and birth for women with diabetes, and maintain it between 4\xa0mmol/litre and 7\xa0mmol/litre. [2008, amended 2015]\n\nConsider intravenous dextrose and insulin infusion from the onset of established labour for women with type\xa01 diabetes. \n\nUse intravenous dextrose and insulin infusion during labour and birth for women with diabetes whose capillary plasma glucose is not maintained between 4\xa0mmol/litre and 7\xa0mmol/litre. [2008, amended 2015]\n\n# Neonatal care\n\n## Initial assessment and criteria for admission to intensive or special care\n\nAdvise women with diabetes to give birth in hospitals where advanced neonatal resuscitation skills are available 24\xa0hours a day. \n\nBabies of women with diabetes should stay with their mothers, unless there are complications or abnormal clinical signs that mean the baby needs to be admitted to intensive or special care. \n\nCarry out blood glucose testing routinely at 2 to 4\xa0hours after birth in babies of women with diabetes. Carry out blood tests for babies with clinical signs of polycythaemia, hyperbilirubinaemia, hypocalcaemia or hypomagnesaemia. \n\nPerform an echocardiogram for babies of women with diabetes if they show clinical signs associated with congenital heart disease or cardiomyopathy, including heart murmur. Base the timing of the examination on the clinical circumstances. \n\nAdmit babies of women with diabetes to the neonatal unit if they have:\n\nhypoglycaemia associated with abnormal clinical signs\n\nrespiratory distress\n\nsigns of cardiac decompensation from congenital heart disease or cardiomyopathy\n\nsigns of neonatal encephalopathy\n\nsigns of polycythaemia, and are likely to need partial exchange transfusion\n\nneed for intravenous fluids\n\nneed for tube feeding (unless adequate support is available on the postnatal ward)\n\njaundice requiring intense phototherapy and frequent monitoring of bilirubinaemia\n\nbeen born before 34\xa0weeks (or between 34 and 36\xa0weeks, if the initial assessment of the baby and their feeding suggests this is clinically appropriate). \n\nDo not transfer babies of women with diabetes to community care until:\n\nthey are at least 24\xa0hours old and\n\nyou are satisfied that the baby is maintaining blood glucose levels and is feeding well. \n\n## Preventing and assessing neonatal hypoglycaemia\n\nAll maternity units should have a written policy for preventing, detecting and managing hypoglycaemia in babies of women with diabetes. \n\nTest the blood glucose of babies of women with diabetes using a quality‑assured method validated for neonatal use (ward‑based glucose electrode or laboratory analysis). \n\nWomen with diabetes should feed their babies:\n\nas soon as possible after birth (within 30\xa0minutes) and then\n\nat frequent intervals (every 2 to 3\xa0hours) until feeding maintains their pre‑feed capillary plasma glucose levels at a minimum of 2.0\xa0mmol/litre. [2008, amended 2015]\n\nOnly use additional measures (such as tube feeding or intravenous dextrose) if:\n\ncapillary plasma glucose values are below 2.0\xa0mmol/litre on 2\xa0consecutive readings despite maximal support for feeding or\n\nthere are abnormal clinical signs or\n\nthe baby will not effectively feed orally. [2008, amended 2015]\n\nFor babies with clinical signs of hypoglycaemia, test blood glucose levels and provide intravenous dextrose as soon as possible. [2008, amended 2015]\n\n# Postnatal care\n\n## Blood glucose control, medicines and breastfeeding\n\nWomen with insulin‑treated pre‑existing diabetes should reduce their insulin immediately after birth and monitor their blood glucose levels to find the appropriate dose. \n\nExplain to women with insulin‑treated pre‑existing diabetes that they are at increased risk of hypoglycaemia in the postnatal period (especially when breastfeeding), and advise them to have a meal or snack available before or during feeds. \n\nWomen who have been diagnosed with gestational diabetes should stop blood glucose‑lowering therapy immediately after birth. \n\nWomen with pre‑existing type\xa02 diabetes who are breastfeeding can resume or continue metformin immediately after birth, but should avoid other oral blood glucose‑lowering therapy while breastfeeding.Note that this is an off-label use of metformin. See NICE's information on prescribing medicines. [2008, amended 2020]\n\nWomen with diabetes who are breastfeeding should continue to avoid any medicines for their diabetes complications that were stopped for safety reasons when they started planning the pregnancy. \n\n## Information and follow-up after birth\n\nRefer women with pre‑existing diabetes back to their routine diabetes care arrangements. \n\nRemind women with diabetes of the importance of contraception and the need for preconception care when planning future pregnancies. \n\nBefore women who were diagnosed with gestational diabetes are transferred to community care, test their blood glucose to exclude persisting hyperglycaemia. \n\nRemind women who were diagnosed with gestational diabetes of the symptoms of hyperglycaemia. \n\nExplain to women who were diagnosed with gestational diabetes about the risks of recurrence in future pregnancies, and offer them diabetes testing when planning future pregnancies. [2008, amended 2015]\n\nFor women who were diagnosed with gestational diabetes and whose blood glucose levels returned to normal after the birth:\n\noffer lifestyle advice (including weight control, diet and exercise)\n\noffer a fasting plasma glucose test 6 to 13\xa0weeks after the birth to exclude diabetes (for practical reasons this might take place at the 6‑week postnatal check)\n\nafter 13\xa0weeks offer a fasting plasma glucose test if this has not been done earlier, or an HbA1c test if a fasting plasma glucose test is not possible\n\ndo not routinely offer a 75-g 2‑hour OGTT\n\noffer a referral into the NHS Diabetes Prevention Programme if eligible based on the results of the fasting plasma glucose test or HbA1c test. [2015, amended 2020]\n\nFor women having a fasting plasma glucose test as the postnatal test:\n\nAdvise women with a fasting plasma glucose level below 6.0\xa0mmol/litre that:\n\n\n\nthey have a low probability of having diabetes at the moment\n\nthey should continue to follow the lifestyle advice (including weight control, diet and exercise) given after the birth\n\nthey will need an annual test to check that their blood glucose levels are normal\n\nthey have a moderate risk of developing type\xa02 diabetes, and offer them advice and guidance in line with the NICE guideline on preventing type 2 diabetes (note that this guideline uses different risk thresholds, because it covers a different population).\n\n\n\nAdvise women with a fasting plasma glucose level between 6.0\xa0mmol/litre and 6.9\xa0mmol/litre that they are at high risk of developing type\xa02 diabetes, and offer them advice, guidance and interventions in line with the NICE guideline on preventing type 2 diabetes (note that this guideline uses different risk thresholds, because it covers a different population).\n\nAdvise women with a fasting plasma glucose level of 7.0\xa0mmol/litre or above that they are likely to have type\xa02 diabetes, and offer them a test to confirm this. \n\nFor women having an HbA1c test as the postnatal test:\n\nAdvise women with an HbA1c level below 39\xa0mmol/mol (5.7%) that:\n\n\n\nthey have a low probability of having diabetes at the moment\n\nthey should continue to follow the lifestyle advice (including weight control, diet and exercise) given after the birth\n\nthey will need an annual test to check that their blood glucose levels are normal\n\nthey have a moderate risk of developing type\xa02 diabetes, and offer them advice and guidance in line with the NICE guideline on preventing type 2 diabetes (note that this guideline uses different risk thresholds, because it covers a different population).\n\n\n\nAdvise women with an HbA1c level between 39\xa0mmol/mol and 47\xa0mmol/mol (5.7% and 6.4%) that they are at high risk of developing type\xa02 diabetes, and offer them advice, guidance and interventions in line with the NICE guideline on preventing type 2 diabetes (note that this guideline uses different risk thresholds, because it covers a different population).\n\nAdvise women with an HbA1c level of 48\xa0mmol/mol (6.5%) or above that they have type\xa02 diabetes, and refer them for further care. \n\nOffer an annual HbA1c test to women with gestational diabetes who have a negative postnatal test for diabetes. \n\nOffer women with gestational diabetes early self‑monitoring of blood glucose or an OGTT in future pregnancies. Offer a subsequent OGTT if the first OGTT results in early pregnancy are normal (see recommendation 1.2.6). [2008, amended 2015]\n\n# Terms used in this guideline\n\n## Continuous glucose monitoring\n\nThis covers both real-time (rtCGM) and intermittently scanned (isCGM, commonly referred to as 'flash') continuous glucose monitoring.\n\n## Disabling hypoglycaemia\n\nRepeated and unpredicted hypoglycaemia, requiring third‑party assistance, that results in continuing anxiety about recurrence and is associated with significant adverse effect on quality of life.\n\n## HbA1c levels\n\nHbA1c values are reported in mmol/mol, using the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) standardised HbA1c test. The equivalent values in %, using the Diabetes Control and Complications Trial (DCCT)‑aligned HbA1c test, are reported in parentheses.\n\n## Level 2 critical care\n\nCare for patients who need detailed observation or intervention, including support for a single failing organ system, postoperative care, and patients 'stepping down' from higher levels of care.", 'Recommendations for research': 'The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Preconception care for women with diabetes: insulin pump therapy and real-time continuous glucose monitoring\n\nWhat are the roles of insulin pump therapy (continuous subcutaneous insulin infusion) and real-time continuous glucose monitoring (rtCGM) in helping women with diabetes to achieve blood glucose targets before pregnancy?\n\nBabies born to women with diabetes have a high risk of having congenital malformations and this risk is greater if blood glucose control is poor around the time of conception. However, lowering the risk to that of women without diabetes would require normalisation of blood glucose levels, and this is difficult to achieve without increasing the risk of serious hypoglycaemia. Insulin pump therapy and rtCGM have been shown to reduce both blood glucose levels and rates of hypoglycaemia in the non‑pregnant population, but it is uncertain if this holds true before conception and in early pregnancy. There is therefore an urgent need to test the effectiveness and acceptability of these technologies in women with diabetes who are planning pregnancy. This would be best undertaken in a randomised controlled trial of women with diabetes who are trying to conceive. Women would be allocated to receive either conventional care (self‑monitoring of blood glucose and insulin adjustment) or insulin pump therapy and rtCGM.\n\n## Testing for gestational diabetes\n\nWhen should testing for gestational diabetes take place – in the first or second trimester?\n\nConventionally, testing for gestational diabetes takes place in the second trimester. Intervention has been shown to improve outcomes for women diagnosed with gestational diabetes. However, maternal age and obesity are increasing, and some women (especially those from populations with a high incidence of type\xa02 diabetes) enter pregnancy with undiagnosed type\xa02 diabetes, but may not be tested for diabetes until the second trimester. This exposes the woman and the fetus to risks resulting from early and prolonged maternal hyperglycaemia. It is presumed that this is associated with increased morbidity. UK population studies are needed to establish the incidence of glucose intolerance in women in the first trimester. Well‑designed randomised controlled trials are needed to establish if testing, diagnosis and intervention in the first rather than the second trimester improves maternal, fetal and neonatal outcomes, including fetal hyperinsulinaemia.\n\n## Barriers to achieving blood glucose targets before and during pregnancy\n\nWhat are the barriers that women experience to achieving blood glucose targets?\n\nIt is vital for normal fetal development in the first trimester that women with pre‑existing diabetes achieve good blood glucose control both before and during pregnancy. Good control also helps to prevent macrosomia and other complications in the third trimester in women with pre‑existing or gestational diabetes. Whereas many women manage to achieve blood glucose targets, a proportion of women continue to find it difficult to do so. A number of factors could be involved, such as health beliefs, a poor understanding of the importance of good blood glucose control, an inability to be able to comply with a demanding regimen of blood glucose testing up to 7\xa0times a day, and the need to adjust insulin dosage. A better understanding of the barriers in this cohort of women is needed so that healthcare professionals can work to overcome them. Robust qualitative studies are needed to explore these barriers, with the aim of improving blood glucose control and fetal outcomes in pregnancy for women with pre‑existing diabetes and women with gestational diabetes.\n\n## Risk of fetal death for women with diabetes\n\nHow can fetuses at risk of intrauterine death be identified in women with diabetes?\n\nUnexpected intrauterine death remains a significant contributor to perinatal mortality in pregnant women with diabetes. Conventional tests of fetal wellbeing (umbilical artery doppler ultrasound, cardiotocography and other biophysical tests) have been shown to have poor sensitivity for predicting such events. Alternative approaches that include measurements of erythropoietin in the amniotic fluid and MRI spectroscopy may be effective, but there is currently insufficient clinical evidence to evaluate them. Well‑designed randomised controlled trials that are sufficiently powered are needed to determine whether these approaches are clinically and cost effective.\n\n## Postnatal treatment for women diagnosed with gestational diabetes\n\nAre there effective long‑term pharmacological interventions to prevent the onset of type\xa02 diabetes that can be recommended postnatally for women who have been diagnosed with gestational diabetes?\n\nGestational diabetes is one of the strongest risk factors for the subsequent development of type\xa02 diabetes: up to 50% of women diagnosed with gestational diabetes develop type\xa02 diabetes within 5\xa0years of the birth. There are some data suggesting that changes in diet and exercise, with or without metformin, can prevent type\xa02 diabetes developing in non‑pregnant middle‑aged people with glucose intolerance, but there are no studies specifically in women with a past history of gestational diabetes. There is thus an urgent need to investigate what interventions may delay or prevent type\xa02 diabetes developing in this high‑risk population of women. Undertaking a formal randomised controlled trial involving long‑term outcomes is often not feasible in practice. However, it would be possible to have a quasi‑randomised study comparing 2\xa0populations of women with similar demographic profiles who had gestational diabetes. One population would be encouraged at their annual check to follow a specific diet and exercise regime and those in the other population would not. The incidence of the development of type\xa02 diabetes in the 2\xa0groups at 5\xa0years, 10\xa0years and 20\xa0years would be compared.', 'Rationale and impact': 'These sections briefly explain why the committee made the recommendations and how they might affect practice.\n\n# Continuous glucose monitoring\n\nRecommendations 1.3.17 to 1.3.20\n\n## Why the committee made the recommendations\n\nThere was evidence comparing real-time continuous glucose monitoring (rtCGM) with intermittently scanned CGM (isCGM) and with intermittent capillary glucose monitoring, for pregnant women with type 1 diabetes.\n\nWhen compared with intermittent capillary glucose monitoring, rtCGM resulted in:\n\nmore women achieving their blood glucose targets\n\nfewer caesarean sections\n\nfewer neonatal intensive care unit (NICU) admissions.\n\nOne retrospective study was identified that compared isCGM with rtCGM. This study showed no clear difference between the 2 monitoring systems in maternal and neonatal outcomes.\n\nHealth economic modelling found that isCGM clearly has the lowest overall cost of the 3 options. It is much less certain that isCGM provides the most benefit (a finding that is in line with the clinical evidence). The committee were concerned by the very low quality of the evidence for isCGM, the accuracy of isCGM (particularly in the hypoglycaemic range) and the number of finger-pricks that would still be needed to use isCGM safely.\n\nThe committee agreed that all the uncertainties in the evidence would be likely to lead to the benefits of isCGM being overestimated. Therefore, they could not be confident that isCGM represents a better use of NHS resources than rtCGM, which had been shown in high-quality evidence to have better outcomes than intermittent capillary glucose monitoring and a 94% chance of being cheaper in the probabilistic sensitivity analysis.\n\nBased on these findings, the committee recommended that rtCGM should be offered to all women with type 1 diabetes to help women meet their pregnancy blood glucose targets and improve neonatal outcomes.\n\nThe committee also noted that some women may be unable to use rtCGM or may prefer using isCGM instead. In these situations they recommended offering isCGM.\n\nThe committee amended the 2015 recommendation on considering rtCGM for pregnant women who are on insulin therapy but do not have type 1 diabetes because they wanted to identify specific scenarios in which rtCGM could be considered.\n\nThe committee believed that education and support are important for pregnant women using continuous glucose monitoring (CGM), to ensure they get the full benefit. Therefore, they updated and expanded the 2015 recommendation on providing support.\n\n## How the recommendations might affect practice\n\nUse of CGM varies across the country, but most centres offer isCGM and/or rtCGM to pregnant women with type 1 diabetes (in accordance with the NHS long-term plan). Because of this, the recommendations are unlikely to cause a major shift in practice.\n\nReturn to recommendations', 'Context': "Approximately 700,000\xa0women give birth in England and Wales each year, and up to 5% of these women have either pre‑existing diabetes or gestational diabetes. Of women who have diabetes during pregnancy, it is estimated that approximately 87.5% have gestational diabetes (which may or may not resolve after pregnancy), 7.5% have type\xa01 diabetes and the remaining 5% have type\xa02 diabetes. The prevalence of type\xa01 diabetes, and especially type\xa02 diabetes, has increased in recent years. The incidence of gestational diabetes is also increasing as a result of higher rates of obesity in the general population and more pregnancies in older women.\n\nDiabetes in pregnancy is associated with risks to the woman and to the developing fetus. Miscarriage, pre‑eclampsia and preterm labour are more common in women with pre‑existing diabetes. In addition, diabetic retinopathy can worsen rapidly during pregnancy. Stillbirth, congenital malformations, macrosomia, birth injury, perinatal mortality and postnatal adaptation problems (such as hypoglycaemia) are more common in babies born to women with pre‑existing diabetes.\n\nThis guideline contains recommendations for managing diabetes and its complications in women who are planning pregnancy and those who are already pregnant. The guideline focuses on areas where additional or different care should be offered to women with diabetes and their newborn babies. Where the evidence supports it, the guideline makes separate recommendations for women with pre‑existing diabetes and women with gestational diabetes. The term 'women' is used in the guideline to refer to all females of childbearing age, including young women who have not yet transferred from paediatric to adult services."}
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https://www.nice.org.uk/guidance/ng3
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This guideline covers managing diabetes and its complications in women who are planning pregnancy or are already pregnant. It aims to improve the diagnosis of gestational diabetes and help women with diabetes to self-manage their blood glucose levels before and during pregnancy.
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0a8ae46bc9a0d6c72426d58fcb2a74f20c0ce44c
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nice
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Pancreatitis
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Pancreatitis
This guideline covers managing acute and chronic pancreatitis in children, young people and adults. It aims to improve quality of life by ensuring that people have the right treatment and follow-up, and get timely information and support after diagnosis.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Information and support
## Patient information
Give people with pancreatitis, and their family members or carers (as appropriate), written and verbal information on the following, where relevant, as soon as possible after diagnosis:
pancreatitis and any proposed investigations and procedures, using diagrams
hereditary pancreatitis, and pancreatitis in children, including specific information on genetic counselling, genetic testing, risk to other family members, and advice on the impact of their pancreatitis on life insurance and travel
the long-term effects of pancreatitis, including effects on the person's quality of life
the harm caused to the pancreas by smoking or alcohol.
Advise people with pancreatitis where they might find reliable high-quality information and support after consultations, from sources such as national and local support groups, regional pancreatitis networks and information services.
Give people with pancreatitis, and their family members or carers (as appropriate), written and verbal information on the following about the management of pancreatitis, when applicable:
why a person may be going through a phase where no treatment is given
that pancreatitis is managed by a multidisciplinary team
the multidisciplinary treatment of pain, including how to access the local pain team and types of pain relief
nutrition advice, including advice on how to take pancreatic enzyme replacement therapy if needed
follow-up and who to contact for relevant advice, including advice needed during episodes of acute illness
psychological care if needed, where available (see the NICE guideline on depression in adults)
pancreatitis services, including the role of specialist centres, and primary care services for people with acute, chronic or hereditary pancreatitis
welfare benefits, education and employment support, and disability services.
For more guidance on giving information, including providing an individualised approach and helping people to actively participate in their care, see the NICE guideline on patient experience in adult NHS services.
Explain to people with severe acute pancreatitis, and their family members or carers (as appropriate), that:
a hospital stay lasting several months is relatively common, including time in critical care
for people who achieve full recovery, time to recover may take at least 3 times as long as their hospital stay
local complications of acute pancreatitis may resolve spontaneously or may take weeks to progress before it is clear that intervention is needed
it may be safer to delay intervention (for example, to allow a fluid collection to mature)
people who have started to make a recovery may have a relapse
although children rarely die from acute pancreatitis, approximately 15% to 20% of adults with severe acute pancreatitis die in hospital.
Tell adults with pancreatitis that there is a NICE guideline on patient experience in adult NHS services that will show them what they can expect about their care.
## Passing information to GPs
Ensure that information passed to GPs includes all of the following, where applicable:
detail on how the person should take their pancreatic enzyme replacement therapy (including dose escalation as necessary)
that the person should be offered HbA1c testing at least every 6 months and bone mineral density assessments every 2 years.
## Lifestyle interventions: alcohol
Advise people with pancreatitis caused by alcohol to stop drinking alcohol.
Advise people with recurrent acute or chronic pancreatitis that is not alcohol-related, that alcohol might exacerbate their pancreatitis.
For guidance on alcohol-use disorders, see the NICE guidelines on the diagnosis and management of physical complications of alcohol-use disorders and the diagnosis, assessment and management of harmful drinking and alcohol dependence.
## Lifestyle interventions: smoking cessation
Be aware of the link between smoking and chronic pancreatitis and advise people with chronic pancreatitis to stop smoking in line with the NICE guideline on tobacco.
# Acute pancreatitis
People with acute pancreatitis usually present with sudden-onset abdominal pain. Nausea and vomiting are often present and there may be a history of gallstones or excessive alcohol intake. Typical physical signs include epigastric tenderness, fever and tachycardia. Diagnosis of acute pancreatitis is confirmed by testing blood lipase or amylase levels, which are usually raised. If raised levels are not found, abdominal CT may confirm pancreatic inflammation.
## Identifying the cause
Do not assume that a person's acute pancreatitis is alcohol-related just because they drink alcohol.
If gallstones and alcohol have been excluded as potential causes of a person's acute pancreatitis, investigate other possible causes such as:
metabolic causes (such as hypercalcaemia or hyperlipidaemia)
prescription drugs
microlithiasis
hereditary causes
autoimmune pancreatitis
ampullary or pancreatic tumours
anatomical anomalies (pancreas divisum).
## Preventing infection
Do not offer prophylactic antimicrobials to people with acute pancreatitis.
## Fluid resuscitation
For guidance on fluid resuscitation, see the NICE guidelines on intravenous fluid therapy in adults in hospital and in children and young people in hospital.
## Nutrition support
Ensure that people with acute pancreatitis are not made 'nil‑by‑mouth' and do not have food withheld unless there is a clear reason for this (for example, vomiting).
Offer enteral nutrition to anyone with severe or moderately severe acute pancreatitis. Start within 72 hours of presentation and aim to meet their nutritional requirements as soon as possible.
Offer anyone with severe or moderately severe acute pancreatitis parenteral nutrition only if enteral nutrition has failed or is contraindicated.
## Managing complications
Offer people with acute pancreatitis an endoscopic approach for managing infected or suspected infected pancreatic necrosis when anatomically possible.
Offer a percutaneous approach when an endoscopic approach is not anatomically possible.
When deciding on how to manage infected pancreatic necrosis, balance the need to debride promptly against the advantages of delaying intervention.
For guidance on managing pseudocysts, see the recommendations in the section on pseudocysts in managing complications of chronic pancreatitis.
For guidance on managing pancreatic ascites and pleural effusion secondary to pancreatitis, see the recommendation in the section on pancreatic ascites and pleural effusion in managing complications of chronic pancreatitis.
For guidance on managing type 3c diabetes secondary to pancreatitis, see the recommendations in the section on type 3c diabetes in managing complications of chronic pancreatitis.
## Referral for specialist treatment
If a person develops necrotic, infective, haemorrhagic or systemic complications of acute pancreatitis:
seek advice from a specialist pancreatic centre within the referral network and
discuss whether to move the person to the specialist centre for treatment of the complications.
When managing acute pancreatitis in children:
seek advice from a paediatric gastroenterology or hepatology unit and a specialist pancreatic centre and
discuss whether to move the child to the specialist centre.
# Chronic pancreatitis
People with chronic pancreatitis usually present with chronic or recurrent abdominal pain. This guideline assumes that people with chronic abdominal pain will already have been investigated using CT scan, ultrasound scan or upper gastrointestinal endoscopy to determine a cause for their symptoms. The guideline committee looked at evidence on diagnosing chronic pancreatitis, and the evidence review can be found in the full guideline. We have made a recommendation for research on the most accurate diagnostic test to identify whether chronic pancreatitis is present in the absence of a clear diagnosis following these tests.
## Investigating upper abdominal pain
Think about chronic pancreatitis as a possible diagnosis for people presenting with chronic or recurrent episodes of upper abdominal pain and refer accordingly.
## Identifying the cause
Do not assume that a person's chronic pancreatitis is alcohol-related just because they drink alcohol. Other causes include:
genetic factors
autoimmune disease, in particular IgG4 disease
metabolic causes
structural or anatomical factors.
## Nutrition support
Be aware that all people with chronic pancreatitis are at high risk of malabsorption, malnutrition and a deterioration in their quality of life.
Use protocols agreed with the specialist pancreatic centre to identify when advice from a specialist dietitian is needed, including advice on food, supplements and long-term pancreatic enzyme replacement therapy, and when to start these interventions.
Consider assessment by a dietitian for anyone diagnosed with chronic pancreatitis.
For guidance on nutrition support for people with chronic alcohol-related pancreatitis, see the section on enzyme supplementation for chronic alcohol-related pancreatitis in the NICE guideline on alcohol-use disorders.
For guidance on nutrition support, see the NICE guideline on nutrition support for adults.
## Managing complications
Consider surgery (open or minimally invasive) as first-line treatment in adults with painful chronic pancreatitis that is causing obstruction of the main pancreatic duct.
Consider extracorporeal shockwave lithotripsy for adults with pancreatic duct obstruction caused by a dominant stone if surgery is unsuitable.
Offer endoscopic ultrasound (EUS)-guided drainage, or endoscopic transpapillary drainage for pancreatic head pseudocysts, to people with symptomatic pseudocysts (for example, those with pain, vomiting or weight loss).
Consider EUS-guided drainage, or endoscopic transpapillary drainage for pancreatic head pseudocysts, for people with non-symptomatic pseudocysts that meet 1 or more of the following criteria:
they are associated with pancreatic duct disruption
they are creating pressure on large vessels or the diaphragm
they are at risk of rupture
there is suspicion of infection.
Consider surgical (laparoscopic or open) drainage of pseudocysts that need intervention if endoscopic therapy is unsuitable or has failed.
For adults with neuropathic pain related to chronic pancreatitis, follow the recommendations in the NICE guideline on neuropathic pain in adults.
Consider referring a person with pancreatic ascites and pleural effusion for management in a specialist pancreatic centre.
Assess people with type 3c diabetes every 6 months for potential benefit of insulin therapy.
For guidance on managing type 3c diabetes for people who are not using insulin therapy, see the NICE guidelines on type 2 diabetes in adults and diagnosing and managing diabetes in children and young people.
For guidance on managing type 3c diabetes for people who need insulin, see:
the recommendations on insulin therapy and insulin delivery (including rotating injection sites within the same body region) in the NICE guidelines on type 1 diabetes in adults and diagnosing and managing diabetes in children and young people
NICE's technology appraisal guidance on continuous subcutaneous insulin infusion for the treatment of diabetes mellitus.
For guidance on education and information for people with pancreatitis and type 3c diabetes requiring insulin, see the recommendations on education and information in the NICE guideline on diagnosing and managing type 1 diabetes in adults, and diagnosing and managing diabetes in children and young people.
For guidance on self-monitoring blood glucose for people with pancreatitis and type 3c diabetes requiring insulin, see the recommendations on blood glucose management in the NICE guideline on diagnosing and managing type 1 diabetes in adults, and blood glucose monitoring in the NICE guideline on diagnosing and managing diabetes in children and young people.
## Follow-up investigation
Offer people with chronic pancreatitis monitoring by clinical and biochemical assessment, to be agreed with the specialist centre, for pancreatic exocrine insufficiency and malnutrition at least every 12 months (every 6 months in under 16s). Adjust the treatment of vitamin and mineral deficiencies accordingly.
Offer adults with chronic pancreatitis a bone density assessment every 2 years.
Be aware that people with chronic pancreatitis have an increased risk of developing pancreatic cancer. The lifetime risk is highest, around 40%, in those with hereditary pancreatitis.
Consider annual monitoring for pancreatic cancer in people with hereditary pancreatitis.
Be aware that people with chronic pancreatitis have a greatly increased risk of developing diabetes, with a lifetime risk as high as 80%. The risk increases with duration of pancreatitis and presence of calcific pancreatitis.
Offer people with chronic pancreatitis monitoring of HbA1c for diabetes at least every 6 months.
# Terms used in this guideline
## Moderately severe acute pancreatitis
Moderately severe acute pancreatitis is characterised by organ failure that resolves within 48 hours (transient organ failure), or local or systemic complications in the absence of persistent organ failure (as defined by the revised Atlanta classification published in GUT).
## Severe acute pancreatitis
Severe acute pancreatitis is characterised by single or multiple organ failure that persists for more than 48 hours (persistent organ failure; as defined by the revised Atlanta classification).
## Type 3c diabetes
Diabetes mellitus secondary to pancreatic disease. When this is associated with pancreatitis, the primary endocrine defect is insufficient insulin secretion (the abnormality in type 1 diabetes) rather than insulin resistance (which is characteristic of type 2 diabetes).# Putting this guideline into practice
We have produced NICE tools and resources to help you put this guideline into practice.
Some issues were highlighted that might need specific thought when implementing the recommendations. These were raised during the development of this guideline. They are:
Models where local centres interact and collaborate with a regional specialist centre for acute pancreatitis are only currently established in some regions. Therefore, this model will need to be implemented across the country to enable the recommendations on specialist referral to be followed.
Networks of dietitians and specialist dietitians need to be established to support the production and dissemination of protocols to identify when advice from a specialist dietitian is needed.
Putting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.
Changes recommended for clinical practice that can be done quickly – like changes in prescribing practice – should be shared quickly. This is because healthcare professionals should use guidelines to guide their work – as is required by professional regulating bodies such as the General Medical and Nursing and Midwifery Councils.
Changes should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).
Different organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.
Here are some pointers to help organisations put NICE guidelines into practice:
. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.
. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.
. Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision.
. Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.
. Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.
. For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.
. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.
. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners.
NICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See NICE's into practice pages for more information.
Also see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.# Context
Acute pancreatitis is acute inflammation of the pancreas and is a common cause of acute abdominal pain. The incidence in the UK is approximately 56 cases per 100,000 people per year. Around 50% of cases are caused by gallstones, 25% by alcohol and 25% by other factors. In 25% of cases, acute pancreatitis is severe and associated with complications such as respiratory or kidney failure, or the development of abdominal fluid collections. In these more severe cases, people often need critical care and a prolonged hospital stay, and the mortality rate is 25%. The overall mortality rate in acute pancreatitis is approximately 5%.
Chronic pancreatitis is a continuous prolonged inflammatory process of the pancreas that results in fibrosis, cyst formation and stricturing of the pancreatic duct. It usually presents with chronic abdominal pain but it can sometimes be painless. The clinical course is variable but most people with chronic pancreatitis have had 1 or more attacks of acute pancreatitis that has resulted in inflammatory change and fibrosis. In some people, however, chronic pancreatitis has a more insidious onset. The intensity of pain can range from mild to severe, even in people with little evidence of pancreatic disease on imaging.
The annual incidence of chronic pancreatitis in western Europe is about 5 new cases per 100,000 people, although this is probably an underestimate. The male to female ratio is 7:1 and the average age of onset is between 36 and 55 years. Alcohol is responsible for 70–80% of cases of chronic pancreatitis. Although cigarette smoking is not thought to be a primary cause in itself, it is strongly associated with chronic pancreatitis and is thought to exacerbate the condition. Chronic pancreatitis may be idiopathic or, in about 5% of cases, caused by hereditary factors (in these cases there is usually a positive family history). Other causes include hypercalcaemia, hyperlipidaemia or autoimmune disease.
Chronic pancreatitis causes a significant reduction in pancreatic function and the majority of people have reduced exocrine (digestive) function and reduced endocrine function (diabetes). They usually need expert dietary advice and medication. Chronic pancreatitis can also give rise to specific complications including painful inflammatory mass and obstructed pancreatic duct, biliary or duodenal obstruction, haemorrhage, or accumulation of fluid in the abdomen (ascites) or chest (pleural effusion). Managing these complications may be difficult because of ongoing comorbidities and social problems such as alcohol or opiate dependence. Chronic pancreatitis significantly increases the risk of pancreatic cancer. This risk is much higher in people with hereditary pancreatitis.# Recommendations for research
The guideline committee has made the following recommendations for research. The committee's full set of recommendations for research are detailed in the full guideline.
# Diagnosis of chronic pancreatitis
In people with suspected (or under investigation for) chronic pancreatitis, whose diagnosis has not been confirmed by the use of 'first‑line' tests (for example, CT scan, ultrasound scan, upper gastrointestinal endoscopy or combinations of these), what is the accuracy of magnetic resonance cholangiopancreatography (MRCP) with or without secretin and endoscopic ultrasound to identify whether chronic pancreatitis is present?
## Why this is important
People with chronic pancreatitis usually present with chronic abdominal pain. However, there are many other causes of chronic abdominal pain (for example, peptic ulcer disease, gallstone disease, gastric cancer, pancreatic cancer and abdominal aortic aneurysm). First-line tests to exclude these other causes include abdominal ultrasound, upper GI endoscopy and abdominal CT scan. Where the diagnosis has still not been confirmed following these first-line tests, it is important to have a clinical algorithm of specialist tests to be able to identify people with chronic pancreatitis. Appropriate management options can then be offered. A diagnostic cohort study is needed to determine the accuracy of MRCP with or without secretin and endoscopic ultrasound in diagnosing chronic pancreatitis.
# Speed of intravenous fluid resuscitation for people with acute pancreatitis
What is the most clinically effective and cost-effective speed of administration of intravenous fluid for resuscitation in people with acute pancreatitis?
## Why this is important
There is clinical uncertainty about the optimal rate of fluid for resuscitation in severe acute pancreatitis. Severe acute pancreatitis causes the depletion of body fluids and reduction of the intravascular volume severe enough to cause hypotension, acute renal failure and pancreatic hypoperfusion, aggravating the damage to the pancreas. In addition, there is conflicting evidence about the effect of aggressive or conservative fluid management on outcomes in other conditions with a pathophysiology.
Current guidelines recommend using goal-directed therapy for fluid management, but do not recommend a particular type of fluid. A randomised controlled trial is needed to determine whether aggressive rates of intravenous fluid administration for the initial period of fluid resuscitation are more clinically or cost effective than conservative rates in people with acute pancreatitis.
# Pain management: chronic pancreatitis
Is the long-term use of opioids more clinically effective and cost effective than non-opioid analgesia (including non-pharmacological analgesia) in people with chronic pain due to chronic pancreatitis?
## Why this is important
Chronic pancreatitis is a complex condition needing biopsychosocial management. The pain is varied in nature, intensity, duration and severity, along with acute exacerbations. It is also multifactorial, making it difficult to have a standard regimen that can work for everyone. Some people also develop psychosocial factors such as reduction in quality of life, relationship issues, addiction to painkillers and financial difficulties.
Chronic pancreatitis is usually managed pharmacologically with a combination of opioids and other interventions. However, the use of opioids in managing chronic pancreatitis is known to cause serious side-effects – including tolerance, addiction, tiredness and constipation. These side-effects are frequently worse than the disease itself. Therefore, the whole rationale for the use of opioids in chronic pancreatitis is questionable. A cohort study is needed to determine how effective long-term opioid use is in this population compared with non-opiate pain management strategies, including analgesia and psychological therapies.
# Pain management: small duct disease
What is the most clinically effective and cost-effective intervention for managing small duct disease (in the absence of pancreatic duct obstruction, inflammatory mass or pseudocyst) in people with chronic pancreatitis presenting with pain?
## Why this is important
Chronic pancreatitis with small duct disease is more difficult to treat than without the disease because there is no anatomically correctable pancreatic abnormality – for example, pancreatic duct obstruction, inflammatory mass or pseudocysts. A randomised controlled trial study is needed to determine what the most effective intervention is for treating small duct disease. The following interventions should be compared with each other and with no treatment: surgery (partial resection, total resection with or without islet transplant, or drainage), endoscopic treatment, or standard care (for example, pharmacological treatment only, enzyme replacement therapy, nerve blocks).
# Management of type 3c diabetes
What is the most clinically effective and cost-effective insulin regimen to minimise hypo- and hyperglycaemia for type 3c diabetes secondary to pancreatitis?
## Why this is important
Type 3c diabetes is associated with metabolic instability and risk of decompensation leading to severe hypoglycaemia and ketoacidosis, in addition to poor quality of life. However, there is no evidence available in this population to inform practice. Therefore, research specifically on type 3c diabetes is essential to inform future updates of key recommendations in this guideline. National adoption of evidence-based insulin management in type 3c diabetes has the potential to cost effectively improve health and wellbeing, reducing the incidence of acute and long-term complications of poorly controlled glucose levels in chronic pancreatitis. A randomised controlled trial is needed to determine the most effective insulin therapy regimen in this population, comparing twice daily insulin injections, an insulin analogue multiple daily dose basal bolus regimen, and insulin pump therapy.
|
{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Information and support\n\n## Patient information\n\nGive people with pancreatitis, and their family members or carers (as appropriate), written and verbal information on the following, where relevant, as soon as possible after diagnosis:\n\npancreatitis and any proposed investigations and procedures, using diagrams\n\nhereditary pancreatitis, and pancreatitis in children, including specific information on genetic counselling, genetic testing, risk to other family members, and advice on the impact of their pancreatitis on life insurance and travel\n\nthe long-term effects of pancreatitis, including effects on the person's quality of life\n\nthe harm caused to the pancreas by smoking or alcohol.\n\nAdvise people with pancreatitis where they might find reliable high-quality information and support after consultations, from sources such as national and local support groups, regional pancreatitis networks and information services.\n\nGive people with pancreatitis, and their family members or carers (as appropriate), written and verbal information on the following about the management of pancreatitis, when applicable:\n\nwhy a person may be going through a phase where no treatment is given\n\nthat pancreatitis is managed by a multidisciplinary team\n\nthe multidisciplinary treatment of pain, including how to access the local pain team and types of pain relief\n\nnutrition advice, including advice on how to take pancreatic enzyme replacement therapy if needed\n\nfollow-up and who to contact for relevant advice, including advice needed during episodes of acute illness\n\npsychological care if needed, where available (see the NICE guideline on depression in adults)\n\npancreatitis services, including the role of specialist centres, and primary care services for people with acute, chronic or hereditary pancreatitis\n\nwelfare benefits, education and employment support, and disability services.\n\nFor more guidance on giving information, including providing an individualised approach and helping people to actively participate in their care, see the NICE guideline on patient experience in adult NHS services.\n\nExplain to people with severe acute pancreatitis, and their family members or carers (as appropriate), that:\n\na hospital stay lasting several months is relatively common, including time in critical care\n\nfor people who achieve full recovery, time to recover may take at least 3\xa0times as long as their hospital stay\n\nlocal complications of acute pancreatitis may resolve spontaneously or may take weeks to progress before it is clear that intervention is needed\n\nit may be safer to delay intervention (for example, to allow a fluid collection to mature)\n\npeople who have started to make a recovery may have a relapse\n\nalthough children rarely die from acute pancreatitis, approximately 15% to 20% of adults with severe acute pancreatitis die in hospital.\n\nTell adults with pancreatitis that there is a NICE guideline on patient experience in adult NHS services that will show them what they can expect about their care.\n\n## Passing information to GPs\n\nEnsure that information passed to GPs includes all of the following, where applicable:\n\ndetail on how the person should take their pancreatic enzyme replacement therapy (including dose escalation as necessary)\n\nthat the person should be offered HbA1c testing at least every 6\xa0months and bone mineral density assessments every 2\xa0years.\n\n## Lifestyle interventions: alcohol\n\nAdvise people with pancreatitis caused by alcohol to stop drinking alcohol.\n\nAdvise people with recurrent acute or chronic pancreatitis that is not alcohol-related, that alcohol might exacerbate their pancreatitis.\n\nFor guidance on alcohol-use disorders, see the NICE guidelines on the diagnosis and management of physical complications of alcohol-use disorders and the diagnosis, assessment and management of harmful drinking and alcohol dependence.\n\n## Lifestyle interventions: smoking cessation\n\nBe aware of the link between smoking and chronic pancreatitis and advise people with chronic pancreatitis to stop smoking in line with the NICE guideline on tobacco.\n\n# Acute pancreatitis\n\nPeople with acute pancreatitis usually present with sudden-onset abdominal pain. Nausea and vomiting are often present and there may be a history of gallstones or excessive alcohol intake. Typical physical signs include epigastric tenderness, fever and tachycardia. Diagnosis of acute pancreatitis is confirmed by testing blood lipase or amylase levels, which are usually raised. If raised levels are not found, abdominal CT may confirm pancreatic inflammation.\n\n## Identifying the cause\n\nDo not assume that a person's acute pancreatitis is alcohol-related just because they drink alcohol.\n\nIf gallstones and alcohol have been excluded as potential causes of a person's acute pancreatitis, investigate other possible causes such as:\n\nmetabolic causes (such as hypercalcaemia or hyperlipidaemia)\n\nprescription drugs\n\nmicrolithiasis\n\nhereditary causes\n\nautoimmune pancreatitis\n\nampullary or pancreatic tumours\n\nanatomical anomalies (pancreas divisum).\n\n## Preventing infection\n\nDo not offer prophylactic antimicrobials to people with acute pancreatitis.\n\n## Fluid resuscitation\n\nFor guidance on fluid resuscitation, see the NICE guidelines on intravenous fluid therapy in adults in hospital and in children and young people in hospital.\n\n## Nutrition support\n\nEnsure that people with acute pancreatitis are not made 'nil‑by‑mouth' and do not have food withheld unless there is a clear reason for this (for example, vomiting).\n\nOffer enteral nutrition to anyone with severe or moderately severe acute pancreatitis. Start within 72\xa0hours of presentation and aim to meet their nutritional requirements as soon as possible.\n\nOffer anyone with severe or moderately severe acute pancreatitis parenteral nutrition only if enteral nutrition has failed or is contraindicated.\n\n## Managing complications\n\nOffer people with acute pancreatitis an endoscopic approach for managing infected or suspected infected pancreatic necrosis when anatomically possible.\n\nOffer a percutaneous approach when an endoscopic approach is not anatomically possible.\n\nWhen deciding on how to manage infected pancreatic necrosis, balance the need to debride promptly against the advantages of delaying intervention.\n\nFor guidance on managing pseudocysts, see the recommendations in the section on pseudocysts in managing complications of chronic pancreatitis.\n\nFor guidance on managing pancreatic ascites and pleural effusion secondary to pancreatitis, see the recommendation in the section on pancreatic ascites and pleural effusion in managing complications of chronic pancreatitis.\n\nFor guidance on managing type\xa03c diabetes secondary to pancreatitis, see the recommendations in the section on type 3c diabetes in managing complications of chronic pancreatitis.\n\n## Referral for specialist treatment\n\nIf a person develops necrotic, infective, haemorrhagic or systemic complications of acute pancreatitis:\n\nseek advice from a specialist pancreatic centre within the referral network and\n\ndiscuss whether to move the person to the specialist centre for treatment of the complications.\n\nWhen managing acute pancreatitis in children:\n\nseek advice from a paediatric gastroenterology or hepatology unit and a specialist pancreatic centre and\n\ndiscuss whether to move the child to the specialist centre.\n\n# Chronic pancreatitis\n\nPeople with chronic pancreatitis usually present with chronic or recurrent abdominal pain. This guideline assumes that people with chronic abdominal pain will already have been investigated using CT scan, ultrasound scan or upper gastrointestinal endoscopy to determine a cause for their symptoms. The guideline committee looked at evidence on diagnosing chronic pancreatitis, and the evidence review can be found in the full guideline. We have made a recommendation for research on the most accurate diagnostic test to identify whether chronic pancreatitis is present in the absence of a clear diagnosis following these tests.\n\n## Investigating upper abdominal pain\n\nThink about chronic pancreatitis as a possible diagnosis for people presenting with chronic or recurrent episodes of upper abdominal pain and refer accordingly.\n\n## Identifying the cause\n\nDo not assume that a person's chronic pancreatitis is alcohol-related just because they drink alcohol. Other causes include:\n\ngenetic factors\n\nautoimmune disease, in particular IgG4 disease\n\nmetabolic causes\n\nstructural or anatomical factors.\n\n## Nutrition support\n\nBe aware that all people with chronic pancreatitis are at high risk of malabsorption, malnutrition and a deterioration in their quality of life.\n\nUse protocols agreed with the specialist pancreatic centre to identify when advice from a specialist dietitian is needed, including advice on food, supplements and long-term pancreatic enzyme replacement therapy, and when to start these interventions.\n\nConsider assessment by a dietitian for anyone diagnosed with chronic pancreatitis.\n\nFor guidance on nutrition support for people with chronic alcohol-related pancreatitis, see the section on enzyme supplementation for chronic alcohol-related pancreatitis in the NICE guideline on alcohol-use disorders.\n\nFor guidance on nutrition support, see the NICE guideline on nutrition support for adults.\n\n## Managing complications\n\nConsider surgery (open or minimally invasive) as first-line treatment in adults with painful chronic pancreatitis that is causing obstruction of the main pancreatic duct.\n\nConsider extracorporeal shockwave lithotripsy for adults with pancreatic duct obstruction caused by a dominant stone if surgery is unsuitable.\n\nOffer endoscopic ultrasound (EUS)-guided drainage, or endoscopic transpapillary drainage for pancreatic head pseudocysts, to people with symptomatic pseudocysts (for example, those with pain, vomiting or weight loss).\n\nConsider EUS-guided drainage, or endoscopic transpapillary drainage for pancreatic head pseudocysts, for people with non-symptomatic pseudocysts that meet 1\xa0or more of the following criteria:\n\nthey are associated with pancreatic duct disruption\n\nthey are creating pressure on large vessels or the diaphragm\n\nthey are at risk of rupture\n\nthere is suspicion of infection.\n\nConsider surgical (laparoscopic or open) drainage of pseudocysts that need intervention if endoscopic therapy is unsuitable or has failed.\n\nFor adults with neuropathic pain related to chronic pancreatitis, follow the recommendations in the NICE guideline on neuropathic pain in adults.\n\nConsider referring a person with pancreatic ascites and pleural effusion for management in a specialist pancreatic centre.\n\nAssess people with type\xa03c diabetes every 6\xa0months for potential benefit of insulin therapy.\n\nFor guidance on managing type\xa03c diabetes for people who are not using insulin therapy, see the NICE guidelines on type\xa02 diabetes in adults and diagnosing and managing diabetes in children and young people.\n\nFor guidance on managing type\xa03c diabetes for people who need insulin, see:\n\nthe recommendations on insulin therapy and insulin delivery (including rotating injection sites within the same body region) in the NICE guidelines on type 1 diabetes in adults and diagnosing and managing diabetes in children and young people\n\nNICE's technology appraisal guidance on continuous subcutaneous insulin infusion for the treatment of diabetes mellitus. [2018, amended 2020]\n\nFor guidance on education and information for people with pancreatitis and type\xa03c diabetes requiring insulin, see the recommendations on education and information in the NICE guideline on diagnosing and managing type\xa01 diabetes in adults, and diagnosing and managing diabetes in children and young people.\n\nFor guidance on self-monitoring blood glucose for people with pancreatitis and type\xa03c diabetes requiring insulin, see the recommendations on blood glucose management in the NICE guideline on diagnosing and managing type\xa01 diabetes in adults, and blood glucose monitoring in the NICE guideline on diagnosing and managing diabetes in children and young people.\n\n## Follow-up investigation\n\nOffer people with chronic pancreatitis monitoring by clinical and biochemical assessment, to be agreed with the specialist centre, for pancreatic exocrine insufficiency and malnutrition at least every 12\xa0months (every 6\xa0months in under\xa016s). Adjust the treatment of vitamin and mineral deficiencies accordingly.\n\nOffer adults with chronic pancreatitis a bone density assessment every 2\xa0years.\n\nBe aware that people with chronic pancreatitis have an increased risk of developing pancreatic cancer. The lifetime risk is highest, around 40%, in those with hereditary pancreatitis.\n\nConsider annual monitoring for pancreatic cancer in people with hereditary pancreatitis.\n\nBe aware that people with chronic pancreatitis have a greatly increased risk of developing diabetes, with a lifetime risk as high as 80%. The risk increases with duration of pancreatitis and presence of calcific pancreatitis.\n\nOffer people with chronic pancreatitis monitoring of HbA1c for diabetes at least every 6\xa0months.\n\n# Terms used in this guideline\n\n## Moderately severe acute pancreatitis\n\nModerately severe acute pancreatitis is characterised by organ failure that resolves within 48\xa0hours (transient organ failure), or local or systemic complications in the absence of persistent organ failure (as defined by the revised Atlanta classification published in GUT).\n\n## Severe acute pancreatitis\n\nSevere acute pancreatitis is characterised by single or multiple organ failure that persists for more than 48\xa0hours (persistent organ failure; as defined by the revised Atlanta classification).\n\n## Type 3c diabetes\n\nDiabetes mellitus secondary to pancreatic disease. When this is associated with pancreatitis, the primary endocrine defect is insufficient insulin secretion (the abnormality in type\xa01 diabetes) rather than insulin resistance (which is characteristic of type\xa02 diabetes).", 'Putting this guideline into practice': "We have produced NICE tools and resources to help you put this guideline into practice.\n\nSome issues were highlighted that might need specific thought when implementing the recommendations. These were raised during the development of this guideline. They are:\n\nModels where local centres interact and collaborate with a regional specialist centre for acute pancreatitis are only currently established in some regions. Therefore, this model will need to be implemented across the country to enable the recommendations on specialist referral to be followed.\n\nNetworks of dietitians and specialist dietitians need to be established to support the production and dissemination of protocols to identify when advice from a specialist dietitian is needed.\n\nPutting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.\n\nChanges recommended for clinical practice that can be done quickly – like changes in prescribing practice – should be shared quickly. This is because healthcare professionals should use guidelines to guide their work – as is required by professional regulating bodies such as the General Medical and Nursing and Midwifery Councils.\n\nChanges should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).\n\nDifferent organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.\n\nHere are some pointers to help organisations put NICE guidelines into practice:\n\n. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.\n\n. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.\n\n. Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision.\n\n. Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.\n\n. Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.\n\n. For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.\n\n. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.\n\n. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners.\n\nNICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See NICE's into practice pages for more information.\n\nAlso see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.", 'Context': 'Acute pancreatitis is acute inflammation of the pancreas and is a common cause of acute abdominal pain. The incidence in the UK is approximately 56\xa0cases per 100,000\xa0people per year. Around 50% of cases are caused by gallstones, 25% by alcohol and 25% by other factors. In 25% of cases, acute pancreatitis is severe and associated with complications such as respiratory or kidney failure, or the development of abdominal fluid collections. In these more severe cases, people often need critical care and a prolonged hospital stay, and the mortality rate is 25%. The overall mortality rate in acute pancreatitis is approximately\xa05%.\n\nChronic pancreatitis is a continuous prolonged inflammatory process of the pancreas that results in fibrosis, cyst formation and stricturing of the pancreatic duct. It usually presents with chronic abdominal pain but it can sometimes be painless. The clinical course is variable but most people with chronic pancreatitis have had 1\xa0or more attacks of acute pancreatitis that has resulted in inflammatory change and fibrosis. In some people, however, chronic pancreatitis has a more insidious onset. The intensity of pain can range from mild to severe, even in people with little evidence of pancreatic disease on imaging.\n\nThe annual incidence of chronic pancreatitis in western Europe is about 5\xa0new cases per 100,000\xa0people, although this is probably an underestimate. The male to female ratio is 7:1 and the average age of onset is between 36\xa0and 55\xa0years. Alcohol is responsible for 70–80% of cases of chronic pancreatitis. Although cigarette smoking is not thought to be a primary cause in itself, it is strongly associated with chronic pancreatitis and is thought to exacerbate the condition. Chronic pancreatitis may be idiopathic or, in about 5% of cases, caused by hereditary factors (in these cases there is usually a positive family history). Other causes include hypercalcaemia, hyperlipidaemia or autoimmune disease.\n\nChronic pancreatitis causes a significant reduction in pancreatic function and the majority of people have reduced exocrine (digestive) function and reduced endocrine function (diabetes). They usually need expert dietary advice and medication. Chronic pancreatitis can also give rise to specific complications including painful inflammatory mass and obstructed pancreatic duct, biliary or duodenal obstruction, haemorrhage, or accumulation of fluid in the abdomen (ascites) or chest (pleural effusion). Managing these complications may be difficult because of ongoing comorbidities and social problems such as alcohol or opiate dependence. Chronic pancreatitis significantly increases the risk of pancreatic cancer. This risk is much higher in people with hereditary pancreatitis.', 'Recommendations for research': "The guideline committee has made the following recommendations for research. The committee's full set of recommendations for research are detailed in the full guideline.\n\n# Diagnosis of chronic pancreatitis\n\nIn people with suspected (or under investigation for) chronic pancreatitis, whose diagnosis has not been confirmed by the use of 'first‑line' tests (for example, CT scan, ultrasound scan, upper gastrointestinal [GI] endoscopy or combinations of these), what is the accuracy of magnetic resonance cholangiopancreatography (MRCP) with or without secretin and endoscopic ultrasound to identify whether chronic pancreatitis is present?\n\n## Why this is important\n\nPeople with chronic pancreatitis usually present with chronic abdominal pain. However, there are many other causes of chronic abdominal pain (for example, peptic ulcer disease, gallstone disease, gastric cancer, pancreatic cancer and abdominal aortic aneurysm). First-line tests to exclude these other causes include abdominal ultrasound, upper GI endoscopy and abdominal CT scan. Where the diagnosis has still not been confirmed following these first-line tests, it is important to have a clinical algorithm of specialist tests to be able to identify people with chronic pancreatitis. Appropriate management options can then be offered. A diagnostic cohort study is needed to determine the accuracy of MRCP with or without secretin and endoscopic ultrasound in diagnosing chronic pancreatitis.\n\n# Speed of intravenous fluid resuscitation for people with acute pancreatitis\n\nWhat is the most clinically effective and cost-effective speed of administration of intravenous fluid for resuscitation in people with acute pancreatitis?\n\n## Why this is important\n\nThere is clinical uncertainty about the optimal rate of fluid for resuscitation in severe acute pancreatitis. Severe acute pancreatitis causes the depletion of body fluids and reduction of the intravascular volume severe enough to cause hypotension, acute renal failure and pancreatic hypoperfusion, aggravating the damage to the pancreas. In addition, there is conflicting evidence about the effect of aggressive or conservative fluid management on outcomes in other conditions with a pathophysiology.\n\nCurrent guidelines recommend using goal-directed therapy for fluid management, but do not recommend a particular type of fluid. A randomised controlled trial is needed to determine whether aggressive rates of intravenous fluid administration for the initial period of fluid resuscitation are more clinically or cost effective than conservative rates in people with acute pancreatitis.\n\n# Pain management: chronic pancreatitis\n\nIs the long-term use of opioids more clinically effective and cost effective than non-opioid analgesia (including non-pharmacological analgesia) in people with chronic pain due to chronic pancreatitis?\n\n## Why this is important\n\nChronic pancreatitis is a complex condition needing biopsychosocial management. The pain is varied in nature, intensity, duration and severity, along with acute exacerbations. It is also multifactorial, making it difficult to have a standard regimen that can work for everyone. Some people also develop psychosocial factors such as reduction in quality of life, relationship issues, addiction to painkillers and financial difficulties.\n\nChronic pancreatitis is usually managed pharmacologically with a combination of opioids and other interventions. However, the use of opioids in managing chronic pancreatitis is known to cause serious side-effects – including tolerance, addiction, tiredness and constipation. These side-effects are frequently worse than the disease itself. Therefore, the whole rationale for the use of opioids in chronic pancreatitis is questionable. A cohort study is needed to determine how effective long-term opioid use is in this population compared with non-opiate pain management strategies, including analgesia and psychological therapies.\n\n# Pain management: small duct disease\n\nWhat is the most clinically effective and cost-effective intervention for managing small duct disease (in the absence of pancreatic duct obstruction, inflammatory mass or pseudocyst) in people with chronic pancreatitis presenting with pain?\n\n## Why this is important\n\nChronic pancreatitis with small duct disease is more difficult to treat than without the disease because there is no anatomically correctable pancreatic abnormality – for example, pancreatic duct obstruction, inflammatory mass or pseudocysts. A randomised controlled trial study is needed to determine what the most effective intervention is for treating small duct disease. The following interventions should be compared with each other and with no treatment: surgery (partial resection, total resection with or without islet transplant, or drainage), endoscopic treatment, or standard care (for example, pharmacological treatment only, enzyme replacement therapy, nerve blocks).\n\n# Management of type\xa03c diabetes\n\nWhat is the most clinically effective and cost-effective insulin regimen to minimise hypo- and hyperglycaemia for type\xa03c diabetes secondary to pancreatitis?\n\n## Why this is important\n\nType 3c diabetes is associated with metabolic instability and risk of decompensation leading to severe hypoglycaemia and ketoacidosis, in addition to poor quality of life. However, there is no evidence available in this population to inform practice. Therefore, research specifically on type\xa03c diabetes is essential to inform future updates of key recommendations in this guideline. National adoption of evidence-based insulin management in type\xa03c diabetes has the potential to cost effectively improve health and wellbeing, reducing the incidence of acute and long-term complications of poorly controlled glucose levels in chronic pancreatitis. A randomised controlled trial is needed to determine the most effective insulin therapy regimen in this population, comparing twice daily insulin injections, an insulin analogue multiple daily dose basal bolus regimen, and insulin pump therapy."}
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https://www.nice.org.uk/guidance/ng104
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This guideline covers managing acute and chronic pancreatitis in children, young people and adults. It aims to improve quality of life by ensuring that people have the right treatment and follow-up, and get timely information and support after diagnosis.
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345b7612cd267cd08c61ce5b60f78ae6be634a60
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nice
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Atezolizumab with bevacizumab for treating advanced or unresectable hepatocellular carcinoma
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Atezolizumab with bevacizumab for treating advanced or unresectable hepatocellular carcinoma
Evidence-based recommendations on atezolizumab (Tecentriq) with bevacizumab (Avastin) for treating advanced or unresectable hepatocellular carcinoma in adults who have not had previous systemic treatment.
# Recommendations
Atezolizumab plus bevacizumab is recommended as an option for treating advanced or unresectable hepatocellular carcinoma (HCC) in adults who have not had previous systemic treatment, only if:
they have Child‑Pugh grade A liver impairment and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and
the company provides it according to the commercial arrangement.
This recommendation is not intended to affect treatment with atezolizumab plus bevacizumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Standard care for advanced or unresectable HCC is either sorafenib or lenvatinib for people who have not had previous systemic treatment. Atezolizumab plus bevacizumab is a potential new treatment option.
Clinical trial evidence shows that people with Child-Pugh grade A liver impairment and an ECOG performance status of 0 or 1 who have atezolizumab plus bevacizumab live longer and have longer before their disease progresses than people who have sorafenib. Results of an indirect comparison suggest that atezolizumab plus bevacizumab is more effective than lenvatinib. But this is uncertain because there is no direct evidence comparing them.
Despite the uncertainty in the indirect comparison, the most likely cost-effectiveness estimates for atezolizumab plus bevacizumab compared with sorafenib and with lenvatinib are within what NICE considers an acceptable use of NHS resources. Therefore, atezolizumab plus bevacizumab is recommended.# Information about atezolizumab plus bevacizumab
# Marketing authorisation
Atezolizumab (Tecentriq, Roche) is indicated 'for the treatment of adult patients with advanced or unresectable hepatocellular carcinoma who have not received prior systemic therapy'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The NHS list price of atezolizumab (60 mg/ml) is £3,807.69 per 20‑ml vial. The NHS list price of bevacizumab (25 mg/ml) is £242.66 per 4‑ml vial and £924.40 per 16‑ml vial (excluding VAT; BNF online, accessed October 2020).
The company has commercial arrangements for atezolizumab and bevacizumab. These make atezolizumab plus bevacizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Roche, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:
It is appropriate to cap the utility values for people with unresectable hepatocellular carcinoma (HCC) so that they do not exceed the age- and sex-matched level of the general population (issue 4, see technical report page 4).
Of the approaches to estimate drug dosing, the most plausible is expected to be between the company's scenario 2 and the ERG's scenario 2b (issue 5, see technical report page 4).
It is appropriate to include the costs of oral chemotherapy wastage in the analysis (issue 6, see technical report page 5).
It is acceptable to use overall-survival data from the IMbrave150 trial that have not been adjusted for the effect of subsequent treatments not recommended in England, as long as the cost of those treatments is included (issues 3 and 7, see technical report pages 3 and 6).It recognised that there were remaining areas of uncertainty associated with the analyses presented, and took these into account in its decision making. It discussed the following issues (issues 1 and 2, see technical report pages 2 and 3) in further detail, which were outstanding after the technical engagement stage.
# Treatment pathway and comparator
## People would welcome a new treatment option
People with advanced or unresectable HCC have few approved systemic treatment options. Prognosis remains poor with rapid progression and short overall survival. The clinical experts explained that there has been little progress in this disease area since the targeted systemic treatments sorafenib and lenvatinib were introduced, and there is a considerable unmet need for people with advanced HCC. They also explained that atezolizumab plus bevacizumab is an intravenous treatment. But people with advanced HCC would prefer it to oral treatments such as sorafenib and lenvatinib if it is more clinically effective. The committee concluded that atezolizumab plus bevacizumab would be welcomed as a new treatment option for people with advanced or unresectable HCC.
## Sorafenib and lenvatinib are relevant comparators for people with Child-Pugh grade A liver impairment and an ECOG status of 0 or 1
The clinical evidence for atezolizumab plus bevacizumab comes from IMbrave150, a randomised controlled trial of 501 people with locally advanced, metastatic or unresectable HCC who had not had systemic treatment. Participants in the trial had Child‑Pugh grade A liver impairment and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. In the company's evidence submission atezolizumab plus bevacizumab was compared with sorafenib and with lenvatinib. The committee noted that NICE guidance recommends sorafenib and lenvatinib for people with Child‑Pugh grade A liver impairment. Lenvatinib is also recommended for people with an ECOG performance status of 0 or 1. The clinical experts advised that both drugs are first-line treatment options in NHS practice, although there is some regional variation across England in which is preferred. They advised that deciding which treatment to use is usually done with the person with HCC, after discussing potential side effects with them. The Cancer Drugs Fund clinical lead advised that about 60% of people have sorafenib and about 40% have lenvatinib. The committee concluded that the company's proposed positioning in the treatment pathway is appropriate, and sorafenib and lenvatinib are both relevant comparators.
# Clinical effectiveness evidence
## Atezolizumab plus bevacizumab is more clinically effective than sorafenib
The IMbrave150 trial excluded people with Child‑Pugh grade B or above liver impairment and people with an ECOG performance status of 2 or more. The committee understood the results may not be generalisable to these groups, but noted that the positioning of atezolizumab plus bevacizumab in people with Child‑Pugh grade A liver impairment and an ECOG performance status of 0 or 1 was in line with the trial population and with NICE's guidance for sorafenib and lenvatinib. In IMbrave150 atezolizumab plus bevacizumab (n=336) was compared with sorafenib (n=165). The ERG noted that IMbrave150 had a higher proportion of people from Asian regions excluding Japan (40%), and more people with hepatitis B compared with the population that would be eligible for treatment with atezolizumab plus bevacizumab in NHS clinical practice. But otherwise, based on clinical expert advice, it considered the trial population to be representative of people who would be eligible for treatment. The median duration of follow up for survival was 8.6 months for all patients and the results were as follows:
Progression-free survival was statistically significantly longer with atezolizumab plus bevacizumab compared with sorafenib (stratified hazard ratio 0.59, 95% confidence interval 0.47 to 0.76).
Median progression-free survival was 6.8 months (95% CI 5.7 to 8.3) with atezolizumab plus bevacizumab, and 4.3 months (95% CI 4.0 to 5.6) with sorafenib.
Overall survival was statistically significantly longer with atezolizumab plus bevacizumab compared with sorafenib (stratified HR 0.58, 95% CI 0.42 to 0.79).
Median overall survival for atezolizumab plus bevacizumab was not reached, but the median for sorafenib was reached (13.2 months, 95% CI 10.4 to not reached).The committee agreed that IMbrave150 was generalisable enough to the population expected to be treated in clinical practice for decision making. It concluded that atezolizumab plus bevacizumab is clinically effective compared with sorafenib in people with Child‑Pugh grade A liver impairment and an ECOG performance status of 0 or 1.
# Indirect treatment comparison
## The company's network meta-analysis is uncertain but acceptable for decision making
Because there was no direct evidence comparing atezolizumab plus bevacizumab with lenvatinib, the company did an indirect treatment comparison to estimate the relative treatment effect. A random effects base-case network meta-analysis (NMA) of log-hazard ratios was done using 3 studies identified from a systematic literature review:
IMbrave150 (atezolizumab plus bevacizumab compared with sorafenib)
REFLECT (lenvatinib compared with sorafenib)
CheckMate 459 (nivolumab compared with sorafenib).Responding to a clarification request from the ERG, the company did a fractional polynomial random effects NMA. The ERG advised that the company's approach was inconsistent because it used direct trial evidence from IMbrave150 to compare with sorafenib and indirect NMA evidence to compare with lenvatinib. The first approach (equivalent to a fixed effects model) allowed for less uncertainty than the NMA approach. The ERG explained that it would have preferred to have seen relative effects for all 3 treatments estimated using a single, coherent random effects model allowing for time-varying treatment effects. The committee noted that at technical engagement, a stakeholder advised that the company's NMA underestimated lenvatinib's effectiveness. The ERG advised that it did not believe this was a credible criticism, and that taking this into account would not address its other methodological concerns. The committee agreed that these methodological concerns increased the uncertainty of the NMA results. But it concluded that it would consider the company's NMA, including its potential limitations, in its decision making.
## Atezolizumab plus bevacizumab is likely to be more clinically effective than lenvatinib
The company's base-case NMA produced the following results for atezolizumab plus bevacizumab:
increased progression-free survival compared with lenvatinib (HR 0.91, 95% credible interval 0.23 to 3.65)
increased overall survival compared with lenvatinib (HR 0.63, 95% CrI 0.32 to 1.25).The ERG advised that the fractional polynomial NMA produced similar results, but with greater uncertainty. The committee noted that the wide credible intervals showed uncertainty in the point estimate of the hazard ratio. It also recalled the ERG's methodological concerns about the company's approach (see section 3.4). The clinical experts advised that sorafenib and lenvatinib are broadly considered to be equally effective in clinical practice. Deciding which to use depends on the individual patient. They advised that they would have expected to see similar results from IMbrave150 if the comparator had been lenvatinib, rather than sorafenib. The committee agreed that the NMA results suggested atezolizumab plus bevacizumab was more effective than lenvatinib. This would be consistent with sorafenib and lenvatinib having similar effectiveness (shown in the non-inferiority REFLECT trial). It concluded that lenvatinib and sorafenib are likely to have similar clinical effectiveness, so atezolizumab plus bevacizumab is likely to be more effective than lenvatinib.
# Modelling overall survival
## The log-normal function is suitable for modelling overall survival, but the log-logistic and generalised gamma functions should also be considered
The company investigated a range of parametric survival distributions fitted independently to each treatment arm to model overall survival. In its base-case analysis the company used the exponential function to predict overall survival. This was informed by a panel of 6 clinical experts, who advised that the survival projections from the exponential function most closely matched survival in NHS practice for sorafenib and lenvatinib. The panel suggested the generalised gamma function may also be plausible. The ERG noted that the exponential function did not provide a good statistical fit to the observed trial data and imposed an unsupported assumption of a constant mortality hazard over time. It explained that comparing survival projections from a closely controlled clinical trial, subject to strict patient selection criteria, with survival in NHS clinical practice is a flawed approach. This is because the trial was likely to achieve better outcomes than in NHS practice. It advised that the log-normal function was the best-fitting model, although the log-logistic and generalised gamma functions also fitted the data well. It explained that there was no strong clinical rationale to favour any of these 3 functions over the other. Therefore, its preferred choice would be the best-fitting log-normal function. After technical engagement, the company agreed that the log-normal distribution was clinically plausible. The clinical experts advised that a constant mortality hazard over time was not plausible for people with advanced HCC. The committee agreed with the ERG and clinical experts that the exponential function should not be used to model overall survival. It noted that lenvatinib was predicted to have higher or lower life expectancy than sorafenib, depending on the choice of overall-survival function. The committee understood that this was an artefact of the company's modelling approach. The choice of survival function for atezolizumab plus bevacizumab and sorafenib was informed directly by IMbrave150 data. Survival for lenvatinib was informed by applying a hazard ratio from the NMA to the function for atezolizumab plus bevacizumab. The committee agreed that it would have been preferable to apply the hazard ratio from the NMA for lenvatinib compared with sorafenib to the sorafenib survival function, because the drugs have a similar mechanism of action. However, it would not expect this to have much effect on cost effectiveness. The committee concluded that it would consider cost-effectiveness results using the log-normal function to model survival, because this was the best-fitting function. But the log-logistic and generalised gamma functions were plausible and should also be considered.
# Exploratory analysis
## The ERG's exploratory analyses for bodyweight and region should be considered as a way of exploring uncertainty
The company included a large number of sensitivity analyses in its submission. The ERG did exploratory analyses to test the effect on cost effectiveness of bodyweight (less than 60 kg compared with 60 kg or more) and region (all regions compared with excluding Asian regions, except Japan). The ERG explained that it was important to explore the potential effect of bodyweight because the dosing of lenvatinib and bevacizumab depend on bodyweight, so it affects associated drug costs. It explained that region was also potentially important because the underlying cause of HCC varies by region. Hepatitis C is more common in Europe, North America and Japan, and hepatitis B is more common in Asia (excluding Japan) and Africa. In Europe and North America, HCC is increasingly associated with metabolic dysfunction-associated fatty liver disease, obesity and exposure to toxic substances. The committee noted that IMbrave150 was done in 17 countries, with 40% of patients from Asia (excluding Japan). The ERG advised that considering the results for all combinations of the 2 bodyweight and 2 region categories allowed the committee to consider possible upper and lower bounds of the cost-effectiveness estimate for a given preferred analysis. The committee noted that the hazard ratio for overall survival was only marginally affected by bodyweight and region. It agreed that it would not be appropriate to make different recommendations for atezolizumab plus bevacizumab based on bodyweight or region. However, it felt that the ERG's exploratory analyses would be useful in considering the uncertainty around the cost-effectiveness estimates. So, it concluded that it would consider the exploratory analyses in its decision making.
# End of life
## Atezolizumab plus bevacizumab meets the criteria to be considered an end of life treatment
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. It reviewed the mean overall-survival estimates from the model. Life expectancy with sorafenib and lenvatinib was less than 24 months. Also, the undiscounted life-years gained for atezolizumab plus bevacizumab were much higher than 3 months, regardless of which overall-survival function was used. The committee therefore concluded that the end of life criteria were met.
# Cost-effectiveness analysis
## The most plausible ICERs are within the range normally considered a cost-effective use of NHS resources
All the ERG's base-case incremental cost-effectiveness ratios (ICERs) for atezolizumab plus bevacizumab, compared with sorafenib and with lenvatinib, were below £50,000 per quality-adjusted life year (QALY) gained. The exact ICERs cannot be reported because of confidential commercial arrangements for the drugs. The ERG's base-case analysis used the log-normal function to model survival and considered all 4 combinations of the bodyweight and region categories. The ICERs were below £50,000 per QALY gained in most of the ERG's exploratory analyses. There was only 1 plausible analysis in which the ICERs exceeded £50,000 per QALY gained. This was in comparison with sorafenib, using the log-logistic distribution to model survival and the least favourable bodyweight and region categories for atezolizumab plus bevacizumab (bodyweight of 60 kg or more and excluding Asian regions, except Japan). The committee recalled that the cost-effectiveness model used indirect NMA evidence to inform the relative effectiveness of lenvatinib, and this evidence was uncertain (see section 3.4). However, it noted that the clinical experts considered lenvatinib and sorafenib to have similar effectiveness (see section 3.5). It agreed that it was reasonable to conclude that atezolizumab plus bevacizumab would be cost effective compared with both lenvatinib and sorafenib. The committee concluded that the most plausible ICER was highly likely to be less than £50,000 per QALY gained for atezolizumab plus bevacizumab compared with sorafenib and with lenvatinib.
# Innovation
## The model adequately captures the benefits of atezolizumab plus bevacizumab
The company considered atezolizumab plus bevacizumab to be innovative because it is a targeted immunotherapy with efficacy in the first-line treatment of advanced and unresectable HCC. The clinical experts noted that it is expected to replace sorafenib and lenvatinib because it improves progression-free survival and overall survival for this population. The committee recognised these benefits for people with advanced or unresectable HCC. However, it concluded that it had not been presented with any additional evidence of benefits that were not captured in the measurement of the QALYs and the resulting cost-effectiveness estimates.
# Conclusion
## Atezolizumab plus bevacizumab is recommended for routine commissioning
The committee acknowledged the need for a better treatment option for adults with advanced or unresectable HCC. The most plausible estimates of cost effectiveness for atezolizumab plus bevacizumab compared with sorafenib and with lenvatinib were within what NICE considers an acceptable use of NHS resources. Therefore, atezolizumab plus bevacizumab is recommended as an option for advanced or unresectable HCC in adults with Child‑Pugh grade A liver impairment and an ECOG performance status of 0 or 1, who have not had previous systemic treatment.
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{'Recommendations': 'Atezolizumab plus bevacizumab is recommended as an option for treating advanced or unresectable hepatocellular carcinoma (HCC) in adults who have not had previous systemic treatment, only if:\n\nthey have Child‑Pugh grade\xa0A liver impairment and an Eastern Cooperative Oncology Group (ECOG) performance status of 0\xa0or\xa01 and\n\nthe company provides it according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with atezolizumab plus bevacizumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nStandard care for advanced or unresectable HCC is either sorafenib or lenvatinib for people who have not had previous systemic treatment. Atezolizumab plus bevacizumab is a potential new treatment option.\n\nClinical trial evidence shows that people with Child-Pugh grade A liver impairment and an ECOG performance status of 0\xa0or\xa01 who have atezolizumab plus bevacizumab live longer and have longer before their disease progresses than people who have sorafenib. Results of an indirect comparison suggest that atezolizumab plus bevacizumab is more effective than lenvatinib. But this is uncertain because there is no direct evidence comparing them.\n\nDespite the uncertainty in the indirect comparison, the most likely cost-effectiveness estimates for atezolizumab plus bevacizumab compared with sorafenib and with lenvatinib are within what NICE considers an acceptable use of NHS resources. Therefore, atezolizumab plus bevacizumab is recommended.', 'Information about atezolizumab plus bevacizumab': "# Marketing authorisation\n\nAtezolizumab (Tecentriq, Roche) is indicated 'for the treatment of adult patients with advanced or unresectable hepatocellular carcinoma who have not received prior systemic therapy'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe NHS list price of atezolizumab (60\xa0mg/ml) is £3,807.69 per 20‑ml vial. The NHS list price of bevacizumab (25\xa0mg/ml) is £242.66 per 4‑ml vial and £924.40 per 16‑ml vial (excluding VAT; BNF online, accessed October\xa02020).\n\nThe company has commercial arrangements for atezolizumab and bevacizumab. These make atezolizumab plus bevacizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Roche, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:\n\nIt is appropriate to cap the utility values for people with unresectable hepatocellular carcinoma (HCC) so that they do not exceed the age- and sex-matched level of the general population (issue\xa04, see technical report page\xa04).\n\nOf the approaches to estimate drug dosing, the most plausible is expected to be between the company's scenario\xa02 and the ERG's scenario\xa02b (issue\xa05, see technical report page\xa04).\n\nIt is appropriate to include the costs of oral chemotherapy wastage in the analysis (issue\xa06, see technical report page\xa05).\n\nIt is acceptable to use overall-survival data from the IMbrave150\xa0trial that have not been adjusted for the effect of subsequent treatments not recommended in England, as long as the cost of those treatments is included (issues\xa03 and\xa07, see technical report pages\xa03 and\xa06).It recognised that there were remaining areas of uncertainty associated with the analyses presented, and took these into account in its decision making. It discussed the following issues (issues\xa01 and\xa02, see technical report pages\xa02 and\xa03) in further detail, which were outstanding after the technical engagement stage.\n\n# Treatment pathway and comparator\n\n## People would welcome a new treatment option\n\nPeople with advanced or unresectable HCC have few approved systemic treatment options. Prognosis remains poor with rapid progression and short overall survival. The clinical experts explained that there has been little progress in this disease area since the targeted systemic treatments sorafenib and lenvatinib were introduced, and there is a considerable unmet need for people with advanced HCC. They also explained that atezolizumab plus bevacizumab is an intravenous treatment. But people with advanced HCC would prefer it to oral treatments such as sorafenib and lenvatinib if it is more clinically effective. The committee concluded that atezolizumab plus bevacizumab would be welcomed as a new treatment option for people with advanced or unresectable HCC.\n\n## Sorafenib and lenvatinib are relevant comparators for people with Child-Pugh grade A liver impairment and an ECOG status of 0 or 1\n\nThe clinical evidence for atezolizumab plus bevacizumab comes from IMbrave150, a randomised controlled trial of 501\xa0people with locally advanced, metastatic or unresectable HCC who had not had systemic treatment. Participants in the trial had Child‑Pugh grade\xa0A liver impairment and an Eastern Cooperative Oncology Group (ECOG) performance status of 0\xa0or\xa01. In the company's evidence submission atezolizumab plus bevacizumab was compared with sorafenib and with lenvatinib. The committee noted that NICE guidance recommends sorafenib and lenvatinib for people with Child‑Pugh grade\xa0A liver impairment. Lenvatinib is also recommended for people with an ECOG performance status of 0\xa0or\xa01. The clinical experts advised that both drugs are first-line treatment options in NHS practice, although there is some regional variation across England in which is preferred. They advised that deciding which treatment to use is usually done with the person with HCC, after discussing potential side effects with them. The Cancer Drugs Fund clinical lead advised that about 60% of people have sorafenib and about 40% have lenvatinib. The committee concluded that the company's proposed positioning in the treatment pathway is appropriate, and sorafenib and lenvatinib are both relevant comparators.\n\n# Clinical effectiveness evidence\n\n## Atezolizumab plus bevacizumab is more clinically effective than sorafenib\n\nThe IMbrave150\xa0trial excluded people with Child‑Pugh grade\xa0B or above liver impairment and people with an ECOG performance status of 2\xa0or\xa0more. The committee understood the results may not be generalisable to these groups, but noted that the positioning of atezolizumab plus bevacizumab in people with Child‑Pugh grade\xa0A liver impairment and an ECOG performance status of 0\xa0or\xa01 was in line with the trial population and with NICE's guidance for sorafenib and lenvatinib. In IMbrave150 atezolizumab plus bevacizumab (n=336) was compared with sorafenib (n=165). The ERG noted that IMbrave150 had a higher proportion of people from Asian regions excluding Japan (40%), and more people with hepatitis\xa0B compared with the population that would be eligible for treatment with atezolizumab plus bevacizumab in NHS clinical practice. But otherwise, based on clinical expert advice, it considered the trial population to be representative of people who would be eligible for treatment. The median duration of follow up for survival was 8.6\xa0months for all patients and the results were as follows:\n\nProgression-free survival was statistically significantly longer with atezolizumab plus bevacizumab compared with sorafenib (stratified hazard ratio [HR] 0.59, 95% confidence interval [CI] 0.47 to 0.76).\n\nMedian progression-free survival was 6.8\xa0months (95% CI 5.7 to 8.3) with atezolizumab plus bevacizumab, and 4.3\xa0months (95% CI 4.0 to 5.6) with sorafenib.\n\nOverall survival was statistically significantly longer with atezolizumab plus bevacizumab compared with sorafenib (stratified HR 0.58, 95% CI 0.42 to 0.79).\n\nMedian overall survival for atezolizumab plus bevacizumab was not reached, but the median for sorafenib was reached (13.2\xa0months, 95% CI 10.4 to not reached).The committee agreed that IMbrave150 was generalisable enough to the population expected to be treated in clinical practice for decision making. It concluded that atezolizumab plus bevacizumab is clinically effective compared with sorafenib in people with Child‑Pugh grade\xa0A liver impairment and an ECOG performance status of 0\xa0or\xa01.\n\n# Indirect treatment comparison\n\n## The company's network meta-analysis is uncertain but acceptable for decision making\n\nBecause there was no direct evidence comparing atezolizumab plus bevacizumab with lenvatinib, the company did an indirect treatment comparison to estimate the relative treatment effect. A random effects base-case network meta-analysis (NMA) of log-hazard ratios was done using 3\xa0studies identified from a systematic literature review:\n\nIMbrave150 (atezolizumab plus bevacizumab compared with sorafenib)\n\nREFLECT (lenvatinib compared with sorafenib)\n\nCheckMate 459 (nivolumab compared with sorafenib).Responding to a clarification request from the ERG, the company did a fractional polynomial random effects NMA. The ERG advised that the company's approach was inconsistent because it used direct trial evidence from IMbrave150 to compare with sorafenib and indirect NMA evidence to compare with lenvatinib. The first approach (equivalent to a fixed effects model) allowed for less uncertainty than the NMA approach. The ERG explained that it would have preferred to have seen relative effects for all 3\xa0treatments estimated using a single, coherent random effects model allowing for time-varying treatment effects. The committee noted that at technical engagement, a stakeholder advised that the company's NMA underestimated lenvatinib's effectiveness. The ERG advised that it did not believe this was a credible criticism, and that taking this into account would not address its other methodological concerns. The committee agreed that these methodological concerns increased the uncertainty of the NMA results. But it concluded that it would consider the company's NMA, including its potential limitations, in its decision making.\n\n## Atezolizumab plus bevacizumab is likely to be more clinically effective than lenvatinib\n\nThe company's base-case NMA produced the following results for atezolizumab plus bevacizumab:\n\nincreased progression-free survival compared with lenvatinib (HR 0.91, 95% credible interval [CrI] 0.23 to 3.65)\n\nincreased overall survival compared with lenvatinib (HR 0.63, 95% CrI 0.32 to 1.25).The ERG advised that the fractional polynomial NMA produced similar results, but with greater uncertainty. The committee noted that the wide credible intervals showed uncertainty in the point estimate of the hazard ratio. It also recalled the ERG's methodological concerns about the company's approach (see section\xa03.4). The clinical experts advised that sorafenib and lenvatinib are broadly considered to be equally effective in clinical practice. Deciding which to use depends on the individual patient. They advised that they would have expected to see similar results from IMbrave150 if the comparator had been lenvatinib, rather than sorafenib. The committee agreed that the NMA results suggested atezolizumab plus bevacizumab was more effective than lenvatinib. This would be consistent with sorafenib and lenvatinib having similar effectiveness (shown in the non-inferiority REFLECT trial). It concluded that lenvatinib and sorafenib are likely to have similar clinical effectiveness, so atezolizumab plus bevacizumab is likely to be more effective than lenvatinib.\n\n# Modelling overall survival\n\n## The log-normal function is suitable for modelling overall survival, but the log-logistic and generalised gamma functions should also be considered\n\nThe company investigated a range of parametric survival distributions fitted independently to each treatment arm to model overall survival. In its base-case analysis the company used the exponential function to predict overall survival. This was informed by a panel of 6\xa0clinical experts, who advised that the survival projections from the exponential function most closely matched survival in NHS practice for sorafenib and lenvatinib. The panel suggested the generalised gamma function may also be plausible. The ERG noted that the exponential function did not provide a good statistical fit to the observed trial data and imposed an unsupported assumption of a constant mortality hazard over time. It explained that comparing survival projections from a closely controlled clinical trial, subject to strict patient selection criteria, with survival in NHS clinical practice is a flawed approach. This is because the trial was likely to achieve better outcomes than in NHS practice. It advised that the log-normal function was the best-fitting model, although the log-logistic and generalised gamma functions also fitted the data well. It explained that there was no strong clinical rationale to favour any of these 3\xa0functions over the other. Therefore, its preferred choice would be the best-fitting log-normal function. After technical engagement, the company agreed that the log-normal distribution was clinically plausible. The clinical experts advised that a constant mortality hazard over time was not plausible for people with advanced HCC. The committee agreed with the ERG and clinical experts that the exponential function should not be used to model overall survival. It noted that lenvatinib was predicted to have higher or lower life expectancy than sorafenib, depending on the choice of overall-survival function. The committee understood that this was an artefact of the company's modelling approach. The choice of survival function for atezolizumab plus bevacizumab and sorafenib was informed directly by IMbrave150 data. Survival for lenvatinib was informed by applying a hazard ratio from the NMA to the function for atezolizumab plus bevacizumab. The committee agreed that it would have been preferable to apply the hazard ratio from the NMA for lenvatinib compared with sorafenib to the sorafenib survival function, because the drugs have a similar mechanism of action. However, it would not expect this to have much effect on cost effectiveness. The committee concluded that it would consider cost-effectiveness results using the log-normal function to model survival, because this was the best-fitting function. But the log-logistic and generalised gamma functions were plausible and should also be considered.\n\n# Exploratory analysis\n\n## The ERG's exploratory analyses for bodyweight and region should be considered as a way of exploring uncertainty\n\nThe company included a large number of sensitivity analyses in its submission. The ERG did exploratory analyses to test the effect on cost effectiveness of bodyweight (less than 60\xa0kg compared with 60\xa0kg or more) and region (all regions compared with excluding Asian regions, except Japan). The ERG explained that it was important to explore the potential effect of bodyweight because the dosing of lenvatinib and bevacizumab depend on bodyweight, so it affects associated drug costs. It explained that region was also potentially important because the underlying cause of HCC varies by region. Hepatitis\xa0C is more common in Europe, North America and Japan, and hepatitis\xa0B is more common in Asia (excluding Japan) and Africa. In Europe and North America, HCC is increasingly associated with metabolic dysfunction-associated fatty liver disease, obesity and exposure to toxic substances. The committee noted that IMbrave150 was done in 17\xa0countries, with 40% of patients from Asia (excluding Japan). The ERG advised that considering the results for all combinations of the 2\xa0bodyweight and 2\xa0region categories allowed the committee to consider possible upper and lower bounds of the cost-effectiveness estimate for a given preferred analysis. The committee noted that the hazard ratio for overall survival was only marginally affected by bodyweight and region. It agreed that it would not be appropriate to make different recommendations for atezolizumab plus bevacizumab based on bodyweight or region. However, it felt that the ERG's exploratory analyses would be useful in considering the uncertainty around the cost-effectiveness estimates. So, it concluded that it would consider the exploratory analyses in its decision making.\n\n# End of life\n\n## Atezolizumab plus bevacizumab meets the criteria to be considered an end of life treatment\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. It reviewed the mean overall-survival estimates from the model. Life expectancy with sorafenib and lenvatinib was less than 24\xa0months. Also, the undiscounted life-years gained for atezolizumab plus bevacizumab were much higher than 3\xa0months, regardless of which overall-survival function was used. The committee therefore concluded that the end of life criteria were met.\n\n# Cost-effectiveness analysis\n\n## The most plausible ICERs are within the range normally considered a cost-effective use of NHS resources\n\nAll the ERG's base-case incremental cost-effectiveness ratios (ICERs) for atezolizumab plus bevacizumab, compared with sorafenib and with lenvatinib, were below £50,000 per quality-adjusted life year (QALY) gained. The exact ICERs cannot be reported because of confidential commercial arrangements for the drugs. The ERG's base-case analysis used the log-normal function to model survival and considered all 4\xa0combinations of the bodyweight and region categories. The ICERs were below £50,000 per QALY gained in most of the ERG's exploratory analyses. There was only 1\xa0plausible analysis in which the ICERs exceeded £50,000 per QALY gained. This was in comparison with sorafenib, using the log-logistic distribution to model survival and the least favourable bodyweight and region categories for atezolizumab plus bevacizumab (bodyweight of 60\xa0kg or more and excluding Asian regions, except Japan). The committee recalled that the cost-effectiveness model used indirect NMA evidence to inform the relative effectiveness of lenvatinib, and this evidence was uncertain (see section\xa03.4). However, it noted that the clinical experts considered lenvatinib and sorafenib to have similar effectiveness (see section\xa03.5). It agreed that it was reasonable to conclude that atezolizumab plus bevacizumab would be cost effective compared with both lenvatinib and sorafenib. The committee concluded that the most plausible ICER was highly likely to be less than £50,000 per QALY gained for atezolizumab plus bevacizumab compared with sorafenib and with lenvatinib.\n\n# Innovation\n\n## The model adequately captures the benefits of atezolizumab plus bevacizumab\n\nThe company considered atezolizumab plus bevacizumab to be innovative because it is a targeted immunotherapy with efficacy in the first-line treatment of advanced and unresectable HCC. The clinical experts noted that it is expected to replace sorafenib and lenvatinib because it improves progression-free survival and overall survival for this population. The committee recognised these benefits for people with advanced or unresectable HCC. However, it concluded that it had not been presented with any additional evidence of benefits that were not captured in the measurement of the QALYs and the resulting cost-effectiveness estimates.\n\n# Conclusion\n\n## Atezolizumab plus bevacizumab is recommended for routine commissioning\n\nThe committee acknowledged the need for a better treatment option for adults with advanced or unresectable HCC. The most plausible estimates of cost effectiveness for atezolizumab plus bevacizumab compared with sorafenib and with lenvatinib were within what NICE considers an acceptable use of NHS resources. Therefore, atezolizumab plus bevacizumab is recommended as an option for advanced or unresectable HCC in adults with Child‑Pugh grade\xa0A liver impairment and an ECOG performance status of 0\xa0or\xa01, who have not had previous systemic treatment."}
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https://www.nice.org.uk/guidance/ta666
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Evidence-based recommendations on atezolizumab (Tecentriq) with bevacizumab (Avastin) for treating advanced or unresectable hepatocellular carcinoma in adults who have not had previous systemic treatment.
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baf94c0d37a1715b56487e19860d9253cffa6303
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nice
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Caplacizumab with plasma exchange and immunosuppression for treating acute acquired thrombotic thrombocytopenic purpura
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Caplacizumab with plasma exchange and immunosuppression for treating acute acquired thrombotic thrombocytopenic purpura
Evidence-based recommendations on caplacizumab (Cablivi) with plasma exchange and immunosuppression for treating acute acquired thrombotic thrombocytopenic purpura in adults, and in young people aged 12 years and over who weigh at least 40 kg.
# Recommendations
Caplacizumab with plasma exchange and immunosuppression is recommended, within its marketing authorisation, as an option for treating an acute episode of acquired thrombotic thrombocytopenic purpura (TTP) in adults, and in young people aged 12 years and over who weigh at least 40 kg. Treatment should be started and supervised by physicians experienced in managing thrombotic microangiopathies. It is recommended only if the company provides caplacizumab according to the commercial arrangement.
Why the committee made these recommendations
Standard care for an acute episode of acquired TTP includes plasma exchange and immunosuppressant medicines. Trial results show that, compared with standard care alone, caplacizumab plus standard care reduces:
the time it takes to bring platelet levels back to normal
the number of plasma exchange treatments needed
time in hospital and intensive care.
Adding caplacizumab likely reduces the long-term complications of acquired TTP and risk of death around the time of an acute episode, but it is unclear by how much. This is because the trial results do not address whether adding caplacizumab improves either length or quality of life in the long term after people stop taking the drug. Also, there are limited reported data on the long-term complications of acquired TTP after an acute episode.
However, the assumptions in the economic modelling are plausible. Also, there are potential benefits with caplacizumab that are not included in the cost-effectiveness estimates. Overall, the estimates are within the range normally considered a cost-effective use of NHS resources. So, caplacizumab is recommended for treating acute acquired TTP.# Information about caplacizumab
# Marketing authorisation indication
Caplacizumab (Cablivi, Sanofi) has a marketing authorisation for treating adults and young people aged 12 years and over who weigh at least 40 kg who are 'experiencing an episode of acquired thrombotic thrombocytopenic purpura, in conjunction with plasma exchange and immunosuppression'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price of caplacizumab is £4,143 per 10‑mg vial (excluding VAT; BNF online, May 2020). The company has a commercial arrangement. This makes caplacizumab available to the NHS with a discount. The size of the discount is commercial in confidence.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Sanofi, a review of this submission by the evidence review group (ERG), the technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
# Current treatments and patient perspectives
## Acquired thrombotic thrombocytopenic purpura is a life-threatening condition associated with long-term morbidity and mortality
Acquired thrombotic thrombocytopenic purpura (TTP) is a rare autoimmune condition characterised by antibodies against ADAMTS13, the enzyme that cleaves von Willebrand factor, a large protein involved in blood clotting. People with low levels of ADAMTS13 activity have a higher risk of clotting. The condition causes blood clots in small blood vessels, which leads to decreased blood flow and oxygen supply to vital organs such as the brain, heart and kidneys. This causes ischaemic damage, can be acutely life-threatening, and, in the longer term, may cause cognitive deficits, depression and hypertension. One clinical expert stated that acquired TTP is the most dangerous acute illness in haematology, with some people transitioning from having no symptoms to death within hours. There are treatments for acquired TTP (see section 3.2), and it can relapse. The patient experts explained that acquired TTP can affect quality of life and, in particular, mental health. The committee was told that people with newly diagnosed acquired TTP are likely to be anxious, which is made worse by them never having heard of the condition. Even when acquired TTP is in 'remission', the condition can relapse. Also, the signs and symptoms of relapse may be non-specific. One patient expert suggested that anxiety itself is a symptom of an upcoming relapse and can lead to long-term depression. The committee concluded that acquired TTP is a life-threatening, stressful condition associated with long-term morbidity and mortality.
## Caplacizumab is added on to, but does not replace, existing treatment with plasma exchange and immunosuppressants
After diagnosis of an acute episode of acquired TTP, current standard treatment involves plasma exchange, ideally within 4 to 8 hours of diagnosis. This involves filtering blood to remove the antibody-containing plasma and replacing discarded plasma with donated plasma to replace ADAMTS13. Immunosuppressant drugs such as corticosteroids and rituximab treat the underlying autoimmune condition, and limit antibody production against ADAMTS13. Caplacizumab binds to von Willebrand factor, inhibiting it from interacting with platelets, and preventing clots. The first dose is given intravenously at the first plasma exchange. The subsequent doses are given subcutaneously daily for up to 30 days after stopping plasma exchange or longer, if necessary, until ADAMTS13 levels normalise. The clinical experts stated that controlling the underlying immune condition can take up to 10 days with rituximab treatment, and that caplacizumab treatment reduces blood clot formation during this time. The clinical experts explained that the longer the blood vessels remained blocked, the higher the risk of illness and dying. They further stated that, because of the risk of relapse, clinicians continue to monitor people with acquired TTP in remission and to offer rituximab to reduce relapse risk. The committee concluded that caplacizumab does not replace existing treatment, but is added to plasma exchange to increase platelet counts and reduce blood clots.
## Plasma exchange is unpleasant, and people with acquired TTP would welcome a treatment that reduces plasma exchange and hospital stays
Although caplacizumab does not replace plasma exchange, it may reduce the number of days of plasma exchange and the volume of plasma needed (see section 3.7). Plasma exchange involves inserting an intravenous catheter, which carries a risk of infection. The clinical experts stated that the catheters are typically replaced every 5 to 7 days. This means that treatments that reduce the number of days of plasma exchange would also reduce the need to replace catheters. The patient experts described how inserting catheters is uncomfortable, painful and stressful, in part, because of infection risk. They stated that, of all the reported benefits of caplacizumab, they most welcome reducing plasma exchange, and time in intensive care. One patient expert who had used caplacizumab stated that people might struggle with injecting caplacizumab at home or with its adverse effects, such as nosebleeds. However, they thought that people would be willing to accept these if treatment reduced hospital stays and the need for plasma exchange. The committee concluded that plasma exchange and hospital stays are unpleasant, and that people with acquired TTP would welcome a treatment that reduces these.
## A new NHS specialised service for acquired TTP is being established
The clinical experts stated that the UK has had fragmented care for people with acquired TTP. This has led to poorer outcomes, including higher death rates outside of specialist centres for acquired TTP. For example, estimates of death rates were 10% to 20% in non-specialist centres and less than 5% in specialist centres. People are currently referred to specialist centres for acquired TTP treatment. However, diagnosis and treatment may be delayed because many clinicians are unaware of acquired TTP, and because of the distance someone has to travel to access a specialist centre. The commissioning lead of the NHS Highly Specialised Services stated that, if recommended, the NHS would commission caplacizumab through a new specialised service. The NHS aims to have up to 9 specialist centres in England, providing clinical expertise and geographical access for patients. If caplacizumab were to be recommended, some people could have it locally, supervised remotely by a specialised centre. A clinical expert said that kits are now available for emergency departments to diagnose acquired TTP within 24 hours. The committee acknowledged that there is regional variation in the time to diagnosis of acquired TTP, in treatment and in patient outcomes. It concluded that a new NHS specialised service will attempt to reduce this variation and improve outcomes.
# Clinical trial results
## The main clinical trial, HERCULES, is broadly generalisable to UK clinical practice
There were 2 placebo-controlled trials of similar design in the clinical trial programme for caplacizumab: HERCULES and TITAN. Both were double-blind randomised controlled trials. TITAN included 75 people and HERCULES included 145 people having an acute episode of acquired TTP. Both compared caplacizumab plus standard care (plasma exchange, immunosuppressant medication including rituximab; from now referred to as caplacizumab) with placebo plus standard care (from now referred to as standard care alone). Because of protocol amendments and violations, TITAN was not used to support the company's application for a marketing authorisation for caplacizumab and was not presented to the committee for its first meeting. Caplacizumab's marketing authorisation states that it should be given before people start plasma exchange. However, in HERCULES, caplacizumab was started after plasma exchange. This was because the time needed to consent and randomise patients could delay plasma exchange, which was neither practical nor safe. One clinical expert stated that, in clinical practice, caplacizumab would be given before and within the same day as plasma exchange. Also, the trial recruited people in specialist centres for acquired TTP rather than from general haematology centres; the clinical experts considered that people in the trial may have had better outcomes than would be seen in overall NHS practice. However, this was unlikely to have affected caplacizumab's relative treatment effect. The trial included only 18 people from the UK, and 1 clinical expert said that:
the people in the trial, and the treatments they had, reflected UK practice
since 2018, some patients under her care have had caplacizumab via a global compassionate use scheme
the trial outcomes in the caplacizumab arm reflected the outcomes she had seen in NHS practice when using caplacizumab through the compassionate use scheme.The committee concluded that results of HERCULES were generalisable to the centres in which caplacizumab would be offered in UK clinical practice.
## The outcomes in HERCULES are clinically relevant, but do not include the short- and long-term complications in the economic model
HERCULES measured clinical outcomes around an acute episode of acquired TTP. Data were collected while people were on treatment for up to 30 days, and for 28 days after they stopped treatment. The committee understood that an observational single-arm extension to HERCULES is ongoing. The primary outcome of the trial was time to platelet normalisation. The clinical experts explained that they considered platelet count to be a surrogate measure for more meaningful outcomes reflecting morbidity and mortality. From a clinical expert, the committee heard that the faster the platelet count is normalised, the lower the risk of complications. Key secondary outcomes in the trial analyses in the company's statistical analysis plan, listed hierarchically, were:
a composite outcome of TTP-related death, disease recurrence while on treatment and major thromboembolic event
disease recurrence alone including the 4‑week follow up
the proportion of people whose condition did not respond to treatment ('refractory' TTP)
time to normalisation of all 3 blood markers of organ damage: lactate dehydrogenase, cardiac troponin and creatinine.Other secondary outcomes such as volume and duration of plasma exchange, time in hospital or intensive care, and death were not tested statistically in line with the company's statistical analysis plan. The clinical experts explained that all the measured outcomes were clinically relevant. The patient experts said that plasma exchange use and time in hospital are important (see section 3.3). The committee concluded that the primary surrogate and the secondary outcomes in HERCULES were clinically relevant. However, it noted that the trial did not measure the effects of caplacizumab in the company's health-economic model (see sections 3.13 to 3.18) on survival, quality of life, disability or mental health in the long term.
## HERCULES shows that caplacizumab reduces time to platelet normalisation, plasma exchange use and duration of hospital stay
The committee reviewed the results of HERCULES, noting that:
Caplacizumab reduced the time to the primary outcome, platelet normalisation. There was a very small (0.2 days) difference in median time to platelet normalisation between the treatments (2.7 days on caplacizumab and 2.9 days on placebo; p<0.01). The clinical experts explained that the rate of platelet normalisation was similar between the 2 trial arms until day 3, but then caplacizumab added benefit to plasma exchange in normalising platelet levels until the autoimmune condition was controlled.
Caplacizumab reduced the secondary composite outcome (12% of people on caplacizumab compared with 49% on standard care alone had an acquired TTP-related death, disease recurrence while on treatment or a major thromboembolic event; p<0.001). The same proportion (8%) of people randomised to each treatment had a major thrombotic event (a component of the composite outcome) during the acute period.
Caplacizumab reduced the proportion of people whose disease recurred while on treatment or in the 28 days after stopping treatment (13% on caplacizumab compared with 38% on standard care alone; p<0.001).
Caplacizumab reduced the proportion of people whose acquired TTP was refractory to plasma exchange treatment (meaning that there was no improvement in platelet count after 5 plasma exchanges and treatment with corticosteroids). No people in the caplacizumab arm had acquired TTP refractory to plasma exchange. The company has said that the proportion whose acquired TTP was refractory in the standard care arm is academic in confidence and cannot be reported here.
Caplacizumab reduced the mean duration of plasma exchange (6 days compared with 9 days on standard care alone), mean volume of plasma exchange (21 litres compared with 36 litres), and mean days in hospital (10 days compared with 14 days) and in intensive care (3 days compared with 10 days). The committee noted that, in the company's statistical plan, these outcomes were described, but not statistically tested. One clinical expert explained that she had seen a similar reduction in number of plasma exchanges and length of hospital stay with caplacizumab in the compassionate use programme in her centre.The committee concluded that caplacizumab is clinically effective in the acute period compared with standard of care alone.
## It is not possible to estimate reliably how much caplacizumab might reduce deaths in the acute period from trial data
The HERCULES trial did not aim to assess whether caplacizumab reduced deaths around an acute episode. The company explained that to do this, it would have needed to recruit more people, which would have been difficult because acquired TTP is rare. Instead, the company used observational data to quantify its claims of caplacizumab's effect on mortality during an acute episode (see section 3.11). The committee noted there were few deaths in the caplacizumab and standard care arms in the trial (including during follow up when people had stopped treatment):
In the first meeting, the company presented data on mortality from HERCULES only: 1 death occurred in the caplacizumab arm (1%) and 3 deaths occurred in the standard care arm (4%). The ERG estimated a risk ratio for death of 0.34 (95% confidence interval 0.04 to 3.22) for caplacizumab compared with standard care only.
In the second meeting, the company presented pooled data from HERCULES and TITAN: 1 death occurred in the caplacizumab arm (1%) and 5 deaths occurred in the standard care arm (4%). The ERG estimated a risk ratio for death of 0.21 (95% CI 0.03 to 1.75) for caplacizumab compared with standard care only.The committee considered that there were too few deaths, even when pooling data from the 2 trials, to estimate accurately the effect of caplacizumab on survival in the acute period. It was aware that the company had chosen not to use the trial data on deaths in its original cost-effectiveness model (see section 3.11), but instead used data from a global compassionate use scheme. The committee noted that the considerable uncertainty reflected in the wide confidence intervals also included the possibility that caplacizumab increased the risk of dying. It concluded that it was not possible to estimate reliably the extent of the benefit using the randomised trial data.
# The company's economic model
## The company's model structure is appropriate for decision making
The company's model had 2 parts: 1 for acute illness and 1 for the rest of a person's life. It also included the possibility of relapse, that is, a person who recovers cycles through the model again. The committee appreciated that people only have treatment with caplacizumab during an acute episode, and that people do not have caplacizumab to prevent relapses. The company modelled events around an acute episode of acquired TTP using a decision-tree model. It used a Markov model to project long-term events for up to 55 years after a person had recovered from an acute episode. The committee understood that the company considered that with caplacizumab, compared with standard care:
In the acute period (decision-tree model):
Treatment decreases the risk of dying (see section 3.11 and section 3.12) from an estimated baseline risk of dying on standard care (see section 3.10).
Treatment improves quality of life because people need fewer plasma exchanges. The extent of this improvement is based on an assumption (see section 3.18).
In the long term (Markov model):
Former treatment with caplacizumab decreases the risk of dying (see section 3.15 and section 3.16) from an estimated baseline risk of dying for people with acquired TTP who had standard care for their acute episode (see section 3.13).
Treatment improves quality of life by decreasing the rate of long-term complications. The modelled complications included cognitive impairment and mental health problems such as depression and anxiety. The company estimated the rates of long-term complications after standard care for the acute episode (see section 3.14).Because there were no long-term data, the company estimated the extent to which caplacizumab reduced the rate of long-term complications by assuming that the treatment effect of caplacizumab for acute outcomes would be the same as its treatment effect for long-term outcomes (see section 3.15 and section 3.16). The company modelled the same rates of relapse on caplacizumab and on standard care alone (see section 3.17). The acute-period model included the costs of treatment and of hospital stay. The long-term model included the costs of treating a relapse and complications of acquired TTP, and of preventative rituximab. The committee noted that many of the treatment effects ascribed to caplacizumab in the model were based on either assumptions or non-trial data, which increased uncertainty (see sections 3.10 to 3.18). However, the committee considered that the economic model captured relevant aspects of acquired TTP, and concluded that its overall structure was appropriate for decision making.
## The submodel reflecting acute disease takes into account that mortality rates on standard care have improved over time
The company and the clinical experts stated that the number of deaths in the trial in both arms were lower than would be expected in clinical practice. Because of this, the company did not use death rates from HERCULES to estimate absolute death rates for standard care in its model. Instead:
In its original submission for the committee's first meeting, the company meta-analysed 129 international studies that had reported deaths around an acute episode of acquired TTP in people who had standard care including plasma exchange. It extracted the probability of dying during an acute episode. This analysis suggested an average probability of dying of 13.2% during an acute hospitalisation. The committee noted that the meta-analysis included studies with very heterogeneous results (the probability of dying ranged from 0% to 57%). The committee noted that the company's meta-analysis had not been adjusted for risk of death at baseline. The committee considered that restricting the analysis to 7 UK studies was more generalisable to the UK. It considered that the most relevant UK studies resulted in a probability of dying during an acute episode of around 7.0%.
In its response to the appraisal consultation document for the committee's second meeting, the company provided a new estimate for deaths on standard care during the acute period of 12.6%, based on a poster presentation (Lester et al. 2015) that reported Hospital Episode Statistics for new cases of acquired TTP and Office of National Statistics data for deaths from acquired TTP between 2003 and 2013.The committee considered that the new estimate for standard care (12.6%) was more generalisable than the estimate from the meta-analysis because it included patients in England only. However, it agreed that it may overestimate the true risk of dying because standard care may have improved since the period during which the data were collected. After the second meeting, the committee concluded that it was likely that the probability of dying during an acute episode on standard care is between 7.0% and 12.6%. For the third and fourth meetings, the company used in the modelling a value of 10%, which the committee accepted.
## The benefit of caplacizumab on mortality in the acute period based on comparing separate sources of observational data may be biased
In its original base case, the company did a naive (unadjusted) comparison of observational data from separate sources to estimate the comparative benefit of caplacizumab compared with standard care on the risk of dying during an acute episode:
For caplacizumab, the company used data from a global compassionate use scheme in which the company provided clinicians with caplacizumab on request (239 people had had treatment up to February 2020). These data suggested an absolute probability of dying on caplacizumab of 3.8% (9 deaths) over a period equivalent to the follow up in HERCULES (the acute episode plus about 3 months).
For standard care, the company used a probability of dying around an acute episode of 13.2% from its meta-analysis (see section 3.10).
Naively comparing the data from these separate populations gave an estimated relative risk for survival with caplacizumab of 0.29 compared with standard care alone. This suggested that caplacizumab reduced the chance of death in the acute period by 71% compared with standard care alone.The committee heard that, in the compassionate use scheme, caplacizumab was given in centres of excellence, and the clinical experts explained that patient outcomes, including the death rate, were better in these centres compared with non-specialist centres (see section 3.4). It agreed that, because caplacizumab would likely be commissioned for use only in these centres, the absolute rate of death for people having treatment with caplacizumab was likely to be valid. However, the committee considered that any relative risk comparing treatment with and without caplacizumab would overestimate the effectiveness of caplacizumab because treatment in specialist centres improve outcomes and that the relative benefit ascribed to caplacizumab was very likely to be confounded. The committee concluded that this bias likely overestimated the clinical and cost effectiveness of caplacizumab.
## The company's estimates of the benefit of caplacizumab on mortality based on trial data are not robust and are overestimated
In response to the appraisal consultation document, the company provided alternative estimates of the benefit of caplacizumab in reducing deaths during an acute episode. In its base case for the second and subsequent appraisal committee meetings, it used a risk ratio of deaths during an acute episode with caplacizumab compared with standard care alone from the clinical trials of caplacizumab (see section 3.8). These risk ratios were 0.21 using pooled HERCULES and TITAN data, and 0.34 using HERCULES data alone. The committee was concerned that the risk ratios calculated from the caplacizumab trials were not robust because they were based on few events. The committee considered that the magnitude of reduction in deaths seemed high compared with the treatment effect of thrombolytic treatments used for other conditions with life-threatening blood clots. It considered that, given the high levels of uncertainty, and taking into account its consideration on other estimates (see section 3.11), a more conservative assumption should be used. The committee, at its second meeting, suggested a relative risk of 0.5. This represented a 50% reduction in acute deaths with caplacizumab as a reasonable modelling assumption, given the uncertainty around the company's estimates. The company chose to continue to model the relative risk of 0.34 in its base case when presenting for the committee's third and fourth meetings. The committee concluded that relative risk reduction of 0.5 reflected a reasonable reduction in mortality given the lack of robust evidence.
## In the long-term submodel, the company's revised calculation of a standardised mortality ratio to estimate death rates is appropriate
To determine the absolute risk of death after an acute episode over the long term in people who had had standard care alone, the company calculated a standardised mortality ratio and applied it to the risk of dying in the UK general population. The standardised mortality ratio reflects observed deaths after standard care during an acute episode divided by the expected number of deaths for the general population of similar age and sex. The company used Upreti et al. (2019), which describes mortality over a median 3‑year follow up in people who survived an acute episode of acquired TTP and who were followed at John Hopkins Hospital, Baltimore, US, between 1995 and 2018. The company calculated the standardised mortality ratio as 8.3 (meaning that a person with acquired TTP is about 8 times more likely to die than a person of the same age and sex without acquired TTP). The company explained that it calculated the ratio using the UK population. The committee appreciated that about 60% of the Upreti cohort comprised people of African-American family origin, and that 14% of deaths were caused by HIV, which likely did not reflect the characteristics of the UK general population. The committee considered that this likely overestimated the standardised mortality ratio. After the second meeting, the company revised its calculations of the standard mortality ratio so that the estimates of mortality reflected the US general population mortality, resulting in a lower standardised mortality ratio of 5.1. In response to consultation, the company provided additional validation of its mortality assumptions and concurred with the committee that there was a paucity of long-term mortality data in this disease area. The committee concluded that the company's revised calculation of a standardised mortality ratio to estimate death rates used an appropriate reference population.
## In the long-term submodel, the rates of complications on standard care modelled by the company may not be generalisable to the UK
After recovering from a first episode of acquired TTP, some people will have long-term complications from ischaemic damage (see section 3.1). The company assumed that treatment with caplacizumab lowers the risk of these complications. In its Markov model, it modelled the prevalence of cognitive impairment and mental health problems (such as depression and anxiety) in people with acquired TTP having standard care alone over the lifetime of the modelled populations. The committee considered that the company's estimates of the prevalence of long-term complications in people with acquired TTP:
did not come from a UK population
included people whose complications were not specifically associated with acquired TTP
reflected estimates of severe depression in people in a TTP support group in the US rather than a random sample of people with acquired TTP in the UK.The committee appreciated the company's attempts to ensure that it had exhausted possible sources of data. It concluded that the company had not shown that the prevalence of long-term complications on standard care in its model were generalisable to current UK practice. However, it further concluded that, in the absence of any other data, it was reasonable to use the company's estimates in the model.
## The relationship between length of hospital stay and long-term complications and death is unclear
Because HERCULES measured outcomes during an acute episode only, it did not provide data for caplacizumab compared with standard care on long-term complications when acquired TTP is in remission. However, the company assumed that previous treatment with caplacizumab reduced complications and extended life in the remission period above and beyond a benefit to mortality in the short term. After estimating a risk of death for people on standard care (see section 3.13), the company assumed that time in intensive care or hospital was causally related to the prevalence of long-term outcomes including cognitive impairment and mental health (including depression, anxiety, post-traumatic stress), and the relative risk of death for caplacizumab compared with standard care in the Markov submodel. It assumed that this equalled the ratio (0.62) of time in intensive care and hospital measured in HERCULES for caplacizumab compared with standard care alone. The committee noted that caplacizumab was not disease modifying and would not be expected to work after people stopped having it. However, the committee understood that reducing thromboses and the likelihood of complications in the short term would reduce the risk of sequalae from these complications in the longer term. The clinical experts stated that a relationship between hospital stay and long-term outcomes was plausible. The committee noted that a relationship between length of stay and the development of subsequent complications in the longer term had not been validated, and that the company had not presented relevant data. The committee recalled that the same proportion of people in each arm of HERCULES developed a major thromboembolic complication during the trial. The company responded that it did not consider that major thromboembolic events would capture differences in microvascular damage between caplacizumab and standard care. The committee was also aware that some people might have pre-existing complications that might prolong stay in hospital and that caplacizumab would not improve or cure. In response to consultation after the committee's first meeting, the company confirmed that were no data specific to acquired TTP to validate a causal relationship between length of hospital stay and long-term outcomes. The committee concluded that it was not possible to validate a causal link between former treatment with caplacizumab and long-term complications and death beyond the end of the trial based on length of hospital stay.
## Time to platelet normalisation is better than hospital stay for estimating long-term outcomes, but uncertainty remains
In response to consultation after the committee's first meeting, the company presented 2 exploratory analyses. These used time to platelet normalisation rather than duration of hospitalisation as an alternative proxy for long-term outcomes. They were:
an analysis based on a randomised controlled trial comparing plasma exchange and another treatment, plasma infusion (Rock et al. 1991), which showed an association between having a shorter time to platelet normalisation and a lower death rate at 6 months
an analysis based on a retrospective cohort study (Liu et al. 2013), which showed that platelet normalisation by 3 days after starting treatment compared with platelet normalisation after 3 days was associated with fewer deaths over 80 months.The committee considered that:
time to platelet normalisation better approximated a person's exposure to microthrombi than time in hospital during an acute episode, and the clinical experts explained that microthrombi increase the risk of long-term complications (see section 3.15)
it was plausible that a causal relationship between time to platelet normalisation in the acute period and long-term complications existed
the exact relationship between time to platelet normalisation and long-term outcomes remained uncertain because:
Liu et al. and Rock et al. did not provide data on the prevalence of long-term complications, other than death, after an acute episode
in both of these studies, some of the deaths would have been during an acute episode rather than afterwards
the studies were several years old, particularly Rock et al., so it was questionable how generalisable they would still be to current NHS.The company adjusted the risk ratio for time to platelet normalisation for caplacizumab compared with standard care in HERCULES. This was to account for the possibility that not all of the benefit of caplacizumab in reducing the time to platelet normalisation would translate to a benefit in reduced long-term complications and deaths. The risk ratio for time to platelet normalisation in HERCULES (0.57) was multiplied by 1.16 (the 85% reduction in time to platelet normalisation in Rock et al. with plasma exchange compared with plasma infusion divided by the 75% reduction in deaths with plasma exchange compared with plasma infusion). The committee considered that the estimated size of benefit with caplacizumab on complications was plausible. However, it thought that there was uncertainty about whether this would translate to a benefit in survival after people had recovered from their acute TTP episode. So, the committee concluded that using an estimated risk ratio of 0.66 to estimate the effect of caplacizumab compared with standard care in reducing long-term cognitive impairment and mental health problems would be appropriate, although still highly uncertain. For the endpoint of death in the Markov submodel, the committee considered in its second committee meeting that a risk of 0.90 was plausible. However, it was willing to consider a value of 0.80 presented by the company to NICE in its third and fourth committee meetings (which represented a midpoint between the company's estimate of 0.66 and 0.90) in its decision making.
## The company's modelled rate of relapse is appropriate, but it is not known whether caplacizumab works equally well if used again
The committee appreciated that someone could have caplacizumab again after each relapse. The company assumed an annual disease relapse rate of 1%, based on the opinions of clinicians it surveyed. One clinical expert at the meeting noted that the increased use of rituximab to prevent relapse meant that the relapse rate in the UK was now lower than it had been before rituximab was standard care. However, he thought that 1% per year was too low, and that a more realistic estimate would be somewhere between 1% and 5%. The company assumed that caplacizumab works as well on retreatment as it does when first used, but did not present data to support this. The committee asked the company whether there was any evidence of antibodies against caplacizumab from the available trial data, and whether the effectiveness of caplacizumab would differ on retreatment. The company stated that it had seen antibodies in some patients. The committee concluded that the relapse rate was likely to be higher than 1% in clinical practice. It was also uncertain about whether caplacizumab was as effective on reuse as with initial use.
## Information on quality of life is not available from HERCULES, and caplacizumab's effect on quality of life remains uncertain
There were no quality-of-life data collected in HERCULES. The company instead used quality-of-life data from people hospitalised with stroke to estimate quality of life during an acute episode of acquired TTP. This resulted in a baseline utility value of 0.64. The committee stated that this appeared to be high, suggesting better quality of life than would be expected for people in hospital for a life-threatening condition (see section 3.1). The patient experts said that this did not reflect how severely an acute episode affected people. In response to consultation after the committee's first meeting, the company revised this assumption so that the utility on standard care was half (0.32) that of caplacizumab (0.64). The committee considered that quality of life would be better around an acute episode with caplacizumab compared with standard care because of the fewer plasma exchanges needed. However, it thought that an assumption of a 25% reduction in quality of life on standard care rather than the company's assumption of a 50% reduction was appropriate. Having heard from the patient experts that acquired TTP affects mental health (see section 3.1), the committee also considered whether quality-of-life estimates for acquired TTP should have included an estimate of the fear of relapse. For the committee's second meeting, the company included an estimate of disutility for fear of relapse. However, the company included it only for patients having standard care, and not for people having caplacizumab. The committee agreed that it had not been proven that caplacizumab reduced relapse frequency, so was not convinced that any disutility would affect the standard care only arm. Furthermore, it agreed that it was likely that the model already included the disutility of a fear of relapse, via anxiety and depression reflected in the Markov submodel. The committee noted that the company had estimated the quality of life associated with cognitive impairment and mental health in the long term. This was based on studies in people with stroke and people with depressive disorder respectively. It acknowledged that cognitive impairment and mental health problems would lower a person's quality of life. However, it recalled that there was no direct evidence that caplacizumab would decrease the likelihood of having these complications or improve quality of life by decreasing these complications (see section 3.15 and section 3.16). The committee noted that the utility values did not have a large effect on incremental cost-effectiveness ratios (ICERs). It concluded that the effect of acquired TTP lowers quality of life, and that treatment with caplacizumab improves quality of life but by how much is uncertain.
## Some potential cost savings associated with caplacizumab may not be included in the company's model
The committee understood that using caplacizumab lowered the cost of plasma exchange and hospital stay compared with best supportive care. The model included cost of testing ADAMTS13 activity, as well as adverse events associated with treatment. The committee noted that the company modelling did not include the costs of escalating treatment for acquired TTP refractory to treatment. This would favour standard care because more people in the standard care arm in HERCULES were refractory to treatment than in the caplacizumab arm (see section 3.7). The company stated that, based on its observations from the compassionate use scheme for caplacizumab, in NHS clinical practice, people would have it for a shorter duration than in the trials. The committee in general prefers not to disassociate estimates of cost and effectiveness from a trial. However, it appreciated that many assumptions about caplacizumab's effectiveness in this model were not taken from the main trial. It also thought that some potential cost savings associated with caplacizumab may not have been included in the company's model.
## To mitigate uncertainty around the modelling assumptions, a conservative approach is preferred
The committee appreciated that the company made attempts to address uncertainty. However, it considered that several assumptions in the model remained uncertain and were at the more optimistic range of what would be seen in clinical practice. It noted that, at the first committee meeting, the company had presented a deterministic ICER (which took a point estimate, or assumption for each model input) and a probabilistic ICER (which represented the average of many runs of the model using a range of values for each model input). The committee noted that these ICERs were similar, but the probabilistic analysis was incomplete because not all of the model inputs had a distribution around the deterministic value. This meant that not all of the uncertainty was accounted for in the probabilistic sensitivity analyses. The committee therefore considered a range of scenarios to test the effect of a range of plausible clinical outcome parameters on the ICER. On balance, it preferred assumptions that were more conservative than the company's base case. Although some uncertainty remained about these parameters, the committee noted that taking a more conservative approach reduced the risk that the ICER had been underestimated. Its preferred assumptions in the acute submodel were:
a midpoint of 10% for the acute absolute mortality rates on standard care (that is, between 7% and 12.6%; see section 3.10)
a risk ratio for acute mortality rates for caplacizumab compared with standard care of 0.5 (see section 3.12)
utility values assuming 25% of the quality of life on standard care compared with caplacizumab. (see section 3.18).The committee's preferred assumptions in the long-term Markov submodel were:
the company's assumptions on prevalence of long-term complications on standard care (see section 3.14)
the company's revised standardised mortality ratio underlying the estimate of the absolute risk of dying for people on standard care (see section 3.13)
the effectiveness of caplacizumab compared with standard care reflecting long-term complications based on the association between time to platelet normalisation (estimated risk ratio of 0.66; see section 3.15 and section 3.16)
an estimated risk ratio of death of 0.8 for caplacizumab compared with standard care (see section 3.16)
a lifetime duration of neuropsychological impairment (see section 3.18)
fear of relapse not modelled separately (see section 3.18)
a relapse rate of 1.5% (see section 3.17).Applying these assumptions and using a revised patient access scheme price discount for caplacizumab resulted in an ICER of £29,537 per quality-adjusted life year (QALY) gained.
## Caplacizumab is innovative
Caplacizumab is the first new treatment for acquired TTP in about 25 years with a different mechanism to the other drugs and treatments that form current standard care. Caplacizumab has additional benefits to standard care. The committee noted that there were benefits that may not have been captured in calculating the QALY. These included reducing the use of scarce NHS resources like plasma or intensive care unit beds. The committee concluded that caplacizumab is innovative.
# Conclusion
## Caplacizumab is a cost-effective use of NHS resources
The committee noted the considerable uncertainty around the estimates of cost effectiveness because of the limited clinical data, particularly around survival in the acute period and the long-term benefits of caplacizumab. It understood that the lack of data was, in part, because of the rarity of acquired TTP. Using the committee's preferred modelling assumptions resulted in an ICER of £29,537 per QALY gained. In line with the NICE methods guide for technology appraisal, when a most plausible ICER is above £20,000 per QALY gained, the committee can take account certain factors, including innovation (see section 3.21). At its fourth meeting, the committee concluded that the ICER for caplacizumab fell within a range considered to be a cost-effective use of NHS resources and recommended caplacizumab as an option for treating acquired TTP.
|
{'Recommendations': 'Caplacizumab with plasma exchange and immunosuppression is recommended, within its marketing authorisation, as an option for treating an acute episode of acquired thrombotic thrombocytopenic purpura (TTP) in adults, and in young people aged 12\xa0years and over who weigh at least 40\xa0kg. Treatment should be started and supervised by physicians experienced in managing thrombotic microangiopathies. It is recommended only if the company provides caplacizumab according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nStandard care for an acute episode of acquired TTP includes plasma exchange and immunosuppressant medicines. Trial results show that, compared with standard care alone, caplacizumab plus standard care reduces:\n\nthe time it takes to bring platelet levels back to normal\n\nthe number of plasma exchange treatments needed\n\ntime in hospital and intensive care.\n\nAdding caplacizumab likely reduces the long-term complications of acquired TTP and risk of death around the time of an acute episode, but it is unclear by how much. This is because the trial results do not address whether adding caplacizumab improves either length or quality of life in the long term after people stop taking the drug. Also, there are limited reported data on the long-term complications of acquired TTP after an acute episode.\n\nHowever, the assumptions in the economic modelling are plausible. Also, there are potential benefits with caplacizumab that are not included in the cost-effectiveness estimates. Overall, the estimates are within the range normally considered a cost-effective use of NHS resources. So, caplacizumab is recommended for treating acute acquired TTP.', 'Information about caplacizumab': "# Marketing authorisation indication\n\nCaplacizumab (Cablivi, Sanofi) has a marketing authorisation for treating adults and young people aged 12\xa0years and over who weigh at least 40\xa0kg who are 'experiencing an episode of acquired thrombotic thrombocytopenic purpura, in conjunction with plasma exchange and immunosuppression'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price of caplacizumab is £4,143 per 10‑mg vial (excluding VAT; BNF online, May\xa02020). The company has a commercial arrangement. This makes caplacizumab available to the NHS with a discount. The size of the discount is commercial in confidence.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Sanofi, a review of this submission by the evidence review group (ERG), the technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Current treatments and patient perspectives\n\n## Acquired thrombotic thrombocytopenic purpura is a life-threatening condition associated with long-term morbidity and mortality\n\nAcquired thrombotic thrombocytopenic purpura (TTP) is a rare autoimmune condition characterised by antibodies against ADAMTS13, the enzyme that cleaves von Willebrand factor, a large protein involved in blood clotting. People with low levels of ADAMTS13 activity have a higher risk of clotting. The condition causes blood clots in small blood vessels, which leads to decreased blood flow and oxygen supply to vital organs such as the brain, heart and kidneys. This causes ischaemic damage, can be acutely life-threatening, and, in the longer term, may cause cognitive deficits, depression and hypertension. One clinical expert stated that acquired TTP is the most dangerous acute illness in haematology, with some people transitioning from having no symptoms to death within hours. There are treatments for acquired TTP (see section\xa03.2), and it can relapse. The patient experts explained that acquired TTP can affect quality of life and, in particular, mental health. The committee was told that people with newly diagnosed acquired TTP are likely to be anxious, which is made worse by them never having heard of the condition. Even when acquired TTP is in 'remission', the condition can relapse. Also, the signs and symptoms of relapse may be non-specific. One patient expert suggested that anxiety itself is a symptom of an upcoming relapse and can lead to long-term depression. The committee concluded that acquired TTP is a life-threatening, stressful condition associated with long-term morbidity and mortality.\n\n## Caplacizumab is added on to, but does not replace, existing treatment with plasma exchange and immunosuppressants\n\nAfter diagnosis of an acute episode of acquired TTP, current standard treatment involves plasma exchange, ideally within 4\xa0to 8\xa0hours of diagnosis. This involves filtering blood to remove the antibody-containing plasma and replacing discarded plasma with donated plasma to replace ADAMTS13. Immunosuppressant drugs such as corticosteroids and rituximab treat the underlying autoimmune condition, and limit antibody production against ADAMTS13. Caplacizumab binds to von Willebrand factor, inhibiting it from interacting with platelets, and preventing clots. The first dose is given intravenously at the first plasma exchange. The subsequent doses are given subcutaneously daily for up to 30\xa0days after stopping plasma exchange or longer, if necessary, until ADAMTS13 levels normalise. The clinical experts stated that controlling the underlying immune condition can take up to 10\xa0days with rituximab treatment, and that caplacizumab treatment reduces blood clot formation during this time. The clinical experts explained that the longer the blood vessels remained blocked, the higher the risk of illness and dying. They further stated that, because of the risk of relapse, clinicians continue to monitor people with acquired TTP in remission and to offer rituximab to reduce relapse risk. The committee concluded that caplacizumab does not replace existing treatment, but is added to plasma exchange to increase platelet counts and reduce blood clots.\n\n## Plasma exchange is unpleasant, and people with acquired TTP would welcome a treatment that reduces plasma exchange and hospital stays\n\nAlthough caplacizumab does not replace plasma exchange, it may reduce the number of days of plasma exchange and the volume of plasma needed (see section\xa03.7). Plasma exchange involves inserting an intravenous catheter, which carries a risk of infection. The clinical experts stated that the catheters are typically replaced every 5\xa0to 7\xa0days. This means that treatments that reduce the number of days of plasma exchange would also reduce the need to replace catheters. The patient experts described how inserting catheters is uncomfortable, painful and stressful, in part, because of infection risk. They stated that, of all the reported benefits of caplacizumab, they most welcome reducing plasma exchange, and time in intensive care. One patient expert who had used caplacizumab stated that people might struggle with injecting caplacizumab at home or with its adverse effects, such as nosebleeds. However, they thought that people would be willing to accept these if treatment reduced hospital stays and the need for plasma exchange. The committee concluded that plasma exchange and hospital stays are unpleasant, and that people with acquired TTP would welcome a treatment that reduces these.\n\n## A new NHS specialised service for acquired TTP is being established\n\nThe clinical experts stated that the UK has had fragmented care for people with acquired TTP. This has led to poorer outcomes, including higher death rates outside of specialist centres for acquired TTP. For example, estimates of death rates were 10%\xa0to\xa020% in non-specialist centres and less than\xa05% in specialist centres. People are currently referred to specialist centres for acquired TTP treatment. However, diagnosis and treatment may be delayed because many clinicians are unaware of acquired TTP, and because of the distance someone has to travel to access a specialist centre. The commissioning lead of the NHS Highly Specialised Services stated that, if recommended, the NHS would commission caplacizumab through a new specialised service. The NHS aims to have up to 9\xa0specialist centres in England, providing clinical expertise and geographical access for patients. If caplacizumab were to be recommended, some people could have it locally, supervised remotely by a specialised centre. A clinical expert said that kits are now available for emergency departments to diagnose acquired TTP within 24\xa0hours. The committee acknowledged that there is regional variation in the time to diagnosis of acquired TTP, in treatment and in patient outcomes. It concluded that a new NHS specialised service will attempt to reduce this variation and improve outcomes.\n\n# Clinical trial results\n\n## The main clinical trial, HERCULES, is broadly generalisable to UK clinical practice\n\nThere were 2\xa0placebo-controlled trials of similar design in the clinical trial programme for caplacizumab: HERCULES and TITAN. Both were double-blind randomised controlled trials. TITAN included 75\xa0people and HERCULES included 145\xa0people having an acute episode of acquired TTP. Both compared caplacizumab plus standard care (plasma exchange, immunosuppressant medication including rituximab; from now referred to as caplacizumab) with placebo plus standard care (from now referred to as standard care alone). Because of protocol amendments and violations, TITAN was not used to support the company's application for a marketing authorisation for caplacizumab and was not presented to the committee for its first meeting. Caplacizumab's marketing authorisation states that it should be given before people start plasma exchange. However, in HERCULES, caplacizumab was started after plasma exchange. This was because the time needed to consent and randomise patients could delay plasma exchange, which was neither practical nor safe. One clinical expert stated that, in clinical practice, caplacizumab would be given before and within the same day as plasma exchange. Also, the trial recruited people in specialist centres for acquired TTP rather than from general haematology centres; the clinical experts considered that people in the trial may have had better outcomes than would be seen in overall NHS practice. However, this was unlikely to have affected caplacizumab's relative treatment effect. The trial included only 18\xa0people from the UK, and 1\xa0clinical expert said that:\n\nthe people in the trial, and the treatments they had, reflected UK practice\n\nsince 2018, some patients under her care have had caplacizumab via a global compassionate use scheme\n\nthe trial outcomes in the caplacizumab arm reflected the outcomes she had seen in NHS practice when using caplacizumab through the compassionate use scheme.The committee concluded that results of HERCULES were generalisable to the centres in which caplacizumab would be offered in UK clinical practice.\n\n## The outcomes in HERCULES are clinically relevant, but do not include the short- and long-term complications in the economic model\n\nHERCULES measured clinical outcomes around an acute episode of acquired TTP. Data were collected while people were on treatment for up to 30\xa0days, and for 28\xa0days after they stopped treatment. The committee understood that an observational single-arm extension to HERCULES is ongoing. The primary outcome of the trial was time to platelet normalisation. The clinical experts explained that they considered platelet count to be a surrogate measure for more meaningful outcomes reflecting morbidity and mortality. From a clinical expert, the committee heard that the faster the platelet count is normalised, the lower the risk of complications. Key secondary outcomes in the trial analyses in the company's statistical analysis plan, listed hierarchically, were:\n\na composite outcome of TTP-related death, disease recurrence while on treatment and major thromboembolic event\n\ndisease recurrence alone including the 4‑week follow up\n\nthe proportion of people whose condition did not respond to treatment ('refractory' TTP)\n\ntime to normalisation of all 3\xa0blood markers of organ damage: lactate dehydrogenase, cardiac troponin and creatinine.Other secondary outcomes such as volume and duration of plasma exchange, time in hospital or intensive care, and death were not tested statistically in line with the company's statistical analysis plan. The clinical experts explained that all the measured outcomes were clinically relevant. The patient experts said that plasma exchange use and time in hospital are important (see section\xa03.3). The committee concluded that the primary surrogate and the secondary outcomes in HERCULES were clinically relevant. However, it noted that the trial did not measure the effects of caplacizumab in the company's health-economic model (see sections\xa03.13 to 3.18) on survival, quality of life, disability or mental health in the long term.\n\n## HERCULES shows that caplacizumab reduces time to platelet normalisation, plasma exchange use and duration of hospital stay\n\nThe committee reviewed the results of HERCULES, noting that:\n\nCaplacizumab reduced the time to the primary outcome, platelet normalisation. There was a very small (0.2\xa0days) difference in median time to platelet normalisation between the treatments (2.7\xa0days on caplacizumab and 2.9\xa0days on placebo; p<0.01). The clinical experts explained that the rate of platelet normalisation was similar between the 2\xa0trial arms until day\xa03, but then caplacizumab added benefit to plasma exchange in normalising platelet levels until the autoimmune condition was controlled.\n\nCaplacizumab reduced the secondary composite outcome (12%\xa0of people on caplacizumab compared with 49%\xa0on standard care alone had an acquired TTP-related death, disease recurrence while on treatment or a major thromboembolic event; p<0.001). The same proportion (8%) of people randomised to each treatment had a major thrombotic event (a component of the composite outcome) during the acute period.\n\nCaplacizumab reduced the proportion of people whose disease recurred while on treatment or in the 28\xa0days after stopping treatment (13%\xa0on caplacizumab compared with 38% on standard care alone; p<0.001).\n\nCaplacizumab reduced the proportion of people whose acquired TTP was refractory to plasma exchange treatment (meaning that there was no improvement in platelet count after 5\xa0plasma exchanges and treatment with corticosteroids). No people in the caplacizumab arm had acquired TTP refractory to plasma exchange. The company has said that the proportion whose acquired TTP was refractory in the standard care arm is academic in confidence and cannot be reported here.\n\nCaplacizumab reduced the mean duration of plasma exchange (6\xa0days compared with 9\xa0days on standard care alone), mean volume of plasma exchange (21\xa0litres compared with 36\xa0litres), and mean days in hospital (10\xa0days compared with 14\xa0days) and in intensive care (3\xa0days compared with 10\xa0days). The committee noted that, in the company's statistical plan, these outcomes were described, but not statistically tested. One clinical expert explained that she had seen a similar reduction in number of plasma exchanges and length of hospital stay with caplacizumab in the compassionate use programme in her centre.The committee concluded that caplacizumab is clinically effective in the acute period compared with standard of care alone.\n\n## It is not possible to estimate reliably how much caplacizumab might reduce deaths in the acute period from trial data\n\nThe HERCULES trial did not aim to assess whether caplacizumab reduced deaths around an acute episode. The company explained that to do this, it would have needed to recruit more people, which would have been difficult because acquired TTP is rare. Instead, the company used observational data to quantify its claims of caplacizumab's effect on mortality during an acute episode (see section\xa03.11). The committee noted there were few deaths in the caplacizumab and standard care arms in the trial (including during follow\xa0up when people had stopped treatment):\n\nIn the first meeting, the company presented data on mortality from HERCULES only: 1\xa0death occurred in the caplacizumab arm (1%) and 3\xa0deaths occurred in the standard care arm (4%). The ERG estimated a risk ratio for death of\xa00.34 (95% confidence interval [CI] 0.04\xa0to\xa03.22) for caplacizumab compared with standard care only.\n\nIn the second meeting, the company presented pooled data from HERCULES and TITAN: 1\xa0death occurred in the caplacizumab arm (1%) and 5\xa0deaths occurred in the standard care arm (4%). The ERG estimated a risk ratio for death of\xa00.21 (95%\xa0CI 0.03\xa0to\xa01.75) for caplacizumab compared with standard care only.The committee considered that there were too few deaths, even when pooling data from the 2\xa0trials, to estimate accurately the effect of caplacizumab on survival in the acute period. It was aware that the company had chosen not to use the trial data on deaths in its original cost-effectiveness model (see section\xa03.11), but instead used data from a global compassionate use scheme. The committee noted that the considerable uncertainty reflected in the wide confidence intervals also included the possibility that caplacizumab increased the risk of dying. It concluded that it was not possible to estimate reliably the extent of the benefit using the randomised trial data.\n\n# The company's economic model\n\n## The company's model structure is appropriate for decision making\n\nThe company's model had 2\xa0parts: 1\xa0for acute illness and 1\xa0for the rest of a person's life. It also included the possibility of relapse, that is, a person who recovers cycles through the model again. The committee appreciated that people only have treatment with caplacizumab during an acute episode, and that people do not have caplacizumab to prevent relapses. The company modelled events around an acute episode of acquired TTP using a decision-tree model. It used a Markov model to project long-term events for up to 55\xa0years after a person had recovered from an acute episode. The committee understood that the company considered that with caplacizumab, compared with standard care:\n\nIn the acute period (decision-tree model):\n\n\n\nTreatment decreases the risk of dying (see section\xa03.11 and\xa0section\xa03.12) from an estimated baseline risk of dying on standard care (see section\xa03.10).\n\nTreatment improves quality of life because people need fewer plasma exchanges. The extent of this improvement is based on an assumption (see section\xa03.18).\n\n\n\nIn the long term (Markov model):\n\n\n\nFormer treatment with caplacizumab decreases the risk of dying (see section\xa03.15 and\xa0section\xa03.16) from an estimated baseline risk of dying for people with acquired TTP who had standard care for their acute episode (see section\xa03.13).\n\nTreatment improves quality of life by decreasing the rate of long-term complications. The modelled complications included cognitive impairment and mental health problems such as depression and anxiety. The company estimated the rates of long-term complications after standard care for the acute episode (see section\xa03.14).Because there were no long-term data, the company estimated the extent to which caplacizumab reduced the rate of long-term complications by assuming that the treatment effect of caplacizumab for acute outcomes would be the same as its treatment effect for long-term outcomes (see section\xa03.15 and\xa0section\xa03.16). The company modelled the same rates of relapse on caplacizumab and on standard care alone (see section\xa03.17). The acute-period model included the costs of treatment and of hospital stay. The long-term model included the costs of treating a relapse and complications of acquired TTP, and of preventative rituximab. The committee noted that many of the treatment effects ascribed to caplacizumab in the model were based on either assumptions or non-trial data, which increased uncertainty (see sections\xa03.10 to 3.18). However, the committee considered that the economic model captured relevant aspects of acquired TTP, and concluded that its overall structure was appropriate for decision making.\n\n\n\n## The submodel reflecting acute disease takes into account that mortality rates on standard care have improved over time\n\nThe company and the clinical experts stated that the number of deaths in the trial in both arms were lower than would be expected in clinical practice. Because of this, the company did not use death rates from HERCULES to estimate absolute death rates for standard care in its model. Instead:\n\nIn its original submission for the committee's first meeting, the company meta-analysed 129\xa0international studies that had reported deaths around an acute episode of acquired TTP in people who had standard care including plasma exchange. It extracted the probability of dying during an acute episode. This analysis suggested an average probability of dying of\xa013.2% during an acute hospitalisation. The committee noted that the meta-analysis included studies with very heterogeneous results (the probability of dying ranged from 0%\xa0to\xa057%). The committee noted that the company's meta-analysis had not been adjusted for risk of death at baseline. The committee considered that restricting the analysis to 7\xa0UK studies was more generalisable to the UK. It considered that the most relevant UK studies resulted in a probability of dying during an acute episode of around\xa07.0%.\n\nIn its response to the appraisal consultation document for the committee's second meeting, the company provided a new estimate for deaths on standard care during the acute period of\xa012.6%, based on a poster presentation (Lester et al. 2015) that reported Hospital Episode Statistics for new cases of acquired TTP and Office of National Statistics data for deaths from acquired TTP between 2003 and 2013.The committee considered that the new estimate for standard care (12.6%) was more generalisable than the estimate from the meta-analysis because it included patients in England only. However, it agreed that it may overestimate the true risk of dying because standard care may have improved since the period during which the data were collected. After the second meeting, the committee concluded that it was likely that the probability of dying during an acute episode on standard care is between\xa07.0% and\xa012.6%. For the third and fourth meetings, the company used in the modelling a value of\xa010%, which the committee accepted.\n\n## The benefit of caplacizumab on mortality in the acute period based on comparing separate sources of observational data may be biased\n\nIn its original base case, the company did a naive (unadjusted) comparison of observational data from separate sources to estimate the comparative benefit of caplacizumab compared with standard care on the risk of dying during an acute episode:\n\nFor caplacizumab, the company used data from a global compassionate use scheme in which the company provided clinicians with caplacizumab on request (239\xa0people had had treatment up to February 2020). These data suggested an absolute probability of dying on caplacizumab of\xa03.8% (9\xa0deaths) over a period equivalent to the follow up in HERCULES (the acute episode plus about 3\xa0months).\n\nFor standard care, the company used a probability of dying around an acute episode of\xa013.2% from its meta-analysis (see section\xa03.10).\n\nNaively comparing the data from these separate populations gave an estimated relative risk for survival with caplacizumab of\xa00.29 compared with standard care alone. This suggested that caplacizumab reduced the chance of death in the acute period by\xa071% compared with standard care alone.The committee heard that, in the compassionate use scheme, caplacizumab was given in centres of excellence, and the clinical experts explained that patient outcomes, including the death rate, were better in these centres compared with non-specialist centres (see section\xa03.4). It agreed that, because caplacizumab would likely be commissioned for use only in these centres, the absolute rate of death for people having treatment with caplacizumab was likely to be valid. However, the committee considered that any relative risk comparing treatment with and without caplacizumab would overestimate the effectiveness of caplacizumab because treatment in specialist centres improve outcomes and that the relative benefit ascribed to caplacizumab was very likely to be confounded. The committee concluded that this bias likely overestimated the clinical and cost effectiveness of caplacizumab.\n\n## The company's estimates of the benefit of caplacizumab on mortality based on trial data are not robust and are overestimated\n\nIn response to the appraisal consultation document, the company provided alternative estimates of the benefit of caplacizumab in reducing deaths during an acute episode. In its base case for the second and subsequent appraisal committee meetings, it used a risk ratio of deaths during an acute episode with caplacizumab compared with standard care alone from the clinical trials of caplacizumab (see section\xa03.8). These risk ratios were\xa00.21 using pooled HERCULES and TITAN data, and\xa00.34 using HERCULES data alone. The committee was concerned that the risk ratios calculated from the caplacizumab trials were not robust because they were based on few events. The committee considered that the magnitude of reduction in deaths seemed high compared with the treatment effect of thrombolytic treatments used for other conditions with life-threatening blood clots. It considered that, given the high levels of uncertainty, and taking into account its consideration on other estimates (see section\xa03.11), a more conservative assumption should be used. The committee, at its second meeting, suggested a relative risk of\xa00.5. This represented a 50%\xa0reduction in acute deaths with caplacizumab as a reasonable modelling assumption, given the uncertainty around the company's estimates. The company chose to continue to model the relative risk of\xa00.34 in its base case when presenting for the committee's third and fourth meetings. The committee concluded that relative risk reduction of\xa00.5 reflected a reasonable reduction in mortality given the lack of robust evidence.\n\n## In the long-term submodel, the company's revised calculation of a standardised mortality ratio to estimate death rates is appropriate\n\nTo determine the absolute risk of death after an acute episode over the long term in people who had had standard care alone, the company calculated a standardised mortality ratio and applied it to the risk of dying in the UK general population. The standardised mortality ratio reflects observed deaths after standard care during an acute episode divided by the expected number of deaths for the general population of similar age and sex. The company used Upreti et al. (2019), which describes mortality over a median 3‑year follow up in people who survived an acute episode of acquired TTP and who were followed at John Hopkins Hospital, Baltimore, US, between 1995 and 2018. The company calculated the standardised mortality ratio as\xa08.3 (meaning that a person with acquired TTP is about 8\xa0times more likely to die than a person of the same age and sex without acquired TTP). The company explained that it calculated the ratio using the UK population. The committee appreciated that about 60%\xa0of the Upreti cohort comprised people of African-American family origin, and that 14%\xa0of deaths were caused by HIV, which likely did not reflect the characteristics of the UK general population. The committee considered that this likely overestimated the standardised mortality ratio. After the second meeting, the company revised its calculations of the standard mortality ratio so that the estimates of mortality reflected the US general population mortality, resulting in a lower standardised mortality ratio of\xa05.1. In response to consultation, the company provided additional validation of its mortality assumptions and concurred with the committee that there was a paucity of long-term mortality data in this disease area. The committee concluded that the company's revised calculation of a standardised mortality ratio to estimate death rates used an appropriate reference population.\n\n## In the long-term submodel, the rates of complications on standard care modelled by the company may not be generalisable to the UK\n\nAfter recovering from a first episode of acquired TTP, some people will have long-term complications from ischaemic damage (see section\xa03.1). The company assumed that treatment with caplacizumab lowers the risk of these complications. In its Markov model, it modelled the prevalence of cognitive impairment and mental health problems (such as depression and anxiety) in people with acquired TTP having standard care alone over the lifetime of the modelled populations. The committee considered that the company's estimates of the prevalence of long-term complications in people with acquired TTP:\n\ndid not come from a UK population\n\nincluded people whose complications were not specifically associated with acquired TTP\n\nreflected estimates of severe depression in people in a TTP support group in the US rather than a random sample of people with acquired TTP in the UK.The committee appreciated the company's attempts to ensure that it had exhausted possible sources of data. It concluded that the company had not shown that the prevalence of long-term complications on standard care in its model were generalisable to current UK practice. However, it further concluded that, in the absence of any other data, it was reasonable to use the company's estimates in the model.\n\n## The relationship between length of hospital stay and long-term complications and death is unclear\n\nBecause HERCULES measured outcomes during an acute episode only, it did not provide data for caplacizumab compared with standard care on long-term complications when acquired TTP is in remission. However, the company assumed that previous treatment with caplacizumab reduced complications and extended life in the remission period above and beyond a benefit to mortality in the short term. After estimating a risk of death for people on standard care (see section\xa03.13), the company assumed that time in intensive care or hospital was causally related to the prevalence of long-term outcomes including cognitive impairment and mental health (including depression, anxiety, post-traumatic stress), and the relative risk of death for caplacizumab compared with standard care in the Markov submodel. It assumed that this equalled the ratio (0.62) of time in intensive care and hospital measured in HERCULES for caplacizumab compared with standard care alone. The committee noted that caplacizumab was not disease modifying and would not be expected to work after people stopped having it. However, the committee understood that reducing thromboses and the likelihood of complications in the short term would reduce the risk of sequalae from these complications in the longer term. The clinical experts stated that a relationship between hospital stay and long-term outcomes was plausible. The committee noted that a relationship between length of stay and the development of subsequent complications in the longer term had not been validated, and that the company had not presented relevant data. The committee recalled that the same proportion of people in each arm of HERCULES developed a major thromboembolic complication during the trial. The company responded that it did not consider that major thromboembolic events would capture differences in microvascular damage between caplacizumab and standard care. The committee was also aware that some people might have pre-existing complications that might prolong stay in hospital and that caplacizumab would not improve or cure. In response to consultation after the committee's first meeting, the company confirmed that were no data specific to acquired TTP to validate a causal relationship between length of hospital stay and long-term outcomes. The committee concluded that it was not possible to validate a causal link between former treatment with caplacizumab and long-term complications and death beyond the end of the trial based on length of hospital stay.\n\n## Time to platelet normalisation is better than hospital stay for estimating long-term outcomes, but uncertainty remains\n\nIn response to consultation after the committee's first meeting, the company presented 2\xa0exploratory analyses. These used time to platelet normalisation rather than duration of hospitalisation as an alternative proxy for long-term outcomes. They were:\n\nan analysis based on a randomised controlled trial comparing plasma exchange and another treatment, plasma infusion (Rock et al. 1991), which showed an association between having a shorter time to platelet normalisation and a lower death rate at 6\xa0months\n\nan analysis based on a retrospective cohort study (Liu et al. 2013), which showed that platelet normalisation by 3\xa0days after starting treatment compared with platelet normalisation after 3\xa0days was associated with fewer deaths over 80\xa0months.The committee considered that:\n\ntime to platelet normalisation better approximated a person's exposure to microthrombi than time in hospital during an acute episode, and the clinical experts explained that microthrombi increase the risk of long-term complications (see section\xa03.15)\n\nit was plausible that a causal relationship between time to platelet normalisation in the acute period and long-term complications existed\n\nthe exact relationship between time to platelet normalisation and long-term outcomes remained uncertain because:\n\n\n\nLiu et al. and Rock et al. did not provide data on the prevalence of long-term complications, other than death, after an acute episode\n\nin both of these studies, some of the deaths would have been during an acute episode rather than afterwards\n\nthe studies were several years old, particularly Rock et al., so it was questionable how generalisable they would still be to current NHS.The company adjusted the risk ratio for time to platelet normalisation for caplacizumab compared with standard care in HERCULES. This was to account for the possibility that not all of the benefit of caplacizumab in reducing the time to platelet normalisation would translate to a benefit in reduced long-term complications and deaths. The risk ratio for time to platelet normalisation in HERCULES (0.57) was multiplied by\xa01.16 (the 85%\xa0reduction in time to platelet normalisation in Rock et al. with plasma exchange compared with plasma infusion divided by the 75%\xa0reduction in deaths with plasma exchange compared with plasma infusion). The committee considered that the estimated size of benefit with caplacizumab on complications was plausible. However, it thought that there was uncertainty about whether this would translate to a benefit in survival after people had recovered from their acute TTP episode. So, the committee concluded that using an estimated risk ratio of\xa00.66 to estimate the effect of caplacizumab compared with standard care in reducing long-term cognitive impairment and mental health problems would be appropriate, although still highly uncertain. For the endpoint of death in the Markov submodel, the committee considered in its second committee meeting that a risk of\xa00.90 was plausible. However, it was willing to consider a value of\xa00.80 presented by the company to NICE in its third and fourth committee meetings (which represented a midpoint between the company's estimate of\xa00.66 and\xa00.90) in its decision making.\n\n\n\n## The company's modelled rate of relapse is appropriate, but it is not known whether caplacizumab works equally well if used again\n\nThe committee appreciated that someone could have caplacizumab again after each relapse. The company assumed an annual disease relapse rate of\xa01%, based on the opinions of clinicians it surveyed. One clinical expert at the meeting noted that the increased use of rituximab to prevent relapse meant that the relapse rate in the UK was now lower than it had been before rituximab was standard care. However, he thought that 1%\xa0per year was too low, and that a more realistic estimate would be somewhere between\xa01% and\xa05%. The company assumed that caplacizumab works as well on retreatment as it does when first used, but did not present data to support this. The committee asked the company whether there was any evidence of antibodies against caplacizumab from the available trial data, and whether the effectiveness of caplacizumab would differ on retreatment. The company stated that it had seen antibodies in some patients. The committee concluded that the relapse rate was likely to be higher than\xa01% in clinical practice. It was also uncertain about whether caplacizumab was as effective on reuse as with initial use.\n\n## Information on quality of life is not available from HERCULES, and caplacizumab's effect on quality of life remains uncertain\n\nThere were no quality-of-life data collected in HERCULES. The company instead used quality-of-life data from people hospitalised with stroke to estimate quality of life during an acute episode of acquired TTP. This resulted in a baseline utility value of\xa00.64. The committee stated that this appeared to be high, suggesting better quality of life than would be expected for people in hospital for a life-threatening condition (see section\xa03.1). The patient experts said that this did not reflect how severely an acute episode affected people. In response to consultation after the committee's first meeting, the company revised this assumption so that the utility on standard care was half (0.32) that of caplacizumab (0.64). The committee considered that quality of life would be better around an acute episode with caplacizumab compared with standard care because of the fewer plasma exchanges needed. However, it thought that an assumption of a 25%\xa0reduction in quality of life on standard care rather than the company's assumption of a 50%\xa0reduction was appropriate. Having heard from the patient experts that acquired TTP affects mental health (see section\xa03.1), the committee also considered whether quality-of-life estimates for acquired TTP should have included an estimate of the fear of relapse. For the committee's second meeting, the company included an estimate of disutility for fear of relapse. However, the company included it only for patients having standard care, and not for people having caplacizumab. The committee agreed that it had not been proven that caplacizumab reduced relapse frequency, so was not convinced that any disutility would affect the standard care only arm. Furthermore, it agreed that it was likely that the model already included the disutility of a fear of relapse, via anxiety and depression reflected in the Markov submodel. The committee noted that the company had estimated the quality of life associated with cognitive impairment and mental health in the long term. This was based on studies in people with stroke and people with depressive disorder respectively. It acknowledged that cognitive impairment and mental health problems would lower a person's quality of life. However, it recalled that there was no direct evidence that caplacizumab would decrease the likelihood of having these complications or improve quality of life by decreasing these complications (see section\xa03.15 and\xa0section\xa03.16). The committee noted that the utility values did not have a large effect on incremental cost-effectiveness ratios (ICERs). It concluded that the effect of acquired TTP lowers quality of life, and that treatment with caplacizumab improves quality of life but by how much is uncertain.\n\n## Some potential cost savings associated with caplacizumab may not be included in the company's model\n\nThe committee understood that using caplacizumab lowered the cost of plasma exchange and hospital stay compared with best supportive care. The model included cost of testing ADAMTS13 activity, as well as adverse events associated with treatment. The committee noted that the company modelling did not include the costs of escalating treatment for acquired TTP refractory to treatment. This would favour standard care because more people in the standard care arm in HERCULES were refractory to treatment than in the caplacizumab arm (see section\xa03.7). The company stated that, based on its observations from the compassionate use scheme for caplacizumab, in NHS clinical practice, people would have it for a shorter duration than in the trials. The committee in general prefers not to disassociate estimates of cost and effectiveness from a trial. However, it appreciated that many assumptions about caplacizumab's effectiveness in this model were not taken from the main trial. It also thought that some potential cost savings associated with caplacizumab may not have been included in the company's model.\n\n## To mitigate uncertainty around the modelling assumptions, a conservative approach is preferred\n\nThe committee appreciated that the company made attempts to address uncertainty. However, it considered that several assumptions in the model remained uncertain and were at the more optimistic range of what would be seen in clinical practice. It noted that, at the first committee meeting, the company had presented a deterministic ICER (which took a point estimate, or assumption for each model input) and a probabilistic ICER (which represented the average of many runs of the model using a range of values for each model input). The committee noted that these ICERs were similar, but the probabilistic analysis was incomplete because not all of the model inputs had a distribution around the deterministic value. This meant that not all of the uncertainty was accounted for in the probabilistic sensitivity analyses. The committee therefore considered a range of scenarios to test the effect of a range of plausible clinical outcome parameters on the ICER. On balance, it preferred assumptions that were more conservative than the company's base case. Although some uncertainty remained about these parameters, the committee noted that taking a more conservative approach reduced the risk that the ICER had been underestimated. Its preferred assumptions in the acute submodel were:\n\na midpoint of\xa010% for the acute absolute mortality rates on standard care (that is, between\xa07% and\xa012.6%; see section\xa03.10)\n\na risk ratio for acute mortality rates for caplacizumab compared with standard care of\xa00.5 (see section\xa03.12)\n\nutility values assuming 25%\xa0of the quality of life on standard care compared with caplacizumab. (see section\xa03.18).The committee's preferred assumptions in the long-term Markov submodel were:\n\nthe company's assumptions on prevalence of long-term complications on standard care (see section\xa03.14)\n\nthe company's revised standardised mortality ratio underlying the estimate of the absolute risk of dying for people on standard care (see section\xa03.13)\n\nthe effectiveness of caplacizumab compared with standard care reflecting long-term complications based on the association between time to platelet normalisation (estimated risk ratio of\xa00.66; see section\xa03.15 and\xa0section\xa03.16)\n\nan estimated risk ratio of death of\xa00.8 for caplacizumab compared with standard care (see section\xa03.16)\n\na lifetime duration of neuropsychological impairment (see section\xa03.18)\n\nfear of relapse not modelled separately (see section\xa03.18)\n\na relapse rate of\xa01.5% (see section\xa03.17).Applying these assumptions and using a revised patient access scheme price discount for caplacizumab resulted in an ICER of £29,537 per quality-adjusted life year (QALY) gained.\n\n## Caplacizumab is innovative\n\nCaplacizumab is the first new treatment for acquired TTP in about 25\xa0years with a different mechanism to the other drugs and treatments that form current standard care. Caplacizumab has additional benefits to standard care. The committee noted that there were benefits that may not have been captured in calculating the QALY. These included reducing the use of scarce NHS resources like plasma or intensive care unit beds. The committee concluded that caplacizumab is innovative.\n\n# Conclusion\n\n## Caplacizumab is a cost-effective use of NHS resources\n\nThe committee noted the considerable uncertainty around the estimates of cost effectiveness because of the limited clinical data, particularly around survival in the acute period and the long-term benefits of caplacizumab. It understood that the lack of data was, in part, because of the rarity of acquired TTP. Using the committee's preferred modelling assumptions resulted in an ICER of £29,537 per QALY gained. In line with the NICE methods guide for technology appraisal, when a most plausible ICER is above £20,000 per QALY gained, the committee can take account certain factors, including innovation (see section\xa03.21). At its fourth meeting, the committee concluded that the ICER for caplacizumab fell within a range considered to be a cost-effective use of NHS resources and recommended caplacizumab as an option for treating acquired TTP."}
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https://www.nice.org.uk/guidance/ta667
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Evidence-based recommendations on caplacizumab (Cablivi) with plasma exchange and immunosuppression for treating acute acquired thrombotic thrombocytopenic purpura in adults, and in young people aged 12 years and over who weigh at least 40 kg.
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nice
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Low back pain and sciatica in over 16s: assessment and management
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Low back pain and sciatica in over 16s: assessment and management
This guideline covers assessing and managing low back pain and sciatica in people aged 16 and over. It outlines physical, psychological, pharmacological and surgical treatments to help people manage their low back pain and sciatica in their daily life. The guideline aims to improve people’s quality of life by promoting the most effective forms of care for low back pain and sciatica.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Assessment of low back pain and sciatica
## Alternative diagnoses
Think about alternative diagnoses when examining or reviewing people with low back pain, particularly if they develop new or changed symptoms. Exclude specific causes of low back pain, for example, cancer, infection, trauma or inflammatory disease such as spondyloarthritis. If serious underlying pathology is suspected, refer to relevant NICE guidelines on:
metastatic spinal cord compression in adults
spinal injury
spondyloarthritis in over 16s
suspected cancer.
## Risk assessment and risk stratification tools
Consider using risk stratification (for example, the STarT Back risk assessment tool) at first point of contact with a healthcare professional for each new episode of low back pain with or without sciatica to inform shared decision-making about stratified management.
Based on risk stratification, consider:
simpler and less intensive support for people with low back pain with or without sciatica likely to improve quickly and have a good outcome (for example, reassurance, advice to keep active and guidance on self-management)
more complex and intensive support for people with low back pain with or without sciatica at higher risk of a poor outcome (for example, exercise programmes with or without manual therapy or using a psychological approach).
## Imaging
Do not routinely offer imaging in a non-specialist setting for people with low back pain with or without sciatica.
Explain to people with low back pain with or without sciatica that if they are being referred for specialist opinion, they may not need imaging.
Consider imaging in specialist settings of care (for example, a musculoskeletal interface clinic or hospital) for people with low back pain with or without sciatica only if the result is likely to change management.
# Non-invasive treatments for low back pain and sciatica
## Non-pharmacological interventions
Provide people with advice and information, tailored to their needs and capabilities, to help them self-manage their low back pain with or without sciatica, at all steps of the treatment pathway. Include:
information on the nature of low back pain and sciatica
encouragement to continue with normal activities.
Consider a group exercise programme (biomechanical, aerobic, mind–body or a combination of approaches) within the NHS for people with a specific episode or flare-up of low back pain with or without sciatica. Take people's specific needs, preferences and capabilities into account when choosing the type of exercise.
Do not offer belts or corsets for managing low back pain with or without sciatica.
Do not offer foot orthotics for managing low back pain with or without sciatica.
Do not offer rocker sole shoes for managing low back pain with or without sciatica.
Do not offer traction for managing low back pain with or without sciatica.
Consider manual therapy (spinal manipulation, mobilisation or soft tissue techniques such as massage) for managing low back pain with or without sciatica, but only as part of a treatment package including exercise, with or without psychological therapy.
Do not offer acupuncture for managing low back pain with or without sciatica.
Do not offer ultrasound for managing low back pain with or without sciatica.
Do not offer percutaneous electrical nerve simulation (PENS) for managing low back pain with or without sciatica.
Do not offer transcutaneous electrical nerve simulation (TENS) for managing low back pain with or without sciatica.
Do not offer interferential therapy for managing low back pain with or without sciatica.
Consider psychological therapies using a cognitive behavioural approach for managing low back pain with or without sciatica but only as part of a treatment package including exercise, with or without manual therapy (spinal manipulation, mobilisation or soft tissue techniques such as massage).
Consider a combined physical and psychological programme, incorporating a cognitive behavioural approach (preferably in a group context that takes into account a person's specific needs and capabilities), for people with persistent low back pain or sciatica:
when they have significant psychosocial obstacles to recovery (for example, avoiding normal activities based on inappropriate beliefs about their condition) or
when previous treatments have not been effective.
Promote and facilitate return to work or normal activities of daily living for people with low back pain with or without sciatica.
## Pharmacological management of sciatica
Do not offer gabapentinoids, other antiepileptics, oral corticosteroids or benzodiazepines for managing sciatica as there is no overall evidence of benefit and there is evidence of harm.
Do not offer opioids for managing chronic sciatica.
If a person is already taking opioids, gabapentinoids or benzodiazepines for sciatica, explain the risks of continuing these medicines. See also the section on reviewing medicines in NICE's guideline on medicines associated with dependence or withdrawal symptoms.
As part of shared decision making about whether to stop opioids, gabapentinoids or benzodiazepines for sciatica, discuss the problems associated with withdrawal with the person.To support discussions with patients about the benefits and harms of these treatment, and safe withdrawal management, see:
NICE's guideline on medicines associated with dependence or withdrawal symptoms
NICE's guideline on shared decision making
the section on medication review in NICE's guideline on medicines optimisation. .
Be aware of the risk of harms and limited evidence of benefit from the use of non-steroidal anti-inflammatory drugs (NSAIDs) in sciatica.
If prescribing NSAIDs for sciatica:
take into account potential differences in gastrointestinal, liver and cardio-renal toxicity, and the person's risk factors, including age
think about appropriate clinical assessment, ongoing monitoring of risk factors, and the use of gastroprotective treatment
use the lowest effective dose for the shortest possible period of time.
For a short explanation of why the committee made the 2020 recommendations and how they might affect practice, see the rationale and impact section on pharmacological management of sciatica .
The committee have also made recommendations for research on opioids for the management of acute sciatica, and antidepressants for the management of sciatica.
Full details of the evidence and the committee's discussion are in evidence review A: pharmacological management of sciatica.
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## Pharmacological management of low back pain
Consider oral NSAIDs for managing low back pain, taking into account potential differences in gastrointestinal, liver and cardio-renal toxicity, and the person's risk factors, including age.
When prescribing oral NSAIDs for low back pain, think about appropriate clinical assessment, ongoing monitoring of risk factors, and the use of gastroprotective treatment.
Prescribe oral NSAIDs for low back pain at the lowest effective dose for the shortest possible period of time.
Consider weak opioids (with or without paracetamol) for managing acute low back pain only if an NSAID is contraindicated, not tolerated or has been ineffective. For guidance on safe prescribing of opioids and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.
Do not offer paracetamol alone for managing low back pain.
Do not routinely offer opioids for managing acute low back pain (see recommendation 1.2.25).
Do not offer opioids for managing chronic low back pain.
Do not offer selective serotonin reuptake inhibitors, serotonin–norepinephrine reuptake inhibitors or tricyclic antidepressants for managing low back pain.
Do not offer gabapentinoids or antiepileptics for managing low back pain.
# Invasive treatments for low back pain and sciatica
## Non-surgical interventions
Do not offer spinal injections for managing low back pain.
Consider referral for assessment for radiofrequency denervation for people with chronic low back pain when:
non-surgical treatment has not worked for them and
the main source of pain is thought to come from structures supplied by the medial branch nerve and
they have moderate or severe levels of localised back pain (rated as 5 or more on a visual analogue scale, or equivalent) at the time of referral.
Only perform radiofrequency denervation in people with chronic low back pain after a positive response to a diagnostic medial branch block.
Do not offer imaging for people with low back pain with specific facet join pain as a prerequisite for radiofrequency denervation.
Consider epidural injections of local anaesthetic and steroid in people with acute and severe sciatica.
Do not use epidural injections for neurogenic claudication in people who have central spinal canal stenosis.
## Surgical interventions
Do not allow a person's BMI, smoking status or psychological distress to influence the decision to refer them for a surgical opinion for sciatica.
Consider spinal decompression for people with sciatica when non-surgical treatment has not improved pain or function and their radiological findings are consistent with sciatic symptoms.
Do not offer spinal fusion for people with low back pain unless as part of a randomised controlled trial.
Do not offer disc replacement in people with low back pain.
# Terms used in this guideline
This section defines terms that have been used in a particular way for this guideline. For other definitions see the NICE glossary and the Think Local, Act Personal Care and Support Jargon Buster.
## Acute
Less than 3 months duration.
## Chronic
A 3-month duration or longer. The intensity of pain may fluctuate over time.
## Weak opioids
See the information on weak opioids in the analgesics section of the BNF.# Recommendations for research
The guideline committee has made the following key recommendations for research.
# Pharmacological therapies
What is the clinical and cost effectiveness of opioids for the management of acute sciatica?
# Pharmacological therapies
What is the clinical and cost effectiveness of antidepressants for the management of sciatica?
For a short explanation of why the committee made the 2020 recommendations for research, see the rationale section on pharmacological management of sciatica .
Full details of the evidence and the committee's discussion are in evidence review A: pharmacological management of sciatica.
Loading. Please wait.
# Pharmacological therapies
What is the clinical and cost effectiveness of benzodiazepines for the management of acute low back pain?
# Pharmacological therapies
What is the clinical and cost effectiveness of codeine with and without paracetamol for the management of acute low back pain?
# Radiofrequency denervation
What is the clinical and cost effectiveness of radiofrequency denervation for chronic low back pain in the long term?
# Epidurals
What is the clinical and cost effectiveness of image-guided compared with non-image-guided epidural injections for people with acute sciatica?
# Spinal fusion
Should people with low back pain be offered spinal fusion as a surgical option?
Full details of the 2016 recommendations for research are in the full guideline.# Rationale and impact
This section briefly explains why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.
# Pharmacological management of sciatica
Recommendations 1.2.16 to 1.2.21
## Why the committee made the recommendations
The evidence showed that gabapentinoids did not improve sciatica symptoms, and oral corticosteroids did not improve pain or function, but may have an impact on quality of life. Both increased the risk of adverse events in the long-term. While there was no evidence of increased risk of adverse events associated with benzodiazepines, there was evidence of poorer response than placebo in terms of pain reduction. The committee considered:
the evidence reviewed,
knowledge of the potential longer-term harms, and
the reclassification of gabapentin and pregabalin as Schedule 3 controlled drugs (April 2019 UK Government drug safety update) because of the evidence for risk of abuse and dependence of these drugs.
The committee agreed that although the evidence about lack of effectiveness was limited, the harms would outweigh the benefits for most people with sciatica and therefore agreed to recommend against the use of gabapentinoids, oral corticosteroids and benzodiazepines for sciatica.
There was no evidence on the use of antiepileptics (other than gabapentinoids) for sciatica. Given the lack of evidence, and the committee's knowledge of potential harms, they agreed to recommend that antiepileptics (including gabapentinoids) should not be used for sciatica.
There was no evidence on the use of opioids for sciatica. Given the lack of evidence and the committee's knowledge of potential harms when used long term, the committee agreed to recommend against the use of opioids for chronic sciatica. However, the committee discussed whether opioids might be effective when used short term for acute sciatica, so made a research recommendation on this topic.
There was no evidence on the use of antidepressants for sciatica. The committee agreed that antidepressants were commonly prescribed for sciatica, and clinical experience suggests they may be of benefit in some people. The committee considered the potential for harm to be less than the harms of prolonged use of opioids. On this basis, the committee made a research recommendation to determine if there was any clinical benefit for their use to treat sciatica.
Limited evidence showed no benefit from NSAIDs for sciatica. The committee discussed that there were also known risks of harms from NSAIDs that most clinicians were aware of so they were unlikely to be continued if they were not helpful. They agreed there was not sufficient evidence to make a recommendation for or against the use of NSAIDs for sciatica, but agreed to include a recommendation highlighting the risk of harms and lack of evidence of benefit as well as a research recommendation on this topic.
The committee were aware that some people may already be using opioids, antiepileptics (including gabapentinoids) and benzodiazepines for long periods for sciatica. Given the potential harms from sudden withdrawal of these medicines, based on consensus, they recommended discussing with the person the potential harms of long-term use and the need to withdraw safely if they chose to do so.
No evidence was identified for paracetamol, nefopam or muscle relaxants other than benzodiazepines for the management of sciatica. The committee agreed that none of these are widely prescribed for sciatica. They noted that advice is already included in this guideline for the use of paracetamol for people with low back pain. Therefore no further recommendations were made regarding management of sciatica alone, and these medicines do not warrant further research.
## How the recommendations might affect practice
These recommendations are expected to reduce the use of gabapentinoids and other antiepileptics, corticosteroids, benzodiazepines and long-term opioid analgesics for sciatica. This will reduce the chance of adverse events and dependence on medicines that are unlikely to provide clinical benefit. It might lead to an increased use of other recommended treatments.
Return to recommendations# Context
Low back pain that is not associated with serious or potentially serious causes has been described in the literature as 'non-specific', 'mechanical', 'musculoskeletal' or 'simple' low back pain. For consistency, we have used the term 'low back pain' throughout this guideline. However, 'non-specific low back pain' was used when creating the review questions. Worldwide, low back pain causes more disability than any other condition. Episodes of back pain usually do not last long, with rapid improvements in pain and disability seen within a few weeks to a few months. Although most back pain episodes get better with initial primary care management, without the need for investigations or referral to specialist services, up to one-third of people say they have persistent back pain of at least moderate intensity a year after an acute episode needing care, and episodes of back pain often recur.
One of the greatest challenges with low back pain is identifying risk factors that may predict when a single back pain episode will become a long-term, persistent pain condition. When this happens, quality of life is often very low and healthcare resource use high.
This guideline gives guidance on the assessment and management of both low back pain and sciatica from first presentation onwards in people aged 16 years and over.
We use 'sciatica' to describe leg pain secondary to lumbosacral nerve root pathology rather than the terms 'radicular pain' or 'radiculopathy', although they are more accurate. This is because 'sciatica' is a term that patients and clinicians understand, and it is widely used in the literature to describe neuropathic leg pain secondary to compressive spinal pathology.
This guideline does not cover the evaluation or care of people with sciatica with progressive neurological deficit or cauda equina syndrome. All clinicians involved in the management of sciatica should be aware of these potential neurological emergencies and know when to refer to an appropriate specialist.
A review of the NICE guideline on neuropathic pain in adults, triggered by an MHRA safety update of the reclassification of gabapentin and pregabalin as controlled drugs, highlighted the need for reconsideration of these as suitable treatments for sciatica. It was decided that update should sit within the guideline for low back pain and sciatica, alongside other treatment recommendations for sciatica.
|
{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Assessment of low back pain and sciatica\n\n## Alternative diagnoses\n\nThink about alternative diagnoses when examining or reviewing people with low back pain, particularly if they develop new or changed symptoms. Exclude specific causes of low back pain, for example, cancer, infection, trauma or inflammatory disease such as spondyloarthritis. If serious underlying pathology is suspected, refer to relevant NICE guidelines on:\n\nmetastatic spinal cord compression in adults\n\nspinal injury\n\nspondyloarthritis in over 16s\n\nsuspected cancer. \n\n## Risk assessment and risk stratification tools\n\nConsider using risk stratification (for example, the STarT Back risk assessment tool) at first point of contact with a healthcare professional for each new episode of low back pain with or without sciatica to inform shared decision-making about stratified management. \n\nBased on risk stratification, consider:\n\nsimpler and less intensive support for people with low back pain with or without sciatica likely to improve quickly and have a good outcome (for example, reassurance, advice to keep active and guidance on self-management)\n\nmore complex and intensive support for people with low back pain with or without sciatica at higher risk of a poor outcome (for example, exercise programmes with or without manual therapy or using a psychological approach). \n\n## Imaging\n\nDo not routinely offer imaging in a non-specialist setting for people with low back pain with or without sciatica. \n\nExplain to people with low back pain with or without sciatica that if they are being referred for specialist opinion, they may not need imaging. \n\nConsider imaging in specialist settings of care (for example, a musculoskeletal interface clinic or hospital) for people with low back pain with or without sciatica only if the result is likely to change management. \n\n# Non-invasive treatments for low back pain and sciatica\n\n## Non-pharmacological interventions\n\nProvide people with advice and information, tailored to their needs and capabilities, to help them self-manage their low back pain with or without sciatica, at all steps of the treatment pathway. Include:\n\ninformation on the nature of low back pain and sciatica\n\nencouragement to continue with normal activities. \n\nConsider a group exercise programme (biomechanical, aerobic, mind–body or a combination of approaches) within the NHS for people with a specific episode or flare-up of low back pain with or without sciatica. Take people's specific needs, preferences and capabilities into account when choosing the type of exercise. \n\nDo not offer belts or corsets for managing low back pain with or without sciatica. \n\nDo not offer foot orthotics for managing low back pain with or without sciatica. \n\nDo not offer rocker sole shoes for managing low back pain with or without sciatica. \n\nDo not offer traction for managing low back pain with or without sciatica. \n\nConsider manual therapy (spinal manipulation, mobilisation or soft tissue techniques such as massage) for managing low back pain with or without sciatica, but only as part of a treatment package including exercise, with or without psychological therapy. \n\nDo not offer acupuncture for managing low back pain with or without sciatica. \n\nDo not offer ultrasound for managing low back pain with or without sciatica. \n\nDo not offer percutaneous electrical nerve simulation (PENS) for managing low back pain with or without sciatica. \n\nDo not offer transcutaneous electrical nerve simulation (TENS) for managing low back pain with or without sciatica. \n\nDo not offer interferential therapy for managing low back pain with or without sciatica. \n\nConsider psychological therapies using a cognitive behavioural approach for managing low back pain with or without sciatica but only as part of a treatment package including exercise, with or without manual therapy (spinal manipulation, mobilisation or soft tissue techniques such as massage). \n\nConsider a combined physical and psychological programme, incorporating a cognitive behavioural approach (preferably in a group context that takes into account a person's specific needs and capabilities), for people with persistent low back pain or sciatica:\n\nwhen they have significant psychosocial obstacles to recovery (for example, avoiding normal activities based on inappropriate beliefs about their condition) or\n\nwhen previous treatments have not been effective. \n\nPromote and facilitate return to work or normal activities of daily living for people with low back pain with or without sciatica. \n\n## Pharmacological management of sciatica\n\nDo not offer gabapentinoids, other antiepileptics, oral corticosteroids or benzodiazepines for managing sciatica as there is no overall evidence of benefit and there is evidence of harm. \n\nDo not offer opioids for managing chronic sciatica. \n\nIf a person is already taking opioids, gabapentinoids or benzodiazepines for sciatica, explain the risks of continuing these medicines. See also the section on reviewing medicines in NICE's guideline on medicines associated with dependence or withdrawal symptoms. \n\nAs part of shared decision making about whether to stop opioids, gabapentinoids or benzodiazepines for sciatica, discuss the problems associated with withdrawal with the person.To support discussions with patients about the benefits and harms of these treatment, and safe withdrawal management, see:\n\nNICE's guideline on medicines associated with dependence or withdrawal symptoms\n\nNICE's guideline on shared decision making\n\nthe section on medication review in NICE's guideline on medicines optimisation. .\n\nBe aware of the risk of harms and limited evidence of benefit from the use of non-steroidal anti-inflammatory drugs (NSAIDs) in sciatica. \n\nIf prescribing NSAIDs for sciatica:\n\ntake into account potential differences in gastrointestinal, liver and cardio-renal toxicity, and the person's risk factors, including age\n\nthink about appropriate clinical assessment, ongoing monitoring of risk factors, and the use of gastroprotective treatment\n\nuse the lowest effective dose for the shortest possible period of time. \n\nFor a short explanation of why the committee made the 2020 recommendations and how they might affect practice, see the rationale and impact section on pharmacological management of sciatica\xa0.\n\nThe committee have also made recommendations for research on opioids for the management of acute sciatica, and antidepressants for the management of sciatica.\n\nFull details of the evidence and the committee's discussion are in evidence review A: pharmacological management of sciatica.\n\nLoading. Please wait.\n\n## Pharmacological management of low back pain\n\nConsider oral NSAIDs for managing low back pain, taking into account potential differences in gastrointestinal, liver and cardio-renal toxicity, and the person's risk factors, including age. \n\nWhen prescribing oral NSAIDs for low back pain, think about appropriate clinical assessment, ongoing monitoring of risk factors, and the use of gastroprotective treatment. \n\nPrescribe oral NSAIDs for low back pain at the lowest effective dose for the shortest possible period of time. \n\nConsider weak opioids (with or without paracetamol) for managing acute low back pain only if an NSAID is contraindicated, not tolerated or has been ineffective. For guidance on safe prescribing of opioids and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms. \n\nDo not offer paracetamol alone for managing low back pain. \n\nDo not routinely offer opioids for managing acute low back pain (see recommendation 1.2.25). \n\nDo not offer opioids for managing chronic low back pain. \n\nDo not offer selective serotonin reuptake inhibitors, serotonin–norepinephrine reuptake inhibitors or tricyclic antidepressants for managing low back pain. \n\nDo not offer gabapentinoids or antiepileptics for managing low back pain. [2016, amended 2020]\n\n# Invasive treatments for low back pain and sciatica\n\n## Non-surgical interventions\n\nDo not offer spinal injections for managing low back pain. \n\nConsider referral for assessment for radiofrequency denervation for people with chronic low back pain when:\n\nnon-surgical treatment has not worked for them and\n\nthe main source of pain is thought to come from structures supplied by the medial branch nerve and\n\nthey have moderate or severe levels of localised back pain (rated as 5 or more on a visual analogue scale, or equivalent) at the time of referral. \n\nOnly perform radiofrequency denervation in people with chronic low back pain after a positive response to a diagnostic medial branch block. \n\nDo not offer imaging for people with low back pain with specific facet join pain as a prerequisite for radiofrequency denervation. \n\nConsider epidural injections of local anaesthetic and steroid in people with acute and severe sciatica. \n\nDo not use epidural injections for neurogenic claudication in people who have central spinal canal stenosis. \n\n## Surgical interventions\n\nDo not allow a person's BMI, smoking status or psychological distress to influence the decision to refer them for a surgical opinion for sciatica. \n\nConsider spinal decompression for people with sciatica when non-surgical treatment has not improved pain or function and their radiological findings are consistent with sciatic symptoms. \n\nDo not offer spinal fusion for people with low back pain unless as part of a randomised controlled trial. \n\nDo not offer disc replacement in people with low back pain. \n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a particular way for this guideline. For other definitions see the NICE glossary and the Think Local, Act Personal Care and Support Jargon Buster.\n\n## Acute\n\nLess than 3\xa0months duration.\n\n## Chronic\n\nA 3-month duration or longer. The intensity of pain may fluctuate over time.\n\n## Weak opioids\n\nSee the information on weak opioids in the analgesics section of the BNF.", 'Recommendations for research': "The guideline committee has made the following key recommendations for research.\n\n# Pharmacological therapies\n\nWhat is the clinical and cost effectiveness of opioids for the management of acute sciatica? \n\n# Pharmacological therapies\n\nWhat is the clinical and cost effectiveness of antidepressants for the management of sciatica? \n\nFor a short explanation of why the committee made the 2020 recommendations for research, see the rationale section on pharmacological management of sciatica\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: pharmacological management of sciatica.\n\nLoading. Please wait.\n\n# Pharmacological therapies\n\nWhat is the clinical and cost effectiveness of benzodiazepines for the management of acute low back pain? \n\n# Pharmacological therapies\n\nWhat is the clinical and cost effectiveness of codeine with and without paracetamol for the management of acute low back pain? \n\n# Radiofrequency denervation\n\nWhat is the clinical and cost effectiveness of radiofrequency denervation for chronic low back pain in the long term? \n\n# Epidurals\n\nWhat is the clinical and cost effectiveness of image-guided compared with non-image-guided epidural injections for people with acute sciatica? \n\n# Spinal fusion\n\nShould people with low back pain be offered spinal fusion as a surgical option? \n\nFull details of the 2016 recommendations for research are in the full guideline.", 'Rationale and impact': "This section briefly explains why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.\n\n# Pharmacological management of sciatica\n\nRecommendations 1.2.16 to 1.2.21\n\n## Why the committee made the recommendations\n\nThe evidence showed that gabapentinoids did not improve sciatica symptoms, and oral corticosteroids did not improve pain or function, but may have an impact on quality of life. Both increased the risk of adverse events in the long-term. While there was no evidence of increased risk of adverse events associated with benzodiazepines, there was evidence of poorer response than placebo in terms of pain reduction. The committee considered:\n\nthe evidence reviewed,\n\nknowledge of the potential longer-term harms, and\n\nthe reclassification of gabapentin and pregabalin as Schedule 3 controlled drugs (April 2019 UK Government drug safety update) because of the evidence for risk of abuse and dependence of these drugs.\n\nThe committee agreed that although the evidence about lack of effectiveness was limited, the harms would outweigh the benefits for most people with sciatica and therefore agreed to recommend against the use of gabapentinoids, oral corticosteroids and benzodiazepines for sciatica.\n\nThere was no evidence on the use of antiepileptics (other than gabapentinoids) for sciatica. Given the lack of evidence, and the committee's knowledge of potential harms, they agreed to recommend that antiepileptics (including gabapentinoids) should not be used for sciatica.\n\nThere was no evidence on the use of opioids for sciatica. Given the lack of evidence and the committee's knowledge of potential harms when used long term, the committee agreed to recommend against the use of opioids for chronic sciatica. However, the committee discussed whether opioids might be effective when used short term for acute sciatica, so made a research recommendation on this topic.\n\nThere was no evidence on the use of antidepressants for sciatica. The committee agreed that antidepressants were commonly prescribed for sciatica, and clinical experience suggests they may be of benefit in some people. The committee considered the potential for harm to be less than the harms of prolonged use of opioids. On this basis, the committee made a research recommendation to determine if there was any clinical benefit for their use to treat sciatica.\n\nLimited evidence showed no benefit from NSAIDs for sciatica. The committee discussed that there were also known risks of harms from NSAIDs that most clinicians were aware of so they were unlikely to be continued if they were not helpful. They agreed there was not sufficient evidence to make a recommendation for or against the use of NSAIDs for sciatica, but agreed to include a recommendation highlighting the risk of harms and lack of evidence of benefit as well as a research recommendation on this topic.\n\nThe committee were aware that some people may already be using opioids, antiepileptics (including gabapentinoids) and benzodiazepines for long periods for sciatica. Given the potential harms from sudden withdrawal of these medicines, based on consensus, they recommended discussing with the person the potential harms of long-term use and the need to withdraw safely if they chose to do so.\n\nNo evidence was identified for paracetamol, nefopam or muscle relaxants other than benzodiazepines for the management of sciatica. The committee agreed that none of these are widely prescribed for sciatica. They noted that advice is already included in this guideline for the use of paracetamol for people with low back pain. Therefore no further recommendations were made regarding management of sciatica alone, and these medicines do not warrant further research.\n\n## How the recommendations might affect practice\n\nThese recommendations are expected to reduce the use of gabapentinoids and other antiepileptics, corticosteroids, benzodiazepines and long-term opioid analgesics for sciatica. This will reduce the chance of adverse events and dependence on medicines that are unlikely to provide clinical benefit. It might lead to an increased use of other recommended treatments.\n\nReturn to recommendations", 'Context': "Low back pain that is not associated with serious or potentially serious causes has been described in the literature as 'non-specific', 'mechanical', 'musculoskeletal' or 'simple' low back pain. For consistency, we have used the term 'low back pain' throughout this guideline. However, 'non-specific low back pain' was used when creating the review questions. Worldwide, low back pain causes more disability than any other condition. Episodes of back pain usually do not last long, with rapid improvements in pain and disability seen within a few weeks to a few months. Although most back pain episodes get better with initial primary care management, without the need for investigations or referral to specialist services, up to one-third of people say they have persistent back pain of at least moderate intensity a year after an acute episode needing care, and episodes of back pain often recur.\n\nOne of the greatest challenges with low back pain is identifying risk factors that may predict when a single back pain episode will become a long-term, persistent pain condition. When this happens, quality of life is often very low and healthcare resource use high.\n\nThis guideline gives guidance on the assessment and management of both low back pain and sciatica from first presentation onwards in people aged 16 years and over.\n\nWe use 'sciatica' to describe leg pain secondary to lumbosacral nerve root pathology rather than the terms 'radicular pain' or 'radiculopathy', although they are more accurate. This is because 'sciatica' is a term that patients and clinicians understand, and it is widely used in the literature to describe neuropathic leg pain secondary to compressive spinal pathology.\n\nThis guideline does not cover the evaluation or care of people with sciatica with progressive neurological deficit or cauda equina syndrome. All clinicians involved in the management of sciatica should be aware of these potential neurological emergencies and know when to refer to an appropriate specialist.\n\nA review of the NICE guideline on neuropathic pain in adults, triggered by an MHRA safety update of the reclassification of gabapentin and pregabalin as controlled drugs, highlighted the need for reconsideration of these as suitable treatments for sciatica. It was decided that update should sit within the guideline for low back pain and sciatica, alongside other treatment recommendations for sciatica."}
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https://www.nice.org.uk/guidance/ng59
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This guideline covers assessing and managing low back pain and sciatica in people aged 16 and over. It outlines physical, psychological, pharmacological and surgical treatments to help people manage their low back pain and sciatica in their daily life. The guideline aims to improve people’s quality of life by promoting the most effective forms of care for low back pain and sciatica.
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1f62665e2a46e33f73a690564e6acaebcc539bbf
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nice
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Peripheral arterial disease: diagnosis and management
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Peripheral arterial disease: diagnosis and management
This guideline covers diagnosing and managing peripheral arterial disease (PAD) in people aged 18 and over. Rapid changes in diagnostic methods, endovascular treatments and vascular services associated with new specialties in surgery and interventional radiology have resulted in considerable uncertainty and variation in practice. This guideline aims to resolve that uncertainty and variation.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Information requirements
Offer all people with peripheral arterial disease oral and written information about their condition. Discuss it with them so they can share decision‑making, and understand the course of the disease and what they can do to help prevent disease progression. Information should include:
the causes of their symptoms and the severity of their disease
the risks of limb loss and/or cardiovascular events associated with peripheral arterial disease
the key modifiable risk factors, such as smoking, control of diabetes, hyperlipidaemia, diet, body weight and exercise (see also the recommendation on secondary prevention of cardiovascular disease in people with peripheral arterial disease)
how to manage pain
all relevant treatment options, including the risks and benefits of each
how they can access support for dealing with depression and anxiety. Ensure that information, tailored to the individual needs of the person, is available at diagnosis and subsequently as required, to allow people to make decisions throughout the course of their treatment.
NICE has produced guidance on the components of good patient experience in adult NHS services. Follow the recommendations in NICE's guideline on patient experience in adult NHS services.
# Secondary prevention of cardiovascular disease in people with peripheral arterial disease
Offer all people with peripheral arterial disease information, advice, support and treatment regarding the secondary prevention of cardiovascular disease, in line with published NICE guidance on:
smoking cessation
diet, weight management and exercise
lipid modification and statin therapy
the prevention, diagnosis and management of diabetes
the prevention, diagnosis and management of high blood pressure
antiplatelet therapy.
# Diagnosis
Assess people for the presence of peripheral arterial disease if they:
have symptoms suggestive of peripheral arterial disease or
have diabetes, non‑healing wounds on the legs or feet or unexplained leg pain or
are being considered for interventions to the leg or foot or
need to use compression hosiery.
Assess people with suspected peripheral arterial disease by:
asking about the presence and severity of possible symptoms of intermittent claudication and critical limb ischaemia
examining the legs and feet for evidence of critical limb ischaemia, for example ulceration
examining the femoral, popliteal and foot pulses
measuring the ankle brachial pressure index (see recommendation 1.3.3).
Measure the ankle brachial pressure index in the following way:
The person should be resting and supine if possible.
Record systolic blood pressure with an appropriately sized cuff in both arms and in the posterior tibial, dorsalis pedis and, where possible, peroneal arteries.
Take measurements manually using a doppler probe of suitable frequency in preference to an automated system.
Document the nature of the doppler ultrasound signals in the foot arteries.
Calculate the index in each leg by dividing the highest ankle pressure by the highest arm pressure.
## Diagnosing peripheral arterial disease in people with diabetes
Do not exclude a diagnosis of peripheral arterial disease in people with diabetes based on a normal or raised ankle brachial pressure index alone.
Do not use pulse oximetry for diagnosing peripheral arterial disease in people with diabetes.
For a short explanation of why the committee made these 2018 recommendations and how they might affect practice, see the rationale and impact section on diagnosis .
Full details of the evidence and the committee's discussion are in evidence review A: determining diagnosis and severity of peripheral arterial disease in people with diabetes.
Loading. Please wait.
# Imaging for revascularisation
Offer duplex ultrasound as first‑line imaging to all people with peripheral arterial disease for whom revascularisation is being considered.
Offer contrast‑enhanced magnetic resonance angiography to people with peripheral arterial disease who need further imaging (after duplex ultrasound) before considering revascularisation.
Offer computed tomography angiography to people with peripheral arterial disease who need further imaging (after duplex ultrasound) if contrast‑enhanced magnetic resonance angiography is contraindicated or not tolerated.
# Management of intermittent claudication
## Supervised exercise programme
Offer a supervised exercise programme to all people with intermittent claudication.
Consider providing a supervised exercise programme for people with intermittent claudication which involves:
hours of supervised exercise a week for a 3‑month period
encouraging people to exercise to the point of maximal pain.
## Angioplasty and stenting
Offer angioplasty for treating people with intermittent claudication only when:
advice on the benefits of modifying risk factors has been reinforced (see the recommendation on secondary prevention of cardiovascular disease in people with peripheral arterial disease) and
a supervised exercise programme has not led to a satisfactory improvement in symptoms and
imaging has confirmed that angioplasty is suitable for the person.
Do not offer primary stent placement for treating people with intermittent claudication caused by aorto‑iliac disease (except complete occlusion) or femoro‑popliteal disease.
Consider primary stent placement for treating people with intermittent claudication caused by complete aorto‑iliac occlusion (rather than stenosis).
Use bare metal stents when stenting is used for treating people with intermittent claudication.
## Bypass surgery and graft types
Offer bypass surgery for treating people with severe lifestyle‑limiting intermittent claudication only when:
angioplasty has been unsuccessful or is unsuitable and
imaging has confirmed that bypass surgery is appropriate for the person.
Use an autologous vein whenever possible for people with intermittent claudication having infra‑inguinal bypass surgery.
## Naftidrofuryl oxalate
Consider naftidrofuryl oxalate for treating people with intermittent claudication, starting with the least costly preparation, only when:
supervised exercise has not led to satisfactory improvement and
the person prefers not to be referred for consideration of angioplasty or bypass surgery.Review progress after 3–6 months and discontinue naftidrofuryl oxalate if there has been no symptomatic benefit.
# Management of critical limb ischaemia
Ensure that all people with critical limb ischaemia are assessed by a vascular multidisciplinary team before treatment decisions are made.
## Revascularisation
Offer angioplasty or bypass surgery for treating people with critical limb ischaemia who require revascularisation, taking into account factors including:
comorbidities
pattern of disease
availability of a vein
patient preference.
Do not offer primary stent placement for treating people with critical limb ischaemia caused by aorto‑iliac disease (except complete occlusion) or femoro‑popliteal disease.
Consider primary stent placement for treating people with critical limb ischaemia caused by complete aorto‑iliac occlusion (rather than stenosis).
Use bare metal stents when stenting is used for treating people with critical limb ischaemia.
Use an autologous vein whenever possible for people with critical limb ischaemia having infra‑inguinal bypass surgery.
## Management of critical limb ischaemic pain
Offer paracetamol, and either weak or strong opioids depending on the severity of pain, to people with critical limb ischaemic pain.To support discussions with patients about the benefits and harms of opioid treatment, and safe withdrawal management, see:
NICE's guideline on medicines associated with dependence or withdrawal symptoms
NICE guideline on shared decision making
the section on medication review in NICE's guideline on medicines optimisation.
Offer drugs such as laxatives and anti‑emetics to manage the adverse effects of strong opioids, in line with the person's needs and preferences.
Refer people with critical limb ischaemic pain to a specialist pain management service if any of the following apply:
their pain is not adequately controlled and revascularisation is inappropriate or impossible
-ngoing high doses of opioids are required for pain control
pain persists after revascularisation or amputation.
Do not offer chemical sympathectomy to people with critical limb ischaemic pain, except in the context of a clinical trial.
## Major amputation
Do not offer major amputation to people with critical limb ischaemia unless all options for revascularisation have been considered by a vascular multidisciplinary team. # Recommendations for research
In 2012 the guideline committee has made the following recommendations for research. The committee's full set of research recommendations is detailed in the full guideline.
As part of the 2018 update, the standing committee made new research recommendations on the effectiveness and reliability of tools for diagnosing peripheral arterial disease in people with diabetes. Details can be found in the evidence review.
# Effectiveness of tools for diagnosing peripheral arterial disease in people with diabetes
What is the most clinically and cost-effective tool for diagnosing peripheral arterial disease in people with diabetes?
## Why this is important
People with diabetes are at higher risk of cardiovascular events and foot problems such as diabetic neuropathy (nerve damage or degeneration), foot ulcer and limb loss. So it is important to have an effective test for diagnosing peripheral arterial disease in this group. At present there are only studies of very low quality (retrospective and prospective cross‑sectional studies) containing small sample sizes. Diagnostic accuracy studies are needed to address this issue, ideally containing cost–utility analysis, comparing diagnostic tools with imaging. In order to explore the importance of early diagnosis, different clinical settings where diagnostic tests are performed should be explored.
# Effectiveness of tools for establishing the severity of peripheral arterial disease in people with diabetes
What is the most clinically and cost-effective tool for establishing the severity of peripheral arterial disease and the impact on mortality, morbidity and limb amputation in people with diabetes?
## Why this is important
Limited evidence suggests that doppler ankle brachial pressure index, toe brachial index and oscillometric ankle brachial index accurately diagnose severity of peripheral arterial disease. However, further research is needed using a robust diagnostic study design (such as a randomised controlled trial) to explore the clinical and cost effectiveness of tools in establishing the severity of disease and outcomes in people with diabetes. Studies should also explore the use of tools in different populations, such as those with neuropathy, and in different settings, for example, nursing homes, where access to services and diagnostic equipment may differ.
# Inter- and intra-rater reliability of assessment tools in the diagnosis of peripheral arterial disease in people with diabetes
What is the inter- and intra-rater reliability of assessment tools in the diagnosis of peripheral arterial disease in people with diabetes?
## Why this is important
Identifying peripheral arterial disease can be a challenge because diagnostic tests are conducted in a number of different settings by healthcare professionals with varying experience of using assessment tools. Data on inter- and intra‑rater reliability of point‑of‑care assessment tools are needed to inform future recommendations for practice. The study should compare diagnostic tests with gold standard imaging. Different clinical and community settings, such as UK primary care setting, should also be taken into account.
# Angioplasty versus bypass surgery for treating people with critical limb ischaemia caused by disease of the infra-geniculate arteries
What is the clinical and cost effectiveness of a 'bypass surgery first' strategy compared with an 'angioplasty first' strategy for treating people with critical limb ischaemia caused by disease of the infra‑geniculate (below the knee) arteries?
## Why this is important
Many people with critical limb ischaemia, especially those with diabetic vascular disease, also have disease of the infra‑geniculate (below the knee) arteries in the calf. For many years, the standard of care has been bypass surgery. Although such surgery may be associated with significant morbidity, the resulting long‑term amputation‑free survival rates are generally good. In recent years there has been a trend towards treating infra‑geniculate disease with angioplasty, on the grounds that it is associated with less morbidity than surgery. However, this change in practice is not evidence‑based, and serious concerns remain about the durability of angioplasty in this anatomical area. A multicentre, randomised controlled trial with a full health economic analysis is required to address this. The primary endpoint should be amputation‑free survival, with secondary endpoints including overall survival, health‑related quality of life, healing of tissue loss, and relief of ischaemic pain.
# Supervised exercise programmes for treating people with intermittent claudication
What is the clinical and cost effectiveness of supervised exercise programmes compared with unsupervised exercise for treating people with intermittent claudication, taking into account the effects on long‑term outcomes and continuing levels of exercise?
## Why this is important
Research has shown that taking part in exercise and physical activity can lead to improvements in symptoms in the short term for people with intermittent claudication. However, the benefits of exercise are quickly lost if it is not frequent and regular. Supervised exercise programmes have been shown to produce superior results when compared with advice to exercise (unsupervised) in the short term, but they are more expensive, and there is a lack of robust evidence on long‑term effectiveness. A community‑based randomised controlled trial is required to compare the long‑term clinical and cost effectiveness of a supervised exercise programme and unsupervised exercise. The trial should enrol people with peripheral arterial disease‑related claudication, but exclude those with previous endovascular or surgical interventions. The primary outcome measure should be maximal walking distance, with secondary outcome measures including quality of life, function, levels of uptake of exercise programmes and long‑term engagement in physical activity.
# Patient attitudes and beliefs about peripheral arterial disease
What is the effect of people's attitudes and beliefs about their peripheral arterial disease on the management and outcome of their condition?
## Why this is important
The evidence reviewed suggested that, among people with peripheral arterial disease, there is a lack of understanding of the causes of the disease, a lack of belief that lifestyle interventions will have a positive impact on disease outcomes, and unrealistic expectations of the outcome of surgical interventions. Much of the research has been conducted on the subpopulation of people with peripheral arterial disease who have been referred for surgical intervention, but little evidence is available for the majority of people diagnosed with peripheral arterial disease in a primary care setting. Research is needed to further investigate attitudes and beliefs in relation to peripheral arterial disease, interventions that might influence these and how these may have an impact on behavioural changes in relation to risk factors for peripheral arterial disease, attitudes to intervention and clinical outcomes.
# Primary versus secondary stenting for treating people with critical limb ischaemia caused by disease of the infra-geniculate arteries
What is the clinical and cost effectiveness of selective stent placement compared with angioplasty plus primary stent placement for treating people with critical limb ischaemia caused by disease of the infra‑geniculate arteries?
## Why this is important
Studies comparing angioplasty plus selective stent placement with primary stent placement have been limited to the aorto‑iliac and femoro‑popliteal segment. There is also a significant group of people with critical ischaemia caused by disease of the infra‑geniculate vessels in which there is a potential for endovascular treatment. Infra‑geniculate disease is more complex to treat by endovascular means, and the risks and benefits of different treatment options may differ from those for the more proximal vessels. A multicentre, randomised controlled trial with a full health economic analysis is required to address the optimum policy as regards the choice of method for angioplasty and stent placement for the infra‑geniculate arteries. The primary endpoint should be amputation‑free survival, with secondary endpoints including overall survival, re‑intervention rates, health‑related quality of life, healing of tissue loss, and relief of ischaemic pain.
# Chemical sympathectomy for managing critical limb ischaemic pain
What is the clinical and cost effectiveness of chemical sympathectomy in comparison with other methods of pain control for managing critical limb ischaemic pain?
## Why this is important
Approximately 1 in 5 people with critical limb ischaemia cannot be offered procedures to improve the blood supply to their leg because of either the pattern of their disease or other comorbidities. In this group the therapeutic options are pain control or primary amputation. Chemical lumbar sympathectomy, which involves the destruction of the lumbar sympathetic chain (usually the L2 and L3 ganglia), has been suggested to reduce pain and improve wound healing, and may prevent amputation in some patients. Initially achieved surgically, it is now most commonly performed using chemical agents such as phenol to destroy the lumbar sympathetic chain. Despite having been used for over 60 years, the role of chemical lumbar sympathectomy remains unclear. Improvement in skin blood flow and modification of pain perception control have been demonstrated, and this has prompted the use of chemical lumbar sympathectomy for treating a range of conditions such as regional pain syndrome, vasospastic conditions and critical limb ischaemia. However, in critical limb ischaemia the use of chemical lumbar sympathectomy varies widely between units in England, the mode of action and indications are unclear, and there is currently no randomised controlled trial evidence demonstrating its clinical value. Therefore a randomised control trial comparing chemical lumbar sympathectomy with other methods of pain relief is recommended. # Rationale and impact for new recommendations
# Diagnosis
Recommendations 1.3.4 and 1.3.5
## Why the committee made the recommendations
Evidence showed that doppler ankle brachial pressure index below an agreed cut-off increased the probability of diagnosing peripheral arterial disease. However, people with diabetes and peripheral arterial disease may have a normal or raised index because of hardening of the arteries. The committee agreed that it was important to highlight this so that healthcare professionals do not exclude peripheral arterial disease in people with diabetes based on a normal or raised ankle brachial pressure index alone.
There was a lack of evidence on the use of pulse oximetry for diagnosing peripheral arterial disease in people with diabetes. The committee noted that a universal cut‑off point had not been established. This could lead to variation in the interpretation of results. It was also noted that pulse oximetry is rarely used in clinical practice for assessing peripheral arterial disease and there was general clinical agreement that it is not a useful test in this context. Therefore, the committee recommended against the use of pulse oximetry for this purpose.
There was not enough evidence on the use of other tests (doppler waveform analysis and toe brachial index) for diagnosing peripheral arterial disease in people with diabetes. However, the committee agreed it was not appropriate to make recommendations against the use of these tests, as there were good theoretical arguments as to why these tests might provide useful diagnostic value. The committee therefore agreed to make research recommendations to inform future practice and any further update of this guidance.
Full details of the evidence and the committee's discussion are in evidence review A: determining the diagnosis and severity of peripheral arterial disease in people with diabetes.
Full details of the evidence and committee discussion for the original (2012) guideline are in: Peripheral arterial disease: full guideline.
## How the recommendations might affect practice
The new recommendations should improve the holistic assessment of peripheral arterial disease in people with diabetes. This is important because this group has a higher risk of cardiovascular events and foot problems such as diabetic neuropathy, foot ulcer and limb loss. The recommendation clarifies the use of ankle brachial pressure index and highlights the importance of interpreting pulse measurements in relation to clinical context, including symptoms.
Return to recommendations# Putting this guideline into practice
Putting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.
Changes recommended for clinical practice that can be done quickly – like changes in prescribing practice – should be shared quickly. This is because healthcare professionals should use guidelines to guide their work – as is required by professional regulating bodies such as the General Medical and Nursing and Midwifery Councils.
Changes should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).
Different organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.
Here are some pointers to help organisations put NICE guidelines into practice:
. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.
. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.
. Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision.
. Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.
. Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.
. For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.
. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.
. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners.
NICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information.
Also see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.# Context
Lower limb peripheral arterial disease (or peripheral arterial disease for short) is a marker for increased risk of cardiovascular events even when it is asymptomatic. The most common initial symptom of peripheral arterial disease is leg pain while walking, known as intermittent claudication. Critical limb ischaemia is a severe manifestation of peripheral arterial disease, and is characterised by severely diminished circulation, ischaemic pain, ulceration, tissue loss and/or gangrene.
The incidence of peripheral arterial disease increases with age. Population studies have found that about 20% of people aged over 60 years have some degree of peripheral arterial disease. Smoking is also an important risk factor, with people who smoke having a greater risk than people who have never smoked. Incidence is also high in people with coronary artery disease and in people with diabetes, meaning that early diagnosis and management of peripheral arterial disease is important . In most people with intermittent claudication the symptoms remain stable, but approximately 20% will develop increasingly severe symptoms with the development of critical limb ischaemia.
Mild symptoms are generally managed in primary care, with referral to secondary care when symptoms do not resolve or deteriorate. There are several treatment options for people with intermittent claudication. These include advice to exercise, management of cardiovascular risk factors (for example, with aspirin or statins) and vasoactive drug treatment (for example, with naftidrofuryl oxalate).
People with severe symptoms that are inadequately controlled are often referred to secondary care for assessment for endovascular treatment (such as angioplasty or stenting), bypass surgery, pain management and/or amputation.
Rapid changes in diagnostic methods, endovascular treatments and vascular services, associated with the emergence of new sub‑specialties in surgery and interventional radiology, has resulted in considerable uncertainty and variation in practice. This guideline aims to resolve that uncertainty and variation.
In 2018 we reviewed the evidence on tests for diagnosing peripheral arterial disease in people with diabetes and added new recommendations for this group.
|
{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Information requirements\n\nOffer all people with peripheral arterial disease oral and written information about their condition. Discuss it with them so they can share decision‑making, and understand the course of the disease and what they can do to help prevent disease progression. Information should include:\n\nthe causes of their symptoms and the severity of their disease\n\nthe risks of limb loss and/or cardiovascular events associated with peripheral arterial disease\n\nthe key modifiable risk factors, such as smoking, control of diabetes, hyperlipidaemia, diet, body weight and exercise (see also the recommendation\xa0on secondary prevention of cardiovascular disease in people with peripheral arterial disease)\n\nhow to manage pain\n\nall relevant treatment options, including the risks and benefits of each\n\nhow they can access support for dealing with depression and anxiety. Ensure that information, tailored to the individual needs of the person, is available at diagnosis and subsequently as required, to allow people to make decisions throughout the course of their treatment. \n\nNICE has produced guidance on the components of good patient experience in adult NHS services. Follow the recommendations in NICE's guideline on patient experience in adult NHS services. \n\n# Secondary prevention of cardiovascular disease in people with peripheral arterial disease\n\nOffer all people with peripheral arterial disease information, advice, support and treatment regarding the secondary prevention of cardiovascular disease, in line with published NICE guidance on:\n\nsmoking cessation\n\ndiet, weight management and exercise\n\nlipid modification and statin therapy\n\nthe prevention, diagnosis and management of diabetes\n\nthe prevention, diagnosis and management of high blood pressure\n\nantiplatelet therapy. \n\n# Diagnosis\n\nAssess people for the presence of peripheral arterial disease if they:\n\nhave symptoms suggestive of peripheral arterial disease\xa0or\n\nhave diabetes, non‑healing wounds on the legs or feet or unexplained leg pain\xa0or\n\nare being considered for interventions to the leg or foot\xa0or\n\nneed to use compression hosiery. \n\nAssess people with suspected peripheral arterial disease by:\n\nasking about the presence and severity of possible symptoms of intermittent claudication and critical limb ischaemia\n\nexamining the legs and feet for evidence of critical limb ischaemia, for example ulceration\n\nexamining the femoral, popliteal and foot pulses\n\nmeasuring the ankle brachial pressure index (see recommendation 1.3.3). \n\nMeasure the ankle brachial pressure index in the following way:\n\nThe person should be resting and supine if possible.\n\nRecord systolic blood pressure with an appropriately sized cuff in both arms and in the posterior tibial, dorsalis pedis and, where possible, peroneal arteries.\n\nTake measurements manually using a doppler probe of suitable frequency in preference to an automated system.\n\nDocument the nature of the doppler ultrasound signals in the foot arteries.\n\nCalculate the index in each leg by dividing the highest ankle pressure by the highest arm pressure. \n\n## Diagnosing peripheral arterial disease in people with diabetes\n\nDo not exclude a diagnosis of peripheral arterial disease in people with diabetes based on a normal or raised ankle brachial pressure index alone. \n\nDo not use pulse oximetry for diagnosing peripheral arterial disease in people with diabetes. \n\nFor a short explanation of why the committee made these 2018 recommendations and how they might affect practice, see the rationale and impact section on diagnosis\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: determining diagnosis and severity of peripheral arterial disease in people with diabetes.\n\nLoading. Please wait.\n\n# Imaging for revascularisation\n\nOffer duplex ultrasound as first‑line imaging to all people with peripheral arterial disease for whom revascularisation is being considered. \n\nOffer contrast‑enhanced magnetic resonance angiography to people with peripheral arterial disease who need further imaging (after duplex ultrasound) before considering revascularisation. \n\nOffer computed tomography angiography to people with peripheral arterial disease who need further imaging (after duplex ultrasound) if contrast‑enhanced magnetic resonance angiography is contraindicated or not tolerated. \n\n# Management of intermittent claudication\n\n## Supervised exercise programme\n\nOffer a supervised exercise programme to all people with intermittent claudication. \n\nConsider providing a supervised exercise programme for people with intermittent claudication which involves:\n\nhours of supervised exercise a week for a 3‑month period\n\nencouraging people to exercise to the point of maximal pain. \n\n## Angioplasty and stenting\n\nOffer angioplasty for treating people with intermittent claudication only when:\n\nadvice on the benefits of modifying risk factors has been reinforced (see the recommendation\xa0on secondary prevention of cardiovascular disease in people with peripheral arterial disease)\xa0and\n\na supervised exercise programme has not led to a satisfactory improvement in symptoms\xa0and\n\nimaging has confirmed that angioplasty is suitable for the person. \n\nDo not offer primary stent placement for treating people with intermittent claudication caused by aorto‑iliac disease (except complete occlusion) or femoro‑popliteal disease. \n\nConsider primary stent placement for treating people with intermittent claudication caused by complete aorto‑iliac occlusion (rather than stenosis). \n\nUse bare metal stents when stenting is used for treating people with intermittent claudication. \n\n## Bypass surgery and graft types\n\nOffer bypass surgery for treating people with severe lifestyle‑limiting intermittent claudication only when:\n\nangioplasty has been unsuccessful or is unsuitable\xa0and\n\nimaging has confirmed that bypass surgery is appropriate for the person. \n\nUse an autologous vein whenever possible for people with intermittent claudication having infra‑inguinal bypass surgery. \n\n## Naftidrofuryl oxalate\n\nConsider naftidrofuryl oxalate for treating people with intermittent claudication, starting with the least costly preparation, only when:\n\nsupervised exercise has not led to satisfactory improvement\xa0and\n\nthe person prefers not to be referred for consideration of angioplasty or bypass surgery.Review progress after 3–6 months and discontinue naftidrofuryl oxalate if there has been no symptomatic benefit. \n\n# Management of critical limb ischaemia\n\nEnsure that all people with critical limb ischaemia are assessed by a vascular multidisciplinary team before treatment decisions are made. \n\n## Revascularisation\n\nOffer angioplasty or bypass surgery for treating people with critical limb ischaemia who require revascularisation, taking into account factors including:\n\ncomorbidities\n\npattern of disease\n\navailability of a vein\n\npatient preference. \n\nDo not offer primary stent placement for treating people with critical limb ischaemia caused by aorto‑iliac disease (except complete occlusion) or femoro‑popliteal disease. \n\nConsider primary stent placement for treating people with critical limb ischaemia caused by complete aorto‑iliac occlusion (rather than stenosis). \n\nUse bare metal stents when stenting is used for treating people with critical limb ischaemia. \n\nUse an autologous vein whenever possible for people with critical limb ischaemia having infra‑inguinal bypass surgery. \n\n## Management of critical limb ischaemic pain\n\nOffer paracetamol, and either weak or strong opioids depending on the severity of pain, to people with critical limb ischaemic pain.To support discussions with patients about the benefits and harms of opioid treatment, and safe withdrawal management, see:\n\nNICE's guideline on medicines associated with dependence or withdrawal symptoms\n\nNICE guideline on shared decision making\n\nthe section on medication review in NICE's guideline on medicines optimisation. [2012, amended 2020]\n\nOffer drugs such as laxatives and anti‑emetics to manage the adverse effects of strong opioids, in line with the person's needs and preferences. \n\nRefer people with critical limb ischaemic pain to a specialist pain management service if any of the following apply:\n\ntheir pain is not adequately controlled and revascularisation is inappropriate or impossible\n\nongoing high doses of opioids are required for pain control\n\npain persists after revascularisation or amputation. \n\nDo not offer chemical sympathectomy to people with critical limb ischaemic pain, except in the context of a clinical trial. \n\n## Major amputation\n\nDo not offer major amputation to people with critical limb ischaemia unless all options for revascularisation have been considered by a vascular multidisciplinary team. ", 'Recommendations for research': "In 2012 the guideline committee has made the following recommendations for research. The committee's full set of research recommendations is detailed in the full guideline.\n\nAs part of the 2018 update, the standing committee made new research recommendations on the effectiveness and reliability of tools for diagnosing peripheral arterial disease in people with diabetes. Details can be found in the evidence review.\n\n# Effectiveness of tools for diagnosing peripheral arterial disease in people with diabetes\n\nWhat is the most clinically and cost-effective tool for diagnosing peripheral arterial disease in people with diabetes?\n\n## Why this is important\n\nPeople with diabetes are at higher risk of cardiovascular events and foot problems such as diabetic neuropathy (nerve damage or degeneration), foot ulcer and limb loss. So it is important to have an effective test for diagnosing peripheral arterial disease in this group. At present there are only studies of very low quality (retrospective and prospective cross‑sectional studies) containing small sample sizes. Diagnostic accuracy studies are needed to address this issue, ideally containing cost–utility analysis, comparing diagnostic tools with imaging. In order to explore the importance of early diagnosis, different clinical settings where diagnostic tests are performed should be explored. \n\n# Effectiveness of tools for establishing the severity of peripheral arterial disease in people with diabetes\n\nWhat is the most clinically and cost-effective tool for establishing the severity of peripheral arterial disease and the impact on mortality, morbidity and limb amputation in people with diabetes?\n\n## Why this is important\n\nLimited evidence suggests that doppler ankle brachial pressure index, toe brachial index and oscillometric ankle brachial index accurately diagnose severity of peripheral arterial disease. However, further research is needed using a robust diagnostic study design (such as a randomised controlled trial) to explore the clinical and cost effectiveness of tools in establishing the severity of disease and outcomes in people with diabetes. Studies should also explore the use of tools in different populations, such as those with neuropathy, and in different settings, for example, nursing homes, where access to services and diagnostic equipment may differ. \n\n# Inter- and intra-rater reliability of assessment tools in the diagnosis of peripheral arterial disease in people with diabetes\n\nWhat is the inter- and intra-rater reliability of assessment tools in the diagnosis of peripheral arterial disease in people with diabetes?\n\n## Why this is important\n\nIdentifying peripheral arterial disease can be a challenge because diagnostic tests are conducted in a number of different settings by healthcare professionals with varying experience of using assessment tools. Data on inter- and intra‑rater reliability of point‑of‑care assessment tools are needed to inform future recommendations for practice. The study should compare diagnostic tests with gold standard imaging. Different clinical and community settings, such as UK primary care setting, should also be taken into account. \n\n# Angioplasty versus bypass surgery for treating people with critical limb ischaemia caused by disease of the infra-geniculate arteries\n\nWhat is the clinical and cost effectiveness of a 'bypass surgery first' strategy compared with an 'angioplasty first' strategy for treating people with critical limb ischaemia caused by disease of the infra‑geniculate (below the knee) arteries?\n\n## Why this is important\n\nMany people with critical limb ischaemia, especially those with diabetic vascular disease, also have disease of the infra‑geniculate (below the knee) arteries in the calf. For many years, the standard of care has been bypass surgery. Although such surgery may be associated with significant morbidity, the resulting long‑term amputation‑free survival rates are generally good. In recent years there has been a trend towards treating infra‑geniculate disease with angioplasty, on the grounds that it is associated with less morbidity than surgery. However, this change in practice is not evidence‑based, and serious concerns remain about the durability of angioplasty in this anatomical area. A multicentre, randomised controlled trial with a full health economic analysis is required to address this. The primary endpoint should be amputation‑free survival, with secondary endpoints including overall survival, health‑related quality of life, healing of tissue loss, and relief of ischaemic pain. \n\n# Supervised exercise programmes for treating people with intermittent claudication\n\nWhat is the clinical and cost effectiveness of supervised exercise programmes compared with unsupervised exercise for treating people with intermittent claudication, taking into account the effects on long‑term outcomes and continuing levels of exercise?\n\n## Why this is important\n\nResearch has shown that taking part in exercise and physical activity can lead to improvements in symptoms in the short term for people with intermittent claudication. However, the benefits of exercise are quickly lost if it is not frequent and regular. Supervised exercise programmes have been shown to produce superior results when compared with advice to exercise (unsupervised) in the short term, but they are more expensive, and there is a lack of robust evidence on long‑term effectiveness. A community‑based randomised controlled trial is required to compare the long‑term clinical and cost effectiveness of a supervised exercise programme and unsupervised exercise. The trial should enrol people with peripheral arterial disease‑related claudication, but exclude those with previous endovascular or surgical interventions. The primary outcome measure should be maximal walking distance, with secondary outcome measures including quality of life, function, levels of uptake of exercise programmes and long‑term engagement in physical activity. \n\n# Patient attitudes and beliefs about peripheral arterial disease\n\nWhat is the effect of people's attitudes and beliefs about their peripheral arterial disease on the management and outcome of their condition?\n\n## Why this is important\n\nThe evidence reviewed suggested that, among people with peripheral arterial disease, there is a lack of understanding of the causes of the disease, a lack of belief that lifestyle interventions will have a positive impact on disease outcomes, and unrealistic expectations of the outcome of surgical interventions. Much of the research has been conducted on the subpopulation of people with peripheral arterial disease who have been referred for surgical intervention, but little evidence is available for the majority of people diagnosed with peripheral arterial disease in a primary care setting. Research is needed to further investigate attitudes and beliefs in relation to peripheral arterial disease, interventions that might influence these and how these may have an impact on behavioural changes in relation to risk factors for peripheral arterial disease, attitudes to intervention and clinical outcomes. \n\n# Primary versus secondary stenting for treating people with critical limb ischaemia caused by disease of the infra-geniculate arteries\n\nWhat is the clinical and cost effectiveness of selective stent placement compared with angioplasty plus primary stent placement for treating people with critical limb ischaemia caused by disease of the infra‑geniculate arteries?\n\n## Why this is important\n\nStudies comparing angioplasty plus selective stent placement with primary stent placement have been limited to the aorto‑iliac and femoro‑popliteal segment. There is also a significant group of people with critical ischaemia caused by disease of the infra‑geniculate vessels in which there is a potential for endovascular treatment. Infra‑geniculate disease is more complex to treat by endovascular means, and the risks and benefits of different treatment options may differ from those for the more proximal vessels. A multicentre, randomised controlled trial with a full health economic analysis is required to address the optimum policy as regards the choice of method for angioplasty and stent placement for the infra‑geniculate arteries. The primary endpoint should be amputation‑free survival, with secondary endpoints including overall survival, re‑intervention rates, health‑related quality of life, healing of tissue loss, and relief of ischaemic pain. \n\n# Chemical sympathectomy for managing critical limb ischaemic pain\n\nWhat is the clinical and cost effectiveness of chemical sympathectomy in comparison with other methods of pain control for managing critical limb ischaemic pain?\n\n## Why this is important\n\nApproximately 1 in 5 people with critical limb ischaemia cannot be offered procedures to improve the blood supply to their leg because of either the pattern of their disease or other comorbidities. In this group the therapeutic options are pain control or primary amputation. Chemical lumbar sympathectomy, which involves the destruction of the lumbar sympathetic chain (usually the L2 and L3 ganglia), has been suggested to reduce pain and improve wound healing, and may prevent amputation in some patients. Initially achieved surgically, it is now most commonly performed using chemical agents such as phenol to destroy the lumbar sympathetic chain. Despite having been used for over 60\xa0years, the role of chemical lumbar sympathectomy remains unclear. Improvement in skin blood flow and modification of pain perception control have been demonstrated, and this has prompted the use of chemical lumbar sympathectomy for treating a range of conditions such as regional pain syndrome, vasospastic conditions and critical limb ischaemia. However, in critical limb ischaemia the use of chemical lumbar sympathectomy varies widely between units in England, the mode of action and indications are unclear, and there is currently no randomised controlled trial evidence demonstrating its clinical value. Therefore a randomised control trial comparing chemical lumbar sympathectomy with other methods of pain relief is recommended. ", 'Rationale and impact for new recommendations': "# Diagnosis\n\nRecommendations 1.3.4 and 1.3.5\n\n## Why the committee made the recommendations\n\nEvidence showed that doppler ankle brachial pressure index below an agreed cut-off increased the probability of diagnosing peripheral arterial disease. However, people with diabetes and peripheral arterial disease may have a normal or raised index because of hardening of the arteries. The committee agreed that it was important to highlight this so that healthcare professionals do not exclude peripheral arterial disease in people with diabetes based on a normal or raised ankle brachial pressure index alone.\n\nThere was a lack of evidence on the use of pulse oximetry for diagnosing peripheral arterial disease in people with diabetes. The committee noted that a universal cut‑off point had not been established. This could lead to variation in the interpretation of results. It was also noted that pulse oximetry is rarely used in clinical practice for assessing peripheral arterial disease and there was general clinical agreement that it is not a useful test in this context. Therefore, the committee recommended against the use of pulse oximetry for this purpose.\n\nThere was not enough evidence on the use of other tests (doppler waveform analysis and toe brachial index) for diagnosing peripheral arterial disease in people with diabetes. However, the committee agreed it was not appropriate to make recommendations against the use of these tests, as there were good theoretical arguments as to why these tests might provide useful diagnostic value. The committee therefore agreed to make research recommendations to inform future practice and any further update of this guidance.\n\nFull details of the evidence and the committee's discussion are in evidence review A: determining the diagnosis and severity of peripheral arterial disease in people with diabetes.\n\nFull details of the evidence and committee discussion for the original (2012) guideline are in: Peripheral arterial disease: full guideline.\n\n## How the recommendations might affect practice\n\nThe new recommendations should improve the holistic assessment of peripheral arterial disease in people with diabetes. This is important because this group has a higher risk of cardiovascular events and foot problems such as diabetic neuropathy, foot ulcer and limb loss. The recommendation clarifies the use of ankle brachial pressure index and highlights the importance of interpreting pulse measurements in relation to clinical context, including symptoms.\n\nReturn to recommendations", 'Putting this guideline into practice': 'Putting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.\n\nChanges recommended for clinical practice that can be done quickly – like changes in prescribing practice – should be shared quickly. This is because healthcare professionals should use guidelines to guide their work – as is required by professional regulating bodies such as the General Medical and Nursing and Midwifery Councils.\n\nChanges should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).\n\nDifferent organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.\n\nHere are some pointers to help organisations put NICE guidelines into practice:\n\n. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.\n\n. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.\n\n. Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision.\n\n. Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.\n\n. Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.\n\n. For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.\n\n. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.\n\n. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners.\n\nNICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information.\n\nAlso see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.', 'Context': 'Lower limb peripheral arterial disease (or peripheral arterial disease for short) is a marker for increased risk of cardiovascular events even when it is asymptomatic. The most common initial symptom of peripheral arterial disease is leg pain while walking, known as intermittent claudication. Critical limb ischaemia is a severe manifestation of peripheral arterial disease, and is characterised by severely diminished circulation, ischaemic pain, ulceration, tissue loss and/or gangrene.\n\nThe incidence of peripheral arterial disease increases with age. Population studies have found that about 20% of people aged over 60\xa0years have some degree of peripheral arterial disease. Smoking is also an important risk factor, with people who smoke having a greater risk than people who have never smoked. Incidence is also high in people with coronary artery disease and in people with diabetes, meaning that early diagnosis and management of peripheral arterial disease is important . In most people with intermittent claudication the symptoms remain stable, but approximately 20% will develop increasingly severe symptoms with the development of critical limb ischaemia.\n\nMild symptoms are generally managed in primary care, with referral to secondary care when symptoms do not resolve or deteriorate. There are several treatment options for people with intermittent claudication. These include advice to exercise, management of cardiovascular risk factors (for example, with aspirin or statins) and vasoactive drug treatment (for example, with naftidrofuryl oxalate).\n\nPeople with severe symptoms that are inadequately controlled are often referred to secondary care for assessment for endovascular treatment (such as angioplasty or stenting), bypass surgery, pain management and/or amputation.\n\nRapid changes in diagnostic methods, endovascular treatments and vascular services, associated with the emergence of new sub‑specialties in surgery and interventional radiology, has resulted in considerable uncertainty and variation in practice. This guideline aims to resolve that uncertainty and variation.\n\nIn 2018 we reviewed the evidence on tests for diagnosing peripheral arterial disease in people with diabetes and added new recommendations for this group.'}
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https://www.nice.org.uk/guidance/cg147
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This guideline covers diagnosing and managing peripheral arterial disease (PAD) in people aged 18 and over. Rapid changes in diagnostic methods, endovascular treatments and vascular services associated with new specialties in surgery and interventional radiology have resulted in considerable uncertainty and variation in practice. This guideline aims to resolve that uncertainty and variation.
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6d63b21de8ce07836e890fb773a0e96c3f638a5a
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nice
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Liraglutide for managing overweight and obesity
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Liraglutide for managing overweight and obesity
Evidence-based recommendations on liraglutide (Saxenda) for managing overweight and obesity alongside a reduced-calorie diet and increased physical activity in adults.
# Recommendations
Liraglutide is recommended as an option for managing overweight and obesity alongside a reduced-calorie diet and increased physical activity in adults, only if:
they have a body mass index (BMI) of at least 35 kg/m2 (or at least 32.5 kg/m2 for members of minority ethnic groups known to be at equivalent risk of the consequences of obesity at a lower BMI than the white population) and
they have non-diabetic hyperglycaemia (defined as a haemoglobin A1c level of 42 mmol/mol to 47 mmol/mol or a fasting plasma glucose level of 5.5 mmol/litre to 6.9 mmol/litre) and
they have a high risk of cardiovascular disease based on risk factors such as hypertension and dyslipidaemia and
it is prescribed in secondary care by a specialist multidisciplinary tier 3 weight management service and
the company provides it according to the commercial arrangement.
This recommendation is not intended to affect treatment with liraglutide that was started in the NHS before this guidance was published. Adults having treatment outside this recommendation may continue without changes to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Management for overweight and obesity in adults includes lifestyle measures alone, lifestyle measures with orlistat, or bariatric (weight loss) surgery.
The company's evidence submission focuses on people with a BMI of at least 35 kg/m2 with non-diabetic hyperglycaemia and a high risk of cardiovascular disease, because this group of people was at high risk of experiencing the adverse consequences of obesity. They were also likely to gain most from liraglutide. The clinical evidence shows that people lose more weight with liraglutide plus lifestyle measures than with lifestyle measures alone. Liraglutide has also been shown to delay the development of type 2 diabetes and cardiovascular disease.
People from some minority ethnic groups are at an equivalent risk of the consequences of obesity at a lower BMI than the white population. NICE's guideline on BMI recommends using lower BMI thresholds for people from south Asian, Chinese, black African and African-Caribbean populations when identifying the risk of developing type 2 diabetes and providing interventions to prevent it. Therefore, a similar adjustment in the BMI threshold is appropriate when considering liraglutide for people from minority ethnic groups known to be at equivalent risk of the consequences of obesity at a lower BMI than the white population.
For people with a high BMI, non-diabetic hyperglycaemia and a high risk of cardiovascular disease the cost-effectiveness estimates are within what is normally considered a cost-effective use of NHS resources. For these people, liraglutide is recommended.# Information about liraglutide
# Marketing authorisation
Liraglutide (Saxenda, Novo Nordisk) is indicated 'as an adjunct to a reduced-calorie diet and increased physical activity for weight management in adult patients with an initial BMI of ≥30 kg/m² (obese), or ≥27 kg/m² to <30 kg/m² (overweight) in the presence of at least one weight-related comorbidity such as dysglycaemia (pre-diabetes or type 2 diabetes mellitus), hypertension, dyslipidaemia or obstructive sleep apnoea'.
# Dosage in the marketing authorisation
For full details of dose schedules, see the summary of product characteristics.
# Price
The list price of liraglutide (Saxenda) is £196.20 for 5 × 6 mg/ml 3‑ml (18 mg) pre-filled pens (excluding VAT; BNF online, accessed September 2020). The company has a commercial arrangement. This makes the Saxenda brand of liraglutide available to the NHS with a discount only if it is purchased through a secondary-care tier 3 weight management service. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Novo Nordisk, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
The appraisal committee recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, table 2, page 35), and took these into account in its decision making. It discussed the following issues (issues 1 to 7) that were outstanding after the technical engagement stage.
# Clinical need
## Living with obesity is restrictive
The patient expert explained that living with obesity is challenging and restrictive. There is stigma associated with being obese. The biological and psychological determinants of obesity are often overlooked with a general perception that people are obese by choice. Current treatment options are limited and there is need for a treatment that deals with biological determinants of obesity. The committee recognised there are limited effective treatment options available for people living with obesity.
## The company submission focuses on a high-risk subgroup
The NICE scope included people with a body mass index (BMI) of 30 kg/m2 or more (obese), or with a BMI from 27 kg/m2 to less than 30 kg/m2 (overweight) in the presence of at least 1 weight-related comorbidity. This is the population in the marketing authorisation. The company only presented evidence for people with a BMI of 35 kg/m2 or more, with pre-diabetes (non-diabetic hyperglycaemia) and a high risk of cardiovascular disease. It stated that these people are at high risk of experiencing the adverse consequences of obesity and are likely to gain the most from liraglutide. It was agreed at technical engagement that the population proposed by the company was clearly identifiable and justified. However, the evidence presented did not allow the committee to make a recommendation for the full population covered by the marketing authorisation. The committee therefore agreed to focus on the population proposed by the company.
# Current management and comparators
## Access to tier 3 weight management services varies
The clinical experts explained that weight management follows NICE's guideline on identification, assessment and management of obesity. In the high-risk population proposed by the company, liraglutide would be offered through specialist multidisciplinary weight management (tier 3) services. These provide dietary, lifestyle and behaviour modification, with or without drug therapy, and psychological support. The clinical experts explained that long-term weight loss would not be achieved without the ongoing and psychological support that is a feature of tier 3 services. Access to these services varies across England. The clinical experts advised that NHS diabetic services have experience of prescribing liraglutide and might provide a suitable alternative when no tier 3 service is available. However, these services may not provide psychological support for weight management. The committee concluded that a tier 3 service is the appropriate context in which liraglutide would be offered but acknowledged that, at present, access to these services varies.
## Orlistat and bariatric surgery are not alternatives to liraglutide for most people
The clinical experts explained that many people decide not to have orlistat or stop taking it because of undesirable side effects. Most people referred to a tier 3 service will have tried and stopped orlistat, so there is a high clinical need for other pharmacological options. The clinical experts explained that liraglutide would only be considered if orlistat or bariatric surgery are not an option for the patient or they do not want to have these treatments. Only around 0.1% of people who are eligible for bariatric surgery have it. The committee concluded that orlistat and bariatric surgery would not be alternatives to liraglutide for most people, and that the appropriate comparator is lifestyle changes without medicines.
# Clinical evidence
## The company's modified intention-to-treat analysis is suitable for decision making
The company presented a post-hoc subgroup analysis of trial 1839. This is a randomised double-blind trial of liraglutide or placebo, alongside diet and exercise. It included 3,721 people with and without pre-diabetes (non-diabetic hyperglycaemia). Pre-diabetes was a pre-defined subgroup of 2,254 people who were followed up for 3 years. The post-hoc subgroup came from this pre-defined pre-diabetes subgroup. It included 800 people with a BMI of 35 kg/m2 or more, with pre-diabetes (defined as a haemoglobin A1c level of 42 mmol/mol to 47 mmol/mol or a fasting plasma glucose level of 5.5 mmol/litre to 6.9 mmol/litre), and a high risk of cardiovascular disease (defined as the presence of 1 or more of: a total cholesterol level of more than 5 mmol/litre, systolic blood pressure of more than 140 mmHg, or a high-density lipoprotein level of less than 1.0 mmol/litre for men and less than 1.3 mmol/litre for women). Weight-related outcomes (BMI and percentage weight loss) significantly favoured liraglutide compared with placebo. Statistically significantly fewer people developed type 2 diabetes with liraglutide than with placebo, and more patients reverted to normal glucose tolerance on liraglutide than on placebo. The committee considered that the trial was of good quality. The post-hoc subgroup population was identifiable, in that it represented a high-risk population of people who were likely to have a higher absolute benefit from liraglutide. The committee noted that the post-hoc subgroup is associated with more uncertainty than the larger pre-defined pre-diabetes trial population. The company explained that its modified intention-to-treat analysis included efficacy data for the full pre-diabetes population. The committee concluded that this analysis was suitable for decision making.
## The cardiovascular benefits of liraglutide are uncertain
The committee considered the evidence from the full population of trial 1839, which did not show a significant reduction in cardiovascular events in people having liraglutide compared with placebo over the 3 years of the trial. It noted the small number of significant cardiovascular events in the trial. The average age of the population was 48, in whom the baseline cardiovascular risk would not be particularly high. The company indicated that weight gain stops around age 67 because of loss of muscle mass, and therefore the average age of patients in the trial was not an unreasonable estimate of those who might be offered liraglutide in clinical practice. The cardiovascular benefit of liraglutide in the company's model was based on risk reduction using surrogate outcomes such as haemoglobin A1c and blood pressure. This approach introduces uncertainty because causal inference requires direct evidence that liraglutide reduces cardiovascular events. This was not provided in the company submission because of lack of long-term evidence. The clinical experts explained that reductions in the surrogate outcomes were likely to reduce long-term cardiovascular risk. The committee accepted the clinical experts' opinion that temporary reductions in weight can result in long-term cardiovascular benefits. The committee acknowledged that relying on surrogates is uncertain but accepted that surrogate outcomes were the only available evidence to estimate cardiovascular benefits.
# Duration of treatment
## Obesity is a long-term condition, therefore limiting treatment to 2 years is not ideal
The committee noted that obesity is a long-term condition. For other long-term conditions, such as hypertension and diabetes, treatment continues long term. The committee sought justification for the company's proposal that all patients who had an initial weight loss of more than 5% (and so continued on treatment), would stop treatment at 2 years. The clinical experts explained that people who have lost weight are likely to want to continue taking the treatment. This was confirmed by the patient expert. The clinical experts also explained that people who experience side effects with minimal weight loss are most likely to stop taking the treatment. They stated that some people take liraglutide until they achieve their desired weight loss then stop taking it, restarting it when they regain weight. The committee had concerns that the company's submission was based on a maximum treatment duration of 2 years. It noted that a 2‑year treatment duration does not address the clinical need to reduce weight and then maintain a reduced weight. Also, it does not reflect the clinical trial. The clinical experts explained that patients are usually discharged from NHS tier 3 weight management services after 2 years of continuous treatment. The committee concluded that treating a chronic condition such as obesity for only 2 years is not ideal. But it accepted that the cost-effectiveness estimate was based on a single course of treatment of no longer than 2 years, and that the assumption that treatment would be stopped at 2 years was reasonable in the context of NHS tier 3 weight management services.
# The company's economic model
## The health states and transitions in the model are suitable for decision making
The company submitted a cohort state-transition model with 10 health states, to estimate the cost effectiveness of liraglutide compared with diet and exercise alone. Transitions between health states were based on estimated type 2 diabetes mellitus status and cardiovascular events (primary and secondary). The model used risk equations and death probabilities. A once-only transition was used to incorporate the proportion of patients reversing from pre-diabetes to normal glucose tolerance based on trial 1839 data. The relative treatment effectiveness was estimated through changes in BMI, systolic blood pressure, total and high-density lipoprotein cholesterol parameters in the risk models. Patients were assumed to have stopped treatment at 2 years and gain weight over the next 3 years, so they return to the weight expected if they had never had treatment. Patients entered the model with pre-diabetes. The committee noted that the risk equations used relative effectiveness on surrogate end points to estimate long-term cardiovascular events, which introduced uncertainty. But it concluded that the health states and transitions in the model were suitable for decision making.
## The cardiovascular risk equations are suitable for decision making
The company's model used risk equations to estimate the long-term risk of myocardial infarction, angina and stroke (including transient ischaemic attack). The risk equations used surrogate effectiveness parameters such as BMI, systolic blood pressure, total cholesterol and high-density lipoprotein. The committee considered that the risk equations were not prognostic on an individual basis and were based on an assumption of a steady-state. The committee acknowledged that there was no clear alternative to the use of risk equations in the model, but it had concerns about the assumptions of cardiovascular outcome benefits that were based on temporary improvements in risk factors. The clinical experts explained that short-term weight loss and temporary improvement in diabetic status can reduce long-term cardiovascular risk. The committee was satisfied that liraglutide, when used as proposed by the company, has a temporary benefit on weight and diabetic status and this could reduce the long-term risk of myocardial infarction, angina and stroke. The company's model included several different risk equations to predict prevention of cardiovascular events, and different risk equations were used in the company's and the ERG's preferred base-case analyses. The committee accepted that the risk equations selected in the company's and ERG's base case were both suitable for decision making.
## The assumptions for weight gain and diabetic status are uncertain
No follow-up data were available on weight gain and diabetic status after stopping treatment in trial 1839. The company assumed that after completing a 2‑year course of liraglutide, weight would gradually increase over the next 3 years. It also assumed that people whose glucose tolerance became normal on treatment would revert to being pre-diabetic after 3 years. The committee noted that people in the model regained their initial weight. But they might be expected to regain more weight after treatment stopped, resulting in a higher weight than before starting treatment. Because no follow-up data were available for weight gain or diabetic status in the 3 years after stopping treatment, the committee accepted the assumptions and the associated uncertainty.
## The model assumes that all people develop type 2 diabetes after a cardiovascular event
The committee discussed the company's 'simplifying' assumption that all people who have a cardiovascular event develop type 2 diabetes within the following year. The clinical experts explained that people are more likely to be diagnosed with type 2 diabetes after a cardiovascular event, but this relationship is not causal. The committee heard that there is no good evidence to determine the proportion of people who develop type 2 diabetes after a cardiovascular event. During technical engagement, the company presented a scenario analysis in which people did not develop type 2 diabetes after a cardiovascular event. The committee had reservations about the simplifying assumption but was reassured by the results of the company's scenario analysis. The committee agreed that the most plausible incremental cost-effectiveness ratio (ICER) would be between the base-case ICERs, which applied the simplifying assumption, and the scenario analysis that did not. The ICER is therefore likely to be within what NICE normally considers a cost-effective use of NHS resources.
# Cost-effectiveness results
## Because of the uncertainty an acceptable ICER is £20,000 per QALY gained
NICE's guide to the methods of technology appraisal notes that above a most plausible ICER of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. Because of the uncertainties in the modelling assumptions, particularly what happens after stopping liraglutide and the calculation of long-term benefits, the committee agreed that an acceptable ICER would not be higher than £20,000 per QALY gained.
## The company's base-case ICER is below £20,000 per QALY gained
The company's base-case analysis:
included clinical-effectiveness estimates from the post-hoc subgroup of trial 1839 (see section 3.5)
implemented the 2‑year treatment duration rule (see section 3.7)
used the UKPDS‑82 risk equation to model primary and secondary cardiovascular disease outcomes (see section 3.9)
assumed that any weight loss returned to the base weight 3 years after treatment discontinuation (see section 3.10)
assumed that type 2 diabetes developed in the first year after a cardiovascular event (see section 3.11).The company's base-case ICER for liraglutide plus diet and exercise compared with diet and exercise alone was £11,293 per QALY gained.
## The ERG's base-case ICER is below £20,000 per QALY gained
The ERG's preferred base-case analysis was similar to the company's base case but included:
the Qrisk‑3 risk equation to predict development of primary cardiovascular disease outcomes (see section 3.9)
the Framingham recurring coronary heart disease risk equation to predict development of secondary cardiovascular disease outcomes (see section 3.9).The ERG's preferred base-case ICER for liraglutide plus diet and exercise compared with diet and exercise alone was £13,569 per QALY gained.
## All the scenario analyses result in ICERs below £20,000 per QALY gained
The company's and the ERG's scenario analyses all resulted in an ICER below £20,000 per QALY gained. The committee agreed that the scenario analyses addressed several areas of uncertainty in the economic model. Specifically, the committee noted that:
the scenario using efficacy data from the whole pre-diabetes population rather than the post-hoc sub group (see section 3.5) reduced the base-case ICER
removing the assumption that type 2 diabetes always develops after a cardiovascular event (see section 3.11) did not increase the ICER above £20,000 per QALY gained in the company's or the ERG's scenarios.
# Other factors
The committee noted that people from some minority ethnic groups are at an equivalent risk of the consequences of obesity at a lower BMI than the white population. NICE's guideline on BMI recommends using lower BMI thresholds for south Asian, Chinese, black African and African-Caribbean populations when identifying the risk of developing type 2 diabetes and providing interventions to prevent it. The committee agreed that a similar adjustment is appropriate when considering liraglutide. It concluded that the BMI threshold of at least 35 kg/m2 should be adjusted appropriately when considering liraglutide for people from minority ethnic groups known to be at equivalent risk of the consequences of obesity at a lower BMI than the white population.
# Conclusion
## Liraglutide is a cost-effective use of NHS resources
The committee noted that the company's and the ERG's base case and scenario analyses resulted in ICERs for liraglutide of less than £20,000 per QALY gained. The committee therefore recommended liraglutide as a cost-effective treatment for use in the NHS for adults with a BMI of at least 35 kg/m2, non-diabetic hyperglycaemia, and a high risk of cardiovascular disease alongside a reduced-calorie diet and increased physical activity. The BMI threshold should be adjusted appropriately for people from minority ethnic groups known to be at equivalent risk of the consequences of obesity at a lower BMI than the white population.
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{'Recommendations': "Liraglutide is recommended as an option for managing overweight and obesity alongside a reduced-calorie diet and increased physical activity in adults, only if:\n\nthey have a body mass index (BMI) of at least 35\xa0kg/m2 (or at least 32.5\xa0kg/m2 for members of minority ethnic groups known to be at equivalent risk of the consequences of obesity at a lower BMI than the white population) and\n\nthey have non-diabetic hyperglycaemia (defined as a haemoglobin\xa0A1c level of 42\xa0mmol/mol to 47\xa0mmol/mol [6.0% to 6.4%] or a fasting plasma glucose level of 5.5\xa0mmol/litre to 6.9\xa0mmol/litre) and\n\nthey have a high risk of cardiovascular disease based on risk factors such as hypertension and dyslipidaemia and\n\nit is prescribed in secondary care by a specialist multidisciplinary tier\xa03 weight management service and\n\nthe company provides it according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with liraglutide that was started in the NHS before this guidance was published. Adults having treatment outside this recommendation may continue without changes to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nManagement for overweight and obesity in adults includes lifestyle measures alone, lifestyle measures with orlistat, or bariatric (weight loss) surgery.\n\nThe company's evidence submission focuses on people with a BMI of at least 35\xa0kg/m2 with non-diabetic hyperglycaemia and a high risk of cardiovascular disease, because this group of people was at high risk of experiencing the adverse consequences of obesity. They were also likely to gain most from liraglutide. The clinical evidence shows that people lose more weight with liraglutide plus lifestyle measures than with lifestyle measures alone. Liraglutide has also been shown to delay the development of type\xa02 diabetes and cardiovascular disease.\n\nPeople from some minority ethnic groups are at an equivalent risk of the consequences of obesity at a lower BMI than the white population. NICE's guideline on BMI recommends using lower BMI thresholds for people from south Asian, Chinese, black African and African-Caribbean populations when identifying the risk of developing type 2 diabetes and providing interventions to prevent it. Therefore, a similar adjustment in the BMI threshold is appropriate when considering liraglutide for people from minority ethnic groups known to be at equivalent risk of the consequences of obesity at a lower BMI than the white population.\n\nFor people with a high BMI, non-diabetic hyperglycaemia and a high risk of cardiovascular disease the cost-effectiveness estimates are within what is normally considered a cost-effective use of NHS resources. For these people, liraglutide is recommended.", 'Information about liraglutide': "# Marketing authorisation\n\nLiraglutide (Saxenda, Novo Nordisk) is indicated 'as an adjunct to a reduced-calorie diet and increased physical activity for weight management in adult patients with an initial BMI of ≥30\xa0kg/m² (obese), or ≥27\xa0kg/m² to <30\xa0kg/m² (overweight) in the presence of at least one weight-related comorbidity such as dysglycaemia (pre-diabetes or type\xa02 diabetes mellitus), hypertension, dyslipidaemia or obstructive sleep apnoea'.\n\n# Dosage in the marketing authorisation\n\nFor full details of dose schedules, see the summary of product characteristics.\n\n# Price\n\nThe list price of liraglutide (Saxenda) is £196.20 for 5\xa0×\xa06\xa0mg/ml 3‑ml (18\xa0mg) pre-filled pens (excluding VAT; BNF online, accessed September\xa02020). The company has a commercial arrangement. This makes the Saxenda brand of liraglutide available to the NHS with a discount only if it is purchased through a secondary-care tier\xa03 weight management service. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Novo Nordisk, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, table\xa02, page\xa035), and took these into account in its decision making. It discussed the following issues (issues\xa01 to 7) that were outstanding after the technical engagement stage.\n\n# Clinical need\n\n## Living with obesity is restrictive\n\nThe patient expert explained that living with obesity is challenging and restrictive. There is stigma associated with being obese. The biological and psychological determinants of obesity are often overlooked with a general perception that people are obese by choice. Current treatment options are limited and there is need for a treatment that deals with biological determinants of obesity. The committee recognised there are limited effective treatment options available for people living with obesity.\n\n## The company submission focuses on a high-risk subgroup\n\nThe NICE scope included people with a body mass index (BMI) of 30\xa0kg/m2 or more (obese), or with a BMI from 27\xa0kg/m2 to less than 30\xa0kg/m2 (overweight) in the presence of at least 1\xa0weight-related comorbidity. This is the population in the marketing authorisation. The company only presented evidence for people with a BMI of 35\xa0kg/m2 or more, with pre-diabetes (non-diabetic hyperglycaemia) and a high risk of cardiovascular disease. It stated that these people are at high risk of experiencing the adverse consequences of obesity and are likely to gain the most from liraglutide. It was agreed at technical engagement that the population proposed by the company was clearly identifiable and justified. However, the evidence presented did not allow the committee to make a recommendation for the full population covered by the marketing authorisation. The committee therefore agreed to focus on the population proposed by the company.\n\n# Current management and comparators\n\n## Access to tier 3 weight management services varies\n\nThe clinical experts explained that weight management follows NICE's guideline on identification, assessment and management of obesity. In the high-risk population proposed by the company, liraglutide would be offered through specialist multidisciplinary weight management (tier\xa03) services. These provide dietary, lifestyle and behaviour modification, with or without drug therapy, and psychological support. The clinical experts explained that long-term weight loss would not be achieved without the ongoing and psychological support that is a feature of tier\xa03 services. Access to these services varies across England. The clinical experts advised that NHS diabetic services have experience of prescribing liraglutide and might provide a suitable alternative when no tier\xa03 service is available. However, these services may not provide psychological support for weight management. The committee concluded that a tier\xa03 service is the appropriate context in which liraglutide would be offered but acknowledged that, at present, access to these services varies.\n\n## Orlistat and bariatric surgery are not alternatives to liraglutide for most people\n\nThe clinical experts explained that many people decide not to have orlistat or stop taking it because of undesirable side effects. Most people referred to a tier\xa03 service will have tried and stopped orlistat, so there is a high clinical need for other pharmacological options. The clinical experts explained that liraglutide would only be considered if orlistat or bariatric surgery are not an option for the patient or they do not want to have these treatments. Only around 0.1%\xa0of people who are eligible for bariatric surgery have it. The committee concluded that orlistat and bariatric surgery would not be alternatives to liraglutide for most people, and that the appropriate comparator is lifestyle changes without medicines.\n\n# Clinical evidence\n\n## The company's modified intention-to-treat analysis is suitable for decision making\n\nThe company presented a post-hoc subgroup analysis of trial\xa01839. This is a randomised double-blind trial of liraglutide or placebo, alongside diet and exercise. It included 3,721\xa0people with and without pre-diabetes (non-diabetic hyperglycaemia). Pre-diabetes was a pre-defined subgroup of 2,254\xa0people who were followed up for 3\xa0years. The post-hoc subgroup came from this pre-defined pre-diabetes subgroup. It included 800\xa0people with a BMI of 35\xa0kg/m2 or more, with pre-diabetes (defined as a haemoglobin\xa0A1c level of 42 mmol/mol to 47\xa0mmol/mol [6.0% to 6.4%] or a fasting plasma glucose level of 5.5 mmol/litre to 6.9\xa0mmol/litre), and a high risk of cardiovascular disease (defined as the presence of 1\xa0or more of: a total cholesterol level of more than 5\xa0mmol/litre, systolic blood pressure of more than 140\xa0mmHg, or a high-density lipoprotein level of less than 1.0\xa0mmol/litre for men and less than 1.3\xa0mmol/litre for women). Weight-related outcomes (BMI and percentage weight loss) significantly favoured liraglutide compared with placebo. Statistically significantly fewer people developed type\xa02 diabetes with liraglutide than with placebo, and more patients reverted to normal glucose tolerance on liraglutide than on placebo. The committee considered that the trial was of good quality. The post-hoc subgroup population was identifiable, in that it represented a high-risk population of people who were likely to have a higher absolute benefit from liraglutide. The committee noted that the post-hoc subgroup is associated with more uncertainty than the larger pre-defined pre-diabetes trial population. The company explained that its modified intention-to-treat analysis included efficacy data for the full pre-diabetes population. The committee concluded that this analysis was suitable for decision making.\n\n## The cardiovascular benefits of liraglutide are uncertain\n\nThe committee considered the evidence from the full population of trial\xa01839, which did not show a significant reduction in cardiovascular events in people having liraglutide compared with placebo over the 3\xa0years of the trial. It noted the small number of significant cardiovascular events in the trial. The average age of the population was 48, in whom the baseline cardiovascular risk would not be particularly high. The company indicated that weight gain stops around age\xa067 because of loss of muscle mass, and therefore the average age of patients in the trial was not an unreasonable estimate of those who might be offered liraglutide in clinical practice. The cardiovascular benefit of liraglutide in the company's model was based on risk reduction using surrogate outcomes such as haemoglobin\xa0A1c and blood pressure. This approach introduces uncertainty because causal inference requires direct evidence that liraglutide reduces cardiovascular events. This was not provided in the company submission because of lack of long-term evidence. The clinical experts explained that reductions in the surrogate outcomes were likely to reduce long-term cardiovascular risk. The committee accepted the clinical experts' opinion that temporary reductions in weight can result in long-term cardiovascular benefits. The committee acknowledged that relying on surrogates is uncertain but accepted that surrogate outcomes were the only available evidence to estimate cardiovascular benefits.\n\n# Duration of treatment\n\n## Obesity is a long-term condition, therefore limiting treatment to 2\xa0years is not ideal\n\nThe committee noted that obesity is a long-term condition. For other long-term conditions, such as hypertension and diabetes, treatment continues long term. The committee sought justification for the company's proposal that all patients who had an initial weight loss of more than 5% (and so continued on treatment), would stop treatment at 2\xa0years. The clinical experts explained that people who have lost weight are likely to want to continue taking the treatment. This was confirmed by the patient expert. The clinical experts also explained that people who experience side effects with minimal weight loss are most likely to stop taking the treatment. They stated that some people take liraglutide until they achieve their desired weight loss then stop taking it, restarting it when they regain weight. The committee had concerns that the company's submission was based on a maximum treatment duration of 2\xa0years. It noted that a 2‑year treatment duration does not address the clinical need to reduce weight and then maintain a reduced weight. Also, it does not reflect the clinical trial. The clinical experts explained that patients are usually discharged from NHS tier\xa03 weight management services after 2\xa0years of continuous treatment. The committee concluded that treating a chronic condition such as obesity for only 2\xa0years is not ideal. But it accepted that the cost-effectiveness estimate was based on a single course of treatment of no longer than 2\xa0years, and that the assumption that treatment would be stopped at 2\xa0years was reasonable in the context of NHS tier\xa03 weight management services.\n\n# The company's economic model\n\n## The health states and transitions in the model are suitable for decision making\n\nThe company submitted a cohort state-transition model with 10\xa0health states, to estimate the cost effectiveness of liraglutide compared with diet and exercise alone. Transitions between health states were based on estimated type\xa02 diabetes mellitus status and cardiovascular events (primary and secondary). The model used risk equations and death probabilities. A once-only transition was used to incorporate the proportion of patients reversing from pre-diabetes to normal glucose tolerance based on trial\xa01839 data. The relative treatment effectiveness was estimated through changes in BMI, systolic blood pressure, total and high-density lipoprotein cholesterol parameters in the risk models. Patients were assumed to have stopped treatment at 2\xa0years and gain weight over the next 3\xa0years, so they return to the weight expected if they had never had treatment. Patients entered the model with pre-diabetes. The committee noted that the risk equations used relative effectiveness on surrogate end points to estimate long-term cardiovascular events, which introduced uncertainty. But it concluded that the health states and transitions in the model were suitable for decision making.\n\n## The cardiovascular risk equations are suitable for decision making\n\nThe company's model used risk equations to estimate the long-term risk of myocardial infarction, angina and stroke (including transient ischaemic attack). The risk equations used surrogate effectiveness parameters such as BMI, systolic blood pressure, total cholesterol and high-density lipoprotein. The committee considered that the risk equations were not prognostic on an individual basis and were based on an assumption of a steady-state. The committee acknowledged that there was no clear alternative to the use of risk equations in the model, but it had concerns about the assumptions of cardiovascular outcome benefits that were based on temporary improvements in risk factors. The clinical experts explained that short-term weight loss and temporary improvement in diabetic status can reduce long-term cardiovascular risk. The committee was satisfied that liraglutide, when used as proposed by the company, has a temporary benefit on weight and diabetic status and this could reduce the long-term risk of myocardial infarction, angina and stroke. The company's model included several different risk equations to predict prevention of cardiovascular events, and different risk equations were used in the company's and the ERG's preferred base-case analyses. The committee accepted that the risk equations selected in the company's and ERG's base case were both suitable for decision making.\n\n## The assumptions for weight gain and diabetic status are uncertain\n\nNo follow-up data were available on weight gain and diabetic status after stopping treatment in trial\xa01839. The company assumed that after completing a 2‑year course of liraglutide, weight would gradually increase over the next 3\xa0years. It also assumed that people whose glucose tolerance became normal on treatment would revert to being pre-diabetic after 3\xa0years. The committee noted that people in the model regained their initial weight. But they might be expected to regain more weight after treatment stopped, resulting in a higher weight than before starting treatment. Because no follow-up data were available for weight gain or diabetic status in the 3\xa0years after stopping treatment, the committee accepted the assumptions and the associated uncertainty.\n\n## The model assumes that all people develop type 2 diabetes after a cardiovascular event\n\nThe committee discussed the company's 'simplifying' assumption that all people who have a cardiovascular event develop type\xa02 diabetes within the following year. The clinical experts explained that people are more likely to be diagnosed with type\xa02 diabetes after a cardiovascular event, but this relationship is not causal. The committee heard that there is no good evidence to determine the proportion of people who develop type\xa02 diabetes after a cardiovascular event. During technical engagement, the company presented a scenario analysis in which people did not develop type\xa02 diabetes after a cardiovascular event. The committee had reservations about the simplifying assumption but was reassured by the results of the company's scenario analysis. The committee agreed that the most plausible incremental cost-effectiveness ratio (ICER) would be between the base-case ICERs, which applied the simplifying assumption, and the scenario analysis that did not. The ICER is therefore likely to be within what NICE normally considers a cost-effective use of NHS resources.\n\n# Cost-effectiveness results\n\n## Because of the uncertainty an acceptable ICER is £20,000 per QALY gained\n\nNICE's guide to the methods of technology appraisal notes that above a most plausible ICER of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. Because of the uncertainties in the modelling assumptions, particularly what happens after stopping liraglutide and the calculation of long-term benefits, the committee agreed that an acceptable ICER would not be higher than £20,000 per QALY gained.\n\n## The company's base-case ICER is below £20,000 per QALY gained\n\nThe company's base-case analysis:\n\nincluded clinical-effectiveness estimates from the post-hoc subgroup of trial\xa01839 (see\xa0section 3.5)\n\nimplemented the 2‑year treatment duration rule (see\xa0section 3.7)\n\nused the UKPDS‑82 risk equation to model primary and secondary cardiovascular disease outcomes (see\xa0section 3.9)\n\nassumed that any weight loss returned to the base weight 3\xa0years after treatment discontinuation (see\xa0section 3.10)\n\nassumed that type\xa02 diabetes developed in the first year after a cardiovascular event (see\xa0section 3.11).The company's base-case ICER for liraglutide plus diet and exercise compared with diet and exercise alone was £11,293 per QALY gained.\n\n## The ERG's base-case ICER is below £20,000 per QALY gained\n\nThe ERG's preferred base-case analysis was similar to the company's base case but included:\n\nthe Qrisk‑3 risk equation to predict development of primary cardiovascular disease outcomes (see\xa0section 3.9)\n\nthe Framingham recurring coronary heart disease risk equation to predict development of secondary cardiovascular disease outcomes (see\xa0section 3.9).The ERG's preferred base-case ICER for liraglutide plus diet and exercise compared with diet and exercise alone was £13,569 per QALY gained.\n\n## All the scenario analyses result in ICERs below £20,000 per QALY gained\n\nThe company's and the ERG's scenario analyses all resulted in an ICER below £20,000 per QALY gained. The committee agreed that the scenario analyses addressed several areas of uncertainty in the economic model. Specifically, the committee noted that:\n\nthe scenario using efficacy data from the whole pre-diabetes population rather than the post-hoc sub group (see\xa0section 3.5) reduced the base-case ICER\n\nremoving the assumption that type 2 diabetes always develops after a cardiovascular event (see\xa0section 3.11) did not increase the ICER above £20,000 per QALY gained in the company's or the ERG's scenarios.\n\n# Other factors\n\nThe committee noted that people from some minority ethnic groups are at an equivalent risk of the consequences of obesity at a lower BMI than the white population. NICE's guideline on BMI recommends using lower BMI thresholds for south Asian, Chinese, black African and African-Caribbean populations when identifying the risk of developing type\xa02 diabetes and providing interventions to prevent it. The committee agreed that a similar adjustment is appropriate when considering liraglutide. It concluded that the BMI threshold of at least 35\xa0kg/m2 should be adjusted appropriately when considering liraglutide for people from minority ethnic groups known to be at equivalent risk of the consequences of obesity at a lower BMI than the white population.\n\n# Conclusion\n\n## Liraglutide is a cost-effective use of NHS resources\n\nThe committee noted that the company's and the ERG's base case and scenario analyses resulted in ICERs for liraglutide of less than £20,000 per QALY gained. The committee therefore recommended liraglutide as a cost-effective treatment for use in the NHS for adults with a BMI of at least 35\xa0kg/m2, non-diabetic hyperglycaemia, and a high risk of cardiovascular disease alongside a reduced-calorie diet and increased physical activity. The BMI threshold should be adjusted appropriately for people from minority ethnic groups known to be at equivalent risk of the consequences of obesity at a lower BMI than the white population."}
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https://www.nice.org.uk/guidance/ta664
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Evidence-based recommendations on liraglutide (Saxenda) for managing overweight and obesity alongside a reduced-calorie diet and increased physical activity in adults.
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66d3b5921171f477766a48b98a98d03625879cc2
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nice
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Upadacitinib for treating severe rheumatoid arthritis
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Upadacitinib for treating severe rheumatoid arthritis
Evidence-based recommendations on upadacitinib (Rinvoq) for severe active rheumatoid arthritis in adults.
# Recommendations
This guidance only includes recommendations for treating severe rheumatoid arthritis.
The scope for this technology appraisal also included moderate rheumatoid arthritis. This is covered by NICE technology appraisal guidance on upadacitinib for treating moderate rheumatoid arthritis.
Upadacitinib, with methotrexate, is recommended as an option for treating active rheumatoid arthritis in adults whose disease has responded inadequately to intensive therapy with a combination of conventional disease-modifying antirheumatic drugs (DMARDs), only if:
disease is severe (a disease activity score of more than 5.1) and
the company provides upadacitinib according to the commercial arrangement.
Upadacitinib, with methotrexate, is recommended as an option for treating active rheumatoid arthritis in adults whose disease has responded inadequately to or who cannot have other DMARDs, including at least 1 biological DMARD, only if:
disease is severe (a DAS28 of more than 5.1) and
they cannot have rituximab and
the company provides upadacitinib according to the commercial arrangement.
Upadacitinib, with methotrexate, is recommended as an option for treating active rheumatoid arthritis in adults whose disease has responded inadequately to rituximab and at least 1 biological DMARD, only if:
disease is severe (a DAS28 of more than 5.1) and
the company provides upadacitinib according to the commercial arrangement.
Upadacitinib can be used as monotherapy for people who cannot take methotrexate because it is contraindicated or because of intolerance, when the criteria in sections 1.1, 1.2 or 1.3 are met.
Continue treatment only if there is a moderate response measured using European League Against Rheumatism (EULAR) criteria at 6 months after starting therapy. After an initial response within 6 months, stop treatment if at least a moderate EULAR response is not maintained.
When using the DAS28, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or communication difficulties that could affect the responses to the DAS28 and make any adjustments they consider appropriate.
These recommendations are not intended to affect treatment with upadacitinib that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Clinical trials show that upadacitinib with methotrexate or conventional DMARDs is more effective than methotrexate or conventional DMARDs for treating moderate to severe active rheumatoid arthritis that has not responded adequately to conventional DMARDs. The trials also show that for moderate to severe active rheumatoid arthritis that has not responded adequately to conventional DMARDs, upadacitinib with methotrexate is more effective than adalimumab with methotrexate or placebo with methotrexate.
Because there are no trials comparing upadacitinib with the full range of biological DMARDs, the company did an indirect comparison. This shows that upadacitinib with conventional DMARDs (including methotrexate) or on its own works as well as the biological DMARDs that NICE has already recommended.
Based on the health-related benefits and costs compared with conventional and biological DMARDs, upadacitinib alone, or with methotrexate, is recommended only for severe active rheumatoid arthritis, in line with recommendations in NICE's technology appraisal guidance on:
sarilumab for moderate to severe rheumatoid arthritis
tofacitinib for moderate to severe rheumatoid arthritis
baricitinib for moderate to severe rheumatoid arthritis
certolizumab pegol for treating rheumatoid arthritis after inadequate response to a TNF-alpha inhibitor
adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis not previously treated with DMARDs or after conventional DMARDs only have failed
tocilizumab for the treatment of rheumatoid arthritis
golimumab for the treatment of rheumatoid arthritis after the failure of previous disease-modifying anti-rheumatic drugs
adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor.# Information about upadacitinib
# Marketing authorisation
Upadacitinib (Rinvoq, AbbVie) is indicated 'for the treatment of moderate to severe active rheumatoid arthritis in adult patients who have responded inadequately to, or who are intolerant to, 1 or more disease-modifying antirheumatic drugs (DMARDs)'. Upadacitinib may be used as monotherapy or with methotrexate.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price for upadacitinib is £805.56 per 28‑day pack (company submission). The average cost for each patient per year is estimated at £10,508, based on the list price. The company has a commercial arrangement. This makes upadacitinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by AbbVie, a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:
the ERG's modelling of severe rheumatoid arthritis treatment sequences was acceptable for decision making
the ERG's application of the network meta-analysis results was acceptable for decision making.
After technical engagement, there were a number of outstanding uncertainties in the analyses (see technical report, pages 13 to 14). The committee took these into account in its decision making.
# Treatments for rheumatoid arthritis
## A range of treatment options is important in rheumatoid arthritis and upadacitinib is an additional option
The patient expert explained that rheumatoid arthritis is a lifetime condition that can severely reduce quality of life. The clinical experts stated that conventional disease-modifying antirheumatic drugs (DMARDs) such as methotrexate are inadequate for many people with active rheumatoid arthritis. The expert also added that for a significant proportion of people who are eligible for treatment with biological DMARDs, their disease inadequately responds to these treatments. Both the clinical and patient experts said it would be helpful to have new treatments for various points in the treatment pathway. The committee concluded that a range of treatment options was important in rheumatoid arthritis and that upadacitinib would be a welcome additional option.
## There is NICE technology appraisal guidance for different points in the rheumatoid arthritis treatment pathway
NICE technology appraisal guidance currently recommends the following DMARDs for severe rheumatoid arthritis:
tofacitinib
baricitinib
adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, and abatacept
sarilumab
tocilizumab.Of these, adalimumab, certolizumab pegol, etanercept, golimumab and infliximab are tumour necrosis factor (TNF)-alpha inhibitors. Tofacitinib and baricitinib are Janus kinase inhibitors, and sarilumab and tocilizumab are interleukin-6 (IL-6) inhibitors. The biological and targeted synthetic DMARDs (adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, abatacept, sarilumab, tofacitinib, baricitinib and tocilizumab) are recommended with methotrexate, in people with severe rheumatoid arthritis that has not responded to intensive treatment with combinations of conventional DMARDs. Disease severity is assessed using the disease activity score (DAS28). A DAS28 of more than 5.1 indicates severe disease (between 3.2 and 5.1 indicates moderate disease, between 2.6 and 3.2 indicates mild disease and 2.6 or less indicates disease remission). For people who have severe disease that has not responded to intensive treatment with conventional DMARDs but who cannot take methotrexate, the guidance recommends that adalimumab, baricitinib, certolizumab pegol, etanercept, tofacitinib, sarilumab or tocilizumab may be used as monotherapy. It recommends treatment should start with the least expensive drug (taking into account administration costs, dose needed and product price per dose) and should only be continued according to European League Against Rheumatism (EULAR) response at 6 months. For people with severe rheumatoid arthritis who have already had at least 1 TNF-alpha inhibitor that has not worked, NICE technology appraisal guidance on adalimumab, etanercept, infliximab, rituximab and abatacept and golimumab recommend the biological DMARD rituximab with methotrexate for treating severe active rheumatoid arthritis. But, if rituximab is contraindicated or withdrawn because of an adverse event, NICE technology appraisal guidance recommends abatacept, adalimumab, etanercept, infliximab, golimumab, tocilizumab, certolizumab pegol, baricitinib, tofacitinib or sarilumab with methotrexate. If methotrexate is contraindicated or withdrawn because of an adverse event, NICE's guidance recommends adalimumab, etanercept, tocilizumab, certolizumab pegol, baricitinib, tofacitinib or sarilumab as monotherapy. NICE technology appraisal guidance also recommends tocilizumab with methotrexate when neither TNF-alpha inhibitors nor rituximab have worked.
## There are 4 different points in the severe disease treatment pathway when upadacitinib might be used
Upadacitinib's marketing authorisation and the company's submission covers its use at 4 points in the treatment pathway, specifically in adults with:
Severe, active rheumatoid arthritis ('severe disease') that has not responded adequately to 2 or more conventional DMARDs. The comparators at this position included abatacept, adalimumab, baricitinib, certolizumab pegol, etanercept, golimumab, infliximab, sarilumab, tocilizumab and tofacitinib, all with methotrexate. If methotrexate was not tolerated or contraindicated, the comparators included adalimumab, baricitinib, certolizumab pegol, etanercept, golimumab, sarilumab, tocilizumab and tofacitinib, each used alone.
Severe disease that has not responded adequately to 1 or more biological DMARD, if rituximab is not a treatment option. The comparators at this position included abatacept, adalimumab, baricitinib, certolizumab pegol, etanercept, golimumab, infliximab, sarilumab, tocilizumab and tofacitinib, all with methotrexate. If methotrexate was not tolerated or contraindicated, the comparators included adalimumab, baricitinib, certolizumab pegol, etanercept, golimumab, sarilumab, tocilizumab and tofacitinib, each used alone.
Severe disease that has not responded adequately to 1 or more biological DMARD, when rituximab is a treatment option. The comparator in this position was rituximab with methotrexate.
Severe disease that has not responded adequately to rituximab and 1 or more biological DMARD. The comparators in this position were sarilumab and tocilizumab, both with methotrexate.The committee also noted that the marketing authorisation includes the use of upadacitinib alone or with methotrexate.
# Clinical effectiveness
## The clinical trials are acceptable for decision making but do not include all relevant comparators
The company's clinical evidence came from 4 randomised controlled trials. The trials included people with moderate to severe rheumatoid arthritis (see section 3.2). The trials were:
SELECT-COMPARE, a phase 3 trial which included people whose disease responded inadequately to methotrexate. Upadacitinib was given with methotrexate and the comparator was adalimumab with methotrexate or placebo with methotrexate.
SELECT-NEXT, a phase 3 trial which included people whose disease responded inadequately to at least 1 conventional DMARD. Upadacitinib was given with conventional DMARDs and the comparator was placebo with conventional DMARDs.
SELECT-MONOTHERAPY, a phase 3 trial which included people whose disease responded inadequately to methotrexate. Upadacitinib was given as a monotherapy and the comparator was methotrexate.
SELECT-BEYOND, a phase 3 trial which included people whose disease responded inadequately to biological DMARDs. Upadacitinib was given with conventional DMARDs and the comparator was conventional DMARDs and placebo.The committee concluded that the trials were relevant and acceptable for decision making but did not include all relevant comparators (see section 3.3).
## The trials show upadacitinib is more clinically effective than adalimumab, conventional DMARDs (including methotrexate) or placebo for moderate to severe disease that has responded inadequately to conventional DMARDs
In SELECT-COMPARE, upadacitinib with methotrexate showed a statistically significant improvement in American College of Rheumatology response (ACR20) at 12 weeks compared with adalimumab with methotrexate or placebo with methotrexate (upadacitinib 71%, adalimumab 63%, p≤0.050; placebo 36%, p≤0.001). In SELECT-NEXT, upadacitinib with conventional DMARDs showed a statistically significant improvement in ACR20 at 12 weeks compared with placebo with conventional DMARDs (upadacitinib 64%, placebo 36%, p≤0.001). In SELECT-MONOTHERAPY, upadacitinib alone showed a statistically significant improvement in ACR20 at 12 weeks compared with methotrexate alone (upadacitinib 68%, methotrexate 41%, p≤0.001). The committee also noted that the ERG and company considered that the safety profile for upadacitinib was similar to other biological DMARDs. The committee concluded that upadacitinib with methotrexate was more clinically effective than adalimumab, placebo with methotrexate or placebo with conventional DMARDs. Also, upadacitinib alone was more clinically effective than methotrexate for moderate to severe rheumatoid arthritis that had responded inadequately to conventional DMARDs.
## The trials show upadacitinib is more clinically effective than placebo for moderate to severe rheumatoid arthritis that has responded inadequately to biological DMARDs
In SELECT-BEYOND, upadacitinib with conventional DMARDs showed a statistically significant improvement in ACR20 at 12 weeks compared with placebo with conventional DMARDs (upadacitinib 65%, placebo 28%, p≤0.001). The committee concluded that upadacitinib with conventional DMARDs was more clinically effective than placebo with conventional DMARDs for moderate to severe rheumatoid arthritis that had responded inadequately to biological DMARDs.
# Indirect comparison
## Network meta-analyses show that upadacitinib with conventional DMARDs or alone works as well as biological DMARDs
Other than the direct comparison with adalimumab, there was no other comparative trial evidence of upadacitinib compared with biological DMARDs. To compare with other biological DMARDs, the company did a network meta-analysis. It did separate analyses for people whose disease responded inadequately to either conventional or biological DMARDs. It also changed ACR responses to EULAR responses to inform treatment-effectiveness estimates used in the economic model. The company used 12- to 14-week data from the clinical trials to estimate EULAR response at week 24. For those whose disease responded inadequately to conventional DMARDs, the network meta-analyses at week 24 showed that:
Upadacitinib with conventional DMARDs gave better EULAR response rates than conventional DMARDs alone.
Upadacitinib with conventional DMARDs gave similar EULAR response rates to biological DMARDs with conventional DMARDs.
Upadacitinib alone gave better EULAR response rates than conventional DMARDs alone.
Upadacitinib alone gave similar EULAR response rates to biological DMARDs alone.For those whose disease responded inadequately to biological DMARDs, the company's network meta-analyses at week 24 showed:
Upadacitinib with conventional DMARDs gave similar EULAR response rates to biological DMARDs with conventional DMARDs.
Upadacitinib alone gave similar EULAR response rates to biological DMARDs alone.The committee noted several limitations of the network meta-analyses:
They relied on EULAR responses that had been mapped from ACR.
They assumed that the same treatment effect applied regardless of the position in the treatment pathway. This did not reflect clinical practice because treatments used later in the treatment pathway are likely to have a lower response rate.
They contained a mixed population and some results were applied to populations who would not have the treatment in clinical practice. For example, evidence from trials using methotrexate and rituximab may be applied to people for whom these treatments are not suitable. However, the committee recognised that, given the limitations of the available data, network meta-analyses stratified by line of treatment may not be possible.The network meta-analyses showed upadacitinib with conventional DMARDs or alone works as well as other biological DMARDs, but the analyses were limited. The committee concluded that for severe disease, there was limited direct trial evidence. Therefore it accepted the network meta-analyses for decision making.
# Economic model inputs and assumptions
## The company and ERG's mapping algorithm to link HAQ and pain scores are plausible methods to estimate utility values
In the company's base case, health-related quality-of-life data were calculated using a mapping function to work out a person's pain score from their Stanford Health Assessment Questionnaire (HAQ) score. HAQ is 1 component of the ACR criteria and scores physical disability and pain from 0 (least disability) to 3 (most severe disability). The mapping function used SELECT trial data, to estimate EQ‑5D values. The ERG noted that NICE's technology appraisal guidance on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis not previously treated with DMARDs or after conventional DMARDs only have failed (from now on referred to as TA375) used data from the National Databank for Rheumatic Diseases dataset to map from HAQ-to-pain score. The ERG explained that while the company's approach may be acceptable, the ERG preferred the mapping based on the National Databank for Rheumatic Diseases dataset. This was because the dataset contained over 100,000 observations. After consultation, the company suggested that the mapping based on the National Databank for Rheumatic Diseases dataset gave some counter-intuitive results. This was because some of the lowest functionality was associated with reduced pain. The company confirmed that this was not seen in its preferred method based on mapping using the clinical trials. The committee was aware that the choice of mapping did not have a large effect on severe disease because health-related quality of life was similar across the different comparators. It noted that the company's method led to lower cost-effectiveness estimates compared with conventional DMARDs. The committee concluded that both the company and ERG approaches were plausible, but noted that the ERG's approach was used in TA375 and was based on a much larger dataset.
# Economic model validation
## The company's model is reasonably consistent with the model used in TA375
The company based its model on the model developed by the assessment group for TA375. The company provided a validation analysis comparing the outputs of its model with those from the model used in TA375 for several treatment sequences. The ERG suggested that the results of this analysis appeared to show that the company's model overestimated quality-adjusted life year (QALY) gains for biological DMARDs compared with conventional DMARDs. It explained that this primarily impacts the cost-effectiveness analysis for moderate disease, when upadacitinib is compared with conventional DMARDs. At the committee meeting, the company advised that it had found errors in the ERG's validation analysis and that its own model produced similar results to the model from TA375. After consultation, the company submitted further validation results that included corrections of 4 errors. The ERG noted that after consultation, the company's results reasonably aligned with TA375. The committee concluded that the company's model was reasonably consistent with the model used in TA375.
# Cost-effectiveness results
## In severe disease, upadacitinib with methotrexate is cost effective after conventional DMARDs
The ERG did analyses for people with severe disease whose disease had responded inadequately to conventional DMARDs. The clinical- and cost-effectiveness estimates for upadacitinib compared with conventional DMARDs were similar to what was previously seen in other technology appraisals for rheumatoid arthritis. Upadacitinib dominated (that is, it was cheaper and more effective than the comparator) or gave an incremental cost-effectiveness ratio (ICER) under £30,000 per QALY gained when confidential comparator discounts were applied. The committee concluded that it could recommend upadacitinib with methotrexate as a cost-effective use of NHS resources for people with severe rheumatoid arthritis whose disease had responded inadequately to conventional DMARDs. This was in line with TA375.
## In severe disease, upadacitinib with methotrexate is not cost effective after biological DMARDs if rituximab is a treatment option
The ERG did an analysis for people with severe disease that has responded inadequately to biological DMARDs when rituximab is a treatment option. In this, upadacitinib with conventional DMARDs was dominated by rituximab with conventional DMARDs (that is, upadacitinib was more expensive and less effective). The committee concluded that upadacitinib with conventional DMARDs was not a cost-effective use of NHS resources for people with severe rheumatoid arthritis whose disease had responded inadequately to biological DMARDs if rituximab was a treatment option. Therefore, it was not recommended at this position in the pathway.
## In severe disease, upadacitinib with methotrexate is cost effective after rituximab and other biological DMARDs
The ERG did analyses for people with severe disease that had not responded adequately to rituximab and other biological DMARDs. In this, the cost-effectiveness estimates for intravenous or subcutaneous tocilizumab with methotrexate compared with upadacitinib with methotrexate were over £100,000 per QALY gained. Sarilumab with methotrexate was dominated by upadacitinib with methotrexate (that is, upadacitinib was less expensive and more effective). The committee therefore recommended upadacitinib with conventional DMARDs for people with severe rheumatoid arthritis whose disease has not responded adequately to rituximab and other biological DMARDs.
## In severe disease, upadacitinib monotherapy is cost effective after conventional DMARDs if methotrexate is not suitable
The marketing authorisation for upadacitinib includes its use as a monotherapy. The committee noted that the clinical- and cost-effectiveness results for upadacitinib monotherapy were similar to those for upadacitinib with methotrexate. It was aware that the available evidence for upadacitinib monotherapy was from people whose disease responded inadequately to methotrexate. The clinical expert explained that methotrexate is not tolerated by some patients or it is contraindicated. In line with TA375, the committee agreed that the minority of people with severe active rheumatoid arthritis who could not tolerate methotrexate should not be treated differently from other people with severe disease, as far as possible. The committee agreed that upadacitinib monotherapy was cost effective for severe active rheumatoid arthritis after conventional DMARDs if methotrexate was not suitable.
# Other factors
## Healthcare professionals should consider any disabilities or communication difficulties when using the DAS28 measure
A potential equality issue was raised during the scoping process, about people with rheumatoid arthritis who have difficulty communicating. For these people, it may be more difficult to assess outcomes when using the DAS28 measure. The committee concluded that healthcare professionals should consider any physical, psychological, sensory or learning disabilities, or communication difficulties that could affect the responses to the DAS28 and make any adjustments they consider appropriate.
## The benefits of upadacitinib can be captured in the cost-effectiveness analysis
Upadacitinib, like other targeted synthetic DMARDs, is taken orally. This is valued by patients. The committee noted that there are also other treatments with a similar mechanism of action available for rheumatoid arthritis. Therefore the committee concluded that all the benefits of upadacitinib can be captured in the model.
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{'Recommendations': "This guidance only includes recommendations for treating severe rheumatoid arthritis.\n\nThe scope for this technology appraisal also included moderate rheumatoid arthritis. This is covered by NICE technology appraisal guidance on upadacitinib for treating moderate rheumatoid arthritis.\n\nUpadacitinib, with methotrexate, is recommended as an option for treating active rheumatoid arthritis in adults whose disease has responded inadequately to intensive therapy with a combination of conventional disease-modifying antirheumatic drugs (DMARDs), only if:\n\ndisease is severe (a disease activity score [DAS28] of more than 5.1) and\n\nthe company provides upadacitinib according to the commercial arrangement.\n\nUpadacitinib, with methotrexate, is recommended as an option for treating active rheumatoid arthritis in adults whose disease has responded inadequately to or who cannot have other DMARDs, including at least 1\xa0biological DMARD, only if:\n\ndisease is severe (a DAS28 of more than 5.1) and\n\nthey cannot have rituximab and\n\nthe company provides upadacitinib according to the commercial arrangement.\n\nUpadacitinib, with methotrexate, is recommended as an option for treating active rheumatoid arthritis in adults whose disease has responded inadequately to rituximab and at least 1 biological DMARD, only if:\n\ndisease is severe (a DAS28 of more than 5.1) and\n\nthe company provides upadacitinib according to the commercial arrangement.\n\nUpadacitinib can be used as monotherapy for people who cannot take methotrexate because it is contraindicated or because of intolerance, when the criteria in sections\xa01.1, 1.2 or 1.3 are met.\n\nContinue treatment only if there is a moderate response measured using European League Against Rheumatism (EULAR) criteria at 6\xa0months after starting therapy. After an initial response within 6\xa0months, stop treatment if at least a moderate EULAR response is not maintained.\n\nWhen using the DAS28, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or communication difficulties that could affect the responses to the DAS28 and make any adjustments they consider appropriate.\n\nThese recommendations are not intended to affect treatment with upadacitinib that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nClinical trials show that upadacitinib with methotrexate or conventional DMARDs is more effective than methotrexate or conventional DMARDs for treating moderate to severe active rheumatoid arthritis that has not responded adequately to conventional DMARDs. The trials also show that for moderate to severe active rheumatoid arthritis that has not responded adequately to conventional DMARDs, upadacitinib with methotrexate is more effective than adalimumab with methotrexate or placebo with methotrexate.\n\nBecause there are no trials comparing upadacitinib with the full range of biological DMARDs, the company did an indirect comparison. This shows that upadacitinib with conventional DMARDs (including methotrexate) or on its own works as well as the biological DMARDs that NICE has already recommended.\n\nBased on the health-related benefits and costs compared with conventional and biological DMARDs, upadacitinib alone, or with methotrexate, is recommended only for severe active rheumatoid arthritis, in line with recommendations in NICE's technology appraisal guidance on:\n\nsarilumab for moderate to severe rheumatoid arthritis\n\ntofacitinib for moderate to severe rheumatoid arthritis\n\nbaricitinib for moderate to severe rheumatoid arthritis\n\ncertolizumab pegol for treating rheumatoid arthritis after inadequate response to a TNF-alpha inhibitor\n\nadalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis not previously treated with DMARDs or after conventional DMARDs only have failed\n\ntocilizumab for the treatment of rheumatoid arthritis\n\ngolimumab for the treatment of rheumatoid arthritis after the failure of previous disease-modifying anti-rheumatic drugs\n\nadalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor.", 'Information about upadacitinib': "# Marketing authorisation\n\nUpadacitinib (Rinvoq, AbbVie) is indicated 'for the treatment of moderate to severe active rheumatoid arthritis in adult patients who have responded inadequately to, or who are intolerant to, 1 or more disease-modifying antirheumatic drugs (DMARDs)'. Upadacitinib may be used as monotherapy or with methotrexate.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price for upadacitinib is £805.56 per 28‑day pack (company submission). The average cost for each patient per year is estimated at £10,508, based on the list price. The company has a commercial arrangement. This makes upadacitinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by AbbVie, a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:\n\nthe ERG's modelling of severe rheumatoid arthritis treatment sequences was acceptable for decision making\n\nthe ERG's application of the network meta-analysis results was acceptable for decision making.\n\nAfter technical engagement, there were a number of outstanding uncertainties in the analyses (see technical report, pages\xa013 to\xa014). The committee took these into account in its decision making.\n\n# Treatments for rheumatoid arthritis\n\n## A range of treatment options is important in rheumatoid arthritis and upadacitinib is an additional option\n\nThe patient expert explained that rheumatoid arthritis is a lifetime condition that can severely reduce quality of life. The clinical experts stated that conventional disease-modifying antirheumatic drugs (DMARDs) such as methotrexate are inadequate for many people with active rheumatoid arthritis. The expert also added that for a significant proportion of people who are eligible for treatment with biological DMARDs, their disease inadequately responds to these treatments. Both the clinical and patient experts said it would be helpful to have new treatments for various points in the treatment pathway. The committee concluded that a range of treatment options was important in rheumatoid arthritis and that upadacitinib would be a welcome additional option.\n\n## There is NICE technology appraisal guidance for different points in the rheumatoid arthritis treatment pathway\n\nNICE technology appraisal guidance currently recommends the following DMARDs for severe rheumatoid arthritis:\n\ntofacitinib\n\nbaricitinib\n\nadalimumab, etanercept, infliximab, certolizumab pegol, golimumab, and abatacept\n\nsarilumab\n\ntocilizumab.Of these, adalimumab, certolizumab pegol, etanercept, golimumab and infliximab are tumour necrosis factor (TNF)-alpha inhibitors. Tofacitinib and baricitinib are Janus kinase inhibitors, and sarilumab and tocilizumab are interleukin-6 (IL-6) inhibitors. The biological and targeted synthetic DMARDs (adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, abatacept, sarilumab, tofacitinib, baricitinib and tocilizumab) are recommended with methotrexate, in people with severe rheumatoid arthritis that has not responded to intensive treatment with combinations of conventional DMARDs. Disease severity is assessed using the disease activity score (DAS28). A DAS28 of more than 5.1 indicates severe disease (between 3.2 and 5.1 indicates moderate disease, between 2.6 and 3.2 indicates mild disease and 2.6 or less indicates disease remission). For people who have severe disease that has not responded to intensive treatment with conventional DMARDs but who cannot take methotrexate, the guidance recommends that adalimumab, baricitinib, certolizumab pegol, etanercept, tofacitinib, sarilumab or tocilizumab may be used as monotherapy. It recommends treatment should start with the least expensive drug (taking into account administration costs, dose needed and product price per dose) and should only be continued according to European League Against Rheumatism (EULAR) response at 6\xa0months. For people with severe rheumatoid arthritis who have already had at least 1\xa0TNF-alpha inhibitor that has not worked, NICE technology appraisal guidance on adalimumab, etanercept, infliximab, rituximab and abatacept and golimumab recommend the biological DMARD rituximab with methotrexate for treating severe active rheumatoid arthritis. But, if rituximab is contraindicated or withdrawn because of an adverse event, NICE technology appraisal guidance recommends abatacept, adalimumab, etanercept, infliximab, golimumab, tocilizumab, certolizumab pegol, baricitinib, tofacitinib or sarilumab with methotrexate. If methotrexate is contraindicated or withdrawn because of an adverse event, NICE's guidance recommends adalimumab, etanercept, tocilizumab, certolizumab pegol, baricitinib, tofacitinib or sarilumab as monotherapy. NICE technology appraisal guidance also recommends tocilizumab with methotrexate when neither TNF-alpha inhibitors nor rituximab have worked.\n\n## There are 4 different points in the severe disease treatment pathway when upadacitinib might be used\n\nUpadacitinib's marketing authorisation and the company's submission covers its use at 4 points in the treatment pathway, specifically in adults with:\n\nSevere, active rheumatoid arthritis ('severe disease') that has not responded adequately to 2 or more conventional DMARDs. The comparators at this position included abatacept, adalimumab, baricitinib, certolizumab pegol, etanercept, golimumab, infliximab, sarilumab, tocilizumab and tofacitinib, all with methotrexate. If methotrexate was not tolerated or contraindicated, the comparators included adalimumab, baricitinib, certolizumab pegol, etanercept, golimumab, sarilumab, tocilizumab and tofacitinib, each used alone.\n\nSevere disease that has not responded adequately to 1 or more biological DMARD, if rituximab is not a treatment option. The comparators at this position included abatacept, adalimumab, baricitinib, certolizumab pegol, etanercept, golimumab, infliximab, sarilumab, tocilizumab and tofacitinib, all with methotrexate. If methotrexate was not tolerated or contraindicated, the comparators included adalimumab, baricitinib, certolizumab pegol, etanercept, golimumab, sarilumab, tocilizumab and tofacitinib, each used alone.\n\nSevere disease that has not responded adequately to 1 or more biological DMARD, when rituximab is a treatment option. The comparator in this position was rituximab with methotrexate.\n\nSevere disease that has not responded adequately to rituximab and 1 or more biological DMARD. The comparators in this position were sarilumab and tocilizumab, both with methotrexate.The committee also noted that the marketing authorisation includes the use of upadacitinib alone or with methotrexate.\n\n# Clinical effectiveness\n\n## The clinical trials are acceptable for decision making but do not include all relevant comparators\n\nThe company's clinical evidence came from 4\xa0randomised controlled trials. The trials included people with moderate to severe rheumatoid arthritis (see section\xa03.2). The trials were:\n\nSELECT-COMPARE, a phase\xa03 trial which included people whose disease responded inadequately to methotrexate. Upadacitinib was given with methotrexate and the comparator was adalimumab with methotrexate or placebo with methotrexate.\n\nSELECT-NEXT, a phase\xa03 trial which included people whose disease responded inadequately to at least 1 conventional DMARD. Upadacitinib was given with conventional DMARDs and the comparator was placebo with conventional DMARDs.\n\nSELECT-MONOTHERAPY, a phase\xa03 trial which included people whose disease responded inadequately to methotrexate. Upadacitinib was given as a monotherapy and the comparator was methotrexate.\n\nSELECT-BEYOND, a phase\xa03 trial which included people whose disease responded inadequately to biological DMARDs. Upadacitinib was given with conventional DMARDs and the comparator was conventional DMARDs and placebo.The committee concluded that the trials were relevant and acceptable for decision making but did not include all relevant comparators (see section\xa03.3).\n\n## The trials show upadacitinib is more clinically effective than adalimumab, conventional DMARDs (including methotrexate) or placebo for moderate to severe disease that has responded inadequately to conventional DMARDs\n\nIn SELECT-COMPARE, upadacitinib with methotrexate showed a statistically significant improvement in American College of Rheumatology response (ACR20) at 12\xa0weeks compared with adalimumab with methotrexate or placebo with methotrexate (upadacitinib 71%, adalimumab 63%, p≤0.050; placebo 36%, p≤0.001). In SELECT-NEXT, upadacitinib with conventional DMARDs showed a statistically significant improvement in ACR20 at 12\xa0weeks compared with placebo with conventional DMARDs (upadacitinib 64%, placebo 36%, p≤0.001). In SELECT-MONOTHERAPY, upadacitinib alone showed a statistically significant improvement in ACR20 at 12\xa0weeks compared with methotrexate alone (upadacitinib 68%, methotrexate 41%, p≤0.001). The committee also noted that the ERG and company considered that the safety profile for upadacitinib was similar to other biological DMARDs. The committee concluded that upadacitinib with methotrexate was more clinically effective than adalimumab, placebo with methotrexate or placebo with conventional DMARDs. Also, upadacitinib alone was more clinically effective than methotrexate for moderate to severe rheumatoid arthritis that had responded inadequately to conventional DMARDs.\n\n## The trials show upadacitinib is more clinically effective than placebo for moderate to severe rheumatoid arthritis that has responded inadequately to biological DMARDs\n\nIn SELECT-BEYOND, upadacitinib with conventional DMARDs showed a statistically significant improvement in ACR20 at 12\xa0weeks compared with placebo with conventional DMARDs (upadacitinib 65%, placebo 28%, p≤0.001). The committee concluded that upadacitinib with conventional DMARDs was more clinically effective than placebo with conventional DMARDs for moderate to severe rheumatoid arthritis that had responded inadequately to biological DMARDs.\n\n# Indirect comparison\n\n## Network meta-analyses show that upadacitinib with conventional DMARDs or alone works as well as biological DMARDs\n\nOther than the direct comparison with adalimumab, there was no other comparative trial evidence of upadacitinib compared with biological DMARDs. To compare with other biological DMARDs, the company did a network meta-analysis. It did separate analyses for people whose disease responded inadequately to either conventional or biological DMARDs. It also changed ACR responses to EULAR responses to inform treatment-effectiveness estimates used in the economic model. The company used 12- to 14-week data from the clinical trials to estimate EULAR response at week\xa024. For those whose disease responded inadequately to conventional DMARDs, the network meta-analyses at week\xa024 showed that:\n\nUpadacitinib with conventional DMARDs gave better EULAR response rates than conventional DMARDs alone.\n\nUpadacitinib with conventional DMARDs gave similar EULAR response rates to biological DMARDs with conventional DMARDs.\n\nUpadacitinib alone gave better EULAR response rates than conventional DMARDs alone.\n\nUpadacitinib alone gave similar EULAR response rates to biological DMARDs alone.For those whose disease responded inadequately to biological DMARDs, the company's network meta-analyses at week\xa024 showed:\n\nUpadacitinib with conventional DMARDs gave similar EULAR response rates to biological DMARDs with conventional DMARDs.\n\nUpadacitinib alone gave similar EULAR response rates to biological DMARDs alone.The committee noted several limitations of the network meta-analyses:\n\nThey relied on EULAR responses that had been mapped from ACR.\n\nThey assumed that the same treatment effect applied regardless of the position in the treatment pathway. This did not reflect clinical practice because treatments used later in the treatment pathway are likely to have a lower response rate.\n\nThey contained a mixed population and some results were applied to populations who would not have the treatment in clinical practice. For example, evidence from trials using methotrexate and rituximab may be applied to people for whom these treatments are not suitable. However, the committee recognised that, given the limitations of the available data, network meta-analyses stratified by line of treatment may not be possible.The network meta-analyses showed upadacitinib with conventional DMARDs or alone works as well as other biological DMARDs, but the analyses were limited. The committee concluded that for severe disease, there was limited direct trial evidence. Therefore it accepted the network meta-analyses for decision making.\n\n# Economic model inputs and assumptions\n\n## The company and ERG's mapping algorithm to link HAQ and pain scores are plausible methods to estimate utility values\n\nIn the company's base case, health-related quality-of-life data were calculated using a mapping function to work out a person's pain score from their Stanford Health Assessment Questionnaire (HAQ) score. HAQ is 1 component of the ACR criteria and scores physical disability and pain from 0 (least disability) to 3 (most severe disability). The mapping function used SELECT trial data, to estimate EQ‑5D values. The ERG noted that NICE's technology appraisal guidance on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis not previously treated with DMARDs or after conventional DMARDs only have failed (from now on referred to as TA375) used data from the National Databank for Rheumatic Diseases dataset to map from HAQ-to-pain score. The ERG explained that while the company's approach may be acceptable, the ERG preferred the mapping based on the National Databank for Rheumatic Diseases dataset. This was because the dataset contained over 100,000\xa0observations. After consultation, the company suggested that the mapping based on the National Databank for Rheumatic Diseases dataset gave some counter-intuitive results. This was because some of the lowest functionality was associated with reduced pain. The company confirmed that this was not seen in its preferred method based on mapping using the clinical trials. The committee was aware that the choice of mapping did not have a large effect on severe disease because health-related quality of life was similar across the different comparators. It noted that the company's method led to lower cost-effectiveness estimates compared with conventional DMARDs. The committee concluded that both the company and ERG approaches were plausible, but noted that the ERG's approach was used in TA375 and was based on a much larger dataset.\n\n# Economic model validation\n\n## The company's model is reasonably consistent with the model used in TA375\n\nThe company based its model on the model developed by the assessment group for TA375. The company provided a validation analysis comparing the outputs of its model with those from the model used in TA375 for several treatment sequences. The ERG suggested that the results of this analysis appeared to show that the company's model overestimated quality-adjusted life year (QALY) gains for biological DMARDs compared with conventional DMARDs. It explained that this primarily impacts the cost-effectiveness analysis for moderate disease, when upadacitinib is compared with conventional DMARDs. At the committee meeting, the company advised that it had found errors in the ERG's validation analysis and that its own model produced similar results to the model from TA375. After consultation, the company submitted further validation results that included corrections of 4\xa0errors. The ERG noted that after consultation, the company's results reasonably aligned with TA375. The committee concluded that the company's model was reasonably consistent with the model used in TA375.\n\n# Cost-effectiveness results\n\n## In severe disease, upadacitinib with methotrexate is cost effective after conventional DMARDs\n\nThe ERG did analyses for people with severe disease whose disease had responded inadequately to conventional DMARDs. The clinical- and cost-effectiveness estimates for upadacitinib compared with conventional DMARDs were similar to what was previously seen in other technology appraisals for rheumatoid arthritis. Upadacitinib dominated (that is, it was cheaper and more effective than the comparator) or gave an incremental cost-effectiveness ratio (ICER) under £30,000 per QALY gained when confidential comparator discounts were applied. The committee concluded that it could recommend upadacitinib with methotrexate as a cost-effective use of NHS resources for people with severe rheumatoid arthritis whose disease had responded inadequately to conventional DMARDs. This was in line with TA375.\n\n## In severe disease, upadacitinib with methotrexate is not cost effective after biological DMARDs if rituximab is a treatment option\n\nThe ERG did an analysis for people with severe disease that has responded inadequately to biological DMARDs when rituximab is a treatment option. In this, upadacitinib with conventional DMARDs was dominated by rituximab with conventional DMARDs (that is, upadacitinib was more expensive and less effective). The committee concluded that upadacitinib with conventional DMARDs was not a cost-effective use of NHS resources for people with severe rheumatoid arthritis whose disease had responded inadequately to biological DMARDs if rituximab was a treatment option. Therefore, it was not recommended at this position in the pathway.\n\n## In severe disease, upadacitinib with methotrexate is cost effective after rituximab and other biological DMARDs\n\nThe ERG did analyses for people with severe disease that had not responded adequately to rituximab and other biological DMARDs. In this, the cost-effectiveness estimates for intravenous or subcutaneous tocilizumab with methotrexate compared with upadacitinib with methotrexate were over £100,000 per QALY gained. Sarilumab with methotrexate was dominated by upadacitinib with methotrexate (that is, upadacitinib was less expensive and more effective). The committee therefore recommended upadacitinib with conventional DMARDs for people with severe rheumatoid arthritis whose disease has not responded adequately to rituximab and other biological DMARDs.\n\n## In severe disease, upadacitinib monotherapy is cost effective after conventional DMARDs if methotrexate is not suitable\n\nThe marketing authorisation for upadacitinib includes its use as a monotherapy. The committee noted that the clinical- and cost-effectiveness results for upadacitinib monotherapy were similar to those for upadacitinib with methotrexate. It was aware that the available evidence for upadacitinib monotherapy was from people whose disease responded inadequately to methotrexate. The clinical expert explained that methotrexate is not tolerated by some patients or it is contraindicated. In line with TA375, the committee agreed that the minority of people with severe active rheumatoid arthritis who could not tolerate methotrexate should not be treated differently from other people with severe disease, as far as possible. The committee agreed that upadacitinib monotherapy was cost effective for severe active rheumatoid arthritis after conventional DMARDs if methotrexate was not suitable.\n\n# Other factors\n\n## Healthcare professionals should consider any disabilities or communication difficulties when using the DAS28 measure\n\nA potential equality issue was raised during the scoping process, about people with rheumatoid arthritis who have difficulty communicating. For these people, it may be more difficult to assess outcomes when using the DAS28 measure. The committee concluded that healthcare professionals should consider any physical, psychological, sensory or learning disabilities, or communication difficulties that could affect the responses to the DAS28 and make any adjustments they consider appropriate.\n\n## The benefits of upadacitinib can be captured in the cost-effectiveness analysis\n\nUpadacitinib, like other targeted synthetic DMARDs, is taken orally. This is valued by patients. The committee noted that there are also other treatments with a similar mechanism of action available for rheumatoid arthritis. Therefore the committee concluded that all the benefits of upadacitinib can be captured in the model."}
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https://www.nice.org.uk/guidance/ta665
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Evidence-based recommendations on upadacitinib (Rinvoq) for severe active rheumatoid arthritis in adults.
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532cf4f9a27027d12dd3b9247f2f20d0bc81c816
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nice
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Venetoclax with obinutuzumab for untreated chronic lymphocytic leukaemia
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Venetoclax with obinutuzumab for untreated chronic lymphocytic leukaemia
Evidence-based recommendations on venetoclax (Venclyxto) with obinutuzumab for untreated chronic lymphocytic leukaemia in adults.
# Recommendations
Venetoclax plus obinutuzumab is recommended as an option for untreated chronic lymphocytic leukaemia (CLL) in adults, only if:
there is a 17p deletion or TP53 mutation, or
there is no 17p deletion or TP53 mutation, and fludarabine plus cyclophosphamide and rituximab (FCR), or bendamustine plus rituximab (BR), is unsuitable, and
the companies provide the drugs according to the commercial arrangements.
Venetoclax plus obinutuzumab is recommended for use within the Cancer Drugs Fund as an option for untreated CLL in adults, only if:
there is no 17p deletion or TP53 mutation, and FCR or BR is suitable, and
the conditions in the managed access agreement for venetoclax plus obinutuzumab are followed.
These recommendations are not intended to affect treatment with venetoclax plus obinutuzumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
People with untreated CLL are offered different treatments depending on whether they are likely to tolerate chemo-immunotherapy, and whether they have certain genetic abnormalities (such as a 17p deletion or TP53 mutation). In people with a 17p deletion or TP53 mutation, CLL does not usually respond well to standard chemo-immunotherapy, and ibrutinib is usually used. In people without a 17p deletion or TP53 mutation, FCR or BR are the most common chemo-immunotherapies used. If FCR or BR is unsuitable, obinutuzumab plus chlorambucil is used instead.
Venetoclax plus obinutuzumab has not been directly compared with ibrutinib in people with a 17p deletion or TP53 mutation, and the results of an indirect comparison are uncertain. The cost-effectiveness estimates suggest that venetoclax plus obinutuzumab is less effective but less costly than ibrutinib. These estimates are within what NICE normally considers an acceptable use of NHS resources, so it is recommended for routine use in the NHS for these people.
Clinical trial evidence shows that, in people without a 17p deletion or TP53 mutation and for whom FCR or BR is unsuitable, CLL treated with venetoclax plus obinutuzumab takes longer to progress than CLL treated with obinutuzumab plus chlorambucil. The cost-effectiveness estimates suggest that venetoclax plus obinutuzumab is more effective and less costly than obinutuzumab plus chlorambucil. Therefore, venetoclax plus obinutuzumab is recommended for routine use in the NHS for these people.
Venetoclax plus obinutuzumab has not been directly compared with FCR or BR in people without a 17p deletion or TP53 mutation and for whom these treatments are suitable. The results of an indirect comparison are uncertain. Also, some of the cost-effectiveness estimates are higher than the range NICE normally considers an acceptable use of NHS resources. Therefore, venetoclax plus obinutuzumab cannot be recommended for routine use in the NHS for these people.
An ongoing clinical trial is directly comparing venetoclax plus obinutuzumab with FCR and BR in people with untreated CLL without a 17p deletion or TP53 mutation for whom these treatments are suitable. Data from this trial could help address the uncertainty about the clinical effectiveness of venetoclax plus obinutuzumab in this population. Venetoclax plus obinutuzumab has the potential to be a cost-effective use of NHS resources. Therefore, it is recommended for use in the Cancer Drugs Fund for these people while the data from the trial are collected.# Information about venetoclax with obinutuzumab
# Marketing authorisation indication
Venetoclax (Venclyxto, AbbVie) with obinutuzumab is indicated 'for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
A 112-pack of 100-mg venetoclax tablets costs £4,789.47 (excluding VAT; BNF online, accessed August 2020). The company has a commercial arrangement. This makes venetoclax available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.
The price of obinutuzumab is £3,312 per 1,000-mg vial (excluding VAT; BNF online, accessed August 2020). Roche has a commercial arrangement. This makes obinutuzumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is Roche's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by AbbVie, a review of this submission by the evidence review group (ERG), the technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that 3 issues were resolved during the technical engagement stage, and agreed that:
adults with untreated chronic lymphocytic leukaemia (CLL) for whom fludarabine plus cyclophosphamide and rituximab (FCR), or bendamustine plus rituximab (BR), is suitable should be considered in the appraisal (issue 1, see technical report page 24)
the most appropriate utility value for the 'pre-progression, off-treatment' health state is 0.7703 (issue 7, see technical report page 56)
venetoclax plus obinutuzumab is likely to have a quality-of-life benefit over obinutuzumab plus chlorambucil, based on feedback from clinical and patient experts.
The committee recognised that there were remaining areas of uncertainty (see technical report table 13, page 65), and took these into account in its decision making. It discussed the issue of long-term survival estimates in people for whom FCR or BR is unsuitable (issues 2, 3 and 4b, see technical report pages 27, 33 and 41). This included uncertainty about how long people who have had venetoclax plus obinutuzumab live, how long before their disease progresses, and how long before they begin having subsequent treatment. The committee also discussed the duration of subsequent treatments (issue 4a, see technical report page 39). The committee discussed how effective venetoclax plus obinutuzumab is at prolonging survival and delaying disease progression compared with ibrutinib when there is a 17p deletion or TP53 mutation, (issues 5 and 6, see technical report pages 46 and 50). During technical engagement, NICE requested that the company provide cost-effectiveness analyses of venetoclax plus obinutuzumab compared with FCR and BR in people for whom FCR or BR is suitable. The committee discussed new issues resulting from these analyses, including how effective venetoclax plus obinutuzumab is at prolonging survival and delaying disease progression compared with FCR and BR.
# Unmet need, clinical management and comparators
## People with untreated CLL would welcome a new treatment option with a fixed treatment duration
The clinical and patient experts noted that people with untreated CLL are a heterogeneous population in terms of mutational status and comorbidities. They agreed that there is an unmet need for an effective, time-limited treatment with fewer side effects than existing treatments available in the NHS in England. They considered that this unmet need is particularly great in the population with a 17p deletion or TP53 mutation. This is because ibrutinib and idelalisib plus rituximab are the only available treatments, and idelalisib is poorly tolerated and not widely used. However, in the population without a 17p deletion or TP53 mutation there is also a need for a greater treatment choice. Around one-third of this population are offered FCR or BR, which are known to have considerable long-term side effects. The committee understood that people have venetoclax plus obinutuzumab for a fixed duration of 12 months, and that it is generally well tolerated. Patient experts highlighted that most current treatments for untreated CLL are taken until disease progression, and that people would value a fixed duration treatment that offers a break from side effects. They also mentioned that some people with untreated CLL have cardiovascular comorbidities, which could prevent them from taking certain treatments such as ibrutinib. The committee concluded that venetoclax plus obinutuzumab would be welcomed as a new treatment option for all people with untreated CLL.
## People with untreated CLL for whom FCR or BR is suitable are a relevant population for venetoclax plus obinutuzumab
The company's original submission included 2 subgroups of people with untreated CLL: those with a 17p deletion or TP53 mutation; and those without a 17p deletion or TP53 mutation for whom FCR or BR is unsuitable. The company's original submission did not include people without a 17p deletion or TP53 mutation for whom FCR or BR is suitable, although this population was in the NICE scope and is included in the marketing authorisation for venetoclax. This subgroup was initially omitted by the company because it did not reflect the population in its clinical trial, CLL14 (see section 3.4). The ERG noted that there is no standard assessment in the UK to determine whether FCR or BR is suitable. In addition, the ERG suggested that physicians in the UK are keen to offer venetoclax plus obinutuzumab to 'fitter' patients, who would otherwise have FCR or BR. Clinical and patient experts considered that people for whom FCR or BR is suitable are a relevant population for the reasons described in section 3.1. The committee agreed that this was an important subgroup to consider.
## Treatment varies depending on mutational status and comorbidities, and the comparators selected by the company are appropriate
Clinical experts confirmed that mutational status and comorbidities affect the available treatment options for people with untreated CLL. They verified that people without a 17p deletion or TP53 mutation who also have comorbidities that make FCR and BR unsuitable for them would be offered obinutuzumab plus chlorambucil. People with a 17p deletion or TP53 mutation would usually be offered ibrutinib. Idelalisib plus rituximab is rarely used in clinical practice because it has an intensive dosing regimen and is associated with increased risk of infection. Finally, the clinical experts stated that people without a 17p deletion or TP53 mutation for whom FCR or BR is suitable would usually be offered either FCR or BR. However, FCR is used more commonly in clinical practice in the NHS, so is the most relevant comparator. The committee agreed that these were the relevant comparators for this appraisal and matched the analyses submitted by the company.
# Clinical effectiveness
## The clinical-effectiveness evidence is largely relevant to NHS clinical practice in England
The company presented results from CLL14 (n=432), an open-label randomised controlled trial comparing venetoclax plus obinutuzumab (n=216) with obinutuzumab plus chlorambucil (n=216). CLL14 included people aged 18 years or over with untreated CLL whose comorbidities made FCR or BR unsuitable treatment options. People in CLL14 had to have a Cumulative Illness Rating Scale (CIRS) score greater than 6, or a creatinine clearance of less than 70 ml/minute (low creatinine clearance levels indicate serious kidney damage). The company considered that these criteria meant that FCR or BR would be unsuitable for similar patients in NHS clinical practice in England. Of the 432 people in CLL14, 49 had a 17p deletion or TP53 mutation. The ERG considered that CLL14 was well designed with a low risk of bias within the limits of the open-label trial design. The ERG noted a discrepancy between the number of cycles of chlorambucil typically offered in NHS clinical practice in England (6 cycles) and the number had in CLL14 (12 cycles). However, it understood that the lower dosage per cycle in CLL14 meant that the overall dose was similar. The ERG also noted that only 8 people in CLL14 were from the UK. Because there is no standard assessment in England to determine the suitability of FCR or BR, the ERG considered it likely that some people included in CLL14 may have been eligible for treatment with FCR or BR in England. The committee was satisfied that CLL14 was representative of NHS clinical practice despite the low number of UK patients. It noted that people with CLL for whom FCR or BR is suitable were now being considered within the appraisal (see section 3.2).
## Venetoclax plus obinutuzumab improves progression-free survival, but the overall survival benefit is likely to be similar to the comparator
After a median follow up of 39.6 months, there was a statistically significant improvement in progression-free survival for venetoclax plus obinutuzumab compared with obinutuzumab plus chlorambucil (hazard ratio 0.31, 95% confidence interval 0.22 to 0.44, p<0.001). Median progression-free survival was not reached in the venetoclax plus obinutuzumab arm and was 35.6 months in the obinutuzumab plus chlorambucil arm. The time between the date of randomisation and the date at which someone was first offered a new anti-leukemic therapy was measured in CLL14 as 'time to next treatment'. Median time to next treatment was not reached in either treatment arm, but the likelihood of starting a new treatment was reduced in the venetoclax plus obinutuzumab arm compared with the obinutuzumab plus chlorambucil arm (HR 0.51, 95% CI 0.34 to 0.78). Median overall survival was not reached in either treatment arm, and there was no difference in overall survival between the 2 arms (HR 1.03, 95% CI 0.60 to 1.75, p=0.92). The committee concluded that the trial data showed that venetoclax plus obinutuzumab improved progression-free survival and time to next treatment compared with obinutuzumab plus chlorambucil. The committee considered that the benefit of venetoclax plus obinutuzumab on overall survival was likely to be similar to obinutuzumab plus chlorambucil, noting that the immaturity of the data meant there was considerable uncertainty.
## The company's indirect treatment comparison with ibrutinib is acceptable for decision making, despite limitations
The comparator in CLL14 was obinutuzumab plus chlorambucil, a combination that is not a relevant comparator in people with a 17p deletion or TP53 mutation (see section 3.3). So, the company did an indirect treatment comparison to compare progression-free and overall survival for venetoclax plus obinutuzumab with ibrutinib. The company used a real-world evidence study published by Mato et al. (2018) for its base-case comparison. This was because it had the largest number of patients with relevant characteristics out of the ibrutinib studies identified. The company's comparison was unanchored because there was no common comparator arm between CLL14 and Mato et al. The results showed that there was no statistically significant difference between venetoclax plus obinutuzumab and ibrutinib in either progression-free survival (HR 1.515, 95% CI 0.619 to 3.703, p=0.363) or overall survival (HR 1.189, 95% CI 0.425 to 3.322, p=0.741), with wide confidence intervals. The ERG identified several areas of uncertainty in the company's indirect treatment comparison. There were 25 people in the venetoclax plus obinutuzumab arm of CLL14 with a 17p deletion or TP53 mutation, and 110 people with a 17p deletion were relevant in Mato et al. The low patient numbers meant that the comparison was underpowered to detect differences between the treatments. There was also considerable heterogeneity between the studies in terms of their design, eligibility criteria and outcomes, which was not adjusted for by the company. The company did a second unadjusted indirect treatment comparison using data from a single-arm study published by Ahn et al. (2018). However, the ERG considered that the results of the comparison using the data from Ahn et al. were as uncertain as those based on the data from Mato et al. The clinical experts highlighted that 17p deletions or TP53 mutations are uncommon, so it is unlikely that head-to-head data will become available comparing venetoclax plus obinutuzumab with ibrutinib. The committee concluded that, despite its limitations, the company's indirect treatment comparison with ibrutinib was acceptable for decision making.
## The network meta-analysis comparing venetoclax plus obinutuzumab with FCR and BR is sufficient for decision making, despite limitations
In response to technical engagement, in the absence of head-to-head trial data, the company submitted a network meta-analysis (NMA) to compare the effect of venetoclax plus obinutuzumab with FCR and BR on progression-free and overall survival in people for whom FCR or BR is suitable. The company's network included 9 trials. It used the data on all patients in the venetoclax plus obinutuzumab arm of CLL14 for the comparison. This included only people who could not have FCR or BR on the basis of their CIRS score and creatinine clearance (see section 3.4). It also included some people with a 17p deletion or TP53 mutation. As described in section 3.4, the ERG considered it likely that some of these people may have been eligible for treatment with FCR or BR in England. The other trials in the company's network had people who were either 'fit' or 'unfit', with fitness determined based on age, CIRS score and fludarabine eligibility. The results suggested a progression-free survival benefit for venetoclax plus obinutuzumab over FCR (HR 0.258, 95% CI 0.151 to 0.481) and BR (HR 0.178, 95% CI 0.109 to 0.312). Overall survival was comparable for venetoclax plus obinutuzumab compared with FCR (HR 0.622, 95% CI 0.273 to 1.789) and BR (HR 0.792, 95% CI 0.378 to 1.969). The ERG considered the company's NMA to have a high degree of uncertainty, noting the substantial heterogeneity between the study populations in the NMA in terms of age and fitness. The wide confidence intervals were of concern to the ERG, as was the sensitivity of the results to the studies included in the NMA. The ERG was unable to reproduce the company's original NMA, so did its own analysis, with similar results to that of the company. The clinical experts explained that venetoclax plus obinutuzumab is very likely to be more efficacious than FCR in people for whom FCR or BR is suitable. They also said that there is no reason why venetoclax plus obinutuzumab would not work well in this patient population. The committee acknowledged this point and concluded that, despite the results of the NMA being highly uncertain, on balance they were sufficient for decision making.
# Adverse effects
## Venetoclax plus obinutuzumab is generally well tolerated compared with current treatments
The results of CLL14 showed that venetoclax plus obinutuzumab had an acceptable tolerability profile compared with obinutuzumab plus chlorambucil. Patient submissions highlighted that venetoclax is occasionally associated with tumour lysis syndrome. This is caused by a rapid breakdown of cancer cells, and can lead to complications such as kidney failure. Three people had tumour lysis syndrome in the venetoclax plus obinutuzumab arm of CLL14 compared with 5 in the obinutuzumab plus chlorambucil arm. The company considered that these results showed the effectiveness of prophylaxis against tumour lysis syndrome for venetoclax plus obinutuzumab. The committee agreed that venetoclax plus obinutuzumab is likely to be generally well tolerated compared with current treatments.
# Cost-effectiveness model structure
## The model structure is appropriate for decision making, despite uncertainty around the duration of subsequent treatment
The company submitted a partitioned survival model with 3 states (progression-free, progressed disease and death). To compare venetoclax plus obinutuzumab with obinutuzumab plus chlorambucil in people for whom FCR or BR is unsuitable, the company used data from CLL14 to estimate progression-free survival, overall survival and time to next treatment using parametric curves fitted to Kaplan–Meier data. Half the patients starting subsequent treatment were modelled to have ibrutinib, and the other half were modelled to have venetoclax plus rituximab. This assumption was applied to both treatment arms. Subsequent treatment costs were accrued from the start of subsequent treatment until death. To compare venetoclax plus obinutuzumab with ibrutinib in people with a 17p deletion or TP53 mutation, the company used the results of the indirect treatment comparison with ibrutinib (see section 3.6) to model the differences in efficacy. Patients having venetoclax plus obinutuzumab as their first-line treatment were modelled to have ibrutinib monotherapy as their subsequent treatment. Patients having ibrutinib as their first-line treatment were modelled to have venetoclax monotherapy as their subsequent treatment, with only new incidences of disease progression or death counting towards the associated costs. To compare venetoclax plus obinutuzumab with FCR and BR when these treatments are suitable, the company used the results of the NMA (see section 3.7) to model the differences in efficacy. The subsequent treatment mix was the same as in people for whom FCR or BR is unsuitable. However, like ibrutinib, only new incidences of disease progression or death counted towards the subsequent treatment costs for FCR and BR. The ERG considered that the company's model structure was largely appropriate. Its clinical expert confirmed that the subsequent treatment mix was consistent with that offered in NHS clinical practice in England. However, the ERG noted that patients were modelled to have subsequent treatments for much longer than the median second-line treatment durations reported in the literature. It suggested that this was likely to bias the analysis against obinutuzumab plus chlorambucil. The committee noted the uncertainty about the duration of subsequent treatment (see section 3.13), but concluded that the model structure was appropriate for decision making.
# Survival extrapolations
## In people for whom FCR or BR is unsuitable, both the company's and ERG's survival extrapolations are relevant for decision making
The company explored various approaches for extrapolating the progression-free survival, overall survival and time-to-next-treatment data in people for whom FCR or BR is unsuitable. It chose an independent log-logistic distribution as its preferred parametric model for progression-free survival, and a dependent exponential distribution to extrapolate overall survival. The company applied the same obinutuzumab plus chlorambucil overall survival extrapolation for both treatment arms, reflecting the immaturity of the data and lack of evidence for an overall survival benefit for venetoclax plus obinutuzumab. The company used an independent log-logistic distribution for time to next treatment, matching the company's progression-free survival distribution, an outcome closely correlated with time to next treatment. The ERG noted that the survival data from CLL14 were very immature. It considered that the company's survival extrapolations were too dependent on the constraint that the hazard rate of death, disease progression, or starting a subsequent treatment could not fall below the background mortality of the age-matched general population. The ERG also noted that the company's extrapolations were optimistic compared with the 5‑year data from the CLL11 trial, an earlier trial that included an obinutuzumab plus chlorambucil treatment arm in a similar patient population to CLL14. For progression-free survival, the ERG instead favoured an independent 2‑knot hazard spline distribution. For a more conservative overall survival distribution, the ERG modelled the overall survival hazard rate from CLL14 up to 3 years. It then fitted an exponential model to the hazard rate from the ERIC study after this point. ERIC was a retrospective study that evaluated the efficacy and safety of obinutuzumab with or without chlorambucil in a similar patient population to CLL14. The ERG's progression-free and overall survival extrapolations were less dependent on the background mortality constraint than those of the company. For time to next treatment, the ERG derived a hazard ratio between progression-free survival and time to next treatment, which it applied to its progression-free survival distribution. Clinical experts considered the ERG's progression-free survival distribution more plausible than that of the company. However, they warned that the CLL11 data were inappropriate for validating the overall survival extrapolations. Clinical practice has evolved since CLL11, and overall survival is expected to be longer for people in CLL14. The clinical experts also explained that it was reasonable to expect that many people will reach the life expectancy of the general population after treatment with venetoclax plus obinutuzumab, and will be functionally cured. The committee concluded that, despite the limitations of the company's and ERG's survival extrapolations, both were relevant for decision making.
## When there is a 17p deletion or TP53 mutation, both the company and ERG's survival extrapolations are relevant for decision making
The company used the same progression-free survival, overall survival and time-to-next-treatment distributions for people with a 17p deletion or TP53 mutation as used in people for whom FCR or BR is unsuitable (see section 3.10). The company applied the progression-free and overall survival hazard ratios from the indirect comparison with ibrutinib (see section 3.6) to generate extrapolations for ibrutinib. The ERG noted that the company's extrapolations resulted in patients spending little time alive after their disease had progressed. The ERG considered that a 1‑knot hazard spline distribution was more plausible for progression-free survival, overall survival and time to next treatment. The committee acknowledged the uncertainty, but concluded that both the company's and ERG's survival extrapolations were relevant for decision making.
## In people for whom FCR or BR is suitable, both the company and ERG's survival extrapolations are relevant for decision making
The company used the same survival extrapolations for people for whom FCR or BR is suitable as for the other 2 subgroups (see section 3.10 and section 3.11). The ERG preferred a 2-knot hazard spline distribution for the progression-free survival extrapolations. This is because it considered that the likelihood of disease progression for people for whom FCR or BR is suitable would be similar to that of people for whom FCR or BR is unsuitable. The committee concluded that both the company's and ERG's progression-free survival extrapolations were relevant for decision making.
# Costs in the cost-effectiveness model
## Subsequent treatment costs are likely to lie between the company's 2 scenarios, both of which are appropriate for decision making
In the company's base-case model, subsequent treatment and its associated costs were modelled to continue from the start of subsequent treatment until death for venetoclax plus obinutuzumab and obinutuzumab plus chlorambucil. The company considered this approach fair. This was because a lack of published evidence meant that it was not possible to create a treatment sequencing model in relapsed or refractory CLL. The company acknowledged that its approach was likely to overestimate subsequent treatment costs. However, it considered that restricting these costs to 1 subsequent treatment line would not align with NHS clinical practice in England. The ERG considered that the company's approach failed to account for periods of no treatment. It was also likely to be biased against obinutuzumab plus chlorambucil because patients having this treatment began having subsequent treatment earlier. In response to technical engagement, the company presented a revised economic model in which the duration of subsequent treatment was constrained by the median durations of second-line treatment reported in the literature. Clinical expert feedback suggested that it was appropriate to model subsequent treatment costs until death because of the continuous nature of salvage treatments for CLL. The committee acknowledged the uncertainty around the duration of subsequent treatment. It concluded that the actual subsequent treatment cost was likely to lie between the company's original and revised approaches, and that both were appropriate for decision making.
# Cost-effectiveness results
## When FCR or BR is unsuitable, venetoclax plus obinutuzumab is more effective and less costly than obinutuzumab plus chlorambucil
The company's base case for all 3 patient subgroups incorporated the ERG's preferred utility value of 0.7703 for the 'pre-progression, off-treatment' health state. In people for whom FCR or BR is unsuitable, the company's deterministic base case showed that venetoclax plus obinutuzumab was more effective and less costly than obinutuzumab plus chlorambucil. The ERG preferred the following assumptions:
an independent 2‑knot hazard spline progression-free survival distribution (see section 3.10)
an overall survival extrapolation derived by fitting an exponential model to the hazard rate from ERIC beyond 3 years (see section 3.10)
time-to-next-treatment extrapolations derived by applying a hazard ratio to the ERG's preferred independent 2‑knot hazard spline progression-free survival distribution (see section 3.10)
subsequent treatment durations constrained by the median durations of second-line treatment reported in the literature (see section 3.13).Venetoclax plus obinutuzumab remained more effective and less costly than obinutuzumab plus chlorambucil using the ERG's preferred assumptions, and in all but 1 scenario explored by the ERG. The committee acknowledged that there was considerable uncertainty around the long-term survival estimates and the duration for which people have subsequent treatments. However, it concluded that, in all scenarios, venetoclax plus obinutuzumab could be considered an acceptable use of NHS resources.
## In people with a 17p deletion or TP53 mutation, the estimates are within the range considered a cost-effective use of NHS resources
The company's deterministic base case showed that venetoclax plus obinutuzumab resulted in cost savings and a quality-adjusted life year (QALY) loss compared with ibrutinib, producing incremental cost-effectiveness ratios (ICERs) that reflected 'savings per QALY lost'. The committee noted that, in situations in which an ICER is derived from a technology that is less effective and less costly than its comparator, the commonly assumed decision rule of accepting ICERs below a given threshold is reversed. So, the higher the ICER, the more cost effective a treatment becomes. The ERG preferred a 1‑knot hazard spline distribution for progression-free survival, overall survival and time to next treatment (see section 3.11). In the ERG's analyses, venetoclax plus obinutuzumab resulted in a cost saving of £199,622 and a QALY loss of 0.363, with an ICER of £549,699 saved per QALY lost. These analyses included the patient access scheme for venetoclax, but not for the comparators or subsequent treatments. The decision-making ICERs used by the committee took account of all available confidential discounts, including those for comparators and follow-up treatments, and were lower. However, they remained within the range NICE normally considers an acceptable use of NHS resources. The committee recalled that that there was considerable uncertainty in the company's indirect treatment comparison (see section 3.6). However, it concluded that, in all scenarios, venetoclax plus obinutuzumab could be considered an acceptable use of NHS resources based on the saving per QALY lost.
## In people for whom FCR or BR is suitable, the ICERs are higher than the range NICE normally considers an acceptable use of NHS resources
The company's deterministic base case suggested that the ICER was £32,669 per QALY gained for venetoclax plus obinutuzumab compared with FCR, and £36,768 per QALY gained compared with BR. The ERG preferred to use the progression-free and overall survival hazard ratios derived from its own NMA (see section 3.7), and a 2‑knot hazard spline distribution progression-free survival (see section 3.12). The ERG's analyses suggest an ICER of £47,494 per QALY gained for venetoclax plus obinutuzumab compared with FCR, and £67,445 per QALY gained compared with BR. With the confidential discounts for obinutuzumab and ibrutinib applied, the ICERs remained above the range normally considered a cost-effective use of NHS resources (that is, £20,000 to £30,000 per QALY gained). The committee focused on the comparison with FCR because it understood that this is more widely used than BR in clinical practice, so is the most relevant comparator (see section 3.3). The committee recalled that the company's NMA was subject to considerable uncertainty (see section 3.7). It understood that the ICERs varied widely if the upper and lower bounds of the progression-free and overall survival hazard ratio confidence intervals were applied. On balance, the committee considered the ERG's preferred analysis to represent the most plausible scenario, although it was still subject to considerable uncertainty. The committee also noted that assuming the effect of venetoclax plus obinutuzumab on overall survival was the same as FCR resulted in an ICER that was higher than the ERG's preferred analysis. The committee concluded that venetoclax plus obinutuzumab could not be recommended for routine use in the NHS in this population.
# Innovation
## There are no additional benefits that are not captured in the quality-adjusted life year calculations
The company considered venetoclax plus obinutuzumab to be an innovative treatment because venetoclax is a first-in-class, oral, selective inhibitor of B‑cell lymphoma 2. It has a unique targeted mechanism of action that distinguishes it from other therapies. Venetoclax plus obinutuzumab also has a fixed treatment duration. This means people can have time without therapy, unlike with most other treatments, which people must have until they stop working. Venetoclax plus obinutuzumab increases the range of treatment options for people with untreated CLL, and avoids the need for chemo-immunotherapy. The committee concluded that venetoclax plus obinutuzumab would be a beneficial additional treatment option. However, it noted that it had not been presented with evidence of any additional benefits that were not captured in the measurement of QALYs.
# Equality considerations
## There are no remaining equality issues relevant to the recommendations
The company's original submission did not include people without a 17p deletion or TP53 mutation for whom FCR or BR is suitable. Patient and professional submissions highlighted that this would potentially deny these people access to a new treatment option that is well tolerated. In response to technical engagement, the company provided cost-effectiveness analyses comparing venetoclax plus obinutuzumab with FCR and BR in people without a 17p deletion or TP53 mutation for whom FCR or BR is suitable. The committee considered these analyses during the appraisal (see section 3.16). No other equality or social value judgement issues were identified by the committee.
# End of life
## Venetoclax plus obinutuzumab does not meet the criteria to be considered a life-extending treatment at the end of life
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. This states that a treatment can be considered as a life-extending treatment at the end of life if: it is indicated for people with a short life expectancy (normally less than 24 months); and it offers an extension to life (normally a mean value of at least an additional 3 months compared with current NHS treatment). The committee considered that the short life expectancy criterion of less than 24 months was not met because people with CLL have a life expectancy of more than 2 years. The committee concluded that venetoclax plus obinutuzumab does not meet the criteria to be considered a life-extending treatment at end of life.
# Cancer Drugs Fund
## Further data collection could address uncertainties in the clinical and cost-effectiveness evidence in people for whom FCR or BR is suitable
Having concluded that venetoclax plus obinutuzumab could not be recommended for routine use in people with untreated CLL when FCR or BR is suitable (see section 3.16), the committee considered whether it could be recommended for use within the Cancer Drugs Fund. It discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum). The committee considered whether the clinical uncertainty associated with venetoclax plus obinutuzumab in this patient population could be addressed through collecting more data. It was aware that CLL13, a randomised controlled trial directly comparing venetoclax plus obinutuzumab with FCR and BR in people with untreated CLL, is currently ongoing. CLL13 has a primary completion date of January 2023, with an interim analysis of progression-free survival planned after 49 months. The committee agreed that:
the company has expressed an interest in venetoclax plus obinutuzumab being considered for funding through the Cancer Drugs Fund in people with untreated CLL for whom FCR or BR is suitable
the relative benefits of venetoclax plus obinutuzumab on progression-free and overall survival compared with FCR and BR are highly uncertain
there is plausible potential that the ICER for venetoclax plus obinutuzumab compared with FCR could fall within the range normally considered a cost-effective use of NHS resources
data on progression-free and overall survival from CLL13 for venetoclax plus obinutuzumab compared with FCR and BR would be a valuable addition to the clinical evidence base and would likely resolve uncertainties around survival
using venetoclax plus obinutuzumab in the NHS in patients for whom FCR or BR is suitable would allow data to be collected using the Systemic Anti-Cancer Therapy dataset, which would more accurately reflect the benefits of its use in clinical practice.
# Conclusions
## Venetoclax plus obinutuzumab is a cost-effective use of NHS resources and is recommended when FCR or BR is unsuitable
The committee noted that there was considerable uncertainty around the long-term survival estimates and the duration for which people for whom FCR or BR is unsuitable had subsequent treatments. However, it acknowledged that, in all scenarios, the ICERs suggested that venetoclax plus obinutuzumab was a cost-effective treatment (see section 3.14). The committee concluded that venetoclax plus obinutuzumab for untreated CLL in adults for whom FCR or BR is unsuitable is a cost-effective use of NHS resources and could be recommended as an option for this population.
## Venetoclax plus obinutuzumab is a cost-effective use of NHS resources and is recommended when there is a 17p deletion or TP53 mutation
The committee noted that there was considerable uncertainty associated with the company's indirect treatment comparison with ibrutinib in people with a 17p deletion or TP53 mutation. However, it acknowledged that, in all scenarios, the ICERs suggested that venetoclax plus obinutuzumab was a cost-effective treatment (see section 3.15). In addition, the committee acknowledged that there is a high unmet need for a new treatment option in this patient population, and that venetoclax plus obinutuzumab would likely represent a tolerable alternative to ibrutinib and idelalisib. The committee concluded that venetoclax plus obinutuzumab for untreated CLL in adults with a 17p deletion or TP53 mutation is a cost-effective use of NHS resources and could be recommended as an option for this population. Given the QALY losses for venetoclax plus obinutuzumab compared with ibrutinib, treatment choice should be a decision made between the doctor and patient. Other factors to consider in making this decision include the adverse events associated with both treatments, and the fixed duration of venetoclax plus obinutuzumab treatment compared with taking ibrutinib until disease progression. The committee also acknowledged that some people have cardiovascular comorbidities that could prevent them from taking ibrutinib (see section 3.1).
## Venetoclax plus obinutuzumab meets the criteria to be included in the Cancer Drugs Fund in people for whom FCR or BR is suitable
The company's NMA suggested that venetoclax plus obinutuzumab is likely to have a progression-free survival benefit compared with FCR and BR. Input from the clinical experts also suggested that it is likely that venetoclax plus obinutuzumab has a survival benefit over FCR in clinical practice. The committee acknowledged that people with this condition strongly desire an alternative to FCR and BR even if these treatments are considered suitable. It also agreed that there is an unmet need for new treatment options, given the heterogeneity of the patient population. The committee also understood that offering venetoclax plus obinutuzumab to these people up front may be beneficial in the long term. Many people treated with FCR or BR do not go into remission (either complete remission or minimal residual disease). They also have long-term side effects that may affect the efficacy of targeted therapies used in later lines. The incidence of a 17p deletion or TP53 mutation is also higher in relapsed or refractory CLL, limiting treatment choice in this setting. The committee noted that the ICER for venetoclax plus obinutuzumab compared with FCR was uncertain. However, it concluded that venetoclax plus obinutuzumab had the plausible potential to satisfy the criteria for routine use if this uncertainty could be reduced. The committee recognised that comparative survival data compared with FCR and BR from CLL13 would allow for a more robust cost-effectiveness estimate. So, it agreed that venetoclax plus obinutuzumab met the criteria to be included in the Cancer Drugs Fund for untreated CLL in adults for whom FCR or BR is suitable.
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{'Recommendations': 'Venetoclax plus obinutuzumab is recommended as an option for untreated chronic lymphocytic leukaemia (CLL) in adults, only if:\n\nthere is a 17p\xa0deletion or TP53\xa0mutation, or\n\nthere is no 17p\xa0deletion or TP53\xa0mutation, and fludarabine plus cyclophosphamide and rituximab (FCR), or bendamustine plus rituximab (BR), is unsuitable, and\n\nthe companies provide the drugs according to the commercial arrangements.\n\nVenetoclax plus obinutuzumab is recommended for use within the Cancer Drugs Fund as an option for untreated CLL in adults, only if:\n\nthere is no 17p\xa0deletion or TP53\xa0mutation, and FCR or BR is suitable, and\n\nthe conditions in the managed access agreement for venetoclax plus obinutuzumab are followed.\n\nThese recommendations are not intended to affect treatment with venetoclax plus obinutuzumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nPeople with untreated CLL are offered different treatments depending on whether they are likely to tolerate chemo-immunotherapy, and whether they have certain genetic abnormalities (such as a 17p\xa0deletion or TP53\xa0mutation). In people with a 17p\xa0deletion or TP53\xa0mutation, CLL does not usually respond well to standard chemo-immunotherapy, and ibrutinib is usually used. In people without a 17p\xa0deletion or TP53\xa0mutation, FCR or BR are the most common chemo-immunotherapies used. If FCR or BR is unsuitable, obinutuzumab plus chlorambucil is used instead.\n\nVenetoclax plus obinutuzumab has not been directly compared with ibrutinib in people with a 17p\xa0deletion or TP53\xa0mutation, and the results of an indirect comparison are uncertain. The cost-effectiveness estimates suggest that venetoclax plus obinutuzumab is less effective but less costly than ibrutinib. These estimates are within what NICE normally considers an acceptable use of NHS resources, so it is recommended for routine use in the NHS for these people.\n\nClinical trial evidence shows that, in people without a 17p\xa0deletion or TP53\xa0mutation and for whom FCR or BR is unsuitable, CLL treated with venetoclax plus obinutuzumab takes longer to progress than CLL treated with obinutuzumab plus chlorambucil. The cost-effectiveness estimates suggest that venetoclax plus obinutuzumab is more effective and less costly than obinutuzumab plus chlorambucil. Therefore, venetoclax plus obinutuzumab is recommended for routine use in the NHS for these people.\n\nVenetoclax plus obinutuzumab has not been directly compared with FCR or BR in people without a 17p\xa0deletion or TP53\xa0mutation and for whom these treatments are suitable. The results of an indirect comparison are uncertain. Also, some of the cost-effectiveness estimates are higher than the range NICE normally considers an acceptable use of NHS resources. Therefore, venetoclax plus obinutuzumab cannot be recommended for routine use in the NHS for these people.\n\nAn ongoing clinical trial is directly comparing venetoclax plus obinutuzumab with FCR and BR in people with untreated CLL without a 17p\xa0deletion or TP53\xa0mutation for whom these treatments are suitable. Data from this trial could help address the uncertainty about the clinical effectiveness of venetoclax plus obinutuzumab in this population. Venetoclax plus obinutuzumab has the potential to be a cost-effective use of NHS resources. Therefore, it is recommended for use in the Cancer Drugs Fund for these people while the data from the trial are collected.', 'Information about venetoclax with obinutuzumab': "# Marketing authorisation indication\n\nVenetoclax (Venclyxto, AbbVie) with obinutuzumab is indicated 'for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nA 112-pack of 100-mg venetoclax tablets costs £4,789.47 (excluding VAT; BNF online, accessed August 2020). The company has a commercial arrangement. This makes venetoclax available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.\n\nThe price of obinutuzumab is £3,312 per 1,000-mg vial (excluding VAT; BNF online, accessed August 2020). Roche has a commercial arrangement. This makes obinutuzumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is Roche's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by AbbVie, a review of this submission by the evidence review group (ERG), the technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that 3\xa0issues were resolved during the technical engagement stage, and agreed that:\n\nadults with untreated chronic lymphocytic leukaemia (CLL) for whom fludarabine plus cyclophosphamide and rituximab (FCR), or bendamustine plus rituximab (BR), is suitable should be considered in the appraisal (issue\xa01, see technical report page\xa024)\n\nthe most appropriate utility value for the 'pre-progression, off-treatment' health state is 0.7703 (issue\xa07, see technical report page\xa056)\n\nvenetoclax plus obinutuzumab is likely to have a quality-of-life benefit over obinutuzumab plus chlorambucil, based on feedback from clinical and patient experts.\n\nThe committee recognised that there were remaining areas of uncertainty (see technical report table\xa013, page\xa065), and took these into account in its decision making. It discussed the issue of long-term survival estimates in people for whom FCR or BR is unsuitable (issues\xa02,\xa03 and\xa04b, see technical report pages\xa027, 33\xa0and\xa041). This included uncertainty about how long people who have had venetoclax plus obinutuzumab live, how long before their disease progresses, and how long before they begin having subsequent treatment. The committee also discussed the duration of subsequent treatments (issue\xa04a, see technical report page\xa039). The committee discussed how effective venetoclax plus obinutuzumab is at prolonging survival and delaying disease progression compared with ibrutinib when there is a 17p\xa0deletion or TP53\xa0mutation, (issues\xa05 and\xa06, see technical report pages\xa046 and\xa050). During technical engagement, NICE requested that the company provide cost-effectiveness analyses of venetoclax plus obinutuzumab compared with FCR and BR in people for whom FCR or BR is suitable. The committee discussed new issues resulting from these analyses, including how effective venetoclax plus obinutuzumab is at prolonging survival and delaying disease progression compared with FCR and BR.\n\n# Unmet need, clinical management and comparators\n\n## People with untreated CLL would welcome a new treatment option with a fixed treatment duration\n\nThe clinical and patient experts noted that people with untreated CLL are a heterogeneous population in terms of mutational status and comorbidities. They agreed that there is an unmet need for an effective, time-limited treatment with fewer side effects than existing treatments available in the NHS in England. They considered that this unmet need is particularly great in the population with a 17p\xa0deletion or TP53\xa0mutation. This is because ibrutinib and idelalisib plus rituximab are the only available treatments, and idelalisib is poorly tolerated and not widely used. However, in the population without a 17p\xa0deletion or TP53\xa0mutation there is also a need for a greater treatment choice. Around one-third of this population are offered FCR or BR, which are known to have considerable long-term side effects. The committee understood that people have venetoclax plus obinutuzumab for a fixed duration of 12\xa0months, and that it is generally well tolerated. Patient experts highlighted that most current treatments for untreated CLL are taken until disease progression, and that people would value a fixed duration treatment that offers a break from side effects. They also mentioned that some people with untreated CLL have cardiovascular comorbidities, which could prevent them from taking certain treatments such as ibrutinib. The committee concluded that venetoclax plus obinutuzumab would be welcomed as a new treatment option for all people with untreated CLL.\n\n## People with untreated CLL for whom FCR or BR is suitable are a relevant population for venetoclax plus obinutuzumab\n\nThe company's original submission included 2\xa0subgroups of people with untreated CLL: those with a 17p\xa0deletion or TP53\xa0mutation; and those without a 17p\xa0deletion or TP53\xa0mutation for whom FCR or BR is unsuitable. The company's original submission did not include people without a 17p\xa0deletion or TP53\xa0mutation for whom FCR or BR is suitable, although this population was in the NICE scope and is included in the marketing authorisation for venetoclax. This subgroup was initially omitted by the company because it did not reflect the population in its clinical trial, CLL14 (see section\xa03.4). The ERG noted that there is no standard assessment in the UK to determine whether FCR or BR is suitable. In addition, the ERG suggested that physicians in the UK are keen to offer venetoclax plus obinutuzumab to 'fitter' patients, who would otherwise have FCR or BR. Clinical and patient experts considered that people for whom FCR or BR is suitable are a relevant population for the reasons described in section\xa03.1. The committee agreed that this was an important subgroup to consider.\n\n## Treatment varies depending on mutational status and comorbidities, and the comparators selected by the company are appropriate\n\nClinical experts confirmed that mutational status and comorbidities affect the available treatment options for people with untreated CLL. They verified that people without a 17p\xa0deletion or TP53\xa0mutation who also have comorbidities that make FCR and BR unsuitable for them would be offered obinutuzumab plus chlorambucil. People with a 17p\xa0deletion or TP53\xa0mutation would usually be offered ibrutinib. Idelalisib plus rituximab is rarely used in clinical practice because it has an intensive dosing regimen and is associated with increased risk of infection. Finally, the clinical experts stated that people without a 17p\xa0deletion or TP53\xa0mutation for whom FCR or BR is suitable would usually be offered either FCR or BR. However, FCR is used more commonly in clinical practice in the NHS, so is the most relevant comparator. The committee agreed that these were the relevant comparators for this appraisal and matched the analyses submitted by the company.\n\n# Clinical effectiveness\n\n## The clinical-effectiveness evidence is largely relevant to NHS clinical practice in England\n\nThe company presented results from CLL14 (n=432), an open-label randomised controlled trial comparing venetoclax plus obinutuzumab (n=216) with obinutuzumab plus chlorambucil (n=216). CLL14 included people aged 18\xa0years or over with untreated CLL whose comorbidities made FCR or BR unsuitable treatment options. People in CLL14 had to have a Cumulative Illness Rating Scale (CIRS) score greater than\xa06, or a creatinine clearance of less than 70\xa0ml/minute (low creatinine clearance levels indicate serious kidney damage). The company considered that these criteria meant that FCR or BR would be unsuitable for similar patients in NHS clinical practice in England. Of the 432\xa0people in CLL14, 49\xa0had a 17p\xa0deletion or TP53\xa0mutation. The ERG considered that CLL14 was well designed with a low risk of bias within the limits of the open-label trial design. The ERG noted a discrepancy between the number of cycles of chlorambucil typically offered in NHS clinical practice in England (6\xa0cycles) and the number had in CLL14 (12\xa0cycles). However, it understood that the lower dosage per cycle in CLL14 meant that the overall dose was similar. The ERG also noted that only 8\xa0people in CLL14 were from the UK. Because there is no standard assessment in England to determine the suitability of FCR or BR, the ERG considered it likely that some people included in CLL14 may have been eligible for treatment with FCR or BR in England. The committee was satisfied that CLL14 was representative of NHS clinical practice despite the low number of UK patients. It noted that people with CLL for whom FCR or BR is suitable were now being considered within the appraisal (see section\xa03.2).\n\n## Venetoclax plus obinutuzumab improves progression-free survival, but the overall survival benefit is likely to be similar to the comparator\n\nAfter a median follow up of 39.6\xa0months, there was a statistically significant improvement in progression-free survival for venetoclax plus obinutuzumab compared with obinutuzumab plus chlorambucil (hazard ratio [HR] 0.31, 95% confidence interval [CI] 0.22\xa0to\xa00.44, p<0.001). Median progression-free survival was not reached in the venetoclax plus obinutuzumab arm and was 35.6\xa0months in the obinutuzumab plus chlorambucil arm. The time between the date of randomisation and the date at which someone was first offered a new anti-leukemic therapy was measured in CLL14 as 'time to next treatment'. Median time to next treatment was not reached in either treatment arm, but the likelihood of starting a new treatment was reduced in the venetoclax plus obinutuzumab arm compared with the obinutuzumab plus chlorambucil arm (HR\xa00.51, 95%\xa0CI 0.34\xa0to\xa00.78). Median overall survival was not reached in either treatment arm, and there was no difference in overall survival between the 2 arms (HR\xa01.03, 95%\xa0CI 0.60\xa0to\xa01.75, p=0.92). The committee concluded that the trial data showed that venetoclax plus obinutuzumab improved progression-free survival and time to next treatment compared with obinutuzumab plus chlorambucil. The committee considered that the benefit of venetoclax plus obinutuzumab on overall survival was likely to be similar to obinutuzumab plus chlorambucil, noting that the immaturity of the data meant there was considerable uncertainty.\n\n## The company's indirect treatment comparison with ibrutinib is acceptable for decision making, despite limitations\n\nThe comparator in CLL14 was obinutuzumab plus chlorambucil, a combination that is not a relevant comparator in people with a 17p\xa0deletion or TP53\xa0mutation (see section\xa03.3). So, the company did an indirect treatment comparison to compare progression-free and overall survival for venetoclax plus obinutuzumab with ibrutinib. The company used a real-world evidence study published by Mato et al. (2018) for its base-case comparison. This was because it had the largest number of patients with relevant characteristics out of the ibrutinib studies identified. The company's comparison was unanchored because there was no common comparator arm between CLL14 and Mato et al. The results showed that there was no statistically significant difference between venetoclax plus obinutuzumab and ibrutinib in either progression-free survival (HR 1.515, 95% CI 0.619 to 3.703, p=0.363) or overall survival (HR 1.189, 95% CI 0.425 to 3.322, p=0.741), with wide confidence intervals. The ERG identified several areas of uncertainty in the company's indirect treatment comparison. There were 25\xa0people in the venetoclax plus obinutuzumab arm of CLL14 with a 17p\xa0deletion or TP53\xa0mutation, and 110\xa0people with a 17p\xa0deletion were relevant in Mato et al. The low patient numbers meant that the comparison was underpowered to detect differences between the treatments. There was also considerable heterogeneity between the studies in terms of their design, eligibility criteria and outcomes, which was not adjusted for by the company. The company did a second unadjusted indirect treatment comparison using data from a single-arm study published by Ahn et al. (2018). However, the ERG considered that the results of the comparison using the data from Ahn et al. were as uncertain as those based on the data from Mato et al. The clinical experts highlighted that 17p\xa0deletions or TP53\xa0mutations are uncommon, so it is unlikely that head-to-head data will become available comparing venetoclax plus obinutuzumab with ibrutinib. The committee concluded that, despite its limitations, the company's indirect treatment comparison with ibrutinib was acceptable for decision making.\n\n## The network meta-analysis comparing venetoclax plus obinutuzumab with FCR and BR is sufficient for decision making, despite limitations\n\nIn response to technical engagement, in the absence of head-to-head trial data, the company submitted a network meta-analysis (NMA) to compare the effect of venetoclax plus obinutuzumab with FCR and BR on progression-free and overall survival in people for whom FCR or BR is suitable. The company's network included 9\xa0trials. It used the data on all patients in the venetoclax plus obinutuzumab arm of CLL14 for the comparison. This included only people who could not have FCR or BR on the basis of their CIRS score and creatinine clearance (see section 3.4). It also included some people with a 17p\xa0deletion or TP53\xa0mutation. As described in section 3.4, the ERG considered it likely that some of these people may have been eligible for treatment with FCR or BR in England. The other trials in the company's network had people who were either 'fit' or 'unfit', with fitness determined based on age, CIRS score and fludarabine eligibility. The results suggested a progression-free survival benefit for venetoclax plus obinutuzumab over FCR (HR 0.258, 95% CI 0.151 to 0.481) and BR (HR 0.178, 95% CI 0.109 to 0.312). Overall survival was comparable for venetoclax plus obinutuzumab compared with FCR (HR 0.622, 95% CI 0.273 to 1.789) and BR (HR 0.792, 95% CI 0.378 to 1.969). The ERG considered the company's NMA to have a high degree of uncertainty, noting the substantial heterogeneity between the study populations in the NMA in terms of age and fitness. The wide confidence intervals were of concern to the ERG, as was the sensitivity of the results to the studies included in the NMA. The ERG was unable to reproduce the company's original NMA, so did its own analysis, with similar results to that of the company. The clinical experts explained that venetoclax plus obinutuzumab is very likely to be more efficacious than FCR in people for whom FCR or BR is suitable. They also said that there is no reason why venetoclax plus obinutuzumab would not work well in this patient population. The committee acknowledged this point and concluded that, despite the results of the NMA being highly uncertain, on balance they were sufficient for decision making.\n\n# Adverse effects\n\n## Venetoclax plus obinutuzumab is generally well tolerated compared with current treatments\n\nThe results of CLL14 showed that venetoclax plus obinutuzumab had an acceptable tolerability profile compared with obinutuzumab plus chlorambucil. Patient submissions highlighted that venetoclax is occasionally associated with tumour lysis syndrome. This is caused by a rapid breakdown of cancer cells, and can lead to complications such as kidney failure. Three people had tumour lysis syndrome in the venetoclax plus obinutuzumab arm of CLL14 compared with 5\xa0in the obinutuzumab plus chlorambucil arm. The company considered that these results showed the effectiveness of prophylaxis against tumour lysis syndrome for venetoclax plus obinutuzumab. The committee agreed that venetoclax plus obinutuzumab is likely to be generally well tolerated compared with current treatments.\n\n# Cost-effectiveness model structure\n\n## The model structure is appropriate for decision making, despite uncertainty around the duration of subsequent treatment\n\nThe company submitted a partitioned survival model with 3\xa0states (progression-free, progressed disease and death). To compare venetoclax plus obinutuzumab with obinutuzumab plus chlorambucil in people for whom FCR or BR is unsuitable, the company used data from CLL14 to estimate progression-free survival, overall survival and time to next treatment using parametric curves fitted to Kaplan–Meier data. Half the patients starting subsequent treatment were modelled to have ibrutinib, and the other half were modelled to have venetoclax plus rituximab. This assumption was applied to both treatment arms. Subsequent treatment costs were accrued from the start of subsequent treatment until death. To compare venetoclax plus obinutuzumab with ibrutinib in people with a 17p\xa0deletion or TP53\xa0mutation, the company used the results of the indirect treatment comparison with ibrutinib (see section\xa03.6) to model the differences in efficacy. Patients having venetoclax plus obinutuzumab as their first-line treatment were modelled to have ibrutinib monotherapy as their subsequent treatment. Patients having ibrutinib as their first-line treatment were modelled to have venetoclax monotherapy as their subsequent treatment, with only new incidences of disease progression or death counting towards the associated costs. To compare venetoclax plus obinutuzumab with FCR and BR when these treatments are suitable, the company used the results of the NMA (see section\xa03.7) to model the differences in efficacy. The subsequent treatment mix was the same as in people for whom FCR or BR is unsuitable. However, like ibrutinib, only new incidences of disease progression or death counted towards the subsequent treatment costs for FCR and BR. The ERG considered that the company's model structure was largely appropriate. Its clinical expert confirmed that the subsequent treatment mix was consistent with that offered in NHS clinical practice in England. However, the ERG noted that patients were modelled to have subsequent treatments for much longer than the median second-line treatment durations reported in the literature. It suggested that this was likely to bias the analysis against obinutuzumab plus chlorambucil. The committee noted the uncertainty about the duration of subsequent treatment (see section\xa03.13), but concluded that the model structure was appropriate for decision making.\n\n# Survival extrapolations\n\n## In people for whom FCR or BR is unsuitable, both the company's and ERG's survival extrapolations are relevant for decision making\n\nThe company explored various approaches for extrapolating the progression-free survival, overall survival and time-to-next-treatment data in people for whom FCR or BR is unsuitable. It chose an independent log-logistic distribution as its preferred parametric model for progression-free survival, and a dependent exponential distribution to extrapolate overall survival. The company applied the same obinutuzumab plus chlorambucil overall survival extrapolation for both treatment arms, reflecting the immaturity of the data and lack of evidence for an overall survival benefit for venetoclax plus obinutuzumab. The company used an independent log-logistic distribution for time to next treatment, matching the company's progression-free survival distribution, an outcome closely correlated with time to next treatment. The ERG noted that the survival data from CLL14 were very immature. It considered that the company's survival extrapolations were too dependent on the constraint that the hazard rate of death, disease progression, or starting a subsequent treatment could not fall below the background mortality of the age-matched general population. The ERG also noted that the company's extrapolations were optimistic compared with the 5‑year data from the CLL11 trial, an earlier trial that included an obinutuzumab plus chlorambucil treatment arm in a similar patient population to CLL14. For progression-free survival, the ERG instead favoured an independent 2‑knot hazard spline distribution. For a more conservative overall survival distribution, the ERG modelled the overall survival hazard rate from CLL14 up to 3\xa0years. It then fitted an exponential model to the hazard rate from the ERIC study after this point. ERIC was a retrospective study that evaluated the efficacy and safety of obinutuzumab with or without chlorambucil in a similar patient population to CLL14. The ERG's progression-free and overall survival extrapolations were less dependent on the background mortality constraint than those of the company. For time to next treatment, the ERG derived a hazard ratio between progression-free survival and time to next treatment, which it applied to its progression-free survival distribution. Clinical experts considered the ERG's progression-free survival distribution more plausible than that of the company. However, they warned that the CLL11 data were inappropriate for validating the overall survival extrapolations. Clinical practice has evolved since CLL11, and overall survival is expected to be longer for people in CLL14. The clinical experts also explained that it was reasonable to expect that many people will reach the life expectancy of the general population after treatment with venetoclax plus obinutuzumab, and will be functionally cured. The committee concluded that, despite the limitations of the company's and ERG's survival extrapolations, both were relevant for decision making.\n\n## When there is a 17p\xa0deletion or TP53\xa0mutation, both the company and ERG's survival extrapolations are relevant for decision making\n\nThe company used the same progression-free survival, overall survival and time-to-next-treatment distributions for people with a 17p\xa0deletion or TP53\xa0mutation as used in people for whom FCR or BR is unsuitable (see section\xa03.10). The company applied the progression-free and overall survival hazard ratios from the indirect comparison with ibrutinib (see section\xa03.6) to generate extrapolations for ibrutinib. The ERG noted that the company's extrapolations resulted in patients spending little time alive after their disease had progressed. The ERG considered that a 1‑knot hazard spline distribution was more plausible for progression-free survival, overall survival and time to next treatment. The committee acknowledged the uncertainty, but concluded that both the company's and ERG's survival extrapolations were relevant for decision making.\n\n## In people for whom FCR or BR is suitable, both the company and ERG's survival extrapolations are relevant for decision making\n\nThe company used the same survival extrapolations for people for whom FCR or BR is suitable as for the other 2\xa0subgroups (see section 3.10 and section 3.11). The ERG preferred a 2-knot hazard spline distribution for the progression-free survival extrapolations. This is because it considered that the likelihood of disease progression for people for whom FCR or BR is suitable would be similar to that of people for whom FCR or BR is unsuitable. The committee concluded that both the company's and ERG's progression-free survival extrapolations were relevant for decision making.\n\n# Costs in the cost-effectiveness model\n\n## Subsequent treatment costs are likely to lie between the company's 2\xa0scenarios, both of which are appropriate for decision making\n\nIn the company's base-case model, subsequent treatment and its associated costs were modelled to continue from the start of subsequent treatment until death for venetoclax plus obinutuzumab and obinutuzumab plus chlorambucil. The company considered this approach fair. This was because a lack of published evidence meant that it was not possible to create a treatment sequencing model in relapsed or refractory CLL. The company acknowledged that its approach was likely to overestimate subsequent treatment costs. However, it considered that restricting these costs to 1\xa0subsequent treatment line would not align with NHS clinical practice in England. The ERG considered that the company's approach failed to account for periods of no treatment. It was also likely to be biased against obinutuzumab plus chlorambucil because patients having this treatment began having subsequent treatment earlier. In response to technical engagement, the company presented a revised economic model in which the duration of subsequent treatment was constrained by the median durations of second-line treatment reported in the literature. Clinical expert feedback suggested that it was appropriate to model subsequent treatment costs until death because of the continuous nature of salvage treatments for CLL. The committee acknowledged the uncertainty around the duration of subsequent treatment. It concluded that the actual subsequent treatment cost was likely to lie between the company's original and revised approaches, and that both were appropriate for decision making.\n\n# Cost-effectiveness results\n\n## When FCR or BR is unsuitable, venetoclax plus obinutuzumab is more effective and less costly than obinutuzumab plus chlorambucil\n\nThe company's base case for all 3\xa0patient subgroups incorporated the ERG's preferred utility value of 0.7703 for the 'pre-progression, off-treatment' health state. In people for whom FCR or BR is unsuitable, the company's deterministic base case showed that venetoclax plus obinutuzumab was more effective and less costly than obinutuzumab plus chlorambucil. The ERG preferred the following assumptions:\n\nan independent 2‑knot hazard spline progression-free survival distribution (see section\xa03.10)\n\nan overall survival extrapolation derived by fitting an exponential model to the hazard rate from ERIC beyond 3\xa0years (see section\xa03.10)\n\ntime-to-next-treatment extrapolations derived by applying a hazard ratio to the ERG's preferred independent 2‑knot hazard spline progression-free survival distribution (see section\xa03.10)\n\nsubsequent treatment durations constrained by the median durations of second-line treatment reported in the literature (see section 3.13).Venetoclax plus obinutuzumab remained more effective and less costly than obinutuzumab plus chlorambucil using the ERG's preferred assumptions, and in all but 1\xa0scenario explored by the ERG. The committee acknowledged that there was considerable uncertainty around the long-term survival estimates and the duration for which people have subsequent treatments. However, it concluded that, in all scenarios, venetoclax plus obinutuzumab could be considered an acceptable use of NHS resources.\n\n## In people with a 17p\xa0deletion or TP53\xa0mutation, the estimates are within the range considered a cost-effective use of NHS resources\n\nThe company's deterministic base case showed that venetoclax plus obinutuzumab resulted in cost savings and a quality-adjusted life year (QALY) loss compared with ibrutinib, producing incremental cost-effectiveness ratios (ICERs) that reflected 'savings per QALY lost'. The committee noted that, in situations in which an ICER is derived from a technology that is less effective and less costly than its comparator, the commonly assumed decision rule of accepting ICERs below a given threshold is reversed. So, the higher the ICER, the more cost effective a treatment becomes. The ERG preferred a 1‑knot hazard spline distribution for progression-free survival, overall survival and time to next treatment (see section\xa03.11). In the ERG's analyses, venetoclax plus obinutuzumab resulted in a cost saving of £199,622 and a QALY loss of 0.363, with an ICER of £549,699 saved per QALY lost. These analyses included the patient access scheme for venetoclax, but not for the comparators or subsequent treatments. The decision-making ICERs used by the committee took account of all available confidential discounts, including those for comparators and follow-up treatments, and were lower. However, they remained within the range NICE normally considers an acceptable use of NHS resources. The committee recalled that that there was considerable uncertainty in the company's indirect treatment comparison (see section\xa03.6). However, it concluded that, in all scenarios, venetoclax plus obinutuzumab could be considered an acceptable use of NHS resources based on the saving per QALY lost.\n\n## In people for whom FCR or BR is suitable, the ICERs are higher than the range NICE normally considers an acceptable use of NHS resources\n\nThe company's deterministic base case suggested that the ICER was £32,669 per QALY gained for venetoclax plus obinutuzumab compared with FCR, and £36,768 per QALY gained compared with BR. The ERG preferred to use the progression-free and overall survival hazard ratios derived from its own NMA (see section\xa03.7), and a 2‑knot hazard spline distribution progression-free survival (see section 3.12). The ERG's analyses suggest an ICER of £47,494 per QALY gained for venetoclax plus obinutuzumab compared with FCR, and £67,445 per QALY gained compared with BR. With the confidential discounts for obinutuzumab and ibrutinib applied, the ICERs remained above the range normally considered a cost-effective use of NHS resources (that is, £20,000 to £30,000 per QALY gained). The committee focused on the comparison with FCR because it understood that this is more widely used than BR in clinical practice, so is the most relevant comparator (see section\xa03.3). The committee recalled that the company's NMA was subject to considerable uncertainty (see section\xa03.7). It understood that the ICERs varied widely if the upper and lower bounds of the progression-free and overall survival hazard ratio confidence intervals were applied. On balance, the committee considered the ERG's preferred analysis to represent the most plausible scenario, although it was still subject to considerable uncertainty. The committee also noted that assuming the effect of venetoclax plus obinutuzumab on overall survival was the same as FCR resulted in an ICER that was higher than the ERG's preferred analysis. The committee concluded that venetoclax plus obinutuzumab could not be recommended for routine use in the NHS in this population.\n\n# Innovation\n\n## There are no additional benefits that are not captured in the quality-adjusted life year calculations\n\nThe company considered venetoclax plus obinutuzumab to be an innovative treatment because venetoclax is a first-in-class, oral, selective inhibitor of B‑cell lymphoma\xa02. It has a unique targeted mechanism of action that distinguishes it from other therapies. Venetoclax plus obinutuzumab also has a fixed treatment duration. This means people can have time without therapy, unlike with most other treatments, which people must have until they stop working. Venetoclax plus obinutuzumab increases the range of treatment options for people with untreated CLL, and avoids the need for chemo-immunotherapy. The committee concluded that venetoclax plus obinutuzumab would be a beneficial additional treatment option. However, it noted that it had not been presented with evidence of any additional benefits that were not captured in the measurement of QALYs.\n\n# Equality considerations\n\n## There are no remaining equality issues relevant to the recommendations\n\nThe company's original submission did not include people without a 17p\xa0deletion or TP53\xa0mutation for whom FCR or BR is suitable. Patient and professional submissions highlighted that this would potentially deny these people access to a new treatment option that is well tolerated. In response to technical engagement, the company provided cost-effectiveness analyses comparing venetoclax plus obinutuzumab with FCR and BR in people without a 17p\xa0deletion or TP53\xa0mutation for whom FCR or BR is suitable. The committee considered these analyses during the appraisal (see section 3.16). No other equality or social value judgement issues were identified by the committee.\n\n# End of life\n\n## Venetoclax plus obinutuzumab does not meet the criteria to be considered a life-extending treatment at the end of life\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. This states that a treatment can be considered as a life-extending treatment at the end of life if: it is indicated for people with a short life expectancy (normally less than 24\xa0months); and it offers an extension to life (normally a mean value of at least an additional 3\xa0months compared with current NHS treatment). The committee considered that the short life expectancy criterion of less than 24\xa0months was not met because people with CLL have a life expectancy of more than 2\xa0years. The committee concluded that venetoclax plus obinutuzumab does not meet the criteria to be considered a life-extending treatment at end of life.\n\n# Cancer Drugs Fund\n\n## Further data collection could address uncertainties in the clinical and cost-effectiveness evidence in people for whom FCR or BR is suitable\n\nHaving concluded that venetoclax plus obinutuzumab could not be recommended for routine use in people with untreated CLL when FCR or BR is suitable (see section\xa03.16), the committee considered whether it could be recommended for use within the Cancer Drugs Fund. It discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum). The committee considered whether the clinical uncertainty associated with venetoclax plus obinutuzumab in this patient population could be addressed through collecting more data. It was aware that CLL13, a randomised controlled trial directly comparing venetoclax plus obinutuzumab with FCR and BR in people with untreated CLL, is currently ongoing. CLL13 has a primary completion date of January 2023, with an interim analysis of progression-free survival planned after 49\xa0months. The committee agreed that:\n\nthe company has expressed an interest in venetoclax plus obinutuzumab being considered for funding through the Cancer Drugs Fund in people with untreated CLL for whom FCR or BR is suitable\n\nthe relative benefits of venetoclax plus obinutuzumab on progression-free and overall survival compared with FCR and BR are highly uncertain\n\nthere is plausible potential that the ICER for venetoclax plus obinutuzumab compared with FCR could fall within the range normally considered a cost-effective use of NHS resources\n\ndata on progression-free and overall survival from CLL13 for venetoclax plus obinutuzumab compared with FCR and BR would be a valuable addition to the clinical evidence base and would likely resolve uncertainties around survival\n\nusing venetoclax plus obinutuzumab in the NHS in patients for whom FCR or BR is suitable would allow data to be collected using the Systemic Anti-Cancer Therapy dataset, which would more accurately reflect the benefits of its use in clinical practice.\n\n# Conclusions\n\n## Venetoclax plus obinutuzumab is a cost-effective use of NHS resources and is recommended when FCR or BR is unsuitable\n\nThe committee noted that there was considerable uncertainty around the long-term survival estimates and the duration for which people for whom FCR or BR is unsuitable had subsequent treatments. However, it acknowledged that, in all scenarios, the ICERs suggested that venetoclax plus obinutuzumab was a cost-effective treatment (see section\xa03.14). The committee concluded that venetoclax plus obinutuzumab for untreated CLL in adults for whom FCR or BR is unsuitable is a cost-effective use of NHS resources and could be recommended as an option for this population.\n\n## Venetoclax plus obinutuzumab is a cost-effective use of NHS resources and is recommended when there is a 17p\xa0deletion or TP53\xa0mutation\n\nThe committee noted that there was considerable uncertainty associated with the company's indirect treatment comparison with ibrutinib in people with a 17p\xa0deletion or TP53\xa0mutation. However, it acknowledged that, in all scenarios, the ICERs suggested that venetoclax plus obinutuzumab was a cost-effective treatment (see section\xa03.15). In addition, the committee acknowledged that there is a high unmet need for a new treatment option in this patient population, and that venetoclax plus obinutuzumab would likely represent a tolerable alternative to ibrutinib and idelalisib. The committee concluded that venetoclax plus obinutuzumab for untreated CLL in adults with a 17p\xa0deletion or TP53\xa0mutation is a cost-effective use of NHS resources and could be recommended as an option for this population. Given the QALY losses for venetoclax plus obinutuzumab compared with ibrutinib, treatment choice should be a decision made between the doctor and patient. Other factors to consider in making this decision include the adverse events associated with both treatments, and the fixed duration of venetoclax plus obinutuzumab treatment compared with taking ibrutinib until disease progression. The committee also acknowledged that some people have cardiovascular comorbidities that could prevent them from taking ibrutinib (see section\xa03.1).\n\n## Venetoclax plus obinutuzumab meets the criteria to be included in the Cancer Drugs Fund in people for whom FCR or BR is suitable\n\nThe company's NMA suggested that venetoclax plus obinutuzumab is likely to have a progression-free survival benefit compared with FCR and BR. Input from the clinical experts also suggested that it is likely that venetoclax plus obinutuzumab has a survival benefit over FCR in clinical practice. The committee acknowledged that people with this condition strongly desire an alternative to FCR and BR even if these treatments are considered suitable. It also agreed that there is an unmet need for new treatment options, given the heterogeneity of the patient population. The committee also understood that offering venetoclax plus obinutuzumab to these people up front may be beneficial in the long term. Many people treated with FCR or BR do not go into remission (either complete remission or minimal residual disease). They also have long-term side effects that may affect the efficacy of targeted therapies used in later lines. The incidence of a 17p\xa0deletion or TP53\xa0mutation is also higher in relapsed or refractory CLL, limiting treatment choice in this setting. The committee noted that the ICER for venetoclax plus obinutuzumab compared with FCR was uncertain. However, it concluded that venetoclax plus obinutuzumab had the plausible potential to satisfy the criteria for routine use if this uncertainty could be reduced. The committee recognised that comparative survival data compared with FCR and BR from CLL13 would allow for a more robust cost-effectiveness estimate. So, it agreed that venetoclax plus obinutuzumab met the criteria to be included in the Cancer Drugs Fund for untreated CLL in adults for whom FCR or BR is suitable."}
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https://www.nice.org.uk/guidance/ta663
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Evidence-based recommendations on venetoclax (Venclyxto) with obinutuzumab for untreated chronic lymphocytic leukaemia in adults.
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770aa5348cbcb6e55e66ca9a5b6235ba6514160e
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nice
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Zio XT for detecting cardiac arrhythmias
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Zio XT for detecting cardiac arrhythmias
Evidence-based recommendations on Zio XT for detecting cardiac arrhythmias.
# Recommendations
Zio XT is recommended as an option for people with suspected cardiac arrhythmias who would benefit from ambulatory electrocardiogram (ECG) monitoring for longer than 24 hours only if NHS organisations collect information on:
resource use associated with use of Zio XT
longer-term clinical consequences for people who have monitoring with Zio XT (such as incidences of further stroke, transient ischaemic attack and other thromboembolisms, arrhythmia-related hospitalisations, mortality, uptake of anticoagulants or other changes in medication related to the monitoring result).
Evidence shows that Zio XT is convenient and easy to wear, with an improved diagnostic yield (a measure of how many people with cardiac arrhythmia are diagnosed) compared with standard 24‑hour Holter monitoring. The technology is likely to be cost neutral or cost saving compared with 24‑hour Holter monitoring, but more evidence is needed.
NHS organisations using Zio XT should make sure that the service complies with general data protection regulations (GDPR), and that informed consent covers how a person's data will be used.
Why the committee made these recommendations
Zio XT is a remote ECG monitoring service used to detect cardiac arrhythmias. The service comprises a wearable single-lead ECG device, a software algorithm that analyses the ECG data and a report for the clinician.
Clinical evidence shows that people prefer Zio XT to standard care in the NHS, which usually involves wearing a continuous ECG monitor such as a 24‑hour Holter monitor. Evidence also shows that Zio XT improves patient wear time and how many people are diagnosed with cardiac arrhythmias compared with 24‑hour Holter monitoring. People can wear Zio XT for up to 14 days, which makes it suitable for people with symptoms of arrhythmia that happen more than 24 hours apart. Diagnostic accuracy evidence shows that the software algorithm performs well in recognising arrhythmias.
The effect of adopting Zio XT on costs and resource is uncertain because there is not enough evidence about resource use and the long-term consequences of using it. However, the estimates suggest that using Zio XT is likely to be cost saving or cost the same as using 24‑hour Holter monitoring. So, NICE recommends Zio XT as an option for detecting cardiac arrhythmias but NHS organisations using it should collect further evidence to resolve the uncertainties.# The technology
# Technology
Zio XT (iRhythm Technologies) is a remote cardiac monitoring service used to detect cardiac arrhythmias. It has 3 components:
Zio biosensor: a wearable single-lead ambulatory electrocardiogram (ECG)
ZEUS: a proprietary, regulated software platform and online portal that stores, analyses and sorts the ECG data to generate a report of the findings
Zio technical report: a clinically actionable summary of the recorded ECG data.The Zio biosensor is placed on the person's left upper chest. It can be fitted in clinic or sent directly to the person where they can fit it themselves at home. It records a continuous beat-to-beat ECG for up to 14 days. The person can also press a button to register when they feel symptoms (patient-captured events). Each Zio biosensor is intended for single-patient use. After the monitoring period is completed, the wearer removes the biosensor and sends it to the company by Freepost. The ECG recordings are analysed using ZEUS's algorithm, overseen by company-based accredited cardiographic technicians. A technical report including arrhythmia episodes, wear and analysis time, and patient-captured events is sent to the prescribing healthcare professional for final analysis and interpretation. There are no patient identifiers in or on the Zio biosensor, and data cannot be accessed if the Zio biosensor was to be physically intercepted.
# Innovative aspects
Zio XT provides a continuous recording of ambulatory cardiac monitoring for up to 14 days. This is a longer monitoring period than continuous ECG monitors used in NHS standard care, such as a Holter monitor, which can be up to 7 days but is usually for between 24 and 48 hours.
The wearer can go about their normal daily activities during monitoring, including showering or bathing, because the device is water resistant. Zio XT can be worn under clothing, so may be more discreet than Holter monitors, which are generally worn in a pouch around the waist or neck or carried in a pocket.
The Zio biosensor has no external leads or wires; this is intended to reduce noise artefacts in the data. Zio XT uses proprietary software to detect arrhythmic events in the ECG data and to create the report that is delivered to the healthcare professional. The intention is to reduce the time needed for NHS staff to analyse the continuous monitoring data.
# Intended use
NICE's guideline on transient loss of consciousness ('blackouts') in over 16s and on managing atrial fibrillation recommend the best ways to detect arrhythmia. The NICE Pathway on heart rhythm conditions describes NICE recommendations on the care pathway for patients. NICE recommends a 12‑lead ECG for the first assessment. If the ECG does not detect arrhythmia, and paroxysmal atrial fibrillation is suspected, ambulatory ECG monitoring is recommended using either Holter monitoring or cardiac event recorders, depending on symptoms and symptom frequency. In people with infrequent blackouts (less than once every 2 weeks), an implantable cardiac monitor may be offered. NICE's diagnostics guidance on implantable cardiac monitors to detect atrial fibrillation after cryptogenic stroke also recommends using an implantable cardiac monitor to detect atrial fibrillation after cryptogenic stroke, if a cardiac arrhythmic cause of stroke is still suspected after ambulatory ECG monitoring.
Zio XT provides another ambulatory ECG monitor option to current standard care (24‑hour Holter monitoring or cardiac event recorder monitoring) for detecting cardiac arrhythmia in people with palpitations, fainting (syncope) and suspected cardiac arrhythmia. People can wear Zio XT for up to 14 days, which makes it suitable for people who experience symptoms of arrhythmia more than 24 hours apart. Zio XT is prescribed by a healthcare professional, most often a cardiologist or GP, in primary, secondary or tertiary care. It may also be prescribed by a stroke clinician or neurologist.
Full details on using Zio XT are in the instructions for use.
# Costs
During consultation, the company revised the cost of monitoring with Zio XT from £310 to £265 per patient (excluding VAT). This figure includes the cost of the biosensor and the cost of analysing and reporting the data.
For more details, see the website for Zio XT.# Evidence
# Clinical evidence
## The clinical evidence comprises 30 published studies
The clinical evidence comprises 17 published studies, which include 169,063 people referred to ambulatory monitoring, and 13 abstracts:
UK-based randomised controlled trial (Kaura et al. 2019)
prospective within-subject comparative studies (Barrett et al. 2014, Eysenck et al. 2019, Rosenberg et al. 2013)
prospective non-comparative studies (Rho et al. 2018, Heckbert et al. 2018, Reed et al. 2018, Schreiber et al. 2014, Steinhubl et al. 2018, Turakhia et al. 2015)
retrospective non-comparative studies (Eisenberg et al. 2014, Go et al. 2018, Schultz et al. 2019, Solomon et al. 2016, Tung et al. 2015, Turakhia et al. 2013, Wineinger et al. 2019)
abstracts (Agarwal et al. 2015, Chandratheva et al. 2017, Ghosh et al. 2018, Hall et al. 2019, Keibel et al. 2015, Malhotra et al. 2018, Miller et al. 2014, Norby et al. 2018, Salazar et al. 2011, Sattar et al. 2012, Su et al. 2014, Turakhia et al. 2012, Ullal et al. 2013).The external assessment centre (EAC) noted that some of the non-comparative studies may have overlapping populations because the data are retrospective. For full details of the clinical evidence, see section 3 of the assessment report, which is in the supporting documents for this guidance.
## Four comparative studies are considered pivotal to the decision problem
Three of the 4 comparative studies compared 14‑day Zio XT with a 24‑hour Holter monitor (Barrett et al. 2014, Kaura et al. 2019, Rosenberg et al. 2013) and 1 compared it with an external loop recorder (the Novacor R. Test; Eysenck et al. 2019). The size of the studies varied, with a total of 357 people, including those with a recent stroke or transient ischaemic attack, people with pacemakers or diagnosed atrial fibrillation, and people with suspected arrhythmia. The EAC considered the multicentre UK randomised controlled trial to be the highest-quality study (Kaura et al. 2019). The EAC considered the other 3 comparative studies to be of adequate quality. The EAC did not do a meta-analysis because it considered the evidence to be too heterogeneous in terms of populations, methodology, comparators, and outcomes reported.
## The UK-based randomised controlled trial has a high withdrawal rate because there was a high refusal rate for the Holter monitor
The randomised controlled trial compared the diagnostic yield of 14‑day Zio XT with 24‑hour Holter monitoring in 116 people with stroke or transient ischaemic attack. People randomised to the Zio XT monitoring arm also had 24‑hour Holter monitoring. There was a high withdrawal rate from both arms of the trial because 20% of the randomised patients refused to use the 24‑hour Holter monitor. This may have biased results. According to the trial authors, the study was adequately powered for the primary outcome. An independent power analysis done by the EAC found that the randomised controlled trial was likely to be underpowered because of the high withdrawal rate. The trial is underpowered for the secondary outcomes, which included anticoagulation use and mortality.
## Evidence suggests that monitoring with Zio XT increases diagnostic yield
Three studies comparing arrhythmia detection rates for Zio XT with 24‑hour Holter monitoring showed an increased diagnostic yield with Zio XT over total wear time. Results from Eysenck et al. (2019) suggested that Zio XT may be more accurate in detecting the presence or absence of atrial fibrillation than the Novacor R. Test (an external event loop monitor, described as current standard practice) but less accurate than pacemaker data (described as gold standard).
## Evidence suggests that patients found Zio XT acceptable and wore it for most of the scheduled days
Evidence from comparative studies suggested that most patients were happy to wear the Zio XT biosensor, with median wear time ranging from 10.8 days (Rosenberg et al. 2013) to 12.8 days (Eysenck et al. 2019) out of a scheduled 14 days. In Eysenck et al. (2019), the Zio XT biosensor was worn for longer than 3 of the other continuous cardiac monitors evaluated. In Barrett et al. (2014), 93.7% of patients found the biosensor comfortable to wear compared with 51.7% for the Holter monitor. A survey of patients from a UK cardiology clinic (Hall et al. 2019) found that Zio XT was statistically significantly preferred to Holter monitoring in terms of shape, comfort, practicality and returning method.
## The diagnostic accuracy of Zio XT and the effect of the technology on clinical outcomes are uncertain from the published evidence
The diagnostic accuracy of Zio XT compared with standard care was not clearly defined in any study. Barrett et al. (2014) and Rosenberg et al. (2013) did some analysis comparing a Holter monitor and Zio XT over the same 24‑hour period with different results. Rosenberg et al. (2013) reported that there was statistically significant agreement between Zio XT and the Holter monitor recordings over the same 24‑hour period. However, Barrett et al. (2014) reported the Holter monitor detected 11 arrhythmia events that were not detected by Zio XT over a simultaneous 24‑hour monitoring period. The authors stated that 2 were caused by Zio XT algorithm misclassification, which was then corrected, and 7 were errors made by the company's report reviewer. A technical study by Hannun et al. (2019) reported good diagnostic performance for the deep neural network used as part of Zio XT compared with a committee of cardiologists. There is no evidence to show that an increased diagnostic yield with Zio XT improves clinical outcomes. The EAC considered that, without more information about diagnostic accuracy, it is not clear if the changes to treatment reported in the studies were an appropriate response to the patient's condition. During consultation, the company submitted unpublished technical data to support diagnostic accuracy claims. This is detailed in section 3.8.
## The evidence for Zio XT is broadly generalisable to NHS practice
Five studies were done in the UK and the EAC considered the evidence is generalisable to the NHS: 2 comparative studies (Kaura et al. 2019, Eysenck et al. 2018), 1 prospective non-comparative study (Reed et al. 2018), and 2 conference abstracts (Chandratheva et al. 2017, Ghosh et al. 2018). The 2 remaining comparative studies were in the US.
# Evidence submitted during consultation
## The company's evidence shows the ZEUS algorithm has good diagnostic accuracy per episode
During consultation, the company submitted technical data reporting the performance of Zio XT's algorithm (ZEUS) at detecting 11 arrhythmia types and sinus rhythm. Using a reference database of known clinical rhythms (over 150 examples of each), the ZEUS algorithm showed a sensitivity of over 90% and a specificity of over 95% for detecting atrial tachycardia (including atrial fibrillation and supraventricular tachycardia) from a total of over 1,400 episodes. Post-market analysis using clinical records processed by Zio XT showed a sensitivity of over 90% for detecting atrial tachycardia from a total of over 50 million episodes. Newcastle EAC reviewed the technical data provided by the company and concluded that Zio XT shows excellent agreement with cardiographic technician assessment of identified arrhythmia episodes. However, it highlighted that the analyses were done per episode and not on a per-patient basis. But it stated that, in principle, good per-episode performance should translate to good per-patient performance.
## An EAC review of artificial intelligence in Zio XT raised no concerns
During consultation, KiTec EAC reviewed the artificial intelligence in Zio XT's ZEUS software. It noted that the algorithm to detect arrythmia uses a fixed deep neural network (a computational model made up of multiple processing layers) and that the training of the system is adequate. The EAC noted it had a large training dataset and that uncommon rhythms were well represented within this dataset. The software also used an external database for validation. The EAC also reviewed the internal quality assurance process and noted that before providing a report to clinicians, the algorithm outputs are checked by the company's cardiographic technicians (certified by The Society for Cardiological Science and Technology and Cardiac Credentialing International). The percentage of electrocardiogram (ECG) traces that are quality assured by cardiographic technicians was not reported but the agreement between algorithms and cardiographic technicians was high (over 99% overall episodic sensitivity in post-market analysis).
## Clinical experience from an NHS trust and a sustainability and transformation partnership does not add to the evidence base
During consultation, 1 NHS trust and 1 sustainability and transformation partnership provided feedback and results from using Zio XT. The EAC reviewed the evidence submitted but did not consider it added anything to the existing evidence base. It concluded that clear conclusions about efficacy could not be drawn from the results because there was not enough information on the patient populations.
# Cost evidence
## The cost evidence comprises 5 published studies
Five published studies reported the economic impact of the technology:
a UK budget impact analysis (Kaura et al. 2019)
a UK study reporting technology costs using data from the REMAP‑AF trial (Eysenck et al. 2019)
a prospective matched cohort study reporting healthcare resource use (Steinhubl et al. 2018)
conference abstracts (Ghosh et al. 2018, Chandratheva et al. 2017).Two studies reported that the technology was cost saving. Two reported it was not cost saving compared with other devices including Holter monitoring. Studies consistently reported that Zio XT is the most efficient in terms of avoiding delays between clinic and diagnosis confirmation.
## The company presented 3 cost models showing that monitoring with Zio XT saves between £55 and £85 per patient over 1 year
The company created 3 de novo cost analyses comparing the 14‑day Zio XT with blended strategies, based on a 24‑hour Holter monitor or a cardiac event recorder, in different care pathways:
The cardiology model (presented as a base case) considered people with symptomatic palpitations or syncope and assessed the costs associated with the diagnostic process only.
The stroke model (presented as a base case) considered people who have had a stroke or transient ischaemic attack and assessed the costs associated with the diagnostic process only.
The downstream stroke model was presented as a scenario analysis and extrapolated the economic consequences of the extra risk of recurrent stroke because of delayed or missed diagnosis of atrial fibrillation. All models had a time horizon of 1 year. Overall, the company's models showed that using Zio XT saves between £55 and £85 per patient because of reductions in repeat testing, referrals or cardiology outpatient review, and events in stroke populations. For full details of the cost evidence, see section 4 of the EAC's assessment report in the supporting documents for this guidance.
## The EAC's changes to the models make monitoring with Zio XT cost incurring
The EAC revised the base-case (cardiology and stroke) models to address some potential limitations:
the proportion of patients having repeat Holter tests after 24‑hour Holter monitoring was changed to 27%
NHS reference costs were used for Holter monitoring rather than Patient Level Information and Costing System (PLICS) data
the cost of an outpatient appointment before discharge was included for all tests. The EAC revised the downstream stroke model to:
include the cost of anticoagulants (and their side effects)
lower the estimated stroke risk
include repeated diagnostic test costs.The EAC considered the downstream stroke cost model the most informative. After these revisions, the EAC concluded that Zio XT is unlikely to be cost saving at the original price when compared with current practice. Zio XT became cost incurring by:
£0.82 per patient per year in the cardiology model
£70.81 per patient per year in the stroke model
£20.83 per patient per year in the downstream stroke model.
## Scenario analyses suggest that cost savings are influenced by the number of repeat tests and outpatient follow-up appointments
The EAC did a scenario analysis to explore the impact of repeat monitoring after a negative test. Zio XT was cost incurring when all monitoring was repeated after a negative test. When monitoring with a 24‑hour Holter or a 7‑day cardiac event recorder was repeated after a negative first test, but Zio XT was not repeated, the technology was cost saving. The EAC also explored the impact of excluding follow-up outpatient appointments after monitoring for some or all tests. Full descriptions of the 5 scenarios explored and results for each of these scenarios can be found in section 2 of the addendum to the EAC's assessment report in the supporting documents for this guidance.
# Cost evidence submitted during consultation
## A revised cost of £265 makes Zio XT cost saving or broadly cost neutral
During consultation, the company revised the cost for the technology to £265 per person. The EAC recalculated the results from the cost modelling with the lower price in the 2 most relevant scenarios, which included the following assumptions:
no appointment needed after a negative result, and no repeated test (scenario 3)
no appointment needed after any negative result, whether or not the test is repeated (scenario 5). The results showed Zio XT is likely to be cost saving or cost neutral compared with standard care in the cardiology model (£59.80 less for scenario 3; £3.47 less for scenario 5 per patient per year). For the stroke model, the results were still cost incurring (£14.93 more for scenario 3; £79.47 more for scenario 5 per patient per year) but the downstream model results for the same population showed the results moved towards Zio XT being cost saving (£72.55 less for scenario 3; £33.79 more for scenario 5 per patient per year). Full results for all 5 scenarios explored can be found in section 1 of the additional economic analyses in the supporting documents for this guidance.
## Increasing the probability of testing with implantable cardiac monitors does not substantially change the cost-modelling results
Additional sensitivity analysis was done to examine the effect of a potential change in the use of implantable cardiac monitors. The experts did not all agree that use of implantable cardiac monitors is likely to increase in the future. In the stroke and cardiology models, a small percentage of patients (2%) who have a negative test will go on to have implantable cardiac monitoring. Increasing the probability of testing with implantable cardiac monitors to 10% did not substantially change the results of the Zio XT cost modelling. For full details, see the additional sensitivity analysis report and additional clinical expert advice in the supporting documents for this guidance.
## Threshold analysis results for repeat tests range from 1.30 to 1.78 per person
The EAC also did a threshold analysis to assess the number of repeat tests per person in the current care arm needed to equalise the cost of Zio XT and current care. The average number of repeat tests after a negative result with either 24‑hour Holter or cardiac event recorders was assumed to be 1.389 per person in the base case. Threshold analysis results ranged from 1.30 to 1.78 repeat tests per person, depending on the model and scenario evaluated. For full details, see the additional sensitivity analysis report in the supporting documents for this guidance.# Committee discussion
# Clinical-effectiveness overview
## Zio XT is an innovative technology which shows promise for ambulatory monitoring
The clinical experts who had experience of using Zio XT explained that it offers continuous monitoring over 14 days and is well accepted by patients. Experts commented on how easy it is to fit and that patients find it acceptable, adding that people are more likely to wear Zio XT for longer. The committee agreed that Zio XT is an innovative design and there is a plausible patient benefit.
## The evidence shows that Zio XT can improve diagnostic yield and patient wear time
Evidence shows that Zio XT can increase patient wear time. Three of the 4 comparative studies showed improved diagnostic yield over total wear time compared with 24‑hour Holter monitoring. Eysenck et al. (2019) reported a longer wear time for Zio XT compared with the R-test (a cardiac event recorder). The clinical experts agreed that it was plausible that monitoring with Zio XT could increase diagnostic yield, primarily because Zio XT is worn for 14 days, which is much longer than the Holter monitor. The clinical experts also advised that Zio XT has usability advantages for patients. It is more discreet and convenient to wear than a Holter monitor and the Zio biosensor stays on better. The committee concluded that Zio XT increases diagnostic yield for detection of cardiac arrhythmias compared with 24‑hour Holter monitoring.
## The committee considers Zio XT to be a diagnostic service for detecting cardiac arrhythmia
The committee questioned whether Zio XT is a diagnostic service. The company said that the Zio XT algorithm highlights areas of concern on the electrocardiogram (ECG) trace, then a company-based cardiac physiologist reviews and confirms the arrhythmia type. A report including a sample of the ECG trace is generated for the referring healthcare professional. The company said that the technology is a decision support tool that provides a report allowing the referring healthcare professional to make a diagnosis. The company also said that full disclosure of ECG traces is available on request. The committee discussed the likely dependence of healthcare professionals on the report and queried the reliability of the data in it. The committee accepted that although Zio XT provides useful information about the number of episodes and type of arrhythmic events, the final diagnosis and treatment decision remains with the referring healthcare professional. The committee concluded that Zio XT is a diagnostic service, which provides information to clinicians to help make a diagnosis.
## Zio XT has good diagnostic accuracy on a per-episode basis
The available published evidence did not provide reliable estimates of diagnostic sensitivity or specificity. Hannun et al. (2019) showed that Zio XT's ZEUS algorithm was able to classify a broad range of distinct arrhythmias and had a similar accuracy to cardiologists. However, the study was not done with the Zio Patch or in a clinical setting. Also, Zio XT's ECG recordings are captured using a single-lead biosensor while Holter monitors use 3 leads. Experts said that although 3‑lead ECG recordings may be better at detecting certain types of arrhythmia, most clinical decisions can be made from 1 lead. At the draft guidance meeting the committee was concerned about the lack of detail for the diagnostic accuracy data and recommended further research. After consultation, the committee considered the technical data provided by the company and the EAC's review of this data. It agreed with the EAC's view that the Zio XT software has good per-episode performance for detecting cardiac arrhythmia and this should translate to good per-patient performance. The committee concluded that Zio XT shows good performance in recognising episodes of identified arrhythmia in ECG traces but noted that publication of future data would be valuable.
## Additional information about the long-term clinical consequences of using Zio XT would be valuable
In their evidence review the EAC queried the effect of an increased diagnostic yield on clinical consequences. It considered that further comparative evidence about how Zio XT affects clinical management of cardiac arrhythmias and patient outcomes would be helpful. The committee understood the limitations of the evidence base and agreed that more information about the long-term clinical consequences of using Zio XT would be valuable.
# Other patient benefits or issues
## Shaving of bodily hair is common to both Zio XT and Holter monitoring and is unlikely to restrict access for patients
Applying the Zio XT biosensor may mean body hair needs to be shaved. Some religions forbid cutting or shaving body hair. The clinical experts advised that shaving is needed for both Zio XT and Holter monitoring. They believed this would not restrict access for particular groups of people and said that, in their experience, most people agree to shave when using the Zio XT biosensor.
# NHS considerations overview
## Zio XT is scalable but there are concerns about its impact on NHS resources
Clinical experts highlighted that there is currently a shortage of cardiac physiologists in the NHS. They noted that more widespread adoption of Zio XT in the NHS may further affect the recruitment of cardiac physiologists if they leave the NHS to work for the service. But they also said that reducing the burden on cardiac physiologists in the NHS of analysing ECG reports should be considered a benefit of Zio XT. The company said that it has the capability to scale up its service to the UK, and that it would adapt a successful model used in the US. The company confirmed that the turnaround time for reports (4 days maximum but usually 24 hours) would not change. The committee was reassured that Zio XT is potentially scalable across the NHS but it was less certain about the impact on the NHS cardiac physiologist workforce.
## Zio XT uses anonymised patient data and appears to comply with privacy laws
The data used for developing and training the algorithm come from a database of anonymised ECG traces from patients who have previously used the service. The committee queried if patients are aware of this when they use the service and discussed considerations for the use of anonymised data in software development and training. The company explained that Zio XT meets all the relevant NHS data governance standards including the NHS Digital Toolkit and general data protection regulation (GDPR) privacy requirements. The committee noted that people give consent for their data to be used and that Zio XT appears to comply with all applicable privacy laws. The committee concluded that NHS organisations using Zio XT should make sure that the service is compliant with GDPR, and that informed consent for the investigation covers how a patient's data will be used.
# Cost-modelling overview
## The EAC's base case does not fully reflect clinical practice regarding outpatient appointments
In its base-case analysis, the EAC assumed that all monitoring tests would be followed up with an outpatient appointment. Clinical advice was that outpatient appointments are not usually needed after a negative result from Zio XT, and that practice varies. In scenarios in which follow-up outpatient appointments were included for standard care but not for Zio XT, Zio XT was cost saving across all 3 of the EAC's revised models. Comments and clinical expert advice received at consultation suggested that an outpatient appointment would normally only be needed after a significant positive result, regardless of the ECG monitoring device used. The committee concluded that out of the scenarios explored by the EAC, 2 scenarios best reflected current clinical practice (see section 3.15).
## Zio XT may have additional benefits not captured in the cost modelling
The committee noted that the long-term clinical benefits of identifying significant arrhythmias were not captured in the stroke or cardiology models, which only evaluated diagnosis costs. The committee considered the downstream stroke model to be more informative because it took into account the benefits in terms of stroke outcomes within the first year, in addition to the cost of diagnosis. However, longer-term benefits were not included. There is no equivalent model for the cardiology patients so the longer-term benefits of earlier diagnosis in this group have not been calculated. The EAC advised that there was not enough information available to model longer-term benefits in the cardiology model. The committee concluded that there are likely to be additional benefits of using Zio XT which have not been captured in the current cost modelling.
## Zio XT is likely to be cost saving or broadly cost neutral, but this is uncertain
After consultation, the EAC presented new cost-modelling results including the reduced price for Zio XT. The committee accepted that this reduction in price made Zio XT slightly cost saving compared with standard care for patients in the cardiology model (people with symptomatic palpitations or syncope). The clinical experts explained that the benefits of Zio XT in this population are likely to be realised with careful patient selection based on frequency of symptoms. The committee considered that Zio XT is most likely to be cost saving when used by patients who have symptoms more than 24 hours apart. For patients who have had ischaemic stroke or a transient ischaemic attack without current evidence of atrial fibrillation, the downstream results show Zio XT is likely to be cost neutral or cost saving. The assumptions about follow-up appointments and repeat tests affected the results significantly. Expert advice showed that there is significant variation in the resources used for monitoring. The committee accepted the limitations of the current models and concluded that Zio XT is likely to be cost saving or broadly cost neutral, but more information is needed about resource use.
## Further information about resource use and the long-term consequences of Zio XT monitoring would be valuable
The committee accepted the EAC's changes to the models but considered there was still uncertainty about resource use and the long-term consequences of using Zio XT. Therefore, it was difficult to draw firm conclusions about the extent of any cost benefits. The committee noted the influence of assumptions about the need for outpatient appointments and the number of repeat tests on the cost modelling and the variation in ECG monitoring practice across the NHS. It concluded that more detailed data from sites that have used Zio XT in their ECG monitoring pathway could provide valuable information about resource use. This could inform the cost modelling and possibly some best practice guidelines for adopting Zio XT. The committee also concluded that further information on the long-term consequences of Zio XT monitoring (such as incidences of further stroke, transient ischaemic attack and other thromboembolisms, arrhythmia-related hospitalisations, mortality, uptake of anticoagulants or other changes in medication related to the monitoring result) would likely strengthen the certainty of cost benefits associated with its use.
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{'Recommendations': "Zio\xa0XT is recommended as an option for people with suspected cardiac arrhythmias who would benefit from ambulatory electrocardiogram (ECG) monitoring for longer than 24\xa0hours only if NHS organisations collect information on:\n\nresource use associated with use of Zio\xa0XT\n\nlonger-term clinical consequences for people who have monitoring with Zio\xa0XT (such as incidences of further stroke, transient ischaemic attack and other thromboembolisms, arrhythmia-related hospitalisations, mortality, uptake of anticoagulants or other changes in medication related to the monitoring result).\n\nEvidence shows that Zio\xa0XT is convenient and easy to wear, with an improved diagnostic yield (a measure of how many people with cardiac arrhythmia are diagnosed) compared with standard 24‑hour Holter monitoring. The technology is likely to be cost neutral or cost saving compared with 24‑hour Holter monitoring, but more evidence is needed.\n\nNHS organisations using Zio\xa0XT should make sure that the service complies with general data protection regulations (GDPR), and that informed consent covers how a person's data will be used.\n\nWhy the committee made these recommendations\n\nZio\xa0XT is a remote ECG monitoring service used to detect cardiac arrhythmias. The service comprises a wearable single-lead ECG device, a software algorithm that analyses the ECG data and a report for the clinician.\n\nClinical evidence shows that people prefer Zio\xa0XT to standard care in the NHS, which usually involves wearing a continuous ECG monitor such as a 24‑hour Holter monitor. Evidence also shows that Zio\xa0XT improves patient wear time and how many people are diagnosed with cardiac arrhythmias compared with 24‑hour Holter monitoring. People can wear Zio\xa0XT for up to 14\xa0days, which makes it suitable for people with symptoms of arrhythmia that happen more than 24\xa0hours apart. Diagnostic accuracy evidence shows that the software algorithm performs well in recognising arrhythmias.\n\nThe effect of adopting Zio\xa0XT on costs and resource is uncertain because there is not enough evidence about resource use and the long-term consequences of using it. However, the estimates suggest that using Zio\xa0XT is likely to be cost saving or cost the same as using 24‑hour Holter monitoring. So, NICE recommends Zio\xa0XT as an option for detecting cardiac arrhythmias but NHS organisations using it should collect further evidence to resolve the uncertainties.", 'The technology': "# Technology\n\nZio\xa0XT (iRhythm Technologies) is a remote cardiac monitoring service used to detect cardiac arrhythmias. It has 3\xa0components:\n\nZio biosensor: a wearable single-lead ambulatory electrocardiogram (ECG)\n\nZEUS: a proprietary, regulated software platform and online portal that stores, analyses and sorts the ECG data to generate a report of the findings\n\nZio technical report: a clinically actionable summary of the recorded ECG data.The Zio biosensor is placed on the person's left upper chest. It can be fitted in clinic or sent directly to the person where they can fit it themselves at home. It records a continuous beat-to-beat ECG for up to 14\xa0days. The person can also press a button to register when they feel symptoms (patient-captured events). Each Zio biosensor is intended for single-patient use. After the monitoring period is completed, the wearer removes the biosensor and sends it to the company by Freepost. The ECG recordings are analysed using ZEUS's algorithm, overseen by company-based accredited cardiographic technicians. A technical report including arrhythmia episodes, wear and analysis time, and patient-captured events is sent to the prescribing healthcare professional for final analysis and interpretation. There are no patient identifiers in or on the Zio biosensor, and data cannot be accessed if the Zio biosensor was to be physically intercepted.\n\n# Innovative aspects\n\nZio\xa0XT provides a continuous recording of ambulatory cardiac monitoring for up to 14\xa0days. This is a longer monitoring period than continuous ECG monitors used in NHS standard care, such as a Holter monitor, which can be up to 7\xa0days but is usually for between 24\xa0and 48\xa0hours.\n\nThe wearer can go about their normal daily activities during monitoring, including showering or bathing, because the device is water resistant. Zio\xa0XT can be worn under clothing, so may be more discreet than Holter monitors, which are generally worn in a pouch around the waist or neck or carried in a pocket.\n\nThe Zio biosensor has no external leads or wires; this is intended to reduce noise artefacts in the data. Zio\xa0XT uses proprietary software to detect arrhythmic events in the ECG data and to create the report that is delivered to the healthcare professional. The intention is to reduce the time needed for NHS staff to analyse the continuous monitoring data.\n\n# Intended use\n\nNICE's guideline on transient loss of consciousness ('blackouts') in over 16s and on managing atrial fibrillation recommend the best ways to detect arrhythmia. The NICE Pathway on heart rhythm conditions describes NICE recommendations on the care pathway for patients. NICE recommends a 12‑lead ECG for the first assessment. If the ECG does not detect arrhythmia, and paroxysmal atrial fibrillation is suspected, ambulatory ECG monitoring is recommended using either Holter monitoring or cardiac event recorders, depending on symptoms and symptom frequency. In people with infrequent blackouts (less than once every 2\xa0weeks), an implantable cardiac monitor may be offered. NICE's diagnostics guidance on implantable cardiac monitors to detect atrial fibrillation after cryptogenic stroke also recommends using an implantable cardiac monitor to detect atrial fibrillation after cryptogenic stroke, if a cardiac arrhythmic cause of stroke is still suspected after ambulatory ECG monitoring.\n\nZio\xa0XT provides another ambulatory ECG monitor option to current standard care (24‑hour Holter monitoring or cardiac event recorder monitoring) for detecting cardiac arrhythmia in people with palpitations, fainting (syncope) and suspected cardiac arrhythmia. People can wear Zio\xa0XT for up to 14\xa0days, which makes it suitable for people who experience symptoms of arrhythmia more than 24\xa0hours apart. Zio\xa0XT is prescribed by a healthcare professional, most often a cardiologist or GP, in primary, secondary or tertiary care. It may also be prescribed by a stroke clinician or neurologist.\n\nFull details on using Zio\xa0XT are in the instructions for use.\n\n# Costs\n\nDuring consultation, the company revised the cost of monitoring with Zio\xa0XT from £310 to £265 per patient (excluding VAT). This figure includes the cost of the biosensor and the cost of analysing and reporting the data.\n\nFor more details, see the website for Zio\xa0XT.", 'Evidence': "# Clinical evidence\n\n## The clinical evidence comprises 30 published studies\n\nThe clinical evidence comprises 17\xa0published studies, which include 169,063\xa0people referred to ambulatory monitoring, and 13\xa0abstracts:\n\nUK-based randomised controlled trial (Kaura et al. 2019)\n\nprospective within-subject comparative studies (Barrett et al. 2014, Eysenck et al. 2019, Rosenberg et al. 2013)\n\nprospective non-comparative studies (Rho et al. 2018, Heckbert et al. 2018, Reed et al. 2018, Schreiber et al. 2014, Steinhubl et al. 2018, Turakhia et al. 2015)\n\nretrospective non-comparative studies (Eisenberg et al. 2014, Go et al. 2018, Schultz et al. 2019, Solomon et al. 2016, Tung et al. 2015, Turakhia et al. 2013, Wineinger et al. 2019)\n\nabstracts (Agarwal et al. 2015, Chandratheva et al. 2017, Ghosh et al. 2018, Hall et al. 2019, Keibel et al. 2015, Malhotra et al. 2018, Miller et al. 2014, Norby et al. 2018, Salazar et al. 2011, Sattar et al. 2012, Su et al. 2014, Turakhia et al. 2012, Ullal et al. 2013).The external assessment centre (EAC) noted that some of the non-comparative studies may have overlapping populations because the data are retrospective. For full details of the clinical evidence, see section 3 of the assessment report, which is in the supporting documents for this guidance.\n\n## Four comparative studies are considered pivotal to the decision problem\n\nThree of the 4\xa0comparative studies compared 14‑day Zio\xa0XT with a 24‑hour Holter monitor (Barrett et al. 2014, Kaura et al. 2019, Rosenberg et al. 2013) and 1\xa0compared it with an external loop recorder (the Novacor R. Test; Eysenck et al. 2019). The size of the studies varied, with a total of 357\xa0people, including those with a recent stroke or transient ischaemic attack, people with pacemakers or diagnosed atrial fibrillation, and people with suspected arrhythmia. The EAC considered the multicentre UK randomised controlled trial to be the highest-quality study (Kaura et al. 2019). The EAC considered the other 3\xa0comparative studies to be of adequate quality. The EAC did not do a meta-analysis because it considered the evidence to be too heterogeneous in terms of populations, methodology, comparators, and outcomes reported.\n\n## The UK-based randomised controlled trial has a high withdrawal rate because there was a high refusal rate for the Holter monitor\n\nThe randomised controlled trial compared the diagnostic yield of 14‑day Zio\xa0XT with 24‑hour Holter monitoring in 116\xa0people with stroke or transient ischaemic attack. People randomised to the Zio\xa0XT monitoring arm also had 24‑hour Holter monitoring. There was a high withdrawal rate from both arms of the trial because 20% of the randomised patients refused to use the 24‑hour Holter monitor. This may have biased results. According to the trial authors, the study was adequately powered for the primary outcome. An independent power analysis done by the EAC found that the randomised controlled trial was likely to be underpowered because of the high withdrawal rate. The trial is underpowered for the secondary outcomes, which included anticoagulation use and mortality.\n\n## Evidence suggests that monitoring with Zio\xa0XT increases diagnostic yield\n\nThree studies comparing arrhythmia detection rates for Zio\xa0XT with 24‑hour Holter monitoring showed an increased diagnostic yield with Zio\xa0XT over total wear time. Results from Eysenck et al. (2019) suggested that Zio\xa0XT may be more accurate in detecting the presence or absence of atrial fibrillation than the Novacor R. Test (an external event loop monitor, described as current standard practice) but less accurate than pacemaker data (described as gold standard).\n\n## Evidence suggests that patients found Zio\xa0XT acceptable and wore it for most of the scheduled days\n\nEvidence from comparative studies suggested that most patients were happy to wear the Zio\xa0XT biosensor, with median wear time ranging from 10.8\xa0days (Rosenberg et al. 2013) to 12.8\xa0days (Eysenck et al. 2019) out of a scheduled 14\xa0days. In Eysenck et al. (2019), the Zio\xa0XT biosensor was worn for longer than 3\xa0of the other continuous cardiac monitors evaluated. In Barrett et al. (2014), 93.7% of patients found the biosensor comfortable to wear compared with 51.7% for the Holter monitor. A survey of patients from a UK cardiology clinic (Hall et al. 2019) found that Zio\xa0XT was statistically significantly preferred to Holter monitoring in terms of shape, comfort, practicality and returning method.\n\n## The diagnostic accuracy of Zio\xa0XT and the effect of the technology on clinical outcomes are uncertain from the published evidence\n\nThe diagnostic accuracy of Zio\xa0XT compared with standard care was not clearly defined in any study. Barrett et al. (2014) and Rosenberg et al. (2013) did some analysis comparing a Holter monitor and Zio\xa0XT over the same 24‑hour period with different results. Rosenberg et al. (2013) reported that there was statistically significant agreement between Zio\xa0XT and the Holter monitor recordings over the same 24‑hour period. However, Barrett et al. (2014) reported the Holter monitor detected 11\xa0arrhythmia events that were not detected by Zio\xa0XT over a simultaneous 24‑hour monitoring period. The authors stated that 2 were caused by Zio\xa0XT algorithm misclassification, which was then corrected, and 7 were errors made by the company's report reviewer. A technical study by Hannun et al. (2019) reported good diagnostic performance for the deep neural network used as part of Zio\xa0XT compared with a committee of cardiologists. There is no evidence to show that an increased diagnostic yield with Zio\xa0XT improves clinical outcomes. The EAC considered that, without more information about diagnostic accuracy, it is not clear if the changes to treatment reported in the studies were an appropriate response to the patient's condition. During consultation, the company submitted unpublished technical data to support diagnostic accuracy claims. This is detailed in section 3.8.\n\n## The evidence for Zio\xa0XT is broadly generalisable to NHS practice\n\nFive studies were done in the UK and the EAC considered the evidence is generalisable to the NHS: 2 comparative studies (Kaura et al. 2019, Eysenck et al. 2018), 1 prospective non-comparative study (Reed et al. 2018), and 2 conference abstracts (Chandratheva et al. 2017, Ghosh et al. 2018). The 2 remaining comparative studies were in the US.\n\n# Evidence submitted during consultation\n\n## The company's evidence shows the ZEUS algorithm has good diagnostic accuracy per episode\n\nDuring consultation, the company submitted technical data reporting the performance of Zio\xa0XT's algorithm (ZEUS) at detecting 11\xa0arrhythmia types and sinus rhythm. Using a reference database of known clinical rhythms (over 150 examples of each), the ZEUS algorithm showed a sensitivity of over 90% and a specificity of over 95% for detecting atrial tachycardia (including atrial fibrillation and supraventricular tachycardia) from a total of over 1,400\xa0episodes. Post-market analysis using clinical records processed by Zio\xa0XT showed a sensitivity of over 90% for detecting atrial tachycardia from a total of over 50\xa0million\xa0episodes. Newcastle EAC reviewed the technical data provided by the company and concluded that Zio\xa0XT shows excellent agreement with cardiographic technician assessment of identified arrhythmia episodes. However, it highlighted that the analyses were done per episode and not on a per-patient basis. But it stated that, in principle, good per-episode performance should translate to good per-patient performance.\n\n## An EAC review of artificial intelligence in Zio\xa0XT raised no concerns\n\nDuring consultation, KiTec EAC reviewed the artificial intelligence in Zio\xa0XT's ZEUS software. It noted that the algorithm to detect arrythmia uses a fixed deep neural network (a computational model made up of multiple processing layers) and that the training of the system is adequate. The EAC noted it had a large training dataset and that uncommon rhythms were well represented within this dataset. The software also used an external database for validation. The EAC also reviewed the internal quality assurance process and noted that before providing a report to clinicians, the algorithm outputs are checked by the company's cardiographic technicians (certified by The Society for Cardiological Science and Technology and Cardiac Credentialing International). The percentage of electrocardiogram (ECG) traces that are quality assured by cardiographic technicians was not reported but the agreement between algorithms and cardiographic technicians was high (over 99% overall episodic sensitivity in post-market analysis).\n\n## Clinical experience from an NHS trust and a sustainability and transformation partnership does not add to the evidence base\n\nDuring consultation, 1\xa0NHS trust and 1\xa0sustainability and transformation partnership provided feedback and results from using Zio\xa0XT. The EAC reviewed the evidence submitted but did not consider it added anything to the existing evidence base. It concluded that clear conclusions about efficacy could not be drawn from the results because there was not enough information on the patient populations.\n\n# Cost evidence\n\n## The cost evidence comprises 5 published studies\n\nFive published studies reported the economic impact of the technology:\n\na UK budget impact analysis (Kaura et al. 2019)\n\na UK study reporting technology costs using data from the REMAP‑AF trial (Eysenck et al. 2019)\n\na prospective matched cohort study reporting healthcare resource use (Steinhubl et al. 2018)\n\nconference abstracts (Ghosh et al. 2018, Chandratheva et al. 2017).Two studies reported that the technology was cost saving. Two reported it was not cost saving compared with other devices including Holter monitoring. Studies consistently reported that Zio\xa0XT is the most efficient in terms of avoiding delays between clinic and diagnosis confirmation.\n\n## The company presented 3 cost models showing that monitoring with Zio\xa0XT saves between £55 and £85 per patient over 1\xa0year\n\nThe company created 3 de novo cost analyses comparing the 14‑day Zio\xa0XT with blended strategies, based on a 24‑hour Holter monitor or a cardiac event recorder, in different care pathways:\n\nThe cardiology model (presented as a base case) considered people with symptomatic palpitations or syncope and assessed the costs associated with the diagnostic process only.\n\nThe stroke model (presented as a base case) considered people who have had a stroke or transient ischaemic attack and assessed the costs associated with the diagnostic process only.\n\nThe downstream stroke model was presented as a scenario analysis and extrapolated the economic consequences of the extra risk of recurrent stroke because of delayed or missed diagnosis of atrial fibrillation. All models had a time horizon of 1\xa0year. Overall, the company's models showed that using Zio\xa0XT saves between £55 and £85 per patient because of reductions in repeat testing, referrals or cardiology outpatient review, and events in stroke populations. For full details of the cost evidence, see section 4 of the EAC's assessment report in the supporting documents for this guidance.\n\n## The EAC's changes to the models make monitoring with Zio\xa0XT cost incurring\n\nThe EAC revised the base-case (cardiology and stroke) models to address some potential limitations:\n\nthe proportion of patients having repeat Holter tests after 24‑hour Holter monitoring was changed to 27%\n\nNHS reference costs were used for Holter monitoring rather than Patient Level Information and Costing System (PLICS) data\n\nthe cost of an outpatient appointment before discharge was included for all tests. The EAC revised the downstream stroke model to:\n\ninclude the cost of anticoagulants (and their side effects)\n\nlower the estimated stroke risk\n\ninclude repeated diagnostic test costs.The EAC considered the downstream stroke cost model the most informative. After these revisions, the EAC concluded that Zio\xa0XT is unlikely to be cost saving at the original price when compared with current practice. Zio\xa0XT became cost incurring by:\n\n£0.82 per patient per year in the cardiology model\n\n£70.81 per patient per year in the stroke model\n\n£20.83 per patient per year in the downstream stroke model.\n\n## Scenario analyses suggest that cost savings are influenced by the number of repeat tests and outpatient follow-up appointments\n\nThe EAC did a scenario analysis to explore the impact of repeat monitoring after a negative test. Zio\xa0XT was cost incurring when all monitoring was repeated after a negative test. When monitoring with a 24‑hour Holter or a 7‑day cardiac event recorder was repeated after a negative first test, but Zio\xa0XT was not repeated, the technology was cost saving. The EAC also explored the impact of excluding follow-up outpatient appointments after monitoring for some or all tests. Full descriptions of the 5\xa0scenarios explored and results for each of these scenarios can be found in section 2 of the addendum to the EAC's assessment report in the supporting documents for this guidance.\n\n# Cost evidence submitted during consultation\n\n## A revised cost of £265 makes Zio\xa0XT cost saving or broadly cost neutral\n\nDuring consultation, the company revised the cost for the technology to £265 per person. The EAC recalculated the results from the cost modelling with the lower price in the 2\xa0most relevant scenarios, which included the following assumptions:\n\nno appointment needed after a negative result, and no repeated test (scenario\xa03)\n\nno appointment needed after any negative result, whether or not the test is repeated (scenario\xa05). The results showed Zio\xa0XT is likely to be cost saving or cost neutral compared with standard care in the cardiology model (£59.80 less for scenario\xa03; £3.47 less for scenario\xa05 per patient per year). For the stroke model, the results were still cost incurring (£14.93 more for scenario\xa03; £79.47 more for scenario\xa05 per patient per year) but the downstream model results for the same population showed the results moved towards Zio\xa0XT being cost saving (£72.55 less for scenario\xa03; £33.79 more for scenario\xa05 per patient per year). Full results for all 5\xa0scenarios explored can be found in section 1 of the additional economic analyses in the supporting documents for this guidance.\n\n## Increasing the probability of testing with implantable cardiac monitors does not substantially change the cost-modelling results\n\nAdditional sensitivity analysis was done to examine the effect of a potential change in the use of implantable cardiac monitors. The experts did not all agree that use of implantable cardiac monitors is likely to increase in the future. In the stroke and cardiology models, a small percentage of patients (2%) who have a negative test will go on to have implantable cardiac monitoring. Increasing the probability of testing with implantable cardiac monitors to 10% did not substantially change the results of the Zio\xa0XT cost modelling. For full details, see the additional sensitivity analysis report and additional clinical expert advice in the supporting documents for this guidance.\n\n## Threshold analysis results for repeat tests range from 1.30 to 1.78 per person\n\nThe EAC also did a threshold analysis to assess the number of repeat tests per person in the current care arm needed to equalise the cost of Zio\xa0XT and current care. The average number of repeat tests after a negative result with either 24‑hour Holter or cardiac event recorders was assumed to be 1.389 per person in the base case. Threshold analysis results ranged from 1.30 to 1.78 repeat tests per person, depending on the model and scenario evaluated. For full details, see the additional sensitivity analysis report in the supporting documents for this guidance.", 'Committee discussion': "# Clinical-effectiveness overview\n\n## Zio\xa0XT is an innovative technology which shows promise for ambulatory monitoring\n\nThe clinical experts who had experience of using Zio\xa0XT explained that it offers continuous monitoring over 14\xa0days and is well accepted by patients. Experts commented on how easy it is to fit and that patients find it acceptable, adding that people are more likely to wear Zio\xa0XT for longer. The committee agreed that Zio\xa0XT is an innovative design and there is a plausible patient benefit.\n\n## The evidence shows that Zio\xa0XT can improve diagnostic yield and patient wear time\n\nEvidence shows that Zio\xa0XT can increase patient wear time. Three of the 4 comparative studies showed improved diagnostic yield over total wear time compared with 24‑hour Holter monitoring. Eysenck et al. (2019) reported a longer wear time for Zio\xa0XT compared with the R-test (a cardiac event recorder). The clinical experts agreed that it was plausible that monitoring with Zio\xa0XT could increase diagnostic yield, primarily because Zio\xa0XT is worn for 14\xa0days, which is much longer than the Holter monitor. The clinical experts also advised that Zio\xa0XT has usability advantages for patients. It is more discreet and convenient to wear than a Holter monitor and the Zio biosensor stays on better. The committee concluded that Zio\xa0XT increases diagnostic yield for detection of cardiac arrhythmias compared with 24‑hour Holter monitoring.\n\n## The committee considers Zio\xa0XT to be a diagnostic service for detecting cardiac arrhythmia\n\nThe committee questioned whether Zio\xa0XT is a diagnostic service. The company said that the Zio\xa0XT algorithm highlights areas of concern on the electrocardiogram (ECG) trace, then a company-based cardiac physiologist reviews and confirms the arrhythmia type. A report including a sample of the ECG trace is generated for the referring healthcare professional. The company said that the technology is a decision support tool that provides a report allowing the referring healthcare professional to make a diagnosis. The company also said that full disclosure of ECG traces is available on request. The committee discussed the likely dependence of healthcare professionals on the report and queried the reliability of the data in it. The committee accepted that although Zio\xa0XT provides useful information about the number of episodes and type of arrhythmic events, the final diagnosis and treatment decision remains with the referring healthcare professional. The committee concluded that Zio\xa0XT is a diagnostic service, which provides information to clinicians to help make a diagnosis.\n\n## Zio\xa0XT has good diagnostic accuracy on a per-episode basis\n\nThe available published evidence did not provide reliable estimates of diagnostic sensitivity or specificity. Hannun et al. (2019) showed that Zio\xa0XT's ZEUS algorithm was able to classify a broad range of distinct arrhythmias and had a similar accuracy to cardiologists. However, the study was not done with the Zio Patch or in a clinical setting. Also, Zio\xa0XT's ECG recordings are captured using a single-lead biosensor while Holter monitors use 3\xa0leads. Experts said that although 3‑lead ECG recordings may be better at detecting certain types of arrhythmia, most clinical decisions can be made from 1\xa0lead. At the draft guidance meeting the committee was concerned about the lack of detail for the diagnostic accuracy data and recommended further research. After consultation, the committee considered the technical data provided by the company and the EAC's review of this data. It agreed with the EAC's view that the Zio\xa0XT software has good per-episode performance for detecting cardiac arrhythmia and this should translate to good per-patient performance. The committee concluded that Zio\xa0XT shows good performance in recognising episodes of identified arrhythmia in ECG traces but noted that publication of future data would be valuable.\n\n## Additional information about the long-term clinical consequences of using Zio\xa0XT would be valuable\n\nIn their evidence review the EAC queried the effect of an increased diagnostic yield on clinical consequences. It considered that further comparative evidence about how Zio\xa0XT affects clinical management of cardiac arrhythmias and patient outcomes would be helpful. The committee understood the limitations of the evidence base and agreed that more information about the long-term clinical consequences of using Zio\xa0XT would be valuable.\n\n# Other patient benefits or issues\n\n## Shaving of bodily hair is common to both Zio\xa0XT and Holter monitoring and is unlikely to restrict access for patients\n\nApplying the Zio\xa0XT biosensor may mean body hair needs to be shaved. Some religions forbid cutting or shaving body hair. The clinical experts advised that shaving is needed for both Zio\xa0XT and Holter monitoring. They believed this would not restrict access for particular groups of people and said that, in their experience, most people agree to shave when using the Zio\xa0XT biosensor.\n\n# NHS considerations overview\n\n## Zio\xa0XT is scalable but there are concerns about its impact on NHS resources\n\nClinical experts highlighted that there is currently a shortage of cardiac physiologists in the NHS. They noted that more widespread adoption of Zio\xa0XT in the NHS may further affect the recruitment of cardiac physiologists if they leave the NHS to work for the service. But they also said that reducing the burden on cardiac physiologists in the NHS of analysing ECG reports should be considered a benefit of Zio\xa0XT. The company said that it has the capability to scale up its service to the UK, and that it would adapt a successful model used in the US. The company confirmed that the turnaround time for reports (4\xa0days maximum but usually 24\xa0hours) would not change. The committee was reassured that Zio\xa0XT is potentially scalable across the NHS but it was less certain about the impact on the NHS cardiac physiologist workforce.\n\n## Zio\xa0XT uses anonymised patient data and appears to comply with privacy laws\n\nThe data used for developing and training the algorithm come from a database of anonymised ECG traces from patients who have previously used the service. The committee queried if patients are aware of this when they use the service and discussed considerations for the use of anonymised data in software development and training. The company explained that Zio\xa0XT meets all the relevant NHS data governance standards including the NHS Digital Toolkit and general data protection regulation (GDPR) privacy requirements. The committee noted that people give consent for their data to be used and that Zio\xa0XT appears to comply with all applicable privacy laws. The committee concluded that NHS organisations using Zio\xa0XT should make sure that the service is compliant with GDPR, and that informed consent for the investigation covers how a patient's data will be used.\n\n# Cost-modelling overview\n\n## The EAC's base case does not fully reflect clinical practice regarding outpatient appointments\n\nIn its base-case analysis, the EAC assumed that all monitoring tests would be followed up with an outpatient appointment. Clinical advice was that outpatient appointments are not usually needed after a negative result from Zio\xa0XT, and that practice varies. In scenarios in which follow-up outpatient appointments were included for standard care but not for Zio\xa0XT, Zio\xa0XT was cost saving across all 3 of the EAC's revised models. Comments and clinical expert advice received at consultation suggested that an outpatient appointment would normally only be needed after a significant positive result, regardless of the ECG monitoring device used. The committee concluded that out of the scenarios explored by the EAC, 2 scenarios best reflected current clinical practice (see section\xa03.15).\n\n## Zio\xa0XT may have additional benefits not captured in the cost modelling\n\nThe committee noted that the long-term clinical benefits of identifying significant arrhythmias were not captured in the stroke or cardiology models, which only evaluated diagnosis costs. The committee considered the downstream stroke model to be more informative because it took into account the benefits in terms of stroke outcomes within the first year, in addition to the cost of diagnosis. However, longer-term benefits were not included. There is no equivalent model for the cardiology patients so the longer-term benefits of earlier diagnosis in this group have not been calculated. The EAC advised that there was not enough information available to model longer-term benefits in the cardiology model. The committee concluded that there are likely to be additional benefits of using Zio\xa0XT which have not been captured in the current cost modelling.\n\n## Zio\xa0XT is likely to be cost saving or broadly cost neutral, but this is uncertain\n\nAfter consultation, the EAC presented new cost-modelling results including the reduced price for Zio\xa0XT. The committee accepted that this reduction in price made Zio\xa0XT slightly cost saving compared with standard care for patients in the cardiology model (people with symptomatic palpitations or syncope). The clinical experts explained that the benefits of Zio\xa0XT in this population are likely to be realised with careful patient selection based on frequency of symptoms. The committee considered that Zio\xa0XT is most likely to be cost saving when used by patients who have symptoms more than 24\xa0hours apart. For patients who have had ischaemic stroke or a transient ischaemic attack without current evidence of atrial fibrillation, the downstream results show Zio\xa0XT is likely to be cost neutral or cost saving. The assumptions about follow-up appointments and repeat tests affected the results significantly. Expert advice showed that there is significant variation in the resources used for monitoring. The committee accepted the limitations of the current models and concluded that Zio\xa0XT is likely to be cost saving or broadly cost neutral, but more information is needed about resource use.\n\n## Further information about resource use and the long-term consequences of Zio\xa0XT monitoring would be valuable\n\nThe committee accepted the EAC's changes to the models but considered there was still uncertainty about resource use and the long-term consequences of using Zio\xa0XT. Therefore, it was difficult to draw firm conclusions about the extent of any cost benefits. The committee noted the influence of assumptions about the need for outpatient appointments and the number of repeat tests on the cost modelling and the variation in ECG monitoring practice across the NHS. It concluded that more detailed data from sites that have used Zio\xa0XT in their ECG monitoring pathway could provide valuable information about resource use. This could inform the cost modelling and possibly some best practice guidelines for adopting Zio\xa0XT. The committee also concluded that further information on the long-term consequences of Zio\xa0XT monitoring (such as incidences of further stroke, transient ischaemic attack and other thromboembolisms, arrhythmia-related hospitalisations, mortality, uptake of anticoagulants or other changes in medication related to the monitoring result) would likely strengthen the certainty of cost benefits associated with its use."}
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https://www.nice.org.uk/guidance/mtg52
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Evidence-based recommendations on Zio XT for detecting cardiac arrhythmias.
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729e961fe14381fd1538833610be1246ba4921dd
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nice
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Darolutamide with androgen deprivation therapy for treating hormone-relapsed non-metastatic prostate cancer
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Darolutamide with androgen deprivation therapy for treating hormone-relapsed non-metastatic prostate cancer
Evidence-based recommendations on darolutamide (Nubeqa) for treating hormone-relapsed prostate cancer in adults at high risk of developing metastatic disease.
# Recommendations
Darolutamide with androgen deprivation therapy (ADT) is recommended, within its marketing authorisation, as an option for treating hormone-relapsed prostate cancer in adults at high risk of developing metastatic disease. It is recommended only if the company provides darolutamide according to the commercial arrangement.
Why the committee made these recommendations
When prostate cancer no longer responds to hormone treatment (ADT), but has not spread beyond the prostate, the only current option is to continue ADT. Darolutamide added to ADT would be another option at this stage.
Clinical trial evidence shows that people taking darolutamide with ADT have more time before their prostate cancer spreads compared with ADT alone. Although the trial results suggest that darolutamide with ADT increases the length of time people live, it is unclear by how much in the long term.
Despite this, the cost-effectiveness estimates are within what NICE normally considers a cost-effective use of NHS resources. So darolutamide with ADT is recommended as an option.# Information about darolutamide
# Marketing authorisation indication
Darolutamide (Nubeqa, Bayer) is indicated 'for the treatment of adult men with non-metastatic castration resistant prostate cancer who are at high risk of developing metastatic disease'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price of darolutamide 300 mg is £4,040 per 112 tablets (excluding VAT; BNF online, accessed September 2020). The company has a commercial arrangement. This makes darolutamide available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Bayer, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
# Treatment pathway
## Few people have hormone-relapsed non-metastatic cancer and treatment aims to delay metastasis
Hormone-relapsed cancer no longer responds to androgen deprivation therapy (ADT). Darolutamide is indicated for treating hormone-relapsed prostate cancer that is at high risk of metastasising. This is the same indication appraised in NICE's technology appraisal guidance on enzalutamide, but enzalutamide is not recommended for this population. ARAMIS, the trial that informed darolutamide's marketing authorisation (see section 3.4) defined high risk as a prostate specific antigen (PSA) level of 2 nanograms per millilitre or more that has doubled in 10 months. The company estimated that around 2% to 3% of people with prostate cancer in the UK have hormone-relapsed non-metastatic prostate cancer. The aim of treatment is to delay metastatic disease, which is associated with reduced quality of life and survival. The committee concluded that a small proportion of people with prostate cancer have hormone-relapsed non-metastatic prostate cancer and treatment aims to delay metastasis.
## There is an unmet need for a treatment for hormone-relapsed non-metastatic prostate cancer, and this causes anxiety for patients
Current treatment for hormone-relapsed non-metastatic prostate cancer is to continue ADT, even though the cancer may not be responding to it. The patient experts explained that people have to wait for their cancer to metastasise before they can get the next effective treatment. This can cause great anxiety for them. They see their PSA levels rising and know they are at high risk of developing metastases, but are not taking an effective treatment. The patient experts commented that detecting metastases as early as possible means people can have the next clinically effective treatment. Metastases are usually detected by an MRI or CT scan. The clinical experts stated that clinicians sometimes offer more frequent scans and more sensitive, but less routinely used, scanning techniques to 'hunt' for metastases. If found, they can prescribe the next clinically effective treatment for patients. They also stated that these scans would reduce if another treatment was available. The patient experts said that having an effective treatment would reduce their anxiety. Also, delaying metastases and the associated symptoms of metastatic disease, which greatly affect quality of life, is really important to them. The committee concluded that there is an unmet need for a clinically effective treatment for hormone-relapsed non-metastatic prostate cancer. This disease causes anxiety for patients and may increase the frequency of MRI and CT scans.
## Darolutamide, enzalutamide or abiraterone are used only once in the prostate cancer treatment pathway
NICE recommends the androgen receptor inhibitors enzalutamide and abiraterone in its technology appraisal guidance on:
enzalutamide for treating metastatic hormone-relapsed prostate cancer before chemotherapy is indicated
enzalutamide for metastatic hormone‑relapsed prostate cancer previously treated with a docetaxel‑containing regimen
abiraterone for treating metastatic hormone-relapsed prostate cancer before chemotherapy is indicated
abiraterone for castration-resistant metastatic prostate cancer previously treated with a docetaxel-containing regimen.These drugs can be used only once in the prostate cancer treatment pathway according to NHS England's commissioning policy. The clinical experts confirmed that this is because of the similar way the 3 drugs work. This means that if a person's prostate cancer metastasised on darolutamide, it would be expected to be resistant to enzalutamide or abiraterone when used as treatments for metastatic disease. The Cancer Drugs Fund clinical lead confirmed that NHS England would not commission enzalutamide or abiraterone after darolutamide. The committee concluded that darolutamide, enzalutamide or abiraterone would be used only once in the treatment pathway for prostate cancer.
# Clinical effectiveness
## The ARAMIS results comparing darolutamide plus ADT with placebo plus ADT are in line with planned analyses
ARAMIS was a double-blind international randomised controlled trial comparing darolutamide plus ADT (n=955) with placebo plus ADT (n=554). Its primary endpoint was metastasis-free survival, that is, the time from randomisation to confirmed evidence of metastasis or death from any cause. Secondary outcomes included, among others, overall survival and time to starting cytotoxic chemotherapy. Exploratory outcomes included quality of life, measured using the EQ-5D questionnaire, and time to starting antineoplastic therapy (other than chemotherapy). The trial also recorded how long people continued to take darolutamide and their reason for stopping it. People entering the study had an MRI and a CT scan and were excluded if they had metastases. The trial pre-specified final analyses for metastasis-free survival and overall survival based on the number of events needed to show a difference between the trial arms for these outcomes. The differences in metastasis-free survival and overall survival between the groups were considered statistically significant at p values of less than or equal to 0.05 and 0.018. The final analysis for metastasis-free survival and interim analyses for overall survival were done in September 2018. At this time, the trial was unblinded and people who had placebo could cross over to have darolutamide if their cancer had not metastasised. The final analysis of overall survival was done in November 2019. The committee concluded that the 2 data cuts reflected the trial's statistical analysis plan.
## Some people in ARAMIS had metastases at baseline, and the trial is generalisable to the population in the NHS
The company did an independent central radiological review of the MRI and CT scans to check eligibility for ARAMIS. This showed that a small proportion of people had metastases at the start of the trial. The company commented that this proportion was higher in the placebo plus ADT arm (7%) than in the darolutamide plus ADT arm (5%). It did analyses adjusting for this (see section 3.9). The committee noted that there may be people in NHS clinical practice diagnosed with non-metastatic prostate cancer who have undetectable metastases on MRI or CT scan. So, the trial population would reflect the population in NHS clinical practice. The committee also appreciated that the central review may have produced false positive results. It concluded that the population in ARAMIS was generalisable to the population seen in NHS clinical practice.
## Darolutamide plus ADT extends metastasis-free survival
In ARAMIS, the median survival on darolutamide plus ADT was 40.4 months and on placebo plus ADT it was 18.4 months. The hazard ratio was 0.41 (95% confidence interval 0.34 to 0.50). The committee concluded that darolutamide plus ADT extended metastasis-free survival and was clinically effective.
## Darolutamide extends overall survival during the trial, but treatments offered for metastatic disease make the longer-term benefit unclear
In the final analysis of overall survival people had been followed for up to 5 years. Only a small proportion of people in both the darolutamide plus ADT arm and the placebo plus ADT arm had died (the proportions are academic in confidence and cannot be reported here). Fewer people died in the darolutamide plus ADT arm than in the placebo plus ADT arm. The hazard ratio for overall survival for darolutamide plus ADT compared with placebo plus ADT and the 95% upper limit of the confidence intervals were less than 1. So, overall survival was better with darolutamide plus ADT (the data are academic in confidence and cannot be reported here). The committee noted that overall survival depends on the treatments for non-metastatic disease and on the follow-on treatments taken after the cancer has metastasised. It discussed the choice of treatments, and the proportion of people taking these treatments in ARAMIS, in relation to NHS practice. It noted that the trial was blinded until September 2018, so investigators would not know a person's first treatment, which could determine the next treatment. The committee also noted that some people in ARAMIS who had enzalutamide or abiraterone for metastatic disease (after first having darolutamide), would not be offered these in NHS practice (see section 3.3). The company suggested that this meant survival after stopping darolutamide may have been underestimated in ARAMIS because abiraterone and enzalutamide are expected to be ineffective after darolutamide. The ERG noted that a smaller proportion of people had abiraterone or enzalutamide after ADT alone than would be expected in the NHS. The clinical experts suggested that survival on enzalutamide, abiraterone or docetaxel after ADT alone was similar. The committee also noted that a smaller proportion of people in each arm of the trial had gone on to have a follow-on treatment than would be expected in the NHS. It concluded that the data suggested that darolutamide extended overall survival over the duration of the trial. But how long this lasted after the trial was unclear, partly because of the follow-on treatments taken after the cancer had metastasised.
## Adjusting the ARAMIS estimates of overall survival is unclear and the results may be biased against darolutamide
In ARAMIS, at the time of the final analysis of the primary endpoint, people randomised to placebo plus ADT whose disease had not metastasised could switch to darolutamide. When ARAMIS was unblinded in September 2018, 170 people in the placebo plus ADT arm switched to darolutamide. The committee noted it could not assess the company's 2 methods (Iterative Parameter Estimation and the Rank Preserving Structural Failure Time method) to adjust for the effect of treatment switching on overall survival because the company did not present details of these analyses. The company stated that adjusting for switching did not greatly affect the estimates of the treatment effect on overall survival and introduced uncertainty. The committee was aware that the key assumption in the methods is that the treatment effect is the same in people who switch to darolutamide and in people who were initially randomised to have darolutamide. The committee did not have evidence for this assumption. The company chose to use unadjusted survival estimates in its model. The committee appreciated that estimates of overall survival benefit with darolutamide plus ADT compared with ADT alone could be conservative. That is, they may underestimate the benefit of darolutamide plus ADT over ADT alone. The committee noted that people who had no metastases in September 2018 and switched from placebo to darolutamide would have been followed only until the final overall survival analysis in November 2019. Given the low death rates over trial follow up, switching may not have had a large effect on the overall survival estimates. The committee concluded that it could not determine whether the assumptions behind the adjustment methods were met. Also, using unadjusted results may bias the overall survival estimates in ARAMIS against darolutamide.
## Adjusting outcomes for people with metastases at baseline by censoring may favour ADT alone
The ARAMIS statistical analysis was done in an intention-to-treat population. However, in the company's economic model the data had an additional adjustment. This involved censoring people who had been found by central independent radiological review to have metastases at baseline. The company used these censored results to make Kaplan–Meier plots of the trial data for metastasis-free survival and overall survival. It extrapolated these data over the period beyond the end of the trial. The committee noted that Kaplan–Meier plots of survival data take into account the number of events and the number of people at risk of having an event over time. Censoring people at baseline may mean that the risk of having an event was slightly underestimated. The committee was concerned about 'informative censoring', that is, the risk of outcomes differing because of censoring. However, the committee noted that because more people in the placebo plus ADT arm had metastases at baseline than in the darolutamide plus ADT arm, the company's approach may have made the extrapolated estimates for ADT alone appear better than if they had been extrapolated without censoring. The committee concluded that censoring people with baseline metastases in ARAMIS may disadvantage darolutamide plus ADT and favour ADT alone.
## Some people choose to stop darolutamide before their cancer metastasises
The clinical experts explained that darolutamide was well tolerated in ARAMIS. The marketing authorisation states that darolutamide plus ADT can be taken until cancer metastases; in ARAMIS around 9% of people stopped treatment because of adverse events. The committee discussed that, in general, people stayed on darolutamide longer based on the analysis of September 2018 than based on the later analysis of November 2019. A clinical expert explained that people may stop treatment even when their PSA levels were stable if they have fatigue, an adverse event that may not normally lead someone to stop treatment. The clinical experts considered this would be more likely to occur later in the study than earlier. The committee questioned whether people would stop treatment if they thought it was stopping their cancer from progressing. It noted the difference in the results from the 2 data cuts and considered that unblinding the study in September 2018 may have affected people's choice to stop darolutamide, but it concluded that the reason for the different results in the 2 data cuts was unclear. Overall, the committee concluded that darolutamide was well tolerated in the trial, but some people chose to stop it before their cancer metastasised.
# Cost effectiveness
## The model structure is appropriate for decision making
To estimate the cost effectiveness of darolutamide plus ADT compared with ADT alone, the company used a partitioned survival model. The company used data on metastasis-free survival and overall survival to model 3 health states: non-metastatic hormone-relapsed prostate cancer, metastatic hormone-relapsed prostate cancer and death. In the non-metastatic health state people could be on or off treatment. In the metastatic health state, the company modelled the costs and utility associated with 3 lines of treatment followed by best supportive care (see section 3.14). Using this type of model meant that time in the metastatic health state was determined by the overall survival estimates and the metastasis-free survival estimates from ARAMIS. The committee considered this to be an appropriate approach. It concluded that the model structure was appropriate for decision making.
## Extrapolating the most mature data and considering a more pessimistic approach are appropriate
The data in the model came from different data cuts:
September 2018 for metastasis-free survival
November 2019 for time to stopping darolutamide and overall survival.The committee understood that no further data were collected on metastasis-free survival, the primary endpoint, after September 2018. It shared the ERG's concerns that the time to stopping darolutamide based on 2019 data was shorter than when based on 2018 data (see section 3.10). The committee noted the ERG's concerns about the possibility that if the time to stopping darolutamide decreased with more mature data, the estimates of metastasis-free survival may also have decreased if this outcome had been measured until 2019. The committee noted that the company extrapolated the 2018 data on metastasis-free survival data with a Weibull model, which gave the best fit. The ERG provided a more pessimistic Gompertz extrapolation of these data to account for the possibility that metastasis-free survival would also decrease had it been measured until 2019. The clinical experts at the meeting stated that the ERG's Gompertz model was overly pessimistic. They expected some people taking darolutamide to still have non-metastatic disease at 7 years, contrary to the ERG's modelling of all people having metastatic disease by this point. The committee concluded that extrapolating from the most mature data was appropriate and using different data cuts introduced uncertainty. It further concluded that considering a more pessimistic extrapolation in addition to the company's extrapolation was reasonable to assess the impact on the cost-effectiveness results (see section 3.19).
## The long-term modelled survival estimates are highly uncertain and it is appropriate to consider other approaches
The company used a Weibull model to extrapolate overall survival beyond the end of ARAMIS. This predicted that 28% of people would be alive in the darolutamide plus ADT arm after 10 years compared with 9% in the ADT alone arm. At 20 years, it predicted that around 2% of people in the darolutamide plus ADT arm and 0% in the ADT alone arm would be alive. The ERG explained that its clinical expert advised that the predictions of long-term survival were reasonable in people who take ADT alone, but the company may have overestimated the proportion of people taking darolutamide plus ADT who would still be alive at 20 years, in part because the modelled cohort had an average age of 74 years. The ERG suggested an alternative extrapolation of the darolutamide plus ADT arm using a generalised gamma extrapolation. This predicted that 7% of people would be alive at 10 years and nobody would be alive at 20 years. The ERG stated that its clinical expert advised that long-term survival on darolutamide would likely be between the values extrapolated by the Weibull and the generalised gamma models. Acknowledging that they lacked long-term experience with darolutamide the clinical experts at the committee meeting stated that they expected around 30% of people in this population to be alive at 10 years and it was plausible that some people would be alive at 20 years. The committee noted that the company's modelled survival for ADT alone seemed lower than what the clinical experts considered plausible. It also noted that there were no longer-term data to validate the modelled long-term survival estimates with either treatment. Because the trial data were immature the committee concluded that the estimates of long-term extrapolated survival were highly uncertain. The committee further concluded it was appropriate to consider these approaches in its decision making:
the company's approach
the ERG's approach using the average of the generalised gamma and Weibull to extrapolate survival on darolutamide beyond the period covered by ARAMIS
-ther ERG scenarios, which reduced the overall survival estimate for darolutamide (see section 3.16).
## The company models fewer active treatments after darolutamide plus ADT than after ADT alone, which reflects expected NHS practice
In the company model, once people had progressed to metastatic disease, they had 3 lines of treatment and then best supportive care. The company presented the different treatment options with the expected proportion of people who would have them. The committee noted:
The company suggested that around 2.5% to 5% of people would have abiraterone after darolutamide in the darolutamide plus ADT arm. The committee noted that the NHS would not offer abiraterone after darolutamide in clinical practice; this may overestimate the costs in the ADT alone arm and bias the cost-effectiveness estimates to favour darolutamide.
A higher proportion of people had best supportive care rather than a clinically effective treatment as their first, second or third treatment after darolutamide plus ADT compared with ADT alone. The committee agreed that this reflected expected NHS practice, that is, people would have fewer active treatment options after darolutamide plus ADT than after ADT alone.
## The ERG's estimates of time on treatments for metastatic disease are more plausible than the company's
The company estimated how long people took treatments for metastatic disease (see section 3.14). It used the median treatment duration for first, second and third treatments for hormone-relapsed metastatic prostate cancer from NICE's technology appraisal guidance on enzalutamide for treating metastatic hormone-relapsed prostate cancer before chemotherapy is indicated and abiraterone for treating metastatic hormone-relapsed prostate cancer before chemotherapy is indicated. The company then estimated the mean time on each treatment from the median times, by assuming an exponential distribution. The committee considered that 2 changes proposed by the ERG to the company's approach were reasonable:
Modelling abiraterone or enzalutamide as second or third treatments for metastatic prostate cancer using observed values for progression-free survival and duration of treatment at this position in the treatment pathway rather than as first treatments, as modelled by the company. The company had used data from trials of abiraterone and enzalutamide for hormone-relapsed metastatic prostate cancer before docetaxel, the COU-AA-302 and PREVAIL trials respectively. The ERG used data from the COU-AA-301 trial for abiraterone and the AFFIRM trial for enzalutamide, which assessed abiraterone and enzalutamide for hormone-relapsed metastatic prostate cancer after docetaxel.
Basing duration of best supportive care on the observed duration of ADT alone taken before chemotherapy in PREVAIL. ADT in PREVAIL was considered to be best supportive care. This was different to the company's approach, which used the average progression-free survival on the active treatments in the company's model (that is, abiraterone, enzalutamide, cabazitaxel, radium-223 and docetaxel) to estimate the duration of best supportive care.The committee concluded that the company's approach to modelling follow-on treatments was broadly appropriate but agreed that the ERG's assumptions were more plausible than the company's.
## It is plausible that survival with metastatic disease after darolutamide plus ADT would be 3 to 4 months shorter than after ADT alone
The company's model predicted that people would live 2 more months with metastatic disease after darolutamide plus ADT than after ADT alone. The committee agreed with the ERG that this was implausible, because people would have access to more active treatments after ADT alone than after darolutamide plus ADT. The ERG did a scenario analysis in which it equalised the hazards of dying in the modelled darolutamide plus ADT arm and in the modelled ADT alone arm at 5 years. This reduced the overall survival estimates for darolutamide. Also, the model predicted that people would live an extra 8 months with metastatic disease after ADT compared with after darolutamide plus ADT. The clinical experts explained that although it was plausible that survival with metastatic disease after ADT alone would be longer than after darolutamide plus ADT, the ERG's scenario overestimated the difference. The clinical experts stated that recent trials of new drugs for hormone-relapsed metastatic prostate cancer had shown a 3 to 4‑month survival advantage compared with a non-active comparator. They said that therefore they would expect survival with metastatic disease after darolutamide plus ADT to be at most 3 to 4 months shorter than after ADT alone. The committee concluded that it was plausible that survival with metastatic disease after darolutamide plus ADT would be 3 to 4 months shorter than after ADT alone.
## The frequency and costs of monitoring and hospital appointments are between the company's and ERG's estimates
The company and ERG had different assumptions on the frequencies of monitoring and costs of hospital appointments. The company based its assumptions on a retrospective cohort study from an NHS trust, which collected data from 44 people with hormone-relapsed non-metastatic prostate cancer since 2011. The committee noted that monitoring practices can change over time. The ERG based its preferences on NICE's technology appraisal guidance on enzalutamide for hormone-relapsed non-metastatic prostate cancer. A patient expert, clinical experts and patient groups explained that people have fewer scans and community nurse visits than suggested by the ERG, but more visits to specialist nurses than suggested by the company. The committee concluded that the frequency and costs of monitoring and hospital appointments would lie between the company's and ERG's estimates.
## The company's modelled utility values are appropriate
The company used EQ-5D data from ARAMIS to estimate that the utility value in the non-metastatic health state was 0.813 in both the darolutamide plus ADT and ADT alone modelled treatment arms. The mean utility value in the metastatic health state took into account the proportions of people having each follow-on treatment and the duration of each treatment. This was 0.731 in the darolutamide plus ADT modelled arm and 0.777 in the ADT alone modelled arm. The company used utility values associated with the various follow-on treatments, and disutility values for symptomatic skeletal events, from NICE's technology appraisal guidance on enzalutamide for non-metastatic hormone relapsed prostate cancer and enzalutamide for metastatic hormone-relapsed prostate cancer before chemotherapy is indicated. The committee concluded that the company's modelled utility values were appropriate.
## The preferred modelling assumptions give an ICER in the range reflecting a cost-effective use of NHS resources
Because darolutamide and the follow-on treatments in the model (abiraterone, enzalutamide, cabazitaxel and radium-223) have confidential patient access schemes, the exact incremental cost-effectiveness ratios (ICERs) cannot be presented here. The committee noted that:
Using a Gompertz model rather than a Weibull model to extrapolate data on metastasis-free survival from ARAMIS increased the ICER from the company's base case.
If survival after metastatic disease was modelled to be longer after ADT alone than after darolutamide plus ADT, this increased the ICER from the company's base case.
Using the ERG's assumptions on monitoring frequency and costs increased the ICER.The committee considered that the most relevant scenarios for decision making were:
The ERG's base case, but with the overall survival hazards in the darolutamide plus ADT arm equalised to ADT alone at 7 years. This scenario estimated that people having darolutamide plus ADT would live 3 months less with metastatic prostate cancer than people having ADT alone. The ICER for this scenario was between £20,000 and £30,000 per quality-adjusted life year (QALY) gained.
The ERG's base case, but with the company's Weibull extrapolation of the ARAMIS data on metastasis-free survival, and the overall survival hazards equalised to ADT alone at and beyond 11 years. This scenario estimated that people having darolutamide plus ADT would live 4 months less with metastatic prostate cancer than people having ADT alone. The ICER for this scenario was under £20,000 per QALY gained.The committee noted that both these scenarios resulted in an ICER for darolutamide plus ADT compared with ADT alone in the range that NICE usually considers a cost-effective use of NHS resources.
## Darolutamide is innovative
The committee agreed that there is an unmet need for clinically effective treatments for hormone-relapsed non-metastatic prostate cancer. Having a treatment that delays metastases by a median of 22 months compared with the only treatment available to patients, ADT alone, is a step change for this population. The committee noted that having an effective treatment for non-metastatic prostate cancer may reduce the number of 'extra' or more sensitive scans being used to detect metastases so that people can then have the next available clinically effective treatment (see section 3.2). This potential benefit had not been included in the company's modelling. The committee concluded that darolutamide plus ADT is innovative.
# Conclusion
## Darolutamide plus ADT is recommended
The committee concluded that its preferred modelling scenarios resulted in an ICER that reflects good value for scarce NHS resources. It noted that darolutamide is clinically effective and innovative, and there is an unmet need for treatment for hormone-relapsed non-metastatic prostate cancer. The committee agreed that darolutamide plus ADT was a cost-effective use of NHS resources for treating hormone-relapsed prostate cancer at high risk of metastasising.
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{'Recommendations': 'Darolutamide with androgen deprivation therapy (ADT) is recommended, within its marketing authorisation, as an option for treating hormone-relapsed prostate cancer in adults at high risk of developing metastatic disease. It is recommended only if the company provides darolutamide according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nWhen prostate cancer no longer responds to hormone treatment (ADT), but has not spread beyond the prostate, the only current option is to continue ADT. Darolutamide added to ADT would be another option at this stage.\n\nClinical trial evidence shows that people taking darolutamide with ADT have more time before their prostate cancer spreads compared with ADT alone. Although the trial results suggest that darolutamide with ADT increases the length of time people live, it is unclear by how much in the long term.\n\nDespite this, the cost-effectiveness estimates are within what NICE normally considers a cost-effective use of NHS resources. So darolutamide with ADT is recommended as an option.', 'Information about darolutamide': "# Marketing authorisation indication\n\nDarolutamide (Nubeqa, Bayer) is indicated 'for the treatment of adult men with non-metastatic castration resistant prostate cancer who are at high risk of developing metastatic disease'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price of darolutamide 300\xa0mg is £4,040 per 112\xa0tablets (excluding VAT; BNF online, accessed September 2020). The company has a commercial arrangement. This makes darolutamide available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Bayer, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Treatment pathway\n\n## Few people have hormone-relapsed non-metastatic cancer and treatment aims to delay metastasis\n\nHormone-relapsed cancer no longer responds to androgen deprivation therapy (ADT). Darolutamide is indicated for treating hormone-relapsed prostate cancer that is at high risk of metastasising. This is the same indication appraised in NICE's technology appraisal guidance on enzalutamide, but enzalutamide is not recommended for this population. ARAMIS, the trial that informed darolutamide's marketing authorisation (see section\xa03.4) defined high risk as a prostate specific antigen (PSA) level of 2\xa0nanograms per millilitre or more that has doubled in 10\xa0months. The company estimated that around 2% to 3% of people with prostate cancer in the UK have hormone-relapsed non-metastatic prostate cancer. The aim of treatment is to delay metastatic disease, which is associated with reduced quality of life and survival. The committee concluded that a small proportion of people with prostate cancer have hormone-relapsed non-metastatic prostate cancer and treatment aims to delay metastasis.\n\n## There is an unmet need for a treatment for hormone-relapsed non-metastatic prostate cancer, and this causes anxiety for patients\n\nCurrent treatment for hormone-relapsed non-metastatic prostate cancer is to continue ADT, even though the cancer may not be responding to it. The patient experts explained that people have to wait for their cancer to metastasise before they can get the next effective treatment. This can cause great anxiety for them. They see their PSA levels rising and know they are at high risk of developing metastases, but are not taking an effective treatment. The patient experts commented that detecting metastases as early as possible means people can have the next clinically effective treatment. Metastases are usually detected by an MRI or CT scan. The clinical experts stated that clinicians sometimes offer more frequent scans and more sensitive, but less routinely used, scanning techniques to 'hunt' for metastases. If found, they can prescribe the next clinically effective treatment for patients. They also stated that these scans would reduce if another treatment was available. The patient experts said that having an effective treatment would reduce their anxiety. Also, delaying metastases and the associated symptoms of metastatic disease, which greatly affect quality of life, is really important to them. The committee concluded that there is an unmet need for a clinically effective treatment for hormone-relapsed non-metastatic prostate cancer. This disease causes anxiety for patients and may increase the frequency of MRI and CT scans.\n\n## Darolutamide, enzalutamide or abiraterone are used only once in the prostate cancer treatment pathway\n\nNICE recommends the androgen receptor inhibitors enzalutamide and abiraterone in its technology appraisal guidance on:\n\nenzalutamide for treating metastatic hormone-relapsed prostate cancer before chemotherapy is indicated\n\nenzalutamide for metastatic hormone‑relapsed prostate cancer previously treated with a docetaxel‑containing regimen\n\nabiraterone for treating metastatic hormone-relapsed prostate cancer before chemotherapy is indicated\n\nabiraterone for castration-resistant metastatic prostate cancer previously treated with a docetaxel-containing regimen.These drugs can be used only once in the prostate cancer treatment pathway according to NHS England's commissioning policy. The clinical experts confirmed that this is because of the similar way the 3\xa0drugs work. This means that if a person's prostate cancer metastasised on darolutamide, it would be expected to be resistant to enzalutamide or abiraterone when used as treatments for metastatic disease. The Cancer Drugs Fund clinical lead confirmed that NHS England would not commission enzalutamide or abiraterone after darolutamide. The committee concluded that darolutamide, enzalutamide or abiraterone would be used only once in the treatment pathway for prostate cancer.\n\n# Clinical effectiveness\n\n## The ARAMIS results comparing darolutamide plus ADT with placebo plus ADT are in line with planned analyses\n\nARAMIS was a double-blind international randomised controlled trial comparing darolutamide plus ADT (n=955) with placebo plus ADT (n=554). Its primary endpoint was metastasis-free survival, that is, the time from randomisation to confirmed evidence of metastasis or death from any cause. Secondary outcomes included, among others, overall survival and time to starting cytotoxic chemotherapy. Exploratory outcomes included quality of life, measured using the EQ-5D questionnaire, and time to starting antineoplastic therapy (other than chemotherapy). The trial also recorded how long people continued to take darolutamide and their reason for stopping it. People entering the study had an MRI and a CT scan and were excluded if they had metastases. The trial pre-specified final analyses for metastasis-free survival and overall survival based on the number of events needed to show a difference between the trial arms for these outcomes. The differences in metastasis-free survival and overall survival between the groups were considered statistically significant at p values of less than or equal to 0.05 and 0.018. The final analysis for metastasis-free survival and interim analyses for overall survival were done in September 2018. At this time, the trial was unblinded and people who had placebo could cross over to have darolutamide if their cancer had not metastasised. The final analysis of overall survival was done in November 2019. The committee concluded that the 2\xa0data cuts reflected the trial's statistical analysis plan.\n\n## Some people in ARAMIS had metastases at baseline, and the trial is generalisable to the population in the NHS\n\nThe company did an independent central radiological review of the MRI and CT scans to check eligibility for ARAMIS. This showed that a small proportion of people had metastases at the start of the trial. The company commented that this proportion was higher in the placebo plus ADT arm (7%) than in the darolutamide plus ADT arm (5%). It did analyses adjusting for this (see section\xa03.9). The committee noted that there may be people in NHS clinical practice diagnosed with non-metastatic prostate cancer who have undetectable metastases on MRI or CT scan. So, the trial population would reflect the population in NHS clinical practice. The committee also appreciated that the central review may have produced false positive results. It concluded that the population in ARAMIS was generalisable to the population seen in NHS clinical practice.\n\n## Darolutamide plus ADT extends metastasis-free survival\n\nIn ARAMIS, the median survival on darolutamide plus ADT was 40.4\xa0months and on placebo plus ADT it was 18.4\xa0months. The hazard ratio was 0.41 (95% confidence interval 0.34 to 0.50). The committee concluded that darolutamide plus ADT extended metastasis-free survival and was clinically effective.\n\n## Darolutamide extends overall survival during the trial, but treatments offered for metastatic disease make the longer-term benefit unclear\n\nIn the final analysis of overall survival people had been followed for up to 5\xa0years. Only a small proportion of people in both the darolutamide plus ADT arm and the placebo plus ADT arm had died (the proportions are academic in confidence and cannot be reported here). Fewer people died in the darolutamide plus ADT arm than in the placebo plus ADT arm. The hazard ratio for overall survival for darolutamide plus ADT compared with placebo plus ADT and the 95% upper limit of the confidence intervals were less than 1. So, overall survival was better with darolutamide plus ADT (the data are academic in confidence and cannot be reported here). The committee noted that overall survival depends on the treatments for non-metastatic disease and on the follow-on treatments taken after the cancer has metastasised. It discussed the choice of treatments, and the proportion of people taking these treatments in ARAMIS, in relation to NHS practice. It noted that the trial was blinded until September 2018, so investigators would not know a person's first treatment, which could determine the next treatment. The committee also noted that some people in ARAMIS who had enzalutamide or abiraterone for metastatic disease (after first having darolutamide), would not be offered these in NHS practice (see section\xa03.3). The company suggested that this meant survival after stopping darolutamide may have been underestimated in ARAMIS because abiraterone and enzalutamide are expected to be ineffective after darolutamide. The ERG noted that a smaller proportion of people had abiraterone or enzalutamide after ADT alone than would be expected in the NHS. The clinical experts suggested that survival on enzalutamide, abiraterone or docetaxel after ADT alone was similar. The committee also noted that a smaller proportion of people in each arm of the trial had gone on to have a follow-on treatment than would be expected in the NHS. It concluded that the data suggested that darolutamide extended overall survival over the duration of the trial. But how long this lasted after the trial was unclear, partly because of the follow-on treatments taken after the cancer had metastasised.\n\n## Adjusting the ARAMIS estimates of overall survival is unclear and the results may be biased against darolutamide\n\nIn ARAMIS, at the time of the final analysis of the primary endpoint, people randomised to placebo plus ADT whose disease had not metastasised could switch to darolutamide. When ARAMIS was unblinded in September 2018, 170\xa0people in the placebo plus ADT arm switched to darolutamide. The committee noted it could not assess the company's 2\xa0methods (Iterative Parameter Estimation and the Rank Preserving Structural Failure Time method) to adjust for the effect of treatment switching on overall survival because the company did not present details of these analyses. The company stated that adjusting for switching did not greatly affect the estimates of the treatment effect on overall survival and introduced uncertainty. The committee was aware that the key assumption in the methods is that the treatment effect is the same in people who switch to darolutamide and in people who were initially randomised to have darolutamide. The committee did not have evidence for this assumption. The company chose to use unadjusted survival estimates in its model. The committee appreciated that estimates of overall survival benefit with darolutamide plus ADT compared with ADT alone could be conservative. That is, they may underestimate the benefit of darolutamide plus ADT over ADT alone. The committee noted that people who had no metastases in September 2018 and switched from placebo to darolutamide would have been followed only until the final overall survival analysis in November 2019. Given the low death rates over trial follow up, switching may not have had a large effect on the overall survival estimates. The committee concluded that it could not determine whether the assumptions behind the adjustment methods were met. Also, using unadjusted results may bias the overall survival estimates in ARAMIS against darolutamide.\n\n## Adjusting outcomes for people with metastases at baseline by censoring may favour ADT alone\n\nThe ARAMIS statistical analysis was done in an intention-to-treat population. However, in the company's economic model the data had an additional adjustment. This involved censoring people who had been found by central independent radiological review to have metastases at baseline. The company used these censored results to make Kaplan–Meier plots of the trial data for metastasis-free survival and overall survival. It extrapolated these data over the period beyond the end of the trial. The committee noted that Kaplan–Meier plots of survival data take into account the number of events and the number of people at risk of having an event over time. Censoring people at baseline may mean that the risk of having an event was slightly underestimated. The committee was concerned about 'informative censoring', that is, the risk of outcomes differing because of censoring. However, the committee noted that because more people in the placebo plus ADT arm had metastases at baseline than in the darolutamide plus ADT arm, the company's approach may have made the extrapolated estimates for ADT alone appear better than if they had been extrapolated without censoring. The committee concluded that censoring people with baseline metastases in ARAMIS may disadvantage darolutamide plus ADT and favour ADT alone.\n\n## Some people choose to stop darolutamide before their cancer metastasises\n\nThe clinical experts explained that darolutamide was well tolerated in ARAMIS. The marketing authorisation states that darolutamide plus ADT can be taken until cancer metastases; in ARAMIS around 9% of people stopped treatment because of adverse events. The committee discussed that, in general, people stayed on darolutamide longer based on the analysis of September 2018 than based on the later analysis of November 2019. A clinical expert explained that people may stop treatment even when their PSA levels were stable if they have fatigue, an adverse event that may not normally lead someone to stop treatment. The clinical experts considered this would be more likely to occur later in the study than earlier. The committee questioned whether people would stop treatment if they thought it was stopping their cancer from progressing. It noted the difference in the results from the 2\xa0data cuts and considered that unblinding the study in September 2018 may have affected people's choice to stop darolutamide, but it concluded that the reason for the different results in the 2\xa0data cuts was unclear. Overall, the committee concluded that darolutamide was well tolerated in the trial, but some people chose to stop it before their cancer metastasised.\n\n# Cost effectiveness\n\n## The model structure is appropriate for decision making\n\nTo estimate the cost effectiveness of darolutamide plus ADT compared with ADT alone, the company used a partitioned survival model. The company used data on metastasis-free survival and overall survival to model 3\xa0health states: non-metastatic hormone-relapsed prostate cancer, metastatic hormone-relapsed prostate cancer and death. In the non-metastatic health state people could be on or off treatment. In the metastatic health state, the company modelled the costs and utility associated with 3\xa0lines of treatment followed by best supportive care (see section\xa03.14). Using this type of model meant that time in the metastatic health state was determined by the overall survival estimates and the metastasis-free survival estimates from ARAMIS. The committee considered this to be an appropriate approach. It concluded that the model structure was appropriate for decision making.\n\n## Extrapolating the most mature data and considering a more pessimistic approach are appropriate\n\nThe data in the model came from different data cuts:\n\nSeptember 2018 for metastasis-free survival\n\nNovember 2019 for time to stopping darolutamide and overall survival.The committee understood that no further data were collected on metastasis-free survival, the primary endpoint, after September 2018. It shared the ERG's concerns that the time to stopping darolutamide based on 2019 data was shorter than when based on 2018 data (see section\xa03.10). The committee noted the ERG's concerns about the possibility that if the time to stopping darolutamide decreased with more mature data, the estimates of metastasis-free survival may also have decreased if this outcome had been measured until 2019. The committee noted that the company extrapolated the 2018 data on metastasis-free survival data with a Weibull model, which gave the best fit. The ERG provided a more pessimistic Gompertz extrapolation of these data to account for the possibility that metastasis-free survival would also decrease had it been measured until 2019. The clinical experts at the meeting stated that the ERG's Gompertz model was overly pessimistic. They expected some people taking darolutamide to still have non-metastatic disease at 7\xa0years, contrary to the ERG's modelling of all people having metastatic disease by this point. The committee concluded that extrapolating from the most mature data was appropriate and using different data cuts introduced uncertainty. It further concluded that considering a more pessimistic extrapolation in addition to the company's extrapolation was reasonable to assess the impact on the cost-effectiveness results (see section\xa03.19).\n\n## The long-term modelled survival estimates are highly uncertain and it is appropriate to consider other approaches\n\nThe company used a Weibull model to extrapolate overall survival beyond the end of ARAMIS. This predicted that 28% of people would be alive in the darolutamide plus ADT arm after 10\xa0years compared with 9% in the ADT alone arm. At 20\xa0years, it predicted that around 2% of people in the darolutamide plus ADT arm and 0% in the ADT alone arm would be alive. The ERG explained that its clinical expert advised that the predictions of long-term survival were reasonable in people who take ADT alone, but the company may have overestimated the proportion of people taking darolutamide plus ADT who would still be alive at 20\xa0years, in part because the modelled cohort had an average age of 74\xa0years. The ERG suggested an alternative extrapolation of the darolutamide plus ADT arm using a generalised gamma extrapolation. This predicted that 7% of people would be alive at 10\xa0years and nobody would be alive at 20\xa0years. The ERG stated that its clinical expert advised that long-term survival on darolutamide would likely be between the values extrapolated by the Weibull and the generalised gamma models. Acknowledging that they lacked long-term experience with darolutamide the clinical experts at the committee meeting stated that they expected around 30% of people in this population to be alive at 10\xa0years and it was plausible that some people would be alive at 20\xa0years. The committee noted that the company's modelled survival for ADT alone seemed lower than what the clinical experts considered plausible. It also noted that there were no longer-term data to validate the modelled long-term survival estimates with either treatment. Because the trial data were immature the committee concluded that the estimates of long-term extrapolated survival were highly uncertain. The committee further concluded it was appropriate to consider these approaches in its decision making:\n\nthe company's approach\n\nthe ERG's approach using the average of the generalised gamma and Weibull to extrapolate survival on darolutamide beyond the period covered by ARAMIS\n\nother ERG scenarios, which reduced the overall survival estimate for darolutamide (see section\xa03.16).\n\n## The company models fewer active treatments after darolutamide plus ADT than after ADT alone, which reflects expected NHS practice\n\nIn the company model, once people had progressed to metastatic disease, they had 3\xa0lines of treatment and then best supportive care. The company presented the different treatment options with the expected proportion of people who would have them. The committee noted:\n\nThe company suggested that around 2.5% to 5% of people would have abiraterone after darolutamide in the darolutamide plus ADT arm. The committee noted that the NHS would not offer abiraterone after darolutamide in clinical practice; this may overestimate the costs in the ADT alone arm and bias the cost-effectiveness estimates to favour darolutamide.\n\nA higher proportion of people had best supportive care rather than a clinically effective treatment as their first, second or third treatment after darolutamide plus ADT compared with ADT alone. The committee agreed that this reflected expected NHS practice, that is, people would have fewer active treatment options after darolutamide plus ADT than after ADT alone.\n\n## The ERG's estimates of time on treatments for metastatic disease are more plausible than the company's\n\nThe company estimated how long people took treatments for metastatic disease (see section\xa03.14). It used the median treatment duration for first, second and third treatments for hormone-relapsed metastatic prostate cancer from NICE's technology appraisal guidance on enzalutamide for treating metastatic hormone-relapsed prostate cancer before chemotherapy is indicated and abiraterone for treating metastatic hormone-relapsed prostate cancer before chemotherapy is indicated. The company then estimated the mean time on each treatment from the median times, by assuming an exponential distribution. The committee considered that 2\xa0changes proposed by the ERG to the company's approach were reasonable:\n\nModelling abiraterone or enzalutamide as second or third treatments for metastatic prostate cancer using observed values for progression-free survival and duration of treatment at this position in the treatment pathway rather than as first treatments, as modelled by the company. The company had used data from trials of abiraterone and enzalutamide for hormone-relapsed metastatic prostate cancer before docetaxel, the COU-AA-302 and PREVAIL trials respectively. The ERG used data from the COU-AA-301 trial for abiraterone and the AFFIRM trial for enzalutamide, which assessed abiraterone and enzalutamide for hormone-relapsed metastatic prostate cancer after docetaxel.\n\nBasing duration of best supportive care on the observed duration of ADT alone taken before chemotherapy in PREVAIL. ADT in PREVAIL was considered to be best supportive care. This was different to the company's approach, which used the average progression-free survival on the active treatments in the company's model (that is, abiraterone, enzalutamide, cabazitaxel, radium-223 and docetaxel) to estimate the duration of best supportive care.The committee concluded that the company's approach to modelling follow-on treatments was broadly appropriate but agreed that the ERG's assumptions were more plausible than the company's.\n\n## It is plausible that survival with metastatic disease after darolutamide plus ADT would be 3 to 4\xa0months shorter than after ADT alone\n\nThe company's model predicted that people would live 2\xa0more months with metastatic disease after darolutamide plus ADT than after ADT alone. The committee agreed with the ERG that this was implausible, because people would have access to more active treatments after ADT alone than after darolutamide plus ADT. The ERG did a scenario analysis in which it equalised the hazards of dying in the modelled darolutamide plus ADT arm and in the modelled ADT alone arm at 5\xa0years. This reduced the overall survival estimates for darolutamide. Also, the model predicted that people would live an extra 8\xa0months with metastatic disease after ADT compared with after darolutamide plus ADT. The clinical experts explained that although it was plausible that survival with metastatic disease after ADT alone would be longer than after darolutamide plus ADT, the ERG's scenario overestimated the difference. The clinical experts stated that recent trials of new drugs for hormone-relapsed metastatic prostate cancer had shown a 3 to 4‑month survival advantage compared with a non-active comparator. They said that therefore they would expect survival with metastatic disease after darolutamide plus ADT to be at most 3 to 4\xa0months shorter than after ADT alone. The committee concluded that it was plausible that survival with metastatic disease after darolutamide plus ADT would be 3 to 4\xa0months shorter than after ADT alone.\n\n## The frequency and costs of monitoring and hospital appointments are between the company's and ERG's estimates\n\nThe company and ERG had different assumptions on the frequencies of monitoring and costs of hospital appointments. The company based its assumptions on a retrospective cohort study from an NHS trust, which collected data from 44\xa0people with hormone-relapsed non-metastatic prostate cancer since 2011. The committee noted that monitoring practices can change over time. The ERG based its preferences on NICE's technology appraisal guidance on enzalutamide for hormone-relapsed non-metastatic prostate cancer. A patient expert, clinical experts and patient groups explained that people have fewer scans and community nurse visits than suggested by the ERG, but more visits to specialist nurses than suggested by the company. The committee concluded that the frequency and costs of monitoring and hospital appointments would lie between the company's and ERG's estimates.\n\n## The company's modelled utility values are appropriate\n\nThe company used EQ-5D data from ARAMIS to estimate that the utility value in the non-metastatic health state was 0.813 in both the darolutamide plus ADT and ADT alone modelled treatment arms. The mean utility value in the metastatic health state took into account the proportions of people having each follow-on treatment and the duration of each treatment. This was 0.731 in the darolutamide plus ADT modelled arm and 0.777 in the ADT alone modelled arm. The company used utility values associated with the various follow-on treatments, and disutility values for symptomatic skeletal events, from NICE's technology appraisal guidance on enzalutamide for non-metastatic hormone relapsed prostate cancer and enzalutamide for metastatic hormone-relapsed prostate cancer before chemotherapy is indicated. The committee concluded that the company's modelled utility values were appropriate.\n\n## The preferred modelling assumptions give an ICER in the range reflecting a cost-effective use of NHS resources\n\nBecause darolutamide and the follow-on treatments in the model (abiraterone, enzalutamide, cabazitaxel and radium-223) have confidential patient access schemes, the exact incremental cost-effectiveness ratios (ICERs) cannot be presented here. The committee noted that:\n\nUsing a Gompertz model rather than a Weibull model to extrapolate data on metastasis-free survival from ARAMIS increased the ICER from the company's base case.\n\nIf survival after metastatic disease was modelled to be longer after ADT alone than after darolutamide plus ADT, this increased the ICER from the company's base case.\n\nUsing the ERG's assumptions on monitoring frequency and costs increased the ICER.The committee considered that the most relevant scenarios for decision making were:\n\nThe ERG's base case, but with the overall survival hazards in the darolutamide plus ADT arm equalised to ADT alone at 7\xa0years. This scenario estimated that people having darolutamide plus ADT would live 3\xa0months less with metastatic prostate cancer than people having ADT alone. The ICER for this scenario was between £20,000 and £30,000 per quality-adjusted life year (QALY) gained.\n\nThe ERG's base case, but with the company's Weibull extrapolation of the ARAMIS data on metastasis-free survival, and the overall survival hazards equalised to ADT alone at and beyond 11\xa0years. This scenario estimated that people having darolutamide plus ADT would live 4\xa0months less with metastatic prostate cancer than people having ADT alone. The ICER for this scenario was under £20,000 per QALY gained.The committee noted that both these scenarios resulted in an ICER for darolutamide plus ADT compared with ADT alone in the range that NICE usually considers a cost-effective use of NHS resources.\n\n## Darolutamide is innovative\n\nThe committee agreed that there is an unmet need for clinically effective treatments for hormone-relapsed non-metastatic prostate cancer. Having a treatment that delays metastases by a median of 22\xa0months compared with the only treatment available to patients, ADT alone, is a step change for this population. The committee noted that having an effective treatment for non-metastatic prostate cancer may reduce the number of 'extra' or more sensitive scans being used to detect metastases so that people can then have the next available clinically effective treatment (see section\xa03.2). This potential benefit had not been included in the company's modelling. The committee concluded that darolutamide plus ADT is innovative.\n\n# Conclusion\n\n## Darolutamide plus ADT is recommended\n\nThe committee concluded that its preferred modelling scenarios resulted in an ICER that reflects good value for scarce NHS resources. It noted that darolutamide is clinically effective and innovative, and there is an unmet need for treatment for hormone-relapsed non-metastatic prostate cancer. The committee agreed that darolutamide plus ADT was a cost-effective use of NHS resources for treating hormone-relapsed prostate cancer at high risk of metastasising."}
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https://www.nice.org.uk/guidance/ta660
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Evidence-based recommendations on darolutamide (Nubeqa) for treating hormone-relapsed prostate cancer in adults at high risk of developing metastatic disease.
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ac87161f37e7283ae6ab8a80a4564c3a7d3132ce
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nice
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Pembrolizumab for untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma
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Pembrolizumab for untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma
Evidence-based recommendations on pembrolizumab (Keytruda) for untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) in adults whose tumours express PD L1 with a combined positive score (CPS) of 1 or more.
# Recommendations
Pembrolizumab is recommended as an option for untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) in adults whose tumours express PD‑L1 with a combined positive score (CPS) of 1 or more. This is only if:
pembrolizumab is given as a monotherapy
pembrolizumab is stopped at 2 years of uninterrupted treatment, or earlier if disease progresses, and
the company provides pembrolizumab according to the commercial arrangement.
This recommendation is not intended to affect treatment with pembrolizumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Treatment of metastatic or unresectable recurrent HNSCC depends on where it starts. If it starts in the oral cavity (mouth), it is usually first treated with cetuximab combination therapy (cetuximab with platinum and 5‑fluorouracil chemotherapy). If it starts outside the oral cavity it is treated with chemotherapy (platinum and 5-FU) alone.
Clinical trial evidence from people who have HNSCC that expresses a biomarker called PD-L1 (with a CPS of 1 or more) shows that, if their cancer started in the oral cavity, pembrolizumab monotherapy works at least as well as cetuximab combination therapy and has lower overall costs. If their cancer started outside the oral cavity, pembrolizumab monotherapy works better than chemotherapy alone. It has higher overall costs but the cost-effectiveness estimates are within what NICE normally considers an acceptable use of NHS resources. Pembrolizumab monotherapy is therefore recommended for both types of HNSCC.
The cost-effectiveness estimates for pembrolizumab combination therapy compared with monotherapy, in both types of HNSCC, are higher than what NICE normally considers an acceptable use of NHS resources. Therefore it is not recommended.# Information about pembrolizumab (monotherapy or in combination)
# Marketing authorisation indication
Pembrolizumab (Keytruda, Merck Sharp & Dohme) has a UK marketing authorisation as monotherapy or with platinum and 5-fluorouracil (5-FU) chemotherapy 'for the first-line treatment of metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) in adults whose tumours express PD-L1 with a CPS ≥ 1'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
Pembrolizumab costs £2,630 for a 100-mg vial, excluding VAT (BNF online, accessed December 2019).
The company has a commercial arrangement. This makes pembrolizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Merck Sharp & Dohme, a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.
# Clinical need
## A new treatment option is needed for people with metastatic or unresectable recurrent head and neck squamous cell carcinoma
The patient experts' submission stated that metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) has a big impact on the people living with the disease, and their carers and families. Having a complete response to treatment, being progression free for as long as possible, and having better quality of life are important to people. The clinical experts explained that this condition can be debilitating, with distressing symptoms such as a sore mouth, finding it hard to swallow or eat, loss of appetite and weight loss. They also said that many people have major surgery, which can change their appearance and have a psychological and social impact on their life. The clinical experts said that pembrolizumab's benefit is that it is better tolerated than existing treatments, including cetuximab, which may cause rash, diarrhoea and low magnesium. The committee concluded that there is a clinical need for an effective treatment that improves quality of life.
## People who would be offered pembrolizumab monotherapy or combination therapy are not clinically distinct populations
The marketing authorisation for pembrolizumab is as a monotherapy or in combination with platinum and 5-fluorouracil (5-FU) chemotherapy. The company did not provide evidence of a clearly defined population for whom pembrolizumab monotherapy would not be appropriate and pembrolizumab combination therapy would be offered instead, or vice versa. The clinical experts explained that combination therapy is usually offered to people with a high disease burden, or whose disease is progressing rapidly or has relapsed after chemotherapy. They also explained that monotherapy is offered to people with a low disease burden, with disease progressing at the expected rate, or to people who are not able to tolerate combination therapy. The summary of product characteristics states that the frequency of adverse reactions with combination therapy is higher than with pembrolizumab monotherapy. It says: 'Physicians should consider the benefit/risk balance of the available treatment options (pembrolizumab monotherapy or pembrolizumab in combination with chemotherapy) before initiating treatment in patients with HNSCC whose tumours express PD-L1'. The committee accepted that the decision about whether someone is offered monotherapy or combination is made on a case-by-case basis. Several clinical factors are considered. Some apply to both groups, such as good performance status, but there are factors that vary depending on the person, such as disease burden and speed of disease progression. The committee concluded that, because the decision about whether someone is offered monotherapy or combination is made on a case-by-case basis, it is not yet possible to clearly define distinct patient populations who would be offered one treatment over the other.
## Cetuximab combination therapy is a relevant comparator for cancer starting in the oral cavity, while chemotherapy alone is relevant for cancer starting outside the oral cavity
The clinical experts explained that people with metastatic or unresectable recurrent HNSCC have either cetuximab combination therapy (cetuximab with platinum and 5-FU chemotherapy) or chemotherapy (platinum and 5‑FU) alone. People whose cancer started in the oral cavity are offered cetuximab combination therapy in line with NICE's technology appraisal guidance on cetuximab for HNSCC. However, the committee heard that some people whose cancer started in the oral cavity may not be considered fit enough to have cetuximab combination therapy because of toxicity. They are offered chemotherapy alone. People whose cancer started outside the oral cavity are offered chemotherapy alone. After failure of first-line treatment, people may be offered further platinum-based chemotherapy, or nivolumab through the Cancer Drugs Fund (see NICE's technology appraisal guidance on nivolumab for HNSCC). People who are not well enough to have further treatment are offered best supportive care. The committee noted that the marketing authorisation for pembrolizumab, as a monotherapy or in combination with chemotherapy, was for the first-line treatment of metastatic or unresectable recurrent HNSCC regardless of where the tumour started. The committee agreed that cetuximab combination therapy was the relevant comparator for pembrolizumab for people whose cancer started in the oral cavity. This is because it is consistent with existing NICE technology appraisal guidance, and because most people offered pembrolizumab are likely to have similar patient characteristics to people offered the cetuximab combination, such as a good performance status. The committee also agreed that chemotherapy alone was the relevant comparator for pembrolizumab for people whose cancer started outside the oral cavity. It acknowledged that this population has limited treatment options because cetuximab is only available for those whose cancer started in the oral cavity.
## Pembrolizumab monotherapy and combination therapy should also be compared with each other
The committee agreed that, because it was not possible to clearly define distinct patient populations who would be offered pembrolizumab monotherapy and pembrolizumab combination therapy (see section 3.2), the 2 treatments should also be compared with each other (for both subgroups: people whose cancer started inside or outside the oral cavity).
# Clinical evidence
## The key clinical trial, KEYNOTE-48, is not wholly applicable to clinical practice in the NHS
The clinical evidence for pembrolizumab came from the ongoing KEYNOTE‑048 randomised controlled trial. People in the trial had metastatic or unresectable recurrent HNSCC and were randomised to pembrolizumab monotherapy (n=301), pembrolizumab combination therapy (with chemotherapy; n=281) or cetuximab combination therapy (n=300). After disease progression people were able to have further treatment, including the anti-PD-L1 drug nivolumab. Because nivolumab is only available in the NHS through the Cancer Drugs Fund (see NICE's technology appraisal guidance for nivolumab for HNSCC), it cannot be considered as a comparator in this appraisal. The company adjusted the overall survival data to account for this by using the simplified 2‑stage method. People included in KEYNOTE‑48 had an Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1. They may be in better health than people with metastatic or unresectable recurrent HNSCC in the NHS. In the comparator arm of KEYNOTE-048, only 31% of people had cancer that started in the oral cavity. The 69% of people whose cancer had started outside the oral cavity had treatment that is not standard care in the NHS: cetuximab combination therapy. In the NHS, these people are offered chemotherapy alone (see section 3.3). The committee agreed that it was not clear what effect this would have on the relative effectiveness of pembrolizumab (monotherapy or in combination) in that subgroup. But it accepted the advice from clinical experts, submitted in response to the appraisal consultation document, that this is unlikely to overestimate the relative efficacy of pembrolizumab, and might potentially underestimate it (see also section 3.8). The committee recognised that KEYNOTE‑048 was a well-conducted trial and was the best available evidence for pembrolizumab. But it concluded that the results of the trial may not be generalisable to clinical practice because the trial was not wholly applicable to current clinical practice in the NHS.
## Pembrolizumab's clinical effectiveness should be considered separately for cancer starting inside or outside the oral cavity
The company submitted evidence for the PD‑L1 with a combined positive score (CPS) of 1 or more trial population, based on a prespecified subgroup analysis of KEYNOTE‑048, in line with its marketing authorisation. Analysis for this population showed that pembrolizumab (monotherapy and in combination) extended overall survival compared with cetuximab combination therapy in people with a CPS of 1 or more. The hazard ratios were 0.71 (95% confidence interval 0.57 to 0.89; p=0.0027) for pembrolizumab monotherapy and 0.62 (95% CI 0.50 to 0.78; p<0.0001) for pembrolizumab combination therapy. However, the committee agreed that, because current treatment options in the NHS are different for cancer that started inside or outside the oral cavity (see section 3.3), it was appropriate to consider the clinical effectiveness of pembrolizumab in those 2 population subgroups. The committee also recalled the conclusion in existing NICE technology appraisal guidance on cetuximab for HNSCC that cetuximab combination therapy might be more effective in people whose cancer started in the oral cavity. Because the efficacy of cetuximab may differ depending on where the cancer has started, the committee agreed it was appropriate to consider the clinical data separately for each subgroup. The company stated that there is no scientific rationale to suggest pembrolizumab would work differently depending on where the cancer started. But in response to the appraisal consultation document, it provided overall survival results from KEYNOTE‑048 for the 2 subgroups (these results are confidential and therefore cannot be reported in detail here). The committee noted that the relative efficacy of pembrolizumab (monotherapy or in combination) may be different in the 2 subgroups, which could be because of the differences in the efficacy of pembrolizumab or cetuximab combination therapy, or because the trial was not designed to analyse differences between the subgroups. The committee also noted that the Kaplan–Meier curves for overall survival for pembrolizumab (monotherapy and in combination) and cetuximab combination therapy crossed over for the subgroup of people whose cancer started in the oral cavity, and the confidence intervals around the hazard ratio included 1. But this was not seen in the cancer starting outside the oral cavity. The committee also noted that, in both subgroups, pembrolizumab combination therapy appeared to offer a small clinical benefit over pembrolizumab monotherapy. The company and the ERG explained that the 2 subgroup analyses should be considered with caution because they were post-hoc analyses not powered to show differences between treatments. The committee concluded that, despite their limitations, subgroup analyses are the most appropriate source of clinical-effectiveness evidence for pembrolizumab decision making.
## Clinical-effectiveness outcomes in the subgroups are uncertain because they do not account for potential imbalances in baseline characteristics
The company also provided the baseline characteristics for both subgroups, in response to a committee request to adjust for any imbalances. The Cancer Drugs Fund clinical lead advised that the modest imbalances in some characteristics would not favour either the pembrolizumab or comparator arms of the trial, but noted that the sample sizes being compared were small. The company explored methods to account for potential imbalances. It concluded that no variables needed to be adjusted for, because all variables had overlapping confidence intervals and there were no obvious baseline differences between treatment groups or subgroups. The company also explained that adjusting for unnecessary confounders could introduce additional uncertainty and bias. The committee noted that no characteristic had a statistically significant effect on the overall survival hazard ratio for pembrolizumab (monotherapy or in combination) compared with cetuximab combination therapy. However, the committee noted that the lack of statistical significance is to be expected when making small, underpowered comparisons. It considered that characteristic imbalances should still be adjusted for when analysing clinical effectiveness in the 2 subgroups. The committee also noted that the company's analysis only explored the impact of baseline characteristics on relative treatment effectiveness, and did not consider whether any were prognostic factors that could affect clinical outcomes regardless of treatment. The committee agreed that the analyses provided by the company did not fully satisfy what it had requested, meaning the clinical-effectiveness outcomes were uncertain, and the extent and direction of this uncertainty was not known. The committee concluded that it would consider this uncertainty in its decision making.
# Indirect treatment comparisons
## The relative effectiveness of pembrolizumab and chemotherapy alone in people with cancer starting outside the oral cavity is uncertain
There was no direct evidence comparing pembrolizumab (monotherapy and in combination) with chemotherapy alone, which is the relevant comparator for cancers that started outside the oral cavity. For the whole PD‑L1 positive CPS 1 or more HNSCC population, the company did a fractional polynomial network meta-analysis to compare pembrolizumab (monotherapy and in combination) with chemotherapy alone. However, this approach was not possible for the subgroup analyses because clinical-effectiveness data specific to cancer starting outside the oral cavity were not available from the key trial comparing cetuximab combination therapy with chemotherapy alone (EXTREME study). Instead, the company used the ERG's preferred approach, using Kaplan–Meier data from the cetuximab combination therapy arm of KEYNOTE‑048 as a proxy for chemotherapy alone for people whose cancer started outside the oral cavity. The clinical experts agreed that this approach was reasonable because the EXTREME trial showed a benefit from cetuximab combination therapy, compared with chemotherapy alone, only in cancers that started in the oral cavity. However, the Cancer Drugs Fund clinical lead advised that this approach may overestimate the effectiveness of platinum and 5‑FU chemotherapy. The committee concluded that using cetuximab data to model outcomes for chemotherapy alone in the subgroup of people whose cancer started outside the oral cavity is subject to uncertainty, but it is the only available evidence for decision making.
# Cost-effectiveness considerations
## The 2-year stopping rule and company's modelling approach are appropriate for decision making
The company presented a 3‑state partitioned survival model (progression free, progressed disease and death) comparing pembrolizumab (monotherapy or in combination) with cetuximab combination therapy or chemotherapy alone. The company included a 2‑year treatment stopping rule in the model. The summary of product characteristics for pembrolizumab states that treatment should continue until disease progression or unacceptable toxicity. However, the 2‑year stopping rule was consistent with the KEYNOTE‑048 study design, and with NICE's technology appraisal guidance on pembrolizumab for other indications. The clinical experts also considered that a 2‑year stopping rule was appropriate for pembrolizumab in this appraisal. The committee concluded that the modelling approach was appropriate for decision making and accepted the 2‑year stopping rule.
## A 5-year treatment benefit for pembrolizumab is appropriate
The company used a time horizon of 20 years to capture all relevant costs and benefits for people having treatment. The company assumed a treatment benefit for pembrolizumab (monotherapy or in combination) for the full 20 years from starting treatment. The committee agreed with the ERG and clinical experts that this assumption was optimistic. The ERG's preferred analyses used a treatment effect over 5 years (that is, applying a hazard ratio of 1 to both the pembrolizumab and cetuximab combination therapy arms 5 years after starting treatment, which is 3 years after stopping treatment). The clinical experts said that conceptually it was possible that pembrolizumab's treatment effect could last up to 10 years because immunotherapies such as pembrolizumab have a different mechanism to cytotoxic therapies. Once anti-tumour immunotherapy occurs, it is plausible that the effect of treatment could be maintained. But the experts highlighted that this was only speculative because there were not much long-term data for pembrolizumab from KEYNOTE‑048. The clinical expert said that the treatment effect duration for pembrolizumab could not be transferred from one disease area to another because of differences in the physiology and genetic profile of the tumours. The committee agreed that, although it was biologically plausible for the treatment effect to continue after stopping pembrolizumab, its duration was uncertain. It noted that the ERG's proposed 5‑year treatment duration was consistent with NICE's technology appraisal guidance for nivolumab for HNSCC. The committee concluded that assuming a 5‑year treatment effect duration was more appropriate, and consistent with the previous head and neck cancer immunotherapy appraisal.
## The Weibull functions are appropriate for modelling overall survival in both subgroups
Because pembrolizumab's cost effectiveness should be considered separately for cancer starting in the oral cavity and in cancer starting outside (see section 3.6), the committee considered that overall survival should also be modelled separately for the 2 subgroups. The company used a piecewise log-normal extrapolation of the Kaplan–Meier curve for overall survival from KEYNOTE‑048 for pembrolizumab (monotherapy and in combination) in both subgroups. The ERG highlighted that using log-normal distributions resulted in clinically implausible long-term survival estimates, in which a small number of people were predicted to have lower mortality rates than the general population. The ERG explained that it preferred the Weibull extrapolations, because they gave more clinically plausible results. The committee concluded that the log-normal extrapolations gave clinically implausible results, and that the Weibull distribution was more appropriate for decision making.
## A lower baseline utility value for progressed disease should be used, sourced from published literature
The company used a utility value of 0.71 to model health-related quality of life in its base-case analysis for people with progressed metastatic disease. Based on the description of the health states in the model, the clinical experts said that this was high for people who are normally in very poor health, and therefore may be overestimated. The committee noted that this utility value was derived from the EQ‑5D questionnaire completed by patients in the KEYNOTE‑048 trial and an appropriate UK value set, which is consistent with the NICE reference case. However, it agreed that this utility value was too high. The committee noted that health-related quality of life was measured in the trial 30 days after progression, but no later. It agreed that the values may be subject to informative censoring. This means the progressed disease utility values were only derived from patients whose disease had progressed within the previous 30 days, which may overestimate the health-related quality of life of all people with progressed disease. The company explained that it is challenging to collect health-related quality of life data from terminally ill people with progressive disease. The committee noted that the company had applied time-to-death utility decrements, which resulted in progressively lower utility values in the final 180, 90 and 30 days before death (the exact values are confidential and therefore cannot be reported here). The committee considered that, because the time-to-death utility decrements were derived from the KEYNOTE‑048 trial, they were at the same risk of informative censoring. The committee considered a lower utility value of 0.66 that the company had sourced from published literature. It noted this value was from the CheckMate 141 trial for nivolumab after platinum chemotherapy, which is a later line of treatment. It agreed that these data represent a slightly different population than in the KEYNOTE‑048 trial. The company stated that the CheckMate 141 trial would have been subject to the same informative censoring bias as KEYNOTE‑048. The committee noted these limitations, but agreed that the company's preferred value of 0.71 was still too high because people with progressed metastatic disease are likely to be in poor health. The committee concluded that it preferred to use the lower utility value for progressed disease, sourced from published literature, but recognised that neither estimate was ideal.
## A fully incremental analysis should be used to determine cost effectiveness
The committee recalled that it was not possible to clearly define distinct patient populations who would be offered pembrolizumab monotherapy or combination therapy (see section 3.2). It recalled that, because people who would be offered pembrolizumab monotherapy and combination therapy are not clinically distinct populations, it was appropriate to compare the 2 regimens with each other (see section 3.4). Therefore, a fully incremental analysis should be used to determine the cost effectiveness of each pembrolizumab regimen.
# End of life
## Pembrolizumab meets the end of life criteria for HNSCC, although this is less certain for cancer starting in the oral cavity
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The committee recalled its decision to consider the 2 subgroups separately (cancer starting inside and outside the oral cavity; see section 3.6). The committee also noted that pembrolizumab was likely to meet both the short life expectancy and the extension of life criteria for the 2 subgroups (cancer starting inside or outside the oral cavity; the exact values are confidential and therefore cannot be reported here). However, it noted that this is less certain for cancer starting in the oral cavity because Kaplan–Meier curves for overall survival cross, and confidence intervals around the hazard ratio include 1. The committee concluded that pembrolizumab (monotherapy or in combination) meets the end of life criteria for cancer starting inside and outside the oral cavity.
# Cost-effectiveness results
## The cost-effectiveness results based on the whole trial population (PD-L1 CPS 1 or more) are not appropriate for decision making
The original company's and ERG's base-case analyses were based on the whole trial population (PD‑L1 CPS 1 or more) and used:
clinical data from the company's fractional polynomial network meta-analysis (company) or Kaplan–Meier data from the cetuximab combination therapy arm of KEYNOTE‑048 (ERG) for the comparison of pembrolizumab with chemotherapy alone for people whose cancer started outside the oral cavity (see section 3.8)
a 20‑year (company) or 5‑year (ERG) duration of treatment effect (see section 3.10)
-verall survival modelled using log-logistic and log-normal curves for pembrolizumab monotherapy and combination therapy, respectively (company), or Weibull curves for both pembrolizumab monotherapy and combination therapy (ERG; see section 3.11)
trial-based utility value for progressed disease state (company and the ERG; see section 3.12)
pairwise comparisons (company) or fully incremental analysis (ERG; see section 3.13).All cost-effectiveness analyses included the company's commercial arrangement for pembrolizumab. Neither the company's nor the ERG's base-case analyses included all of the committee's preferred assumptions (see section 3.16). Therefore, neither analysis was appropriate for its decision making, and the committee agreed not to consider them further.
## Pembrolizumab monotherapy is a cost-effective use of NHS resources for people whose cancer started in the oral cavity
The committee's preferred modelling assumptions used:
efficacy data from subgroup analyses (by cancer origin; see section 3.6, section 3.7 and section 3.11)
a 5‑year duration of treatment effect (see section 3.10)
Weibull curves to model overall survival (see section 3.11)
a lower baseline utility value for progressed disease (see section 3.12)
fully incremental analysis (see section 3.13).Using these assumptions, a revised confidential discount for pembrolizumab, and the confidential discount for cetuximab, pembrolizumab monotherapy dominated (that is, was more effective and cost less than) cetuximab combination therapy for people whose cancer started in the oral cavity. The committee recalled that the clinical-effectiveness data were uncertain, because they were from a post-hoc subgroup analysis (see section 3.6) and had not been adjusted for imbalances in baseline characteristics (see section 3.7). It also recalled that the Kaplan–Meier curves for overall survival crossed over for this subgroup, and the confidence intervals around the hazard ratio included 1 (see section 3.6). The committee noted that the survival gain for pembrolizumab monotherapy over cetuximab combination therapy predicted by the model for this subgroup was caused by differences in the long-term extrapolations. However, it agreed that, even if the long-term survival gain was not realised in clinical practice, and instead the treatments were only equally effective, pembrolizumab monotherapy would still be dominant. The committee concluded that pembrolizumab monotherapy is a cost-effective use of NHS resources for people with metastatic or unresectable recurrent HNSCC whose cancer started in the oral cavity.
## Pembrolizumab monotherapy is a cost-effective use of NHS resources for people whose cancer started outside the oral cavity
The committee recalled its preferred modelling assumptions (see section 3.16). Using these assumptions and a revised confidential discount for pembrolizumab, the most plausible fully incremental cost-effectiveness ratio (ICER) for people with cancer that started outside the oral cavity was below £50,000 per quality-adjusted life year (QALY) gained for pembrolizumab monotherapy compared with chemotherapy alone (the exact ICER is confidential and cannot be reported here). The committee recalled the high level of uncertainty in the clinical-effectiveness estimates, which were based on post-hoc subgroup analyses (see section 3.6) and had not been adjusted for imbalances in baseline characteristics (see section 3.7). However, it also recalled that using cetuximab data from KEYNOTE‑048 may overestimate the effectiveness of chemotherapy alone (see section 3.8), although the magnitude of this is unknown. It recalled that people whose cancer started outside the oral cavity currently have limited treatment options because cetuximab is only available for those whose cancer started in the oral cavity (NICE's technology appraisal guidance on cetuximab for HNSCC; see section 3.3). The committee was aware that only deterministic ICERs had been presented, but noted that probabilistic ICERs would be similar. The committee concluded that pembrolizumab monotherapy is likely to be cost effective for people with metastatic or unresectable recurrent HNSCC whose cancer started outside the oral cavity.
## Pembrolizumab combination therapy is not cost effective for cancer that started inside or outside the oral cavity
The committee recalled its preferred modelling assumptions, and that fully incremental analysis should be used (see section 3.16). Using these assumptions and a revised confidential discount for pembrolizumab, the most plausible fully incremental ICERs for pembrolizumab combination therapy were substantially higher than £50,000 per QALY gained, compared with pembrolizumab monotherapy, regardless of where the tumour started (the exact ICERs are confidential and cannot be reported here). The incremental cost of combination therapy was mainly because of the administration of chemotherapy, and it provided relatively little additional clinical benefit. Therefore, the committee concluded that pembrolizumab combination therapy is not cost effective for people with metastatic or unresectable recurrent HNSCC, regardless of where the tumour started.
# Cancer Drugs Fund
## Pembrolizumab combination therapy is not recommended for use in the Cancer Drugs Fund
The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum). The company had not expressed an interest in the technology being considered for funding through the Cancer Drugs Fund. The Cancer Drugs Fund clinical lead advised that the KEYNOTE‑048 trial data are very mature (almost complete), making it unlikely that using pembrolizumab combination therapy in the Cancer Drugs Fund would generate data that would resolve any uncertainties for cancer starting inside or outside the oral cavity. The committee concluded that pembrolizumab combination therapy did not meet the criteria to be considered for inclusion in the Cancer Drugs Fund, so did not recommend it for use within the Cancer Drugs Fund.
# Other factors
## There are no equalities issues
No relevant equalities issues were identified.
## There are no additional benefits not already captured in the economic analysis
The committee considered the innovative nature of pembrolizumab (monotherapy and in combination). The committee understood that improvements in survival and reduced adverse effects are important for people with this condition. The committee was aware of the impact of the disease on the person's carer and family (see section 3.1) and took this into account in its decision making. But it noted that no evidence was provided. It concluded that pembrolizumab (monotherapy and in combination) could be considered an important treatment option for this population, but there were no additional benefits associated with this treatment that had not been captured in the economic analysis.
# Conclusion
## Pembrolizumab monotherapy is recommended for HNSCC
The committee acknowledged that there is a clinical need for an effective treatment that improves quality of life for people with metastatic or unresectable recurrent HNSCC (see section 3.1). It also acknowledged that people whose cancer started outside the oral cavity currently have limited treatment options because cetuximab is only available for those whose cancer started in the oral cavity (NICE's technology appraisal guidance on cetuximab for HNSCC; see section 3.3). The committee agreed that KEYNOTE‑048 was not wholly applicable to NHS practice (see section 3.5). Because current treatment options are different for cancer that started inside or outside the oral cavity, the committee considered all clinical and cost-effectiveness analyses by primary tumour location (see section 3.6). It noted the limitations of post-hoc subgroup analyses (see section 3.6) and that imbalances in baseline patient characteristics for the 2 subgroups had not been adjusted for (see section 3.7). While accepting that these limitations introduced uncertainty, the committee agreed that the subgroup analyses provided the most appropriate source of clinical-effectiveness data to consider in its decision making. The committee also agreed that a lower utility value for progressed disease, sourced from published literature, more accurately represented the experience of people with progressed metastatic disease, who are normally in very poor health (see section 3.12). The committee also agreed that pembrolizumab monotherapy and combination therapy should be compared with each other in a fully incremental analysis, because people who would be offered each regimen are not clinically distinct populations (see section 3.2, section 3.4 and section 3.13). In summary, it concluded that pembrolizumab:
monotherapy is a cost-effective use of NHS resources for people whose cancer started inside or outside the oral cavity, compared with cetuximab combination therapy or chemotherapy alone
combination therapy is not a cost-effective use of NHS resources for people whose cancer started inside or outside the oral cavity, compared with pembrolizumab monotherapy.Treatment with pembrolizumab should be stopped after 2 years of uninterrupted treatment, or earlier if disease progresses.
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{'Recommendations': 'Pembrolizumab is recommended as an option for untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) in adults whose tumours express PD‑L1 with a combined positive score (CPS) of 1\xa0or more. This is only if:\n\npembrolizumab is given as a monotherapy\n\npembrolizumab is stopped at 2\xa0years of uninterrupted treatment, or earlier if disease progresses, and\n\nthe company provides pembrolizumab according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with pembrolizumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nTreatment of metastatic or unresectable recurrent HNSCC depends on where it starts. If it starts in the oral cavity (mouth), it is usually first treated with cetuximab combination therapy (cetuximab with platinum and 5‑fluorouracil [5-FU] chemotherapy). If it starts outside the oral cavity it is treated with chemotherapy (platinum and 5-FU) alone.\n\nClinical trial evidence from people who have HNSCC that expresses a biomarker called PD-L1 (with a CPS of 1\xa0or more) shows that, if their cancer started in the oral cavity, pembrolizumab monotherapy works at least as well as cetuximab combination therapy and has lower overall costs. If their cancer started outside the oral cavity, pembrolizumab monotherapy works better than chemotherapy alone. It has higher overall costs but the cost-effectiveness estimates are within what NICE normally considers an acceptable use of NHS resources. Pembrolizumab monotherapy is therefore recommended for both types of HNSCC.\n\nThe cost-effectiveness estimates for pembrolizumab combination therapy compared with monotherapy, in both types of HNSCC, are higher than what NICE normally considers an acceptable use of NHS resources. Therefore it is not recommended.', 'Information about pembrolizumab (monotherapy or in combination)': "# Marketing authorisation indication\n\nPembrolizumab (Keytruda, Merck Sharp & Dohme) has a UK marketing authorisation as monotherapy or with platinum and 5-fluorouracil (5-FU) chemotherapy 'for the first-line treatment of metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) in adults whose tumours express PD-L1 with a CPS [combined positive score] ≥ 1'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nPembrolizumab costs £2,630 for a 100-mg vial, excluding VAT (BNF online, accessed December 2019).\n\nThe company has a commercial arrangement. This makes pembrolizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Merck Sharp & Dohme, a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.\n\n# Clinical need\n\n## A new treatment option is needed for people with metastatic or unresectable recurrent head and neck squamous cell carcinoma\n\nThe patient experts' submission stated that metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) has a big impact on the people living with the disease, and their carers and families. Having a complete response to treatment, being progression free for as long as possible, and having better quality of life are important to people. The clinical experts explained that this condition can be debilitating, with distressing symptoms such as a sore mouth, finding it hard to swallow or eat, loss of appetite and weight loss. They also said that many people have major surgery, which can change their appearance and have a psychological and social impact on their life. The clinical experts said that pembrolizumab's benefit is that it is better tolerated than existing treatments, including cetuximab, which may cause rash, diarrhoea and low magnesium. The committee concluded that there is a clinical need for an effective treatment that improves quality of life.\n\n## People who would be offered pembrolizumab monotherapy or combination therapy are not clinically distinct populations\n\nThe marketing authorisation for pembrolizumab is as a monotherapy or in combination with platinum and 5-fluorouracil (5-FU) chemotherapy. The company did not provide evidence of a clearly defined population for whom pembrolizumab monotherapy would not be appropriate and pembrolizumab combination therapy would be offered instead, or vice versa. The clinical experts explained that combination therapy is usually offered to people with a high disease burden, or whose disease is progressing rapidly or has relapsed after chemotherapy. They also explained that monotherapy is offered to people with a low disease burden, with disease progressing at the expected rate, or to people who are not able to tolerate combination therapy. The summary of product characteristics states that the frequency of adverse reactions with combination therapy is higher than with pembrolizumab monotherapy. It says: 'Physicians should consider the benefit/risk balance of the available treatment options (pembrolizumab monotherapy or pembrolizumab in combination with chemotherapy) before initiating treatment in patients with HNSCC whose tumours express PD-L1'. The committee accepted that the decision about whether someone is offered monotherapy or combination is made on a case-by-case basis. Several clinical factors are considered. Some apply to both groups, such as good performance status, but there are factors that vary depending on the person, such as disease burden and speed of disease progression. The committee concluded that, because the decision about whether someone is offered monotherapy or combination is made on a case-by-case basis, it is not yet possible to clearly define distinct patient populations who would be offered one treatment over the other.\n\n## Cetuximab combination therapy is a relevant comparator for cancer starting in the oral cavity, while chemotherapy alone is relevant for cancer starting outside the oral cavity\n\nThe clinical experts explained that people with metastatic or unresectable recurrent HNSCC have either cetuximab combination therapy (cetuximab with platinum and 5-FU chemotherapy) or chemotherapy (platinum and 5‑FU) alone. People whose cancer started in the oral cavity are offered cetuximab combination therapy in line with NICE's technology appraisal guidance on cetuximab for HNSCC. However, the committee heard that some people whose cancer started in the oral cavity may not be considered fit enough to have cetuximab combination therapy because of toxicity. They are offered chemotherapy alone. People whose cancer started outside the oral cavity are offered chemotherapy alone. After failure of first-line treatment, people may be offered further platinum-based chemotherapy, or nivolumab through the Cancer Drugs Fund (see NICE's technology appraisal guidance on nivolumab for HNSCC). People who are not well enough to have further treatment are offered best supportive care. The committee noted that the marketing authorisation for pembrolizumab, as a monotherapy or in combination with chemotherapy, was for the first-line treatment of metastatic or unresectable recurrent HNSCC regardless of where the tumour started. The committee agreed that cetuximab combination therapy was the relevant comparator for pembrolizumab for people whose cancer started in the oral cavity. This is because it is consistent with existing NICE technology appraisal guidance, and because most people offered pembrolizumab are likely to have similar patient characteristics to people offered the cetuximab combination, such as a good performance status. The committee also agreed that chemotherapy alone was the relevant comparator for pembrolizumab for people whose cancer started outside the oral cavity. It acknowledged that this population has limited treatment options because cetuximab is only available for those whose cancer started in the oral cavity.\n\n## Pembrolizumab monotherapy and combination therapy should also be compared with each other\n\nThe committee agreed that, because it was not possible to clearly define distinct patient populations who would be offered pembrolizumab monotherapy and pembrolizumab combination therapy (see section 3.2), the 2\xa0treatments should also be compared with each other (for both subgroups: people whose cancer started inside or outside the oral cavity).\n\n# Clinical evidence\n\n## The key clinical trial, KEYNOTE-48, is not wholly applicable to clinical practice in the NHS\n\nThe clinical evidence for pembrolizumab came from the ongoing KEYNOTE‑048 randomised controlled trial. People in the trial had metastatic or unresectable recurrent HNSCC and were randomised to pembrolizumab monotherapy (n=301), pembrolizumab combination therapy (with chemotherapy; n=281) or cetuximab combination therapy (n=300). After disease progression people were able to have further treatment, including the anti-PD-L1 drug nivolumab. Because nivolumab is only available in the NHS through the Cancer Drugs Fund (see NICE's technology appraisal guidance for nivolumab for HNSCC), it cannot be considered as a comparator in this appraisal. The company adjusted the overall survival data to account for this by using the simplified 2‑stage method. People included in KEYNOTE‑48 had an Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1. They may be in better health than people with metastatic or unresectable recurrent HNSCC in the NHS. In the comparator arm of KEYNOTE-048, only 31% of people had cancer that started in the oral cavity. The 69% of people whose cancer had started outside the oral cavity had treatment that is not standard care in the NHS: cetuximab combination therapy. In the NHS, these people are offered chemotherapy alone (see section 3.3). The committee agreed that it was not clear what effect this would have on the relative effectiveness of pembrolizumab (monotherapy or in combination) in that subgroup. But it accepted the advice from clinical experts, submitted in response to the appraisal consultation document, that this is unlikely to overestimate the relative efficacy of pembrolizumab, and might potentially underestimate it (see also section 3.8). The committee recognised that KEYNOTE‑048 was a well-conducted trial and was the best available evidence for pembrolizumab. But it concluded that the results of the trial may not be generalisable to clinical practice because the trial was not wholly applicable to current clinical practice in the NHS.\n\n## Pembrolizumab's clinical effectiveness should be considered separately for cancer starting inside or outside the oral cavity\n\nThe company submitted evidence for the PD‑L1 with a combined positive score (CPS) of 1\xa0or more trial population, based on a prespecified subgroup analysis of KEYNOTE‑048, in line with its marketing authorisation. Analysis for this population showed that pembrolizumab (monotherapy and in combination) extended overall survival compared with cetuximab combination therapy in people with a CPS of 1\xa0or more. The hazard ratios were 0.71 (95% confidence interval [CI] 0.57 to 0.89; p=0.0027) for pembrolizumab monotherapy and 0.62 (95% CI 0.50 to 0.78; p<0.0001) for pembrolizumab combination therapy. However, the committee agreed that, because current treatment options in the NHS are different for cancer that started inside or outside the oral cavity (see section 3.3), it was appropriate to consider the clinical effectiveness of pembrolizumab in those 2\xa0population subgroups. The committee also recalled the conclusion in existing NICE technology appraisal guidance on cetuximab for HNSCC that cetuximab combination therapy might be more effective in people whose cancer started in the oral cavity. Because the efficacy of cetuximab may differ depending on where the cancer has started, the committee agreed it was appropriate to consider the clinical data separately for each subgroup. The company stated that there is no scientific rationale to suggest pembrolizumab would work differently depending on where the cancer started. But in response to the appraisal consultation document, it provided overall survival results from KEYNOTE‑048 for the 2\xa0subgroups (these results are confidential and therefore cannot be reported in detail here). The committee noted that the relative efficacy of pembrolizumab (monotherapy or in combination) may be different in the 2\xa0subgroups, which could be because of the differences in the efficacy of pembrolizumab or cetuximab combination therapy, or because the trial was not designed to analyse differences between the subgroups. The committee also noted that the Kaplan–Meier curves for overall survival for pembrolizumab (monotherapy and in combination) and cetuximab combination therapy crossed over for the subgroup of people whose cancer started in the oral cavity, and the confidence intervals around the hazard ratio included\xa01. But this was not seen in the cancer starting outside the oral cavity. The committee also noted that, in both subgroups, pembrolizumab combination therapy appeared to offer a small clinical benefit over pembrolizumab monotherapy. The company and the ERG explained that the 2\xa0subgroup analyses should be considered with caution because they were post-hoc analyses not powered to show differences between treatments. The committee concluded that, despite their limitations, subgroup analyses are the most appropriate source of clinical-effectiveness evidence for pembrolizumab decision making.\n\n## Clinical-effectiveness outcomes in the subgroups are uncertain because they do not account for potential imbalances in baseline characteristics\n\nThe company also provided the baseline characteristics for both subgroups, in response to a committee request to adjust for any imbalances. The Cancer Drugs Fund clinical lead advised that the modest imbalances in some characteristics would not favour either the pembrolizumab or comparator arms of the trial, but noted that the sample sizes being compared were small. The company explored methods to account for potential imbalances. It concluded that no variables needed to be adjusted for, because all variables had overlapping confidence intervals and there were no obvious baseline differences between treatment groups or subgroups. The company also explained that adjusting for unnecessary confounders could introduce additional uncertainty and bias. The committee noted that no characteristic had a statistically significant effect on the overall survival hazard ratio for pembrolizumab (monotherapy or in combination) compared with cetuximab combination therapy. However, the committee noted that the lack of statistical significance is to be expected when making small, underpowered comparisons. It considered that characteristic imbalances should still be adjusted for when analysing clinical effectiveness in the 2\xa0subgroups. The committee also noted that the company's analysis only explored the impact of baseline characteristics on relative treatment effectiveness, and did not consider whether any were prognostic factors that could affect clinical outcomes regardless of treatment. The committee agreed that the analyses provided by the company did not fully satisfy what it had requested, meaning the clinical-effectiveness outcomes were uncertain, and the extent and direction of this uncertainty was not known. The committee concluded that it would consider this uncertainty in its decision making.\n\n# Indirect treatment comparisons\n\n## The relative effectiveness of pembrolizumab and chemotherapy alone in people with cancer starting outside the oral cavity is uncertain\n\nThere was no direct evidence comparing pembrolizumab (monotherapy and in combination) with chemotherapy alone, which is the relevant comparator for cancers that started outside the oral cavity. For the whole PD‑L1 positive CPS\xa01 or more HNSCC population, the company did a fractional polynomial network meta-analysis to compare pembrolizumab (monotherapy and in combination) with chemotherapy alone. However, this approach was not possible for the subgroup analyses because clinical-effectiveness data specific to cancer starting outside the oral cavity were not available from the key trial comparing cetuximab combination therapy with chemotherapy alone (EXTREME study). Instead, the company used the ERG's preferred approach, using Kaplan–Meier data from the cetuximab combination therapy arm of KEYNOTE‑048 as a proxy for chemotherapy alone for people whose cancer started outside the oral cavity. The clinical experts agreed that this approach was reasonable because the EXTREME trial showed a benefit from cetuximab combination therapy, compared with chemotherapy alone, only in cancers that started in the oral cavity. However, the Cancer Drugs Fund clinical lead advised that this approach may overestimate the effectiveness of platinum and 5‑FU chemotherapy. The committee concluded that using cetuximab data to model outcomes for chemotherapy alone in the subgroup of people whose cancer started outside the oral cavity is subject to uncertainty, but it is the only available evidence for decision making.\n\n# Cost-effectiveness considerations\n\n## The 2-year stopping rule and company's modelling approach are appropriate for decision making\n\nThe company presented a 3‑state partitioned survival model (progression free, progressed disease and death) comparing pembrolizumab (monotherapy or in combination) with cetuximab combination therapy or chemotherapy alone. The company included a 2‑year treatment stopping rule in the model. The summary of product characteristics for pembrolizumab states that treatment should continue until disease progression or unacceptable toxicity. However, the 2‑year stopping rule was consistent with the KEYNOTE‑048 study design, and with NICE's technology appraisal guidance on pembrolizumab for other indications. The clinical experts also considered that a 2‑year stopping rule was appropriate for pembrolizumab in this appraisal. The committee concluded that the modelling approach was appropriate for decision making and accepted the 2‑year stopping rule.\n\n## A 5-year treatment benefit for pembrolizumab is appropriate\n\nThe company used a time horizon of 20\xa0years to capture all relevant costs and benefits for people having treatment. The company assumed a treatment benefit for pembrolizumab (monotherapy or in combination) for the full 20\xa0years from starting treatment. The committee agreed with the ERG and clinical experts that this assumption was optimistic. The ERG's preferred analyses used a treatment effect over 5\xa0years (that is, applying a hazard ratio of 1 to both the pembrolizumab and cetuximab combination therapy arms 5\xa0years after starting treatment, which is 3\xa0years after stopping treatment). The clinical experts said that conceptually it was possible that pembrolizumab's treatment effect could last up to 10\xa0years because immunotherapies such as pembrolizumab have a different mechanism to cytotoxic therapies. Once anti-tumour immunotherapy occurs, it is plausible that the effect of treatment could be maintained. But the experts highlighted that this was only speculative because there were not much long-term data for pembrolizumab from KEYNOTE‑048. The clinical expert said that the treatment effect duration for pembrolizumab could not be transferred from one disease area to another because of differences in the physiology and genetic profile of the tumours. The committee agreed that, although it was biologically plausible for the treatment effect to continue after stopping pembrolizumab, its duration was uncertain. It noted that the ERG's proposed 5‑year treatment duration was consistent with NICE's technology appraisal guidance for nivolumab for HNSCC. The committee concluded that assuming a 5‑year treatment effect duration was more appropriate, and consistent with the previous head and neck cancer immunotherapy appraisal.\n\n## The Weibull functions are appropriate for modelling overall survival in both subgroups\n\nBecause pembrolizumab's cost effectiveness should be considered separately for cancer starting in the oral cavity and in cancer starting outside (see section 3.6), the committee considered that overall survival should also be modelled separately for the 2\xa0subgroups. The company used a piecewise log-normal extrapolation of the Kaplan–Meier curve for overall survival from KEYNOTE‑048 for pembrolizumab (monotherapy and in combination) in both subgroups. The ERG highlighted that using log-normal distributions resulted in clinically implausible long-term survival estimates, in which a small number of people were predicted to have lower mortality rates than the general population. The ERG explained that it preferred the Weibull extrapolations, because they gave more clinically plausible results. The committee concluded that the log-normal extrapolations gave clinically implausible results, and that the Weibull distribution was more appropriate for decision making.\n\n## A lower baseline utility value for progressed disease should be used, sourced from published literature\n\nThe company used a utility value of 0.71 to model health-related quality of life in its base-case analysis for people with progressed metastatic disease. Based on the description of the health states in the model, the clinical experts said that this was high for people who are normally in very poor health, and therefore may be overestimated. The committee noted that this utility value was derived from the EQ‑5D questionnaire completed by patients in the KEYNOTE‑048 trial and an appropriate UK value set, which is consistent with the NICE reference case. However, it agreed that this utility value was too high. The committee noted that health-related quality of life was measured in the trial 30\xa0days after progression, but no later. It agreed that the values may be subject to informative censoring. This means the progressed disease utility values were only derived from patients whose disease had progressed within the previous 30\xa0days, which may overestimate the health-related quality of life of all people with progressed disease. The company explained that it is challenging to collect health-related quality of life data from terminally ill people with progressive disease. The committee noted that the company had applied time-to-death utility decrements, which resulted in progressively lower utility values in the final 180, 90 and 30\xa0days before death (the exact values are confidential and therefore cannot be reported here). The committee considered that, because the time-to-death utility decrements were derived from the KEYNOTE‑048 trial, they were at the same risk of informative censoring. The committee considered a lower utility value of 0.66 that the company had sourced from published literature. It noted this value was from the CheckMate\xa0141 trial for nivolumab after platinum chemotherapy, which is a later line of treatment. It agreed that these data represent a slightly different population than in the KEYNOTE‑048 trial. The company stated that the CheckMate\xa0141 trial would have been subject to the same informative censoring bias as KEYNOTE‑048. The committee noted these limitations, but agreed that the company's preferred value of 0.71 was still too high because people with progressed metastatic disease are likely to be in poor health. The committee concluded that it preferred to use the lower utility value for progressed disease, sourced from published literature, but recognised that neither estimate was ideal.\n\n## A fully incremental analysis should be used to determine cost effectiveness\n\nThe committee recalled that it was not possible to clearly define distinct patient populations who would be offered pembrolizumab monotherapy or combination therapy (see section 3.2). It recalled that, because people who would be offered pembrolizumab monotherapy and combination therapy are not clinically distinct populations, it was appropriate to compare the 2\xa0regimens with each other (see section 3.4). Therefore, a fully incremental analysis should be used to determine the cost effectiveness of each pembrolizumab regimen.\n\n# End of life\n\n## Pembrolizumab meets the end of life criteria for HNSCC, although this is less certain for cancer starting in the oral cavity\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The committee recalled its decision to consider the 2\xa0subgroups separately (cancer starting inside and outside the oral cavity; see section 3.6). The committee also noted that pembrolizumab was likely to meet both the short life expectancy and the extension of life criteria for the 2\xa0subgroups (cancer starting inside or outside the oral cavity; the exact values are confidential and therefore cannot be reported here). However, it noted that this is less certain for cancer starting in the oral cavity because Kaplan–Meier curves for overall survival cross, and confidence intervals around the hazard ratio include 1. The committee concluded that pembrolizumab (monotherapy or in combination) meets the end of life criteria for cancer starting inside and outside the oral cavity.\n\n# Cost-effectiveness results\n\n## The cost-effectiveness results based on the whole trial population (PD-L1 CPS\xa01 or more) are not appropriate for decision making\n\nThe original company's and ERG's base-case analyses were based on the whole trial population (PD‑L1 CPS\xa01 or more) and used:\n\nclinical data from the company's fractional polynomial network meta-analysis (company) or Kaplan–Meier data from the cetuximab combination therapy arm of KEYNOTE‑048 (ERG) for the comparison of pembrolizumab with chemotherapy alone for people whose cancer started outside the oral cavity (see section 3.8)\n\na 20‑year (company) or 5‑year (ERG) duration of treatment effect (see section 3.10)\n\noverall survival modelled using log-logistic and log-normal curves for pembrolizumab monotherapy and combination therapy, respectively (company), or Weibull curves for both pembrolizumab monotherapy and combination therapy (ERG; see section 3.11)\n\ntrial-based utility value for progressed disease state (company and the ERG; see section 3.12)\n\npairwise comparisons (company) or fully incremental analysis (ERG; see section 3.13).All cost-effectiveness analyses included the company's commercial arrangement for pembrolizumab. Neither the company's nor the ERG's base-case analyses included all of the committee's preferred assumptions (see section 3.16). Therefore, neither analysis was appropriate for its decision making, and the committee agreed not to consider them further.\n\n## Pembrolizumab monotherapy is a cost-effective use of NHS resources for people whose cancer started in the oral cavity\n\nThe committee's preferred modelling assumptions used:\n\nefficacy data from subgroup analyses (by cancer origin; see section 3.6, section 3.7 and section 3.11)\n\na 5‑year duration of treatment effect (see section 3.10)\n\nWeibull curves to model overall survival (see section 3.11)\n\na lower baseline utility value for progressed disease (see section 3.12)\n\nfully incremental analysis (see section 3.13).Using these assumptions, a revised confidential discount for pembrolizumab, and the confidential discount for cetuximab, pembrolizumab monotherapy dominated (that is, was more effective and cost less than) cetuximab combination therapy for people whose cancer started in the oral cavity. The committee recalled that the clinical-effectiveness data were uncertain, because they were from a post-hoc subgroup analysis (see section 3.6) and had not been adjusted for imbalances in baseline characteristics (see section 3.7). It also recalled that the Kaplan–Meier curves for overall survival crossed over for this subgroup, and the confidence intervals around the hazard ratio included 1 (see section 3.6). The committee noted that the survival gain for pembrolizumab monotherapy over cetuximab combination therapy predicted by the model for this subgroup was caused by differences in the long-term extrapolations. However, it agreed that, even if the long-term survival gain was not realised in clinical practice, and instead the treatments were only equally effective, pembrolizumab monotherapy would still be dominant. The committee concluded that pembrolizumab monotherapy is a cost-effective use of NHS resources for people with metastatic or unresectable recurrent HNSCC whose cancer started in the oral cavity.\n\n## Pembrolizumab monotherapy is a cost-effective use of NHS resources for people whose cancer started outside the oral cavity\n\nThe committee recalled its preferred modelling assumptions (see section 3.16). Using these assumptions and a revised confidential discount for pembrolizumab, the most plausible fully incremental cost-effectiveness ratio (ICER) for people with cancer that started outside the oral cavity was below £50,000 per quality-adjusted life year (QALY) gained for pembrolizumab monotherapy compared with chemotherapy alone (the exact ICER is confidential and cannot be reported here). The committee recalled the high level of uncertainty in the clinical-effectiveness estimates, which were based on post-hoc subgroup analyses (see section 3.6) and had not been adjusted for imbalances in baseline characteristics (see section 3.7). However, it also recalled that using cetuximab data from KEYNOTE‑048 may overestimate the effectiveness of chemotherapy alone (see section 3.8), although the magnitude of this is unknown. It recalled that people whose cancer started outside the oral cavity currently have limited treatment options because cetuximab is only available for those whose cancer started in the oral cavity (NICE's technology appraisal guidance on cetuximab for HNSCC; see section 3.3). The committee was aware that only deterministic ICERs had been presented, but noted that probabilistic ICERs would be similar. The committee concluded that pembrolizumab monotherapy is likely to be cost effective for people with metastatic or unresectable recurrent HNSCC whose cancer started outside the oral cavity.\n\n## Pembrolizumab combination therapy is not cost effective for cancer that started inside or outside the oral cavity\n\nThe committee recalled its preferred modelling assumptions, and that fully incremental analysis should be used (see section 3.16). Using these assumptions and a revised confidential discount for pembrolizumab, the most plausible fully incremental ICERs for pembrolizumab combination therapy were substantially higher than £50,000 per QALY gained, compared with pembrolizumab monotherapy, regardless of where the tumour started (the exact ICERs are confidential and cannot be reported here). The incremental cost of combination therapy was mainly because of the administration of chemotherapy, and it provided relatively little additional clinical benefit. Therefore, the committee concluded that pembrolizumab combination therapy is not cost effective for people with metastatic or unresectable recurrent HNSCC, regardless of where the tumour started.\n\n# Cancer Drugs Fund\n\n## Pembrolizumab combination therapy is not recommended for use in the Cancer Drugs Fund\n\nThe committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum). The company had not expressed an interest in the technology being considered for funding through the Cancer Drugs Fund. The Cancer Drugs Fund clinical lead advised that the KEYNOTE‑048 trial data are very mature (almost complete), making it unlikely that using pembrolizumab combination therapy in the Cancer Drugs Fund would generate data that would resolve any uncertainties for cancer starting inside or outside the oral cavity. The committee concluded that pembrolizumab combination therapy did not meet the criteria to be considered for inclusion in the Cancer Drugs Fund, so did not recommend it for use within the Cancer Drugs Fund.\n\n# Other factors\n\n## There are no equalities issues\n\nNo relevant equalities issues were identified.\n\n## There are no additional benefits not already captured in the economic analysis\n\nThe committee considered the innovative nature of pembrolizumab (monotherapy and in combination). The committee understood that improvements in survival and reduced adverse effects are important for people with this condition. The committee was aware of the impact of the disease on the person's carer and family (see section 3.1) and took this into account in its decision making. But it noted that no evidence was provided. It concluded that pembrolizumab (monotherapy and in combination) could be considered an important treatment option for this population, but there were no additional benefits associated with this treatment that had not been captured in the economic analysis.\n\n# Conclusion\n\n## Pembrolizumab monotherapy is recommended for HNSCC\n\nThe committee acknowledged that there is a clinical need for an effective treatment that improves quality of life for people with metastatic or unresectable recurrent HNSCC (see section 3.1). It also acknowledged that people whose cancer started outside the oral cavity currently have limited treatment options because cetuximab is only available for those whose cancer started in the oral cavity (NICE's technology appraisal guidance on cetuximab for HNSCC; see section 3.3). The committee agreed that KEYNOTE‑048 was not wholly applicable to NHS practice (see section 3.5). Because current treatment options are different for cancer that started inside or outside the oral cavity, the committee considered all clinical and cost-effectiveness analyses by primary tumour location (see section 3.6). It noted the limitations of post-hoc subgroup analyses (see section 3.6) and that imbalances in baseline patient characteristics for the 2\xa0subgroups had not been adjusted for (see section 3.7). While accepting that these limitations introduced uncertainty, the committee agreed that the subgroup analyses provided the most appropriate source of clinical-effectiveness data to consider in its decision making. The committee also agreed that a lower utility value for progressed disease, sourced from published literature, more accurately represented the experience of people with progressed metastatic disease, who are normally in very poor health (see section 3.12). The committee also agreed that pembrolizumab monotherapy and combination therapy should be compared with each other in a fully incremental analysis, because people who would be offered each regimen are not clinically distinct populations (see section 3.2, section 3.4 and section 3.13). In summary, it concluded that pembrolizumab:\n\nmonotherapy is a cost-effective use of NHS resources for people whose cancer started inside or outside the oral cavity, compared with cetuximab combination therapy or chemotherapy alone\n\ncombination therapy is not a cost-effective use of NHS resources for people whose cancer started inside or outside the oral cavity, compared with pembrolizumab monotherapy.Treatment with pembrolizumab should be stopped after 2\xa0years of uninterrupted treatment, or earlier if disease progresses."}
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https://www.nice.org.uk/guidance/ta661
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Evidence-based recommendations on pembrolizumab (Keytruda) for untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) in adults whose tumours express PD L1 with a combined positive score (CPS) of 1 or more.
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ce475a8f9964e9b826fd0ebdf66847e70c126cb2
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nice
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Drug-eluting stents for the treatment of coronary artery disease
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Drug-eluting stents for the treatment of coronary artery disease
Evidence-based recommendations on using drug-eluting stents in adults.
# Guidance
Drug-eluting stents are recommended for use in percutaneous coronary intervention for treating stable angina, within their instructions for use, only if:
the target artery to be treated has less than a 3-mm calibre or the lesion is longer than 15 mm, and
the price difference between drug-eluting stents and bare-metal stents is no more than £300. For recommendations on drug-eluting stents for people with unstable angina, non-ST-segment-elevation myocardial infarction (NSTEMI) or ST-segment-elevation myocardial infarction (STEMI), see recommendation 1.1.18 and recommendation 1.2.18 in NICE's guideline on acute coronary syndromes.# Clinical need and practice
Coronary artery disease is also known as coronary heart disease (CHD) and ischaemic heart disease. It is narrowing (stenosis) of the coronary arteries as a result of deposition of atherosclerotic plaque, which results in an insufficient supply of oxygen to the heart muscle. CHD may affect one or more arteries, which may be of different diameters (calibres). The stenosis of arteries may be partial or total. Coronary artery stenosis may be asymptomatic or may lead to angina – chest pain that may be severe enough to restrict or prevent exertion. A critical reduction of the blood supply to the heart may result in myocardial infarction (MI) or death.
Mortality rates from CHD are decreasing but CHD remains the most common cause of mortality in the UK. It accounted for nearly 117,500 deaths in the UK in 2002 (about 103,000 deaths in England and Wales). CHD is also the cause of considerable morbidity and loss of ability to lead a normal life. In the UK, annually, approximately 259,500 people experience an acute MI and approximately 341,500 new cases of angina (the most common form of CHD morbidity) are reported. In Europe, CHD has been estimated to account for 9.7% of total disability-adjusted life years lost.
Mortality and morbidity rates associated with CHD vary by socioeconomic group (rates are higher in lower socioeconomic groups), by geographical area (rates are highest in Wales, North West England, and the Northern England and Yorkshire regions, and lowest in South East England) and by ethnic group (for example, CHD rates are highest among people from the Indian subcontinent living in the UK). The prevalence of CHD also increases with age and is higher in men than women. The disease is more common in people with high serum cholesterol and/or high blood pressure, in people who have type 1 or type 2 diabetes mellitus, in people who smoke, and in people who are physically inactive and/or obese.
The symptoms and health risks associated with a stenosed artery may be treated medically, by modifying risk factors (for example, smoking, hyperlipidaemia, obesity and hyperglycaemia) and/or by drug treatment (for example, beta-adrenergic blockers, nitrates, calcium-channel blockers, antiplatelet agents and/or statins).
If these medical treatments fail or are inappropriate, two invasive therapies are available. The first, coronary artery bypass grafting (CABG), involves major cardiac surgery. The second, balloon angioplasty (or percutaneous transluminal coronary angioplasty) involves a widening from within the artery using a balloon catheter, which is inserted through a femoral artery. When inflated, the balloon increases the calibre of the artery. Most percutaneous transluminal coronary angioplasty procedures involve the use of stents. A stent is a thin wire-mesh tube loaded over an angioplasty balloon. When the balloon inflates, the stent expands like a scaffold to hold the vessel open, and is left behind after the balloon is deflated and withdrawn. Percutaneous coronary intervention (PCI) is a generic term that encompasses percutaneous transluminal coronary angioplasty with or without stenting. The comparison of CABG with PCI including coronary artery stents (bare-metal and drug-eluting) was covered by NICE technology appraisal guidance 71 and is not dealt with in this appraisal.
One of the criteria for comparing the clinical effectiveness of PCI with stents with standard PCI (without stents) is the incidence of subsequent attacks of angina and major adverse coronary events (MACEs), which include death, MI and the need for further revascularisation procedures (CABG or repeat PCI).
A number of problems with PCI may occur. Recoil of the artery which happens when the balloon is deflated, usually occurs immediately or within 24 hours of completing the procedure, and may be associated with acute occlusive dissection of the vessel and require emergency CABG. In the medium term restenosis of the artery after the procedure may occur and has two main causes: contraction of the outer layer of the artery secondary to an injury reaction (3 to 6 months after the procedure) and proliferation of smooth muscle cells within the arterial wall (4 to 6 months after the procedure), leading to intimal hyperplasia. As a consequence of restenosis, a repeat procedure may be required and the rate of reintervention is greater in patients who have arteries of small calibre ('small vessels' – less than 3 mm in calibre), saphenous vein grafts and long lesions (longer than 15 mm) or total occlusions. People with diabetes, who commonly have arteries affected by atherosclerosis, also have a higher rate of restenosis.
Stent technology (type and platform, including the design, alloy used and strut thickness) has developed rapidly, and recent advances aim to reduce the likelihood of restenosis. Because restenosis is correlated with the degree of inflammation present at the time of angioplasty, drug-eluting stents (DESs) were developed. These are bare-metal stents (BMSs) coated with a drug, usually an immune suppressant, to reduce inflammation or an antimitotic agent to reduce cell proliferation. The drug reaches therapeutic concentrations in local tissues only and may not be detectable systemically, thus avoiding systemic adverse effects. A subsequent development was the use of a drug–polymer mix where the drug is held temporarily in place within a polymer 'painted' onto the metallic stent, allowing the drug to elute slowly into surrounding tissues. However, not all stents are polymer based.
According to British Cardiovascular Intervention Society (BCIS) data, approximately 70,000 PCI procedures were undertaken in the UK in 2005, equating to 1165 per million of the population. In England, the number of procedures per million of the population was 1169, and in Wales, 873.
The National Service Framework for CHD set a target in March 2000 for revascularisations (PCIs and CABGs), of at least 1500 per million of the population (750 for each type of intervention).
According to BCIS data, in the UK, the proportion of PCI procedures using stents rose steeply between 1993 and 1999, from below 10% to nearly 80%. It continued to increase, although more slowly, to about 94% in 2005. Data for DES use were not available before 2002. In 2003 it was reported that 17% of all stents used in the UK were DESs. In 2005 this had risen to around 62% in the UK, 60% in England and 77% in Wales. Given the increases in numbers of PCI procedures, it may be that utilisation rates are now much higher than this.
There is a risk of stent thrombosis associated with the use of both types of stent (DESs and BMSs). To prevent thrombosis occurring, patients are required to use an antiplatelet drug, such as clopidogrel, in addition to aspirin during and after the implantation of a stent. Following data published in 2006, the US Food and Drugs Administration (FDA)'s Circulatory Devices Systems Advisory Panel recommended that the duration of clopidogrel use should be extended in patients receiving a DES. The American College of Cardiologists/American Heart Association PCI guidelines (also endorsed by the Society for Cardiovascular Angiography Interventions) and the BCIS have recommended that for patients receiving DESs the duration of clopidogrel use should be increased to at least 12 months, after which time continuation of clopidogrel should be reviewed taking into account the risk for further events on an individual patient basis.# The technologies
This technology appraisal focuses on DESs only. The preceding appraisal of DESs (NICE technology appraisal guidance 71) considered only three devices (Taxus, Cypher and Dexamet) because at the time of publication, these were the only DESs that had been granted Conformité Européene (CE) marking for use within EU countries. Eight additional DESs have been included in this appraisal.
Each DES has an instruction for use (IFU) document that includes the indications for which the specific device can be used. The indications for use for each DES vary, although the majority specify the sizes of vessels (diameter and length) to be treated and are in accordance with their CE marking. Also included in the IFU documents are details of side effects and specific contraindications for DESs.
Different drugs elute from the stents that are included in this appraisal: paclitaxel is a broad-spectrum antimitotic agent that inhibits cell division; sirolimus (previously known as rapamycin) is an immunosuppressive agent that reduces inflammation; ABT-578 is a synthetic analogue of sirolimus; everolimus is an immunosuppressive agent that is closely related to sirolimus; tacrolimus is an immunosuppressive agent; and dexamethasone is a synthetic adrenocortical steroid that reduces inflammation. These drugs may elute at different rates, depending on the presence or absence of additional polymer coatings on the stent.
The following list prices for DESs exclude VAT.
The DES Axxion (Biosensors Limited) is a non-polymeric paclitaxel-eluting stent (PES) with a list price of £995 (BMS equivalent: Nexus).
The DES CoStar (Biotronik Limited) is a non-polymeric PES (BMS equivalent: DepoStent). CoStar was originally included in this appraisal but is no longer available.
The DES Taxus (Boston Scientific) is a polymeric PES with a list price of £1300 (BMS equivalent: Express).
The second-generation DES Taxus Liberté (Boston Scientific) is a polymeric PES with a list price of £1300 (BMS equivalent: Liberté).
The DES Cypher (Cordis Corporation) is a polymeric sirolimus-eluting stent (SES) with a list price of £1340 (BMS equivalent: Bx Velocity).
The second-generation DES Cypher Select (Cordis Corporation) is a polymeric SES with a list price of £1340 (BMS equivalent: Sonic).
The DES Endeavor (Medtronic AVE) is a polymeric sirolimus analogue ABT‑578 (zotarolimus)-eluting stent (ZES) with a list price of £1450 (BMS equivalent: Driver).
The DES Janus (Sorin) is a polymeric tacrolimus-eluting stent (TES) with a list price of £1500 (BMS equivalent: Janis).
The DES Xience V (Guidant Ltd) is a polymeric everolimus-eluting stent (EES) with a list price of £1500 (BMS equivalent: Multi-Link Vision).
The DES Dexamet (Abbott Vascular Devices Ltd) is a polymeric dexamethasone-eluting stent (BMS equivalent: BiodivYsio). Dexamet was originally included in this appraisal but is no longer available in the EU.
The DES Yukon (Kiwimed Ltd) is a non-polymeric stent that can be coated with any drug to be eluted and has a list price of £650.
As list prices are not commonly used for procuring devices in the NHS, updated prices of DESs and BMSs were sought from the NHS Purchasing and Supply Agency. Procurement of devices is complex and it should be noted that the prices for DES and BMS are driven by a number of factors including the: market conditions at the time of contracting; contract period; renewal date for the procurement arrangements (contracts are usually updated annually and the most recent contracts show significant decreases in the prices of DESs); volume commitment; period commitment; combination of period and volume commitment; product rationalisation or standardisation; retrospective threshold discounts (for example, free set quantities of stents when agreed volumes have been exceeded); consignment stock (for instance, when a supplier provides an inventory to trust); and other added value inclusive arrangements (for example, the provision of additional training and related equipment).
From the sample 2007/08 data received from the NHS Purchasing and Supply Agency for NHS organisations in England for the stents included in this appraisal, the mean price of DES was £529 and the mean price of BMS was £131. The price difference between DESs compared with BMSs ranged from £203 to £615 across a number of Health Authorities in England, although it should be noted that the higher price differences tended to be seen in the older contracts which will be re-tendered in due course, in accordance with relevant contract renewal schedules.# Evidence and interpretation
The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).
# Clinical effectiveness
## DESs versus BMSs – evidence from randomised controlled trials
A total of 17 randomised controlled trials (RCTs) were identified that compared DESs with BMSs, and data from all 17 were included for at least one outcome in the meta-analysis.
studies compared an SES (Cypher) with the equivalent BMS.
Four studies compared a PES (Taxus) with the equivalent BMS.
One study compared both an SES (Cypher) and a PES (Taxus) with a newer BMS.
One study compared the ZES (Endeavor) with the equivalent BMS.
One study compared the EES (Xience V) with the equivalent BMS.No RCT evidence has yet been reported for the Axxion, CoStar, Dexamet or Janus stents. Limited RCT data were available for the Yukon stent.
Study outcomes used in the RCTs included rates of mortality, acute MI, target lesion revascularisation (TLR), target vessel revascularisation (TVR), composite events (major adverse coronary event and/or target vessel failure ), angiographic binary restenosis and late luminal loss. Revascularisation was usually prompted by protocol-driven angiographic evidence of restenosis either for all participants or for a selected subgroup of participants. Only one trial (BASKET) explicitly reported that no protocol-driven angiographic follow-up was included. This trial compared both SES (Cypher) and PES (Taxus) DESs with a newer BMS in a three-arm study.
All but three of the 17 RCTs were multicentre trials. Study size ranged from 60 to over 1300 patients. Of the 17 trials, 11 included patients with single lesions. The studies covered a range of vessel diameters from 2.25 mm to 4.00 mm, although the lower range was not reported in some studies. Lesion length also varied, ranging from 10 mm to 33 mm, although again the data were not always reported. All studies permitted the inclusion of people with diabetes, and all but three studies excluded acute or evolving MI. The presence of unprotected left main coronary artery excluded patients from many trials, as did severe calcification or tortuosity, total occlusion, bifurcation, the presence of thrombus in the target vessel, previous PCI within 30 days or PCI other than balloon required as part of the study intervention.
A total of 12 trials described the co-therapies used. Aspirin was prescribed before intervention in 11 of these studies and used after the procedure in all 12. Clopidogrel was used as an antiplatelet therapy in all of the 12 studies; ticlopidine was available for use as an alternative to clopidogrel in five studies. In one trial, tirofiban, used in combination with a DES, was compared with abciximab used with a BMS. The duration of antiplatelet therapy after intervention ranged from 2 months in three trials to 1 year in one study.
Meta-analysis was carried out by the Assessment Group for rates of mortality, acute MI, TLR, TVR, composite event (MACE and/or TVF), angiographic binary restenosis and late luminal loss. Analysis of mortality, acute MI and event rates used pooled results from over 7000 participants. Data in the form of an odds ratio (OR) and 95% confidence interval (95% CI) were analysed using the Mantel–Haenszel method fixed-effect model. For continuous outcomes, weighted mean differences (WMDs) were analysed. Where there was significant heterogeneity, analysis using a random-effects model was also undertaken.
In addition to analyses of the individual studies, pooled estimates (giving the OR and 95% CI) were provided for each 'eluted drug' group (for example, comparing a PES and all BMSs in the paclitaxel studies). Data related to the SES (Cypher) and the sirolimus-analogue stent, ZES (Endeavor) in some instances were pooled and presented as pooled SES results. All eluted drug group results were also pooled to obtain estimates for a meta-analysis of any-type DESs compared with any-type BMSs. The meta-analysis was performed for available data at follow-ups of up to 1 month, 6 to 9 months, 1 year, 2 years and 3 years. The Assessment Group assumed, when making decisions about the appropriateness of combining data, that all BMSs are similar and, likewise, all DESs are similar except in the drug delivered; and that the stent design and the insertion system do not have an impact on clinical outcomes.
For rates of mortality and rates of acute MI, one study found a statistically significant difference in favour of the SES (Cypher) compared with the BMS for MI at 6 to 9 months (OR 0.19, 95% CI 0.04, 0.87). There were no statistically significant differences between the DES and the BMS in the individual studies for all other follow-up periods analysed to 3 years. There were no statistically significant differences between the DES and the BMS for the pooled eluted drug groups (PES and pooled SESs) and for the pooled analyses of any-type DES compared with any-type BMS for any of the follow-up periods.
For event rate (MACE and TVF), the individual studies of PES (Taxus), SES (Cypher) and ZES (Endeavor), and the pooled eluted drug groups analysis showed statistically significant differences in favour of DESs over BMSs. This was also the case for the overall meta-analysis, which favoured any-type DESs over any-type BMSs at all follow-up time points: 6 to 9 months (OR 0.46, 95% CI 0.40 to 0.53), 1 year (OR 0.39, 95% CI 0.33 to 0.47), 2 years (OR 0.43, 95% CI 0.34 to 0.54) and 3 years (OR 0.42, 95% CI 0.32 to 0.55). Statistical heterogeneity was indicated at the 6 to 9 months follow-up; a random-effect analysis for this time point showed only a small effect on the OR (OR 0.44, 95% CI 0.36 to 0.54). The difference between the EES (Xience V) and the BMS was not statistically significant at the only follow-up period (6 to 9 months).
For TVR, not all individual studies of PES (Taxus) showed statistical significance compared with BMSs for all time periods up to 3 years. The individual studies for SESs (Cypher) and ZESs (Endeavor) all showed statistical significance over BMSs up to 3 years. The pooled eluted drug groups analysis showed statistically significant differences in favour of a PES (Taxus) over BMSs at follow-up time points up to 2 years: 6 to 9 months (OR 0.54, 95% CI 0.43 to 0.68), 1 year (OR 0.40, 95% CI 0.29 to 0.55) and 2 years (OR 0.45, 95% CI 0.34 to 0.59). At 3 years, the difference was no longer statistically significant, but the data at this time point were derived from a single, relatively small study that may have been underpowered. TVR data for a SES (Cypher) versus a BMS were available for two trials at 6 to 9 months and for single trials at 1 and 3 years. These showed statistically significantly differences in favour of the SES (Cypher) compared with the BMS at: 6 to 9 months (OR 0.33, 95% CI 0.18, 0.62), 1 year (OR 0.34, 95% CI 0.19 to 0.60) and 3 years (OR 0.35, 95% CI 0.25 to 0.49). TVR data for the ZES (Endeavor) at 6 to 9 months, the only time period available, was statistically significant in favour of the ZES over the BMS (OR 0.41, 95% CI 0.27 to 0.63). There were no data for EES (Xience V) for this outcome measure.
Rates of revascularisation (TLR) at 1 year for procedures carried out with a DES within individual trials were less than 5%, and typically in the 10% to 25% range for procedures that used a BMS. For example, in three trials of PES (Taxus), the rates were 0%, 4.7% and 4.2% for the DES compared with 10.0%, 12.9% and 14.7% for the BMS, respectively. Rates at 1 year in three trials of a SES (Cypher) were 4.6%, 0% and 4.9% for the DES compared with 24.9%, 13.6% and 20.0% for the BMS, respectively. For TLR, the pooled eluted drug groups analysis showed statistically significant differences in favour of a PES (Taxus) over BMSs at follow-up periods of up to 2 years: 6 to 9 months (OR 0.37, 95% CI 0.28 to 0.49), 1 year (OR 0.26, 95% CI 0.18 to 0.39) and 2 years (OR 0.28, 95% CI 0.20 to 0.40). At 3 years, the difference was no longer statistically significant, but the data at this time point were derived from a single, relatively small study that may have been underpowered. TLR data for a SES (Cypher) showed it to be statistically significantly more effective than a BMS at all time points up to 3 years: 6 to 9 months (OR 0.21, 95% CI 0.15 to 0.30), 1 year (OR 0.17, 95% CI 0.12 to 0.25), 2 years (OR 0.22, 95% CI 0.15 to 0.30) and 3 years (OR 0.25, 95% CI 0.17 to 0.36). The data for the ZES (Endeavor) at the follow-up period of 6‑9 months showed it to be statistically significantly more effective than the BMS (OR 0.35, 95% CI 0.22, 0.56). Lower rates of TLR (3.8% versus 21.4%) were apparent for the EES (Xience V) group at 6 months (the only follow-up period) but the difference was not statistically significant. For TLR, the meta-analyses showed statistically significant differences in favour of any-type DES over any-type BMS, with improved rates of lesion revascularisation at all follow-up time points up to 3 years: 6 to 9 months (OR 0.30, 95% CI 0.25 to 0.37), 1 year (OR 0.21, 95% CI 0.16 to 0.27), 2 years (OR 0.24, 95% CI 0.19 to 0.31) and 3 years (OR 0.25, 95% CI 0.17 to 0.35).
## DES versus BMS – DESs with non-RCT data
The TES (Janus) was examined in a non-controlled study as was the PES (Taxus Liberté). A range of formulations of the PES (CoStar) was evaluated in two non-randomised controlled studies, and the Yukon DES was evaluated in a dose-ranging non-randomised controlled study comparing Yukon coated with sirolimus with the same stent carrying no drug. The Dexamet DES was studied in one non-randomised study of Dexamet compared with a BMS and four non-controlled studies (including two registries).
Outcome data were limited due to the short follow-up periods: 30 days for the PES (Taxus Liberté) study; 4 months for one PES (CoStar) study and 1 year for the other PES (CoStar) study; 6 months for the Dexamet studies and for the TES stent; and up to 1 year for the SES (Yukon) study. Angiographic outcomes, binary restenosis and/or late loss were reported for the PES (CoStar), Dexamet and the SES (Yukon). Because of the variety of DESs considered in these studies, the methodological limits of the available studies, and the varied and limited follow-up, the Assessment Group did not consider pooled analysis to be appropriate.
For the TES (Janus), limited data were reported; at 30 days no events (death, MI or TLR) had occurred. For the PES (Taxus Liberté) the data available at 30 days were marked as commercial in confidence. For the PES (CoStar), the only data available were for one of the two arms at 1 year for one trial and interim data from two of the four arms of the other ongoing study.
Data for the SES (Yukon) were reported at 1 month and 1 year. No deaths occurred in the first month. Rates of acute MI up to 1 month were 1.8% in the SES group and 1.3% in the BMS group. At 1 year, the composite of death or non-fatal MI was 2.7% for the Yukon SES and 3.9% for the BMS. No statistically significant differences were detected. At 1 year, TLR was reported in 12.6% of the SES group and 21.5% of the BMS group, and the difference was statistically significant in favour of the SES (OR 0.53, 95% CI 0.34 to 0.81).
The non-randomised trial that compared Dexamet (DES) with a BMS reported no deaths among the 100 participants receiving either stent and only one incidence of acute MI, which was in the BMS group, up to a mean of 8 months' follow-up. Revascularisations for this time period were 2% TLR in the DES group and 10% TLR (12% TVR) in the BMS group. Composite rates of MACEs, consisting entirely of revascularisations, were 2% for the DES and 12% for the BMS. Neither of these comparisons showed statistically significant differences.
## DES versus DES
Eight RCTs comparing different DES types were identified by the Assessment Group. Six RCTs compared a SES (Cypher) with a PES (Taxus) (including one trial that was also assessed in the DES versus BMS clinical section because it had a BMS arm as well as two DES arms), one studied SES (Cypher) in comparison with the newer SES (Cypher Select) and one compared the Yukon, as a SES, with a PES (Taxus).
Six trials were conducted in only one or two centres in European countries, and two were multicentre and multinational. Study sizes ranged from 200 to 1350 patients. Two trials were distinct in that they did not incorporate planned angiographic assessment of trial participants. Only two trials presented randomisation details and none of the studies presented adequate information on whether the RCTs were conducted under 'blind' conditions. One study did not present an intention-to-treat analysis, and for two studies it was unclear whether events were reported according to the original randomised allocations.
A meta-analysis was conducted according to which pairing of DES types was compared within trials (most commonly this was the SES versus the PES ). No total pooled effect estimate was calculated across multiple groupings of DES versus DES trials.
There were no statistically significant differences in rates of mortality or acute MI for any of the pairings of DES types.
For TLR, one individual study showed a statistically significantly better rate of TLR, at 6 to 9 months, with the SES (Cypher) compared with the PES (Taxus) (OR 0.56, 95% CI 0.33 to 0.93). Only one RCT had data available beyond 9 months; in this study, rates of TLR at 1 year were 5.7% for the SES (Cypher) compared with 9.0% for the PES (Taxus); the difference was not statistically significant. The Assessment Group's pooled analysis of TLR up to 9 months was statistically significant in favour of the SES (Cypher) over the PES (Taxus) (OR 0.70, 95% CI 0.51 to 0.97).
A statistically significant reduction in TVR with the SES (Cypher) compared with the PES (Taxus) was determined from a meta-analysis of two trials at 6 to 9 months (OR 0.59, 95% CI 0.39 to 0.89). A reduction in the composite event rate (MACE) at 6 to 9 months was also statistically significant with the SES (Cypher) compared with the PES (Taxus) (OR 0.75, 95% CI 0.59 to 0.96).
## Effects of DESs on the risks of thrombosis, MI and mortality
In December 2006, following publication of data on longer-term risks associated with DES (thrombosis, MI and mortality), the FDA convened a public meeting of its Circulatory System Devices Advisory Panel to review and analyse the available data and to provide recommendations for appropriate actions to address this issue. In January 2007, the Circulatory System Devices Advisory Panel made recommendations to the FDA. The Panel stated, 'When the DES, which are indicated for use in the USA (SES ) and (PES ), are used in accordance with their approved indications both are associated with a small increase in stent thrombosis compared with BMS at 1 year after stent implantation; the increased risk of stent thrombosis was not associated with an increased risk of death or MI compared with BMS; and the concerns about thrombosis do not outweigh the benefits of DES compared with BMS when DES are implanted within the limits of their approved indications for use.' The FDA stated that a longer duration of antiplatelet therapy may be beneficial, and this has led to the recommendation in the PCI guideline of the American College of Cardiologists/American Heart Association (endorsed by the Society for Cardiovascular Angiography Interventions) that in patients receiving DESs the duration of clopidogrel use should be increased to 12 months. The BCIS has also recommended 12 months' use of clopidogrel in patients receiving a DES.
The Circulatory System Devices Advisory Panel also considered use of DESs in patients with more complex coronary lesions than those studied to support initial marketing approval ('off-label' use). The Panel agreed that use of DESs 'off-label' is associated with an increased risk of stent thrombosis, MI or death compared with 'on-label' use, and until more data are available DES labels (IFUs) should state that when DESs are used off-label, patient outcomes may not be the same as the results observed in the clinical trials conducted to support marketing approval. The FDA has since defined off-label use to mean the use of a medical product for treatments other than those for which the product was initially approved; or use not explicitly included in product labelling (intended use and IFU). The UK Medicines and Healthcare Products Regulatory Agency (MHRA) supports this definition of off-label use for the DESs that have been approved for use in Europe.
Each DES included in this appraisal has an IFU document that lists the indications for which it can be used. The sizes of vessels (diameter and length) to be treated are stated in the majority of the IFUs, as are the specific contraindications. The FDA considers that although patients with diabetes were included in the pivotal trials, the number of patients was insufficient for either the SES (Cypher) or the PES (Taxus) to earn a specific labelled indication for people with diabetes. The UK MHRA supports the view of the FDA with regard to individuals with diabetes and only one of the DESs, the PES (Taxus), included in this appraisal has recently been specifically indicated for people with diabetes.
## Summary
There were no statistically significant differences detected in death or MI between the pooled subgroups and pooled any-type DES groups. The pooled DES analysis indicated that revascularisation rates were reduced by approximately three quarters compared with BMSs, consistent across most studies of the PES (Taxus) and SESs (Cypher; Endeavor at 6 to 9 months). The benefits of DESs over BMSs for TLR were seen at 1 year, and this significant difference was maintained for up to 3 years. For the TVR outcome there were statistically significant differences in favour of any-type DES over BMS for most of the time points assessed.
# Cost effectiveness
## Published literature
A total of 10 full economic evaluations were included in the assessment report, all of which compared an SES with a BMS, although four evaluations also included a PES. One of the evaluations was conducted in the UK; the rest were conducted in the USA, Canada or the rest of Europe. Seven evaluations used a 1-year time horizon, one used 2 years, one used 6 months and one used a patient's lifetime. Of the 10 evaluations, nine estimated that the cost of DESs incurred a price premium/difference (the difference in cost between a given BMS and the drug-eluting equivalent), which ranged from £233 to £1225. Four of the evaluations reported health outcomes in terms of quality-adjusted life years (QALYs). Three evaluations provided incremental costs per QALY for a general population, and these costs ranged from US$27,450 to Can$96,523 (approximately US$93,000). The fourth evaluation did not include a general population because subgroups were found to be too dissimilar for comparison. Two evaluations reported the incremental cost-effectiveness ratio (ICER) per repeat revascularisation avoided; one estimated it to be US$1650 over 1 year and the other estimated it to be approximately US$7000 over 2 years. The majority of evaluations concluded that DESs are more cost effective than BMSs for patients with types of arteries that have a higher risk of restenosis, although there was great disparity between evaluations, with a variety of outcomes and a range of ICERs being reported.
Only one economic study, carried out alongside the BASKET RCT, reflected clinical practice because no protocol-driven angiographic follow-up was included. This study's results suggested that, at a threshold of €7800 per MACE avoided, DESs could potentially be cost effective in the following subgroups of patients: those older than 65 years; those with more than one segment treated; those with triple-vessel disease; those with a stent length of more than 20 mm; and those with small stent diameters.
## Manufacturers' economic models
Three models were submitted by DES manufacturers.
The decision analytic model from Boston Scientific compared the PES (Taxus) with the equivalent BMS, for a general population and for subgroups. The incremental costs per QALY at 1 year were given as £29,587 for the overall population and £1020 for patients with diabetes. For patients with small vessels and long lesions, the PES (Taxus) was dominant (both more effective and less costly than the BMS). For the PES (Taxus) at 2 years, the incremental cost per QALY for the overall population was given as £13,394, and it was dominant for patients with small vessels and those with diabetes. The model was highly sensitive to variations in the duration of clopidogrel therapy and the average number of stents used. In the manufacturer's sensitivity analyses, when the number of stents used per procedure was increased from 1.4 to 1.7, in line with the Assessment Group's model, the estimated cost per QALY at 1 year for the overall population increased to £56,731; however, the subgroup estimates were only marginally increased. If the duration of clopidogrel therapy after DES implantation was increased from 6 to 12 months, the cost per QALY at 12 months increased to £71,634 for the total population and to over £30,000 for the subgroup with diabetes.
The decision analytic model from Cordis compared the SES (Cypher) with the equivalent BMS for a 'no-risk-factor' population and for subgroups. The model was split into a two-way analysis of the BMS versus the SES (Cypher) and a three-way analysis of the BMS versus the PES (Taxus) versus the SES (Cypher). In extending the three-way analysis to 2 years, an indirect comparison was undertaken that made an assumption that the BMSs in both trials (Boston Scientific and Cordis BMS) are equivalent. The cost data for the technologies (the BMS and Taxus) were considered by the Assessment Group to be overestimated and when the Assessment Group re-ran the model increasing the SES (Cypher) price premium over the equivalent BMS from £433 to £695, the incremental cost per QALY increased from £29,259 to £69,613 for the 'no risk factor' subgroup; from £10,178 to £39,508 for the small-vessels subgroup; from £16,460 to £49,345 for the long-lesions subgroup; and from £9702 to £38,446 for the group with diabetes.
The Markov model presented by Medtronic compared the ZES (Endeavor ) with Medtronic's comparable BMS, for a total population. The submission measured costs and benefits at 5 years, extrapolating the 9-month trial data. In one scenario, the two arms were assumed to be equivalent in terms of risk of repeat revascularisations after 1 year. The incremental cost per QALY was estimated at £11,220. No subgroup analyses were undertaken. The Assessment Group found the model to be highly sensitive to baseline TVR rates and the number of index stents used. If baseline TVR rates were reduced below 12% (for both the BMS and the ZES), then the ICER exceeded £30,000. If the average number of stents used for the index procedure was increased to 1.4, the ICER increased to £39,174. The Assessment Group noted that the two factors to which the model was sensitive were taken from a single positive trial.
The submission from Kiwimed compared an SES (Yukon) with the Kiwimed BMS for a total population. The effectiveness data were taken from the SES (Cypher) trials, so an untested assumption was made that the SES (Yukon) has equivalent effectiveness to the SES (Cypher). Extrapolation from 2 to 5 years was undertaken using an assumption that patients remained in the same health state that they were in at the end of 1 year. Kiwimed's submission stated that the model results indicated that the SES (Yukon) was dominant compared with the BMS in the total population. In a sensitivity analysis varying the cost of the stent and the probability of restenosis, the ICERs for the SES (Yukon) were always under £30,000 per QALY.
## Assessment Group model: methods
The Assessment Group's model used the framework from the original appraisal with some minor modifications as follows: the time horizon was restricted to 1 year, so no discounting was necessary; particular risk groups were examined; in addition to the modelling of any-type DES compared with BMS, some head to head comparisons were conducted (SES (Cypher) compared with the PES (Taxus).
A difference between the effectiveness of DES and BMS was only seen with regard to revascularisation (TLR and TVR) and event rate (MACE and TVF). For these endpoints, the clinical trials show evidence of differences between DESs and BMSs at 1 year. The clinical trials show evidence in favour of DESs over all follow-up periods up to 3 years with a trend towards the greatest benefit occurring within the first year.
In the Assessment Group's model the most important factors in determining the incremental cost were the additional cost per DES implanted (price premium/difference) and the number of stents implanted per patient. The most important factors in determining benefit in the model were the absolute risk of revascularisation for patients treated with a BMS and the risk reduction attributable to the use of a DES.
The acquisition cost of a given stent may vary in different settings because of negotiated procurement discounts. The Assessment Group in their economic evaluation used the prices from a market survey of NHS purchasers. The survey was conducted by the NHS Purchasing and Supply Agency in May/June 2005 to identify the prices in contracts covering the period 2004/05 for both DESs and BMSs. The combined data from 12 purchasing bodies covering 20 hospital trusts provided consistent estimates of average unit prices and of the differences in price between DESs and BMSs. Results were provided for the two main suppliers of DESs: Boston Scientific (Taxus) and Cordis Corporation (Cypher). The effective sale price per Taxus PES (excluding VAT) was £815. Because there was only one recorded instance of a significant local volume discount agreement for Cypher in the survey, the average sample price for the Cypher SES (excluding VAT) was £937. The estimated average price for a BMS in the survey (excluding VAT) was £278, so the price differences are £537 and £659 per DES for Taxus and Cypher, respectively.
Information received during the consultation period for the appraisal consultation document suggested that the prices for DESs had decreased since the 2005 survey. Therefore updated prices were sought from the NHS Purchasing and Supply Agency. From the sample 2007/08 data received from the NHS Purchasing and Supply Agency for NHS organisations in England for the stents included in this appraisal, the mean price of DES was £529 and the mean price of BMS was £131. The price difference between DESs compared with BMSs ranged from £203 to £615 across a number of Health Authorities in England.
To calculate the PCI procedure costs it was necessary to subtract the included costs of stents (DES and BMS) from the published PCI costs, and then to add back the model estimates of the number of stents, the type of stent and the cost per stent. In the final analyses, the Assessment Group assumed a wastage rate of 1%.
The Assessment Group base-case analysis used results from two observational studies of stented patients treated at the Liverpool Cardiothoracic Centre, to convert the efficacy of any-type DES to effectiveness estimates for repeat revascularisations and lesions treated in repeat revascularisations. The Assessment Group found that 51% of patients who underwent a second PCI required repeat treatment to previously treated lesions only. An additional 17% of patients received repeat treatment to a target lesion at the same time as treatment to a previously untreated lesion in the same vessel; these are the patients in whom DESs can be expected to produce benefit. Applying these proportions to the relative risk reduction from the trials of 74.6% (for TLR obtained from the meta-analysis of any-type DES trials) yielded an expected risk reduction in all revascularisations at 12 months of between 38% (95% CI 32 to 44%) and 50% (95% CI 44 to 57%). The Assessment Group also considered the likely benefit that any-type DES may offer in reducing the number of lesions treated in repeat revascularisations. When applied to the TLR relative risk reductions from the meta-analysis, this suggested that the reduction in the number of lesions treated in subsequent interventions was between 37% (95% CI 31 to 42%) and 53% (95% CI 47 to 59%) based on TLR (the Assessment Group counted lesions treated but excluded cases undergoing CABG rather than PCI). The Assessment Group noted that the BASKET trial, which did not include protocol-driven angiography, reported a risk reduction for DESs of 41% at 6 months. The Assessment Group therefore used 41% for the risk reduction associated with DESs in its base-case analyses.
The Assessment Group stated that the ICERs of any-type DESs compared with any-type BMSs are very dependent on the estimates of relative risk reduction in revascularisations and on the absolute rate of revascularisation in the types of patients in whom they are used. The absolute rates of revascularisation were derived from the Liverpool Cardiothoracic Centre audit data, and the potential of benefit was reassessed on the basis of the audit data concerning those patients in whom the repeat procedure required treatment of new lesions. This resulted in an absolute rate of revascularisation for all patients of 7.43%. The Assessment Group also carried out sensitivity analyses, varying rates of revascularisation for all patients up to 13%, based on trial data.
Using the Liverpool Cardiothoracic Centre audit data, the Assessment Group developed separate risk models for elective and non-elective patients using patient and lesion characteristics known at the time of the index intervention. Risk factors for the patients were identified in the assessment report as being calcification, angulation greater than 45 degrees, restenotic lesion, triple-vessel disease, vessel diameter of less than 2 mm and prior CABG. In the final analyses, the absolute rates of repeat revascularisations for the conventional risk factors (long lesions, small vessels, diabetes and all combinations of these) were provided using the Liverpool audit data. The Assessment Group stated that, because none of these three factors in the multivariate model achieved conventional significance using the Liverpool audit data, the individual relative risks have wide confidence intervals and should be considered only as illustrative. The mean 12-month repeat revascularisation rate for all patients with small vessels was 15.25% (95% CI 9.38% to 22.24%), with a rate difference p = 0.02; for those with long lesions it was 10.23% (95% CI 8.10% to 12.57%), p = 0.09; and for those with diabetes it was 10.61% (95% CI 7.52% to 14.14%), p = 0.14.
The Assessment Group used patient survey data from the Health Outcomes Data Repository (HoDAR) database for its utility values. The difference in HoDAR health-related quality of life scores between patients with severe angina and those recovered from revascularisation (0.158) was similar to the ARTS trial result (0.16), which was used in the previous appraisal. The assumptions made by the Assessment Group in the final analyses for disutilities associated with CABG versus PCI in the 6-week period following the procedure were that for a 2-week post-operative period, patients undergoing CABG experience a very low quality of life (0.0), and for the next 2 weeks the mean utility score recovers in a linear fashion achieving full benefit (0.660) by 4 weeks after the operation. Patients undergoing PCI were assumed to recover full benefit linearly over a 2-week period following the procedure. The Assessment Group concluded additionally that there was no evidence to suggest an effect on the rate of acute MI or mortality with CABG compared with PCI plus stenting.
When BMSs and DESs were compared, the meta-analysis showed a trend towards increased numbers of non-fatal acute MIs with BMSs. The Assessment Group concluded in their analyses that based on the reviewed evidence, the maximum likely effect of this is equivalent to, per patient, an overall cost saving of about £13 and a utility gain of about 0.00055 when DESs are used.
The clinical evidence from the meta-analyses in the assessment report suggested that the SES (Cypher) reduces repeat revascularisations compared with the PES (Taxus). Because most of the clinical trials were limited to 6 to 9 months' duration, the Assessment Group carried out the economic evaluation assuming clinical equivalence and distinguished between stents only on the basis of price.
In the additional analyses requested by the Committee, the Assessment Group undertook sensitivity analyses by varying a number of the parameters in the original model. The results of the sensitivity analyses were presented as a number of tables containing the ICERs for a range of price premiums, for a range of absolute risks of revascularisation of BMSs, for the total population of stented patients and the risk-factor groups (small vessel, long lesion, diabetes and all combinations of these). Tables were presented for different numbers of stents (mean number, 1, 2 or 3) per patient. The Assessment Group also undertook new sensitivity analyses that took account of an additional 9 months' use of clopidogrel in patients receiving DESs, in accordance with the recent BCIS recommendations. These additional costs were applied only to 56% of the patient population because it was suggested by Consultees that 44% of patients would have acute coronary syndrome and therefore already be receiving 12 months' treatment with clopidogrel in accordance with 'Clopidogrel in the treatment of non-ST-segment-elevation acute coronary syndrome' (NICE technology appraisal guidance 80).
The Assessment Group, at the request of the Committee, also provided estimates based on the analyses using a relative risk reduction with DESs of 55% as the base case and a sensitivity analysis of 65%. These relative risk reductions with DESs were used for a rate of revascularisation, using BMSs, of 11%, which was obtained from combining results for all patients (equivalent to 10% for elective and 13% for non-elective patients). The corresponding risk of revascularisation using BMSs for the risk groups and the mean number of stents were also calculated from the combined datasets for the elective and non-elective patients.
Following consultation, the Assessment Group provided two additional analyses. The first additional analysis updated the 2003/04 resource costs with reference costs from 2005/06. The waiting times for PCI and CABG were updated from 20 to 20.5 weeks for PCI and from 13 to 20.9 weeks for CABG. The number of patients with acute coronary syndrome was changed from 44% to 48.5%, and consequently the number of patients receiving an extra 9 months' treatment with clopidogrel was reduced from 56% to 51.5%.
In addition to the changes to resource costs, waiting times and number of patients with acute coronary syndrome, the second additional analysis included new parameters based on alternative suggestions from the BCIS. The Assessment Group modified BCIS's suggestion regarding the presentational case-mix. The following parameters were used in the model: the percentages of elective and non-elective patients were changed from 68% to 57% for elective patients and from 32% to 43% for non-elective patients; the absolute risk of revascularisation of BMS for all patients was changed from 11% to 13% by combining 11.5% of elective and 15% on non-elective patients from the Liverpool Cardiothoracic Centre audit dataset; the relative risks for revascularisation in high-risk groups were set to 1.75 for small vessels, 1.35 for long lesions and 1.52 for diabetes; and the relative risk reductions from using DES were set to 60% for all patients; 69% for patients with small vessels; 70% for patients with long lesions and 61% for patients with diabetes.
## Assessment Group model: results
Based on the Liverpool Cardiothoracic Centre audit data, the Assessment Group's original base-case scenario as described in 4.2.20 assumes the overall repeat revascularisation rate for the total population of stented patients in the UK at 12 months after PCI with BMSs is 7.43%. Using 7.43% for all patients, the absolute rates of repeat revascularisation for the risk factors become: 7.8% for long lesions; 9.0% for diabetes; and 9.9% for small vessels. Using the overall mean number of stents implanted per patient from the Liverpool Cardiothoracic Centre audit data (1.615) and assuming a price difference of £600 (approximate average of the price difference of the PES Taxus and the SES Cypher, from the survey data) the resulting incremental costs per QALY for each of the groups of elective patients are approximately: £407,000 for all patients; £380,000 for long lesions; £340,000 for diabetes; and £306,000 for small vessels. Using the overall mean number of stents implanted per patient for non-elective patients (1.467) the resulting incremental costs per QALY for each of the groups, at a price difference of £600, are: £282,000 for all patients; £250,000 for long lesions; £353,000 for diabetes; and £94,000 for small vessels.
Based on the Liverpool Cardiothoracic Centre audit data, the Assessment Group's re-analysis of the base-case scenario assumes an 11% overall revascularisation rate for the total population of stented patients in the UK at 12 months after PCI with BMSs. Using 11% for all patients, the absolute rates of repeat revascularisation for the risk factors become: 11.7% for long lesions; 11.6% for diabetes; and 19% for small vessels. The relative risk reduction with DESs is assumed to be 55%. Using the overall mean number of stents implanted per patient from the Liverpool audit data, both elective and non-elective (1.571) and assuming a price difference of £600 (approximate average of the price difference of the PES and the SES , from the survey data) the resulting incremental costs per QALY for each of the groups of patients are approximately: £213,000 for all patients; £183,000 for long lesions; £180,000 for diabetes; and £146,000 for small vessels. Assuming a price difference of £300 the resulting incremental costs per QALY for each of the groups of patients are approximately: £101,000 for all patients; £85,000 for long lesions; £84,000 for diabetes; and £59,000 for small vessels.
For the Assessment Group's sensitivity analysis for the combined elective and non-elective data, using a relative risk reduction with DESs of 65% and a price difference of £600, the resulting incremental costs per QALY for each of the groups of patients are approximately: £174,000 for all patients; £148,000 for long lesions; £146,000 for diabetes; and £116,000 for small vessels. Assuming a price difference of £300 the resulting incremental costs per QALY for each of the groups of patients are approximately: £78,000 for all patients; £65,000 for long lesions; £64,000 for diabetes; and £41,000 for small vessels.
The Assessment Group's additional analysis as described in 4.2.22, assuming a price difference of £600 for the base case (55% relative risk reduction of DES), results in incremental costs per QALY for each of the groups of patients of approximately: £171,000 for all patients; £158,000 for long lesions; £156,000 for diabetes; and £124,000 for small vessels. Assuming a price difference of £300 the resulting incremental costs per QALY for each of the groups of patients are approximately: £74,000 for all patients; £66,000 for long lesions; £65,000 for diabetes; and £41,000 for small vessels. For the updated Assessment Group's sensitivity analysis (65% for the relative risk reduction of DES) the resulting incremental costs per QALY, for a price difference of £600, for each of the groups of patients are approximately: £137,000 for all patients; £126,000 for long lesions; £124,000 for diabetes; and £95,000 for small vessels. Assuming a price difference of £300 the resulting incremental costs per QALY for each of the groups of patients are approximately: £54,000 for all patients; £47,000 for long lesions; £46,000 for diabetes; and £25,000 for small vessels.
The Assessment Group's second additional analysis, as described in 4.2.23, resulted in incremental costs per QALY for each of the groups of patients, assuming a price difference of £600, of approximately: £111,000 for all patients; £51,000 for long lesions; £53,000 for diabetes; and £59,000 for small vessels. Assuming a price difference of £300 the resulting incremental costs per QALY for each of the groups of patients are approximately: £38,000 for all patients; £3,000 for long lesions; £4,000 for diabetes; and £4,000 for small vessels.
# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of DESs, having considered evidence on the nature of the condition and the value placed on the benefits of DESs by people with coronary artery disease, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources.
The Committee considered the evidence on the clinical effectiveness of DESs in the treatment of CHD. The Committee acknowledged that the clinical trials showed that the use of any-type DESs reduced the rate of revascularisation in the target lesions and the target vessels, at all follow-up time points up to 3 years, compared with any-type BMSs. The Committee noted not just the trial data, but also the recent discussions on the effects of DESs on the risks of thrombosis, MI, and mortality, and accepted the findings of the FDA review that any-type DESs conferred no statistically significant benefits in mortality or acute MI rates over any-type BMSs. The Committee concluded that the key benefit of DESs is the reduction in rates of revascularisation in target lesions and target vessels compared with BMSs.
The Committee considered whether there was any evidence to suggest that there were differences in the clinical effectiveness of the various types of DESs. It noted that only four of the eleven DESs had been compared with each other in head-to-head RCTs. The majority of data comparing revascularisation rates were between the SES (Cypher) and the PES (Taxus). The Committee noted that the SES (Cypher) showed a statistically significant reduction in TLR, TVR and MACEs compared with the PES (Taxus), at 9 months. It was also noted that at 1 year, for the only outcome available, rates of TLR for the SES (Cypher) compared with the PES (Taxus) showed no statistically significant difference. The Committee heard testimony from the clinical specialists that different DESs are clinically comparable and that, in practice, any of the DESs would be used, although those with the greater evidence-base would be first choice.
The Committee considered the evidence to suggest that there were groups of patients whose vessel anatomy was more likely to be subject to restenosis. The absolute rate of revascularisation in these groups was greater than that of other patients and they therefore had the potential to gain a greater relative benefit from DESs than other patients, and this was taken into account by the sensitivity analysis in the assessment group's economic model. The Committee considered the risk factors derived by the Assessment Group using the Liverpool Cardiothoracic Centre audit data, but it heard testimony from the clinical specialists that small vessels (less than 3 mm in calibre), long lesions (longer than 15 mm) and diabetes were the risk factors most consistently reported and that made most sense clinically. The Committee noted that, although the Assessment Group's analysis of the Liverpool Cardiothoracic Centre audit data did not prove that any of these were statistically significant risk factors, taking account of other studies, small-vessel disease and long lesions were better predictors of risk groups than diabetes, and are particularly prevalent in patients with CAD who also have diabetes. The Committee was also mindful of the regulatory concerns about the 'off-label' use of DESs. The Committee concluded that small vessels and long lesions should be considered as separate risk factors whereas diabetes should not be considered as a separate risk factor.
The Committee noted that the Assessment Group's model was based on the Liverpool Cardiothoracic Centre audit data that distinguished elective and non-elective (emergency) patients. The Committee heard testimony from the clinical specialists that in clinical practice the differences between these patient groups specifically related to the mode of their presentation with acute coronary syndromes, that is, non-ST-segment-elevated MI or unstable angina, and to the use of adjunctive treatments, in particular anti-platelet therapy. Due to the lack of other differences the Committee concluded that elective and non-elective patients should be considered together but that the merging of the estimates should take account of the proportions of elective and non-elective patients seen in clinical practice.
In considering the cost effectiveness of DESs compared with BMSs, the Committee noted that the model structure used by the Assessment Group was appropriate. The Committee discussed the key parameters that drove the Assessment Group's economic model. It considered the absolute rate of revascularisation of BMSs in the total population of stented patients and noted that the Assessment Group used 7.43% for patients in its base case in the assessment report. The Committee heard testimony from the clinical specialists that the rate of revascularisation of BMSs was around 12% in the published literature. It noted that some of these published trials included protocol-driven angiography and revascularisation and therefore were likely to be an overestimate of actual revascularisation rates in clinical practice in the UK. The Committee noted that the Liverpool Cardiothoracic Centre audit data revascularisation rates were lower than those from other data sets including the BASKET trial (11%), which had not included protocol-driven angiography, and the Scottish Registry (11.5%). The Committee discussed the range of possible values for revascularisation and their relevance to UK practice and concluded that a rate of 11% for the absolute rate of revascularisation was a reasonable estimate for UK practice.
The Committee considered the relative reduction in the risk of target lesion revascularisation with DESs. The Committee noted that the trial data typically gave a relative risk reduction of 75%, but considered that this figure might over-estimate the real-life benefit of DESs because it is derived from the trials that included protocol-driven angiography and revascularisation. The Committee heard that the BASKET trial, which had not included protocol-driven angiography, had a relative risk reduction with DESs of 41% at 12 months. The Committee looked at the adjusted relative risk reduction with DESs used by the Assessment Group, and acknowledged that their approach reflected the number of patients, and not the target lesions, that would benefit from DESs. The Committee noted that the Assessment Group's figure was in line with the BASKET trial. The Committee heard from the clinical specialists that the most plausible relative risk reduction with DESs from the clinical evidence was likely to be in the range 50% to 60% for the base case and 61% to 70% for high-risk groups. Given the variation in data the Committee considered a relative risk reduction with DESs over BMSs of 55% in the base case, and of 65% in a sensitivity analysis for the higher risk groups were the most plausible.
The Committee considered the mean number of stents used for each of the risk groups from the Liverpool Cardiothoracic Centre audit data and concluded that the estimate of mean number of stents per patient (1.6 for elective patients, 1.5 for non-elective patients) was likely to be a representative figure of the number used in all patients in the UK and could be used as a base case for consideration of the benefits of DESs.
The Committee was mindful of data in the literature on the mortality and morbidity of CABG and repeat angiography. After reviewing the utility values in the Assessment Group's model the Committee acknowledged the possibility that there could be an additional disutility associated with CABG during the initial 6 weeks following the procedure compared with PCI. The Committee accepted the Assessment Group's revisions for this parameter.
The Committee noted the current UK recommendation that clopidogrel should be given for an additional 9 months in patients receiving a DES and it therefore considered it appropriate that this should be taken account of in the cost-effectiveness analysis. The Committee also accepted the consultation suggestions that patients with acute coronary syndrome would already be receiving 12 months' treatment with clopidogrel and that no additional costs would be incurred in this population.
The Committee heard testimony from the clinical specialists and received information during the consultation period that in some areas procurement arrangements had resulted in a price difference of £300 for DESs over BMSs. The Committee also received information that although no nationally procured price currently existed for DESs, price differences that were less than £300 did exist in some regions. The Committee agreed that as this price difference existed in some regions, it was reasonable to assume that DESs could be procured in this way across all regions within the NHS and, therefore, it could be considered as an appropriate costing option in its considerations.
After agreeing on the parameters to use in the Assessment Group's model, the Committee discussed the resulting ICERs for the base case and risk groups, assuming:
the absolute risk of revascularisation with BMSs for the total population is 11%, with resulting risks of revascularisation for small vessels of 19% and for long lesions of 11.7%
the mean number of stents per patient is 1.571
the relative risk reduction with DESs for the base case is 55% for the total population, and 65% for patients with small vessels and long lesions
price differences of DESs over BMSs of £600 and £300. At a relative risk reduction of 55% with DESs, the resulting ICER for the total population of patients was associated with a cost per QALY of approximately £171,000 at a price difference of £600 and £74,000 at a price difference of £300. For the higher risk groups of patients (that is, those with long lesions and those with small vessels) using a DES, with a relative risk reduction of 65%, the resulting ICERs were associated with costs per QALYs of £126,000 and £95,000, respectively, at a price difference of £600 and £47,000 and £25,000, respectively, at a price difference of £300.
Reflecting the testimony of the clinical specialists and the comments received during consultation, the Committee noted the small differences in the key parameters between those that the Committee had previously agreed and those suggested by BCIS. The Committee noted that the ICERs resulting from using the parameter values suggested by the BCIS into the Assessment Group's model for a price difference of £600 were associated with costs per QALYs of approximately: £111,000 for all patients; £51,000 for long lesions; £53,000 for diabetes; and £59,000 for small vessels. For a price difference of £300 the resulting ICERs were associated with costs per QALYs below £5000 for patients with small vessels and long lesions. The Committee was not, however, persuaded that all of the parameter values suggested by BCIS were plausible, but it agreed that the percentages of elective and non-elective patients at presentation should be 57% elective to 43% non-elective. The Committee noted that taking account of this assumption would decrease the ICERs seen in the updated analysis for long lesions and small vessels (see 4.3.12), which means that, at a price difference of £300, the plausible ICERs would be much lower than cost per QALYs of £47,000 and £25,000, respectively.
The Committee agreed that DESs could not be considered a cost-effective use of NHS resources at a price difference of £600. After considering the alternative parameter values presented by the Assessment Group and BCIS, the Committee concluded that on balance at a price difference between DESs and BMSs of not more than £300, DESs could be considered a cost effective option in patients with small vessels and long lesions, and should be recommended for use in these patient groups. The Committee's decision was based on a price difference of £300 between BMSs and DESs. The Committee noted that procurement arrangements for DESs at a price difference of £300 was already in place within many NHS regions and achievable across the NHS as a whole. The Committee understood that the mean absolute price of a BMS, to the NHS, was £131.# Recommendations for further research
The Committee noted that there are a number of trials under way comparing the clinical effectiveness of DESs with their equivalent BMS and/or with other DESs at longer follow-up periods.
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{'Guidance': "Drug-eluting stents are recommended for use in percutaneous coronary intervention for treating stable angina, within their instructions for use, only if:\n\nthe target artery to be treated has less than a 3-mm calibre or the lesion is longer than 15\xa0mm, and\n\nthe price difference between drug-eluting stents and bare-metal stents is no more than £300. For recommendations on drug-eluting stents for people with unstable angina, non-ST-segment-elevation myocardial infarction (NSTEMI) or ST-segment-elevation myocardial infarction (STEMI), see recommendation\xa01.1.18 and recommendation\xa01.2.18 in NICE's guideline on acute coronary syndromes.", 'Clinical need and practice': "Coronary artery disease is also known as coronary heart disease (CHD) and ischaemic heart disease. It is narrowing (stenosis) of the coronary arteries as a result of deposition of atherosclerotic plaque, which results in an insufficient supply of oxygen to the heart muscle. CHD may affect one or more arteries, which may be of different diameters (calibres). The stenosis of arteries may be partial or total. Coronary artery stenosis may be asymptomatic or may lead to angina – chest pain that may be severe enough to restrict or prevent exertion. A critical reduction of the blood supply to the heart may result in myocardial infarction (MI) or death.\n\nMortality rates from CHD are decreasing but CHD remains the most common cause of mortality in the UK. It accounted for nearly 117,500 deaths in the UK in 2002 (about 103,000 deaths in England and Wales). CHD is also the cause of considerable morbidity and loss of ability to lead a normal life. In the UK, annually, approximately 259,500 people experience an acute MI and approximately 341,500 new cases of angina (the most common form of CHD morbidity) are reported. In Europe, CHD has been estimated to account for 9.7% of total disability-adjusted life years lost.\n\nMortality and morbidity rates associated with CHD vary by socioeconomic group (rates are higher in lower socioeconomic groups), by geographical area (rates are highest in Wales, North West England, and the Northern England and Yorkshire regions, and lowest in South East England) and by ethnic group (for example, CHD rates are highest among people from the Indian subcontinent living in the UK). The prevalence of CHD also increases with age and is higher in men than women. The disease is more common in people with high serum cholesterol and/or high blood pressure, in people who have type 1 or type 2 diabetes mellitus, in people who smoke, and in people who are physically inactive and/or obese.\n\nThe symptoms and health risks associated with a stenosed artery may be treated medically, by modifying risk factors (for example, smoking, hyperlipidaemia, obesity and hyperglycaemia) and/or by drug treatment (for example, beta-adrenergic blockers, nitrates, calcium-channel blockers, antiplatelet agents and/or statins).\n\nIf these medical treatments fail or are inappropriate, two invasive therapies are available. The first, coronary artery bypass grafting (CABG), involves major cardiac surgery. The second, balloon angioplasty (or percutaneous transluminal coronary angioplasty) involves a widening from within the artery using a balloon catheter, which is inserted through a femoral artery. When inflated, the balloon increases the calibre of the artery. Most percutaneous transluminal coronary angioplasty procedures involve the use of stents. A stent is a thin wire-mesh tube loaded over an angioplasty balloon. When the balloon inflates, the stent expands like a scaffold to hold the vessel open, and is left behind after the balloon is deflated and withdrawn. Percutaneous coronary intervention (PCI) is a generic term that encompasses percutaneous transluminal coronary angioplasty with or without stenting. The comparison of CABG with PCI including coronary artery stents (bare-metal and drug-eluting) was covered by NICE technology appraisal guidance\xa071 and is not dealt with in this appraisal.\n\nOne of the criteria for comparing the clinical effectiveness of PCI with stents with standard PCI (without stents) is the incidence of subsequent attacks of angina and major adverse coronary events (MACEs), which include death, MI and the need for further revascularisation procedures (CABG or repeat PCI).\n\nA number of problems with PCI may occur. Recoil of the artery which happens when the balloon is deflated, usually occurs immediately or within 24\xa0hours of completing the procedure, and may be associated with acute occlusive dissection of the vessel and require emergency CABG. In the medium term restenosis of the artery after the procedure may occur and has two main causes: contraction of the outer layer of the artery secondary to an injury reaction (3 to 6\xa0months after the procedure) and proliferation of smooth muscle cells within the arterial wall (4 to 6\xa0months after the procedure), leading to intimal hyperplasia. As a consequence of restenosis, a repeat procedure may be required and the rate of reintervention is greater in patients who have arteries of small calibre ('small vessels' – less than 3\xa0mm in calibre), saphenous vein grafts and long lesions (longer than 15\xa0mm) or total occlusions. People with diabetes, who commonly have arteries affected by atherosclerosis, also have a higher rate of restenosis.\n\nStent technology (type and platform, including the design, alloy used and strut thickness) has developed rapidly, and recent advances aim to reduce the likelihood of restenosis. Because restenosis is correlated with the degree of inflammation present at the time of angioplasty, drug-eluting stents (DESs) were developed. These are bare-metal stents (BMSs) coated with a drug, usually an immune suppressant, to reduce inflammation or an antimitotic agent to reduce cell proliferation. The drug reaches therapeutic concentrations in local tissues only and may not be detectable systemically, thus avoiding systemic adverse effects. A subsequent development was the use of a drug–polymer mix where the drug is held temporarily in place within a polymer 'painted' onto the metallic stent, allowing the drug to elute slowly into surrounding tissues. However, not all stents are polymer based.\n\nAccording to British Cardiovascular Intervention Society (BCIS) data, approximately 70,000 PCI procedures were undertaken in the UK in 2005, equating to 1165 per million of the population. In England, the number of procedures per million of the population was 1169, and in Wales, 873.\n\nThe National Service Framework for CHD set a target in March 2000 for revascularisations (PCIs and CABGs), of at least 1500 per million of the population (750 for each type of intervention).\n\nAccording to BCIS data, in the UK, the proportion of PCI procedures using stents rose steeply between 1993 and 1999, from below 10% to nearly 80%. It continued to increase, although more slowly, to about 94% in 2005. Data for DES use were not available before 2002. In 2003 it was reported that 17% of all stents used in the UK were DESs. In 2005 this had risen to around 62% in the UK, 60% in England and 77% in Wales. Given the increases in numbers of PCI procedures, it may be that utilisation rates are now much higher than this.\n\nThere is a risk of stent thrombosis associated with the use of both types of stent (DESs and BMSs). To prevent thrombosis occurring, patients are required to use an antiplatelet drug, such as clopidogrel, in addition to aspirin during and after the implantation of a stent. Following data published in 2006, the US Food and Drugs Administration (FDA)'s Circulatory Devices Systems Advisory Panel recommended that the duration of clopidogrel use should be extended in patients receiving a DES. The American College of Cardiologists/American Heart Association PCI guidelines (also endorsed by the Society for Cardiovascular Angiography Interventions) and the BCIS have recommended that for patients receiving DESs the duration of clopidogrel use should be increased to at least 12\xa0months, after which time continuation of clopidogrel should be reviewed taking into account the risk for further events on an individual patient basis.", 'The technologies': 'This technology appraisal focuses on DESs only. The preceding appraisal of DESs (NICE technology appraisal guidance\xa071) considered only three devices (Taxus, Cypher and Dexamet) because at the time of publication, these were the only DESs that had been granted Conformité Européene (CE) marking for use within EU countries. Eight additional DESs have been included in this appraisal.\n\nEach DES has an instruction for use (IFU) document that includes the indications for which the specific device can be used. The indications for use for each DES vary, although the majority specify the sizes of vessels (diameter and length) to be treated and are in accordance with their CE marking. Also included in the IFU documents are details of side effects and specific contraindications for DESs.\n\nDifferent drugs elute from the stents that are included in this appraisal: paclitaxel is a broad-spectrum antimitotic agent that inhibits cell division; sirolimus (previously known as rapamycin) is an immunosuppressive agent that reduces inflammation; ABT-578 is a synthetic analogue of sirolimus; everolimus is an immunosuppressive agent that is closely related to sirolimus; tacrolimus is an immunosuppressive agent; and dexamethasone is a synthetic adrenocortical steroid that reduces inflammation. These drugs may elute at different rates, depending on the presence or absence of additional polymer coatings on the stent.\n\nThe following list prices for DESs exclude VAT.\n\nThe DES Axxion (Biosensors Limited) is a non-polymeric paclitaxel-eluting stent (PES) with a list price of £995 (BMS equivalent: Nexus).\n\nThe DES CoStar (Biotronik Limited) is a non-polymeric PES (BMS equivalent: DepoStent). CoStar was originally included in this appraisal but is no longer available.\n\nThe DES Taxus (Boston Scientific) is a polymeric PES with a list price of £1300 (BMS equivalent: Express).\n\nThe second-generation DES Taxus Liberté (Boston Scientific) is a polymeric PES with a list price of £1300 (BMS equivalent: Liberté).\n\nThe DES Cypher (Cordis Corporation) is a polymeric sirolimus-eluting stent (SES) with a list price of £1340 (BMS equivalent: Bx Velocity).\n\nThe second-generation DES Cypher Select (Cordis Corporation) is a polymeric SES with a list price of £1340 (BMS equivalent: Sonic).\n\nThe DES Endeavor (Medtronic AVE) is a polymeric sirolimus analogue ABT‑578 (zotarolimus)-eluting stent (ZES) with a list price of £1450 (BMS equivalent: Driver).\n\nThe DES Janus (Sorin) is a polymeric tacrolimus-eluting stent (TES) with a list price of £1500 (BMS equivalent: Janis).\n\nThe DES Xience V (Guidant Ltd) is a polymeric everolimus-eluting stent (EES) with a list price of £1500 (BMS equivalent: Multi-Link Vision).\n\nThe DES Dexamet (Abbott Vascular Devices Ltd) is a polymeric dexamethasone-eluting stent (BMS equivalent: BiodivYsio). Dexamet was originally included in this appraisal but is no longer available in the EU.\n\nThe DES Yukon (Kiwimed Ltd) is a non-polymeric stent that can be coated with any drug to be eluted and has a list price of £650.\n\nAs list prices are not commonly used for procuring devices in the NHS, updated prices of DESs and BMSs were sought from the NHS Purchasing and Supply Agency. Procurement of devices is complex and it should be noted that the prices for DES and BMS are driven by a number of factors including the: market conditions at the time of contracting; contract period; renewal date for the procurement arrangements (contracts are usually updated annually and the most recent contracts show significant decreases in the prices of DESs); volume commitment; period commitment; combination of period and volume commitment; product rationalisation or standardisation; retrospective threshold discounts (for example, free set quantities of stents when agreed volumes have been exceeded); consignment stock (for instance, when a supplier provides an inventory to trust); and other added value inclusive arrangements (for example, the provision of additional training and related equipment).\n\nFrom the sample 2007/08 data received from the NHS Purchasing and Supply Agency for NHS organisations in England for the stents included in this appraisal, the mean price of DES was £529 and the mean price of BMS was £131. The price difference between DESs compared with BMSs ranged from £203 to £615 across a number of Health Authorities in England, although it should be noted that the higher price differences tended to be seen in the older contracts which will\xa0be re-tendered\xa0in due course, in accordance with relevant contract renewal schedules.', 'Evidence and interpretation': "The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).\n\n# Clinical effectiveness\n\n## DESs versus BMSs – evidence from randomised controlled trials\n\nA total of 17 randomised controlled trials (RCTs) were identified that compared DESs with BMSs, and data from all 17 were included for at least one outcome in the meta-analysis.\n\nstudies compared an SES (Cypher) with the equivalent BMS.\n\nFour studies compared a PES (Taxus) with the equivalent BMS.\n\nOne study compared both an SES (Cypher) and a PES (Taxus) with a newer BMS.\n\nOne study compared the ZES (Endeavor) with the equivalent BMS.\n\nOne study compared the EES (Xience V) with the equivalent BMS.No RCT evidence has yet been reported for the Axxion, CoStar, Dexamet or Janus stents. Limited RCT data were available for the Yukon stent.\n\nStudy outcomes used in the RCTs included rates of mortality, acute MI, target lesion revascularisation (TLR), target vessel revascularisation (TVR), composite events (major adverse coronary event [MACE] and/or target vessel failure [TVF]), angiographic binary restenosis and late luminal loss. Revascularisation was usually prompted by protocol-driven angiographic evidence of restenosis either for all participants or for a selected subgroup of participants. Only one trial (BASKET) explicitly reported that no protocol-driven angiographic follow-up was included. This trial compared both SES (Cypher) and PES (Taxus) DESs with a newer BMS in a three-arm study.\n\nAll but three of the 17 RCTs were multicentre trials. Study size ranged from 60 to over 1300 patients. Of the 17 trials, 11 included patients with single lesions. The studies covered a range of vessel diameters from 2.25\xa0mm to 4.00\xa0mm, although the lower range was not reported in some studies. Lesion length also varied, ranging from 10\xa0mm to 33\xa0mm, although again the data were not always reported. All studies permitted the inclusion of people with diabetes, and all but three studies excluded acute or evolving MI. The presence of unprotected left main coronary artery excluded patients from many trials, as did severe calcification or tortuosity, total occlusion, bifurcation, the presence of thrombus in the target vessel, previous PCI within 30\xa0days or PCI other than balloon required as part of the study intervention.\n\nA total of 12 trials described the co-therapies used. Aspirin was prescribed before intervention in 11 of these studies and used after the procedure in all 12. Clopidogrel was used as an antiplatelet therapy in all of the 12 studies; ticlopidine was available for use as an alternative to clopidogrel in five studies. In one trial, tirofiban, used in combination with a DES, was compared with abciximab used with a BMS. The duration of antiplatelet therapy after intervention ranged from 2\xa0months in three trials to 1\xa0year in one\xa0study.\n\nMeta-analysis was carried out by the Assessment Group for rates of mortality, acute MI, TLR, TVR, composite event (MACE and/or TVF), angiographic binary restenosis and late luminal loss. Analysis of mortality, acute MI and event rates used pooled results from over 7000 participants. Data in the form of an odds ratio (OR) and 95% confidence interval (95% CI) were analysed using the Mantel–Haenszel method fixed-effect model. For continuous outcomes, weighted mean differences (WMDs) were analysed. Where there was significant heterogeneity, analysis using a random-effects model was also undertaken.\n\nIn addition to analyses of the individual studies, pooled estimates (giving the OR and 95% CI) were provided for each 'eluted drug' group (for example, comparing a PES [Taxus] and all BMSs in the paclitaxel studies). Data related to the SES (Cypher) and the sirolimus-analogue stent, ZES (Endeavor) in some instances were pooled and presented as pooled SES results. All eluted drug group results were also pooled to obtain estimates for a meta-analysis of any-type DESs compared with any-type BMSs. The meta-analysis was performed for available data at follow-ups of up to 1\xa0month, 6 to 9\xa0months, 1\xa0year, 2\xa0years and 3\xa0years. The Assessment Group assumed, when making decisions about the appropriateness of combining data, that all BMSs are similar and, likewise, all DESs are similar except in the drug delivered; and that the stent design and the insertion system do not have an impact on clinical outcomes.\n\nFor rates of mortality and rates of acute MI, one study found a statistically significant difference in favour of the SES (Cypher) compared with the BMS for MI at 6 to 9\xa0months (OR 0.19, 95% CI 0.04, 0.87). There were no statistically significant differences between the DES and the BMS in the individual studies for all other follow-up periods analysed to 3\xa0years. There were no statistically significant differences between the DES and the BMS for the pooled eluted drug groups (PES [Taxus] and pooled SESs) and for the pooled analyses of any-type DES compared with any-type BMS for any of the follow-up periods.\n\nFor event rate (MACE and TVF), the individual studies of PES (Taxus), SES (Cypher) and ZES (Endeavor), and the pooled eluted drug groups analysis showed statistically significant differences in favour of DESs over BMSs. This was also the case for the overall meta-analysis, which favoured any-type DESs over any-type BMSs at all follow-up time points: 6 to 9\xa0months (OR 0.46, 95% CI 0.40 to 0.53), 1\xa0year (OR\xa00.39, 95% CI 0.33 to 0.47), 2\xa0years (OR 0.43, 95% CI 0.34 to 0.54) and 3\xa0years (OR 0.42, 95% CI 0.32 to 0.55). Statistical heterogeneity was indicated at the 6 to 9\xa0months follow-up; a random-effect analysis for this time point showed only a small effect on the OR (OR 0.44, 95% CI 0.36 to 0.54). The difference between the EES (Xience V) and the BMS was not statistically significant at the only follow-up period (6 to 9\xa0months).\n\nFor TVR, not all individual studies of PES (Taxus) showed statistical significance compared with BMSs for all time periods up to 3\xa0years. The individual studies for SESs (Cypher) and ZESs (Endeavor) all showed statistical significance over BMSs up to 3\xa0years. The pooled eluted drug groups analysis showed statistically significant differences in favour of a PES (Taxus) over BMSs at follow-up time points up to 2\xa0years: 6 to 9\xa0months (OR 0.54, 95% CI 0.43 to 0.68), 1\xa0year (OR\xa00.40, 95% CI 0.29 to 0.55) and 2\xa0years (OR 0.45, 95% CI 0.34 to 0.59). At 3\xa0years, the difference was no longer statistically significant, but the data at this time point were derived from a single, relatively small study that may have been underpowered. TVR data for a SES (Cypher) versus a BMS were available for two trials at 6 to 9\xa0months and for single trials at 1 and 3\xa0years. These showed statistically significantly differences in favour of the SES (Cypher) compared with the BMS at: 6 to 9\xa0months (OR 0.33, 95% CI 0.18, 0.62), 1\xa0year (OR\xa00.34, 95% CI 0.19 to 0.60) and 3\xa0years (OR 0.35, 95% CI 0.25 to 0.49). TVR data for the ZES (Endeavor) at 6 to 9\xa0months, the only time period available, was statistically significant in favour of the ZES over the BMS (OR 0.41, 95% CI 0.27 to 0.63). There were no data for EES (Xience V) for this outcome measure.\n\nRates of revascularisation (TLR) at 1\xa0year for procedures carried out with a DES within individual trials were less than 5%, and typically in the 10% to 25% range for procedures that used a BMS. For example, in three trials of PES (Taxus), the rates were 0%, 4.7% and 4.2% for the DES compared with 10.0%, 12.9% and 14.7% for the BMS, respectively. Rates at 1\xa0year in three trials of a SES (Cypher) were 4.6%, 0% and 4.9% for the DES compared with 24.9%, 13.6% and 20.0% for the BMS, respectively. For TLR, the pooled eluted drug groups analysis showed statistically significant differences in favour of a PES (Taxus) over BMSs at follow-up periods of up to 2\xa0years: 6 to 9\xa0months (OR 0.37, 95% CI 0.28 to 0.49), 1\xa0year (OR 0.26, 95% CI 0.18 to 0.39) and 2\xa0years (OR 0.28, 95% CI 0.20 to 0.40). At 3\xa0years, the difference was no longer statistically significant, but the data at this time point were derived from a single, relatively small study that may have been underpowered. TLR data for a SES (Cypher) showed it to be statistically significantly more effective than a BMS at all time points up to 3\xa0years: 6 to 9\xa0months (OR\xa00.21, 95% CI 0.15 to 0.30), 1\xa0year (OR 0.17, 95% CI 0.12 to 0.25), 2\xa0years (OR 0.22, 95% CI 0.15 to 0.30) and 3\xa0years (OR 0.25, 95% CI 0.17 to 0.36). The data for the ZES (Endeavor) at the follow-up period of 6‑9\xa0months showed it to be statistically significantly more effective than the BMS (OR 0.35, 95% CI 0.22, 0.56). Lower rates of TLR (3.8% versus 21.4%) were apparent for the EES (Xience V) group at 6\xa0months (the only follow-up period) but the difference was not statistically significant. For TLR, the meta-analyses showed statistically significant differences in favour of any-type DES over any-type BMS, with improved rates of lesion revascularisation at all follow-up time points up to 3\xa0years: 6 to 9\xa0months (OR 0.30, 95% CI 0.25 to 0.37), 1\xa0year (OR 0.21, 95% CI 0.16 to 0.27), 2\xa0years (OR 0.24, 95% CI 0.19 to 0.31) and 3\xa0years (OR\xa00.25, 95% CI 0.17 to 0.35).\n\n## DES versus BMS – DESs with non-RCT data\n\nThe TES (Janus) was examined in a non-controlled study as was the PES (Taxus Liberté). A range of formulations of the PES (CoStar) was evaluated in two non-randomised controlled studies, and the Yukon DES was evaluated in a dose-ranging non-randomised controlled study comparing Yukon coated with sirolimus with the same stent carrying no drug. The Dexamet DES was studied in one non-randomised study of Dexamet compared with a BMS and four non-controlled studies (including two registries).\n\nOutcome data were limited due to the short follow-up periods: 30\xa0days for the PES (Taxus Liberté) study; 4\xa0months for one PES (CoStar) study and 1\xa0year for the other PES (CoStar) study; 6\xa0months for the Dexamet studies and for the TES stent; and up to 1\xa0year for the SES (Yukon) study. Angiographic outcomes, binary restenosis and/or late loss were reported for the PES (CoStar), Dexamet and the SES (Yukon). Because of the variety of DESs considered in these studies, the methodological limits of the available studies, and the varied and limited follow-up, the Assessment Group did not consider pooled analysis to be appropriate.\n\nFor the TES (Janus), limited data were reported; at 30\xa0days no events (death, MI or TLR) had occurred. For the PES (Taxus Liberté) the data available at 30\xa0days were marked as commercial in confidence. For the PES (CoStar), the only data available were for one of the two arms at 1\xa0year for one trial and interim data from two of the four arms of the other ongoing study.\n\nData for the SES (Yukon) were reported at 1\xa0month and 1\xa0year. No deaths occurred in the first month. Rates of acute MI up to 1\xa0month were 1.8% in the SES group and 1.3% in the BMS group. At 1\xa0year, the composite of death or non-fatal MI was 2.7% for the Yukon SES and 3.9% for the BMS. No statistically significant differences were detected. At 1\xa0year, TLR was reported in 12.6% of the SES group and 21.5% of the BMS group, and the difference was statistically significant in favour of the SES (OR 0.53, 95% CI 0.34 to 0.81).\n\nThe non-randomised trial that compared Dexamet (DES) with a BMS reported no deaths among the 100 participants receiving either stent and only one incidence of acute MI, which was in the BMS group, up to a mean of 8\xa0months' follow-up. Revascularisations for this time period were 2% TLR in the DES group and 10% TLR (12% TVR) in the BMS group. Composite rates of MACEs, consisting entirely of revascularisations, were 2% for the DES and 12% for the BMS. Neither of these comparisons showed statistically significant differences.\n\n## DES versus DES\n\nEight RCTs comparing different DES types were identified by the Assessment Group. Six RCTs compared a SES (Cypher) with a PES (Taxus) (including one trial that was also assessed in the DES versus BMS clinical section because it had a BMS arm as well as two DES arms), one studied SES (Cypher) in comparison with the newer SES (Cypher Select) and one compared the Yukon, as a SES, with a PES (Taxus).\n\nSix trials were conducted in only one or two centres in European countries, and two were multicentre and multinational. Study sizes ranged from 200 to 1350 patients. Two trials were distinct in that they did not incorporate planned angiographic assessment of trial participants. Only two trials presented randomisation details and none of the studies presented adequate information on whether the RCTs were conducted under 'blind' conditions. One study did not present an intention-to-treat analysis, and for two studies it was unclear whether events were reported according to the original randomised allocations.\n\nA meta-analysis was conducted according to which pairing of DES types was compared within trials (most commonly this was the SES [Cypher] versus the PES [Taxus]). No total pooled effect estimate was calculated across multiple groupings of DES versus DES trials.\n\nThere were no statistically significant differences in rates of mortality or acute MI for any of the pairings of DES types.\n\nFor TLR, one individual study showed a statistically significantly better rate of TLR, at 6 to 9\xa0months, with the SES (Cypher) compared with the PES (Taxus) (OR 0.56, 95% CI 0.33 to 0.93). Only one RCT had data available beyond 9\xa0months; in this study, rates of TLR at 1\xa0year were 5.7% for the SES (Cypher) compared with 9.0% for the PES (Taxus); the difference was not statistically significant. The Assessment Group's pooled analysis of TLR up to 9\xa0months was statistically significant in favour of the SES (Cypher) over the PES (Taxus) (OR 0.70, 95% CI 0.51 to 0.97).\n\nA statistically significant reduction in TVR with the SES (Cypher) compared with the PES (Taxus) was determined from a meta-analysis of two trials at 6 to 9\xa0months (OR 0.59, 95% CI 0.39 to 0.89). A reduction in the composite event rate (MACE) at 6 to 9\xa0months was also statistically significant with the SES (Cypher) compared with the PES (Taxus) (OR 0.75, 95% CI 0.59 to 0.96).\n\n## Effects of DESs on the risks of thrombosis, MI and mortality\n\nIn December 2006, following publication of data on longer-term risks associated with DES (thrombosis, MI and mortality), the FDA convened a public meeting of its Circulatory System Devices Advisory Panel to review and analyse the available data and to provide recommendations for appropriate actions to address this issue. In January 2007, the Circulatory System Devices Advisory Panel made recommendations to the FDA. The Panel stated, 'When the DES, which are indicated for use in the USA (SES [Cypher]) and (PES [Taxus]), are used in accordance with their approved indications both are associated with a small increase in stent thrombosis compared with BMS at 1\xa0year after stent implantation; the increased risk of stent thrombosis was not associated with an increased risk of death or MI compared with BMS; and the concerns about thrombosis do not outweigh the benefits of DES compared with BMS when DES are implanted within the limits of their approved indications for use.' The FDA stated that a longer duration of antiplatelet therapy may be beneficial, and this has led to the recommendation in the PCI guideline of the American College of Cardiologists/American Heart Association (endorsed by the Society for Cardiovascular Angiography Interventions) that in patients receiving DESs the duration of clopidogrel use should be increased to 12\xa0months. The BCIS has also recommended 12\xa0months' use of clopidogrel in patients receiving a DES.\n\nThe Circulatory System Devices Advisory Panel also considered use of DESs in patients with more complex coronary lesions than those studied to support initial marketing approval ('off-label' use). The Panel agreed that use of DESs 'off-label' is associated with an increased risk of stent thrombosis, MI or death compared with 'on-label' use, and until more data are available DES labels (IFUs) should state that when DESs are used off-label, patient outcomes may not be the same as the results observed in the clinical trials conducted to support marketing approval. The FDA has since defined off-label use to mean the use of a medical product for treatments other than those for which the product was initially approved; or use not explicitly included in product labelling (intended use and IFU). The UK Medicines and Healthcare Products Regulatory Agency (MHRA) supports this definition of off-label use for the DESs that have been approved for use in Europe.\n\nEach DES included in this appraisal has an IFU document that lists the indications for which it can be used. The sizes of vessels (diameter and length) to be treated are stated in the majority of the IFUs, as are the specific contraindications. The FDA considers that although patients with diabetes were included in the pivotal trials, the number of patients was insufficient for either the SES (Cypher) or the PES (Taxus) to earn a specific labelled indication for people with diabetes. The UK MHRA supports the view of the FDA with regard to individuals with diabetes and only one of the DESs, the PES (Taxus), included in this appraisal has recently been specifically indicated for people with diabetes.\n\n## Summary\n\nThere were no statistically significant differences detected in death or MI between the pooled subgroups and pooled any-type DES groups. The pooled DES analysis indicated that revascularisation rates were reduced by approximately three quarters compared with BMSs, consistent across most studies of the PES (Taxus) and SESs (Cypher; Endeavor at 6 to 9\xa0months). The benefits of DESs over BMSs for TLR were seen at 1\xa0year, and this significant difference was maintained for up to 3\xa0years. For the TVR outcome there were statistically significant differences in favour of any-type DES over BMS for most of the time points assessed.\n\n# Cost effectiveness\n\n## Published literature\n\nA total of 10 full economic evaluations were included in the assessment report, all of which compared an SES with a BMS, although four evaluations also included a PES. One of the evaluations was conducted in the UK; the rest were conducted in the USA, Canada or the rest of Europe. Seven evaluations used a 1-year time horizon, one used 2\xa0years, one used 6\xa0months and one used a patient's lifetime. Of the 10 evaluations, nine estimated that the cost of DESs incurred a price premium/difference (the difference in cost between a given BMS and the drug-eluting equivalent), which ranged from £233 to £1225. Four of the evaluations reported health outcomes in terms of quality-adjusted life years (QALYs). Three evaluations provided incremental costs per QALY for a general population, and these costs ranged from US$27,450 to Can$96,523 (approximately US$93,000). The fourth evaluation did not include a general population because subgroups were found to be too dissimilar for comparison. Two evaluations reported the incremental cost-effectiveness ratio (ICER) per repeat revascularisation avoided; one estimated it to be US$1650 over 1\xa0year and the other estimated it to be approximately US$7000 over 2\xa0years. The majority of evaluations concluded that DESs are more cost effective than BMSs for patients with types of arteries that have a higher risk of restenosis, although there was great disparity between evaluations, with a variety of outcomes and a range of ICERs being reported.\n\nOnly one economic study, carried out alongside the BASKET RCT, reflected clinical practice because no protocol-driven angiographic follow-up was included. This study's results suggested that, at a threshold of €7800 per MACE avoided, DESs could potentially be cost effective in the following subgroups of patients: those older than 65\xa0years; those with more than one segment treated; those with triple-vessel disease; those with a stent length of more than 20\xa0mm; and those with small stent diameters.\n\n## Manufacturers' economic models\n\nThree models were submitted by DES manufacturers.\n\nThe decision analytic model from Boston Scientific compared the PES (Taxus) with the equivalent BMS, for a general population and for subgroups. The incremental costs per QALY at 1\xa0year were given as £29,587 for the overall population and £1020 for patients with diabetes. For patients with small vessels and long lesions, the PES (Taxus) was dominant (both more effective and less costly than the BMS). For the PES (Taxus) at 2\xa0years, the incremental cost per QALY for the overall population was given as £13,394, and it was dominant for patients with small vessels and those with diabetes. The model was highly sensitive to variations in the duration of clopidogrel therapy and the average number of stents used. In the manufacturer's sensitivity analyses, when the number of stents used per procedure was increased from 1.4 to 1.7, in line with the Assessment Group's model, the estimated cost per QALY at 1\xa0year for the overall population increased to £56,731; however, the subgroup estimates were only marginally increased. If the duration of clopidogrel therapy after DES implantation was increased from 6 to 12\xa0months, the cost per QALY at 12\xa0months increased to £71,634 for the total population and to over £30,000 for the subgroup with diabetes.\n\nThe decision analytic model from Cordis compared the SES (Cypher) with the equivalent BMS for a 'no-risk-factor' population and for subgroups. The model was split into a two-way analysis of the BMS versus the SES (Cypher) and a three-way analysis of the BMS versus the PES (Taxus) versus the SES (Cypher). In extending the three-way analysis to 2\xa0years, an indirect comparison was undertaken that made an assumption that the BMSs in both trials (Boston Scientific and Cordis BMS) are equivalent. The cost data for the technologies (the BMS and Taxus) were considered by the Assessment Group to be overestimated and when the Assessment Group re-ran the model increasing the SES (Cypher) price premium over the equivalent BMS from £433 to £695, the incremental cost per QALY increased from £29,259 to £69,613 for the 'no risk factor' subgroup; from £10,178 to £39,508 for the small-vessels subgroup; from £16,460 to £49,345 for the long-lesions subgroup; and from £9702 to £38,446 for the group with diabetes.\n\nThe Markov model presented by Medtronic compared the ZES (Endeavor [sirolimus analogue ABT-578]) with Medtronic's comparable BMS, for a total population. The submission measured costs and benefits at 5\xa0years, extrapolating the 9-month trial data. In one scenario, the two arms were assumed to be equivalent in terms of risk of repeat revascularisations after 1\xa0year. The incremental cost per QALY was estimated at £11,220. No subgroup analyses were undertaken. The Assessment Group found the model to be highly sensitive to baseline TVR rates and the number of index stents used. If baseline TVR rates were reduced below 12% (for both the BMS and the ZES), then the ICER exceeded £30,000. If the average number of stents used for the index procedure was increased to 1.4, the ICER increased to £39,174. The Assessment Group noted that the two factors to which the model was sensitive were taken from a single positive trial.\n\nThe submission from Kiwimed compared an SES (Yukon) with the Kiwimed BMS for a total population. The effectiveness data were taken from the SES (Cypher) trials, so an untested assumption was made that the SES (Yukon) has equivalent effectiveness to the SES (Cypher). Extrapolation from 2 to 5\xa0years was undertaken using an assumption that patients remained in the same health state that they were in at the end of 1\xa0year. Kiwimed's submission stated that the model results indicated that the SES (Yukon) was dominant compared with the BMS in the total population. In a sensitivity analysis varying the cost of the stent and the probability of restenosis, the ICERs for the SES (Yukon) were always under £30,000 per QALY.\n\n## Assessment Group model: methods\n\nThe Assessment Group's model used the framework from the original appraisal with some minor modifications as follows: the time horizon was restricted to 1\xa0year, so no discounting was necessary; particular risk groups were examined; in addition to the modelling of any-type DES compared with BMS, some head to head comparisons were conducted (SES (Cypher) compared with the PES (Taxus).\n\nA difference between the effectiveness of DES and BMS was only seen with regard to revascularisation (TLR and TVR) and event rate (MACE and TVF). For these endpoints, the clinical trials show evidence of differences between DESs and BMSs at 1\xa0year. The clinical trials show evidence in favour of DESs over all follow-up periods up to 3\xa0years with a trend towards the greatest benefit occurring within the first year.\n\nIn the Assessment Group's model the most important factors in determining the incremental cost were the additional cost per DES implanted (price premium/difference) and the number of stents implanted per patient. The most important factors in determining benefit in the model were the absolute risk of revascularisation for patients treated with a BMS and the risk reduction attributable to the use of a DES.\n\nThe acquisition cost of a given stent may vary in different settings because of negotiated procurement discounts. The Assessment Group in their economic evaluation used the prices from a market survey of NHS purchasers. The survey was conducted by the NHS Purchasing and Supply Agency in May/June 2005 to identify the prices in contracts covering the period 2004/05 for both DESs and BMSs. The combined data from 12 purchasing bodies covering 20 hospital trusts provided consistent estimates of average unit prices and of the differences in price between DESs and BMSs. Results were provided for the two main suppliers of DESs: Boston Scientific (Taxus) and Cordis Corporation (Cypher). The effective sale price per Taxus PES (excluding VAT) was £815. Because there was only one recorded instance of a significant local volume discount agreement for Cypher in the survey, the average sample price for the Cypher SES (excluding VAT) was £937. The estimated average price for a BMS in the survey (excluding VAT) was £278, so the price differences are £537 and £659 per DES for Taxus and Cypher, respectively.\n\nInformation received during the consultation period for the appraisal consultation document suggested that the prices for DESs had decreased since the 2005 survey. Therefore updated prices were sought from the NHS Purchasing and Supply Agency. From the sample 2007/08 data received from the NHS Purchasing and Supply Agency for NHS organisations in England for the stents included in this appraisal, the mean price of DES was £529 and the mean price of BMS was £131. The price difference between DESs compared with BMSs ranged from £203 to £615 across a number of Health Authorities in England.\n\nTo calculate the PCI procedure costs it was necessary to subtract the included costs of stents (DES and BMS) from the published PCI costs, and then to add back the model estimates of the number of stents, the type of stent and the cost per stent. In the final analyses, the Assessment Group assumed a wastage rate of 1%.\n\nThe Assessment Group base-case analysis used results from two observational studies of stented patients treated at the Liverpool Cardiothoracic Centre, to convert the efficacy of any-type DES to effectiveness estimates for repeat revascularisations and lesions treated in repeat revascularisations. The Assessment Group found that 51% of patients who underwent a second PCI required repeat treatment to previously treated lesions only. An additional 17% of patients received repeat treatment to a target lesion at the same time as treatment to a previously untreated lesion in the same vessel; these are the patients in whom DESs can be expected to produce benefit. Applying these proportions to the relative risk reduction from the trials of 74.6% (for TLR obtained from the meta-analysis of any-type DES trials) yielded an expected risk reduction in all revascularisations at 12\xa0months of between 38% (95% CI 32 to 44%) and 50% (95% CI 44 to 57%). The Assessment Group also considered the likely benefit that any-type DES may offer in reducing the number of lesions treated in repeat revascularisations. When applied to the TLR relative risk reductions from the meta-analysis, this suggested that the reduction in the number of lesions treated in subsequent interventions was between 37% (95% CI 31 to 42%) and 53% (95% CI 47 to 59%) based on TLR (the Assessment Group counted lesions treated but excluded cases undergoing CABG rather than PCI). The Assessment Group noted that the BASKET trial, which did not include protocol-driven angiography, reported a risk reduction for DESs of 41% at 6\xa0months. The Assessment Group therefore used 41% for the risk reduction associated with DESs in its base-case analyses.\n\nThe Assessment Group stated that the ICERs of any-type DESs compared with any-type BMSs are very dependent on the estimates of relative risk reduction in revascularisations and on the absolute rate of revascularisation in the types of patients in whom they are used. The absolute rates of revascularisation were derived from the Liverpool Cardiothoracic Centre audit data, and the potential of benefit was reassessed on the basis of the audit data concerning those patients in whom the repeat procedure required treatment of new lesions. This resulted in an absolute rate of revascularisation for all patients of 7.43%. The Assessment Group also carried out sensitivity analyses, varying rates of revascularisation for all patients up to 13%, based on trial data.\n\nUsing the Liverpool Cardiothoracic Centre audit data, the Assessment Group developed separate risk models for elective and non-elective patients using patient and lesion characteristics known at the time of the index intervention. Risk factors for the patients were identified in the assessment report as being calcification, angulation greater than 45 degrees, restenotic lesion, triple-vessel disease, vessel diameter of less than 2\xa0mm and prior CABG. In the final analyses, the absolute rates of repeat revascularisations for the conventional risk factors (long lesions, small vessels, diabetes and all combinations of these) were provided using the Liverpool audit data. The Assessment Group stated that, because none of these three factors in the multivariate model achieved conventional significance using the Liverpool audit data, the individual relative risks have wide confidence intervals and should be considered only as illustrative. The mean 12-month repeat revascularisation rate for all patients with small vessels was 15.25% (95% CI 9.38% to 22.24%), with a rate difference p\xa0=\xa00.02; for those with long lesions it was 10.23% (95% CI 8.10% to 12.57%), p\xa0=\xa00.09; and for those with diabetes it was 10.61% (95% CI 7.52% to 14.14%), p\xa0=\xa00.14.\n\nThe Assessment Group used patient survey data from the Health Outcomes Data Repository (HoDAR) database for its utility values. The difference in HoDAR health-related quality of life scores between patients with severe angina and those recovered from revascularisation (0.158) was similar to the ARTS trial result (0.16), which was used in the previous appraisal. The assumptions made by the Assessment Group in the final analyses for disutilities associated with CABG versus PCI in the 6-week period following the procedure were that for a 2-week post-operative period, patients undergoing CABG experience a very low quality of life (0.0), and for the next 2\xa0weeks the mean utility score recovers in a linear fashion achieving full benefit (0.660) by 4\xa0weeks after the operation. Patients undergoing PCI were assumed to recover full benefit linearly over a 2-week period following the procedure. The Assessment Group concluded additionally that there was no evidence to suggest an effect on the rate of acute MI or mortality with CABG compared with PCI plus stenting.\n\nWhen BMSs and DESs were compared, the meta-analysis showed a trend towards increased numbers of non-fatal acute MIs with BMSs. The Assessment Group concluded in their analyses that based on the reviewed evidence, the maximum likely effect of this is equivalent to, per patient, an overall cost saving of about £13 and a utility gain of about 0.00055 when DESs are used.\n\nThe clinical evidence from the meta-analyses in the assessment report suggested that the SES (Cypher) reduces repeat revascularisations compared with the PES (Taxus). Because most of the clinical trials were limited to 6 to 9\xa0months' duration, the Assessment Group carried out the economic evaluation assuming clinical equivalence and distinguished between stents only on the basis of price.\n\nIn the additional analyses requested by the Committee, the Assessment Group undertook sensitivity analyses by varying a number of the parameters in the original model. The results of the sensitivity analyses were presented as a number of tables containing the ICERs for a range of price premiums, for a range of absolute risks of revascularisation of BMSs, for the total population of stented patients and the risk-factor groups (small vessel, long lesion, diabetes and all combinations of these). Tables were presented for different numbers of stents (mean number, 1, 2 or 3) per patient. The Assessment Group also undertook new sensitivity analyses that took account of an additional 9\xa0months' use of clopidogrel in patients receiving DESs, in accordance with the recent BCIS recommendations. These additional costs were applied only to 56% of the patient population because it was suggested by Consultees that 44% of patients would have acute coronary syndrome and therefore already be receiving 12\xa0months' treatment with clopidogrel in accordance with 'Clopidogrel in the treatment of non-ST-segment-elevation acute coronary syndrome' (NICE technology appraisal guidance\xa080).\n\nThe Assessment Group, at the request of the Committee, also provided estimates based on the analyses using a relative risk reduction with DESs of 55% as the base case and a sensitivity analysis of 65%. These relative risk reductions with DESs were used for a rate of revascularisation, using BMSs, of 11%, which was obtained from combining results for all patients (equivalent to 10% for elective and 13% for non-elective patients). The corresponding risk of revascularisation using BMSs for the risk groups and the mean number of stents were also calculated from the combined datasets for the elective and non-elective patients.\n\nFollowing consultation, the Assessment Group provided two additional analyses. The first additional analysis updated the 2003/04 resource costs with reference costs from 2005/06. The waiting times for PCI and CABG were updated from 20 to 20.5 weeks for PCI and from 13 to 20.9 weeks for CABG. The number of patients with acute coronary syndrome was changed from 44% to 48.5%, and consequently the number of patients receiving an extra 9\xa0months' treatment with clopidogrel was reduced from 56% to 51.5%.\n\nIn addition to the changes to resource costs, waiting times and number of patients with acute coronary syndrome, the second additional analysis included new parameters based on alternative suggestions from the BCIS. The Assessment Group modified BCIS's suggestion regarding the presentational case-mix. The following parameters were used in the model: the percentages of elective and non-elective patients were changed from 68% to 57% for elective patients and from 32% to 43% for non-elective patients; the absolute risk of revascularisation of BMS for all patients was changed from 11% to 13% by combining 11.5% of elective and 15% on non-elective patients from the Liverpool Cardiothoracic Centre audit dataset; the relative risks for revascularisation in high-risk groups were set to 1.75 for small vessels, 1.35 for long lesions and 1.52 for diabetes; and the relative risk reductions from using DES were set to 60% for all patients; 69% for patients with small vessels; 70% for patients with long lesions and 61% for patients with diabetes.\n\n## Assessment Group model: results\n\nBased on the Liverpool Cardiothoracic Centre audit data, the Assessment Group's original base-case scenario as described in 4.2.20 assumes the overall repeat revascularisation rate for the total population of stented patients in the UK at 12 months after PCI with BMSs is 7.43%. Using 7.43% for all patients, the absolute rates of repeat revascularisation for the risk factors become: 7.8% for long lesions; 9.0% for diabetes; and 9.9% for small vessels. Using the overall mean number of stents implanted per patient from the Liverpool Cardiothoracic Centre audit data (1.615) and assuming a price difference of £600 (approximate average of the price difference of the PES Taxus and the SES Cypher, from the survey data) the resulting incremental costs per QALY for each of the groups of elective patients are approximately: £407,000 for all patients; £380,000 for long lesions; £340,000 for diabetes; and £306,000 for small vessels. Using the overall mean number of stents implanted per patient for non-elective patients (1.467) the resulting incremental costs per QALY for each of the groups, at a price difference of £600, are: £282,000 for all patients; £250,000 for long lesions; £353,000 for diabetes; and £94,000 for small vessels.\n\nBased on the Liverpool Cardiothoracic Centre audit data, the Assessment Group's re-analysis of the base-case scenario assumes an 11% overall revascularisation rate for the total population of stented patients in the UK at 12\xa0months after PCI with BMSs. Using 11% for all patients, the absolute rates of repeat revascularisation for the risk factors become: 11.7% for long lesions; 11.6% for diabetes; and 19% for small vessels. The relative risk reduction with DESs is assumed to be 55%. Using the overall mean number of stents implanted per patient from the Liverpool audit data, both elective and non-elective (1.571) and assuming a price difference of £600 (approximate average of the price difference of the PES [Taxus] and the SES [Cypher], from the survey data) the resulting incremental costs per QALY for each of the groups of patients are approximately: £213,000 for all patients; £183,000 for long lesions; £180,000 for diabetes; and £146,000 for small vessels. Assuming a price difference of £300 the resulting incremental costs per QALY for each of the groups of patients are approximately: £101,000 for all patients; £85,000 for long lesions; £84,000 for diabetes; and £59,000 for small vessels.\n\nFor the Assessment Group's sensitivity analysis for the combined elective and non-elective data, using a relative risk reduction with DESs of 65% and a price difference of £600, the resulting incremental costs per QALY for each of the groups of patients are approximately: £174,000 for all patients; £148,000 for long lesions; £146,000 for diabetes; and £116,000 for small vessels. Assuming a price difference of £300 the resulting incremental costs per QALY for each of the groups of patients are approximately: £78,000 for all patients; £65,000 for long lesions; £64,000 for diabetes; and £41,000 for small vessels.\n\nThe Assessment Group's additional analysis as described in 4.2.22, assuming a price difference of £600 for the base case (55% relative risk reduction of DES), results in incremental costs per QALY for each of the groups of patients of approximately: £171,000 for all patients; £158,000 for long lesions; £156,000 for diabetes; and £124,000 for small vessels. Assuming a price difference of £300 the resulting incremental costs per QALY for each of the groups of patients are approximately: £74,000 for all patients; £66,000 for long lesions; £65,000 for diabetes; and £41,000 for small vessels. For the updated Assessment Group's sensitivity analysis (65% for the relative risk reduction of DES) the resulting incremental costs per QALY, for a price difference of £600, for each of the groups of patients are approximately: £137,000 for all patients; £126,000 for long lesions; £124,000 for diabetes; and £95,000 for small vessels. Assuming a price difference of £300 the resulting incremental costs per QALY for each of the groups of patients are approximately: £54,000 for all patients; £47,000 for long lesions; £46,000 for diabetes; and £25,000 for small vessels.\n\nThe Assessment Group's second additional analysis, as described in 4.2.23, resulted in incremental costs per QALY for each of the groups of patients, assuming a price difference of £600, of approximately: £111,000 for all patients; £51,000 for long lesions; £53,000 for diabetes; and £59,000 for small vessels. Assuming a price difference of £300 the resulting incremental costs per QALY for each of the groups of patients are approximately: £38,000 for all patients; £3,000 for long lesions; £4,000 for diabetes; and £4,000 for small vessels.\n\n# Consideration of the evidence\n\nThe Appraisal Committee reviewed the data available on the clinical and cost effectiveness of DESs, having considered evidence on the nature of the condition and the value placed on the benefits of DESs by people with coronary artery disease, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources.\n\nThe Committee considered the evidence on the clinical effectiveness of DESs in the treatment of CHD. The Committee acknowledged that the clinical trials showed that the use of any-type DESs reduced the rate of revascularisation in the target lesions and the target vessels, at all follow-up time points up to 3\xa0years, compared with any-type BMSs. The Committee noted not just the trial data, but also the recent discussions on the effects of DESs on the risks of thrombosis, MI, and mortality, and accepted the findings of the FDA review that any-type DESs conferred no statistically significant benefits in mortality or acute MI rates over any-type BMSs. The Committee concluded that the key benefit of DESs is the reduction in rates of revascularisation in target lesions and target vessels compared with BMSs.\n\nThe Committee considered whether there was any evidence to suggest that there were differences in the clinical effectiveness of the various types of DESs. It noted that only four of the eleven DESs had been compared with each other in head-to-head RCTs. The majority of data comparing revascularisation rates were between the SES (Cypher) and the PES (Taxus). The Committee noted that the SES (Cypher) showed a statistically significant reduction in TLR, TVR and MACEs compared with the PES (Taxus), at 9\xa0months. It was also noted that at 1\xa0year, for the only outcome available, rates of TLR for the SES (Cypher) compared with the PES (Taxus) showed no statistically significant difference. The Committee heard testimony from the clinical specialists that different DESs are clinically comparable and that, in practice, any of the DESs would be used, although those with the greater evidence-base would be first choice.\n\nThe Committee considered the evidence to suggest that there were groups of patients whose vessel anatomy was more likely to be subject to restenosis. The absolute rate of revascularisation in these groups was greater than that of other patients and they therefore had the potential to gain a greater relative benefit from DESs than other patients, and this was taken into account by the sensitivity analysis in the assessment group's economic model. The Committee considered the risk factors derived by the Assessment Group using the Liverpool Cardiothoracic Centre audit data, but it heard testimony from the clinical specialists that small vessels (less than 3\xa0mm in calibre), long lesions (longer than 15\xa0mm) and diabetes were the risk factors most consistently reported and that made most sense clinically. The Committee noted that, although the Assessment Group's analysis of the Liverpool Cardiothoracic Centre audit data did not prove that any of these were statistically significant risk factors, taking account of other studies, small-vessel disease and long lesions were better predictors of risk groups than diabetes, and are particularly prevalent in patients with CAD who also have diabetes. The Committee was also mindful of the regulatory concerns about the 'off-label' use of DESs. The Committee concluded that small vessels and long lesions should be considered as separate risk factors whereas diabetes should not be considered as a separate risk factor.\n\nThe Committee noted that the Assessment Group's model was based on the Liverpool Cardiothoracic Centre audit data that distinguished elective and non-elective (emergency) patients. The Committee heard testimony from the clinical specialists that in clinical practice the differences between these patient groups specifically related to the mode of their presentation with acute coronary syndromes, that is, non-ST-segment-elevated MI or unstable angina, and to the use of adjunctive treatments, in particular anti-platelet therapy. Due to the lack of other differences the Committee concluded that elective and non-elective patients should be considered together but that the merging of the estimates should take account of the proportions of elective and non-elective patients seen in clinical practice.\n\nIn considering the cost effectiveness of DESs compared with BMSs, the Committee noted that the model structure used by the Assessment Group was appropriate. The Committee discussed the key parameters that drove the Assessment Group's economic model. It considered the absolute rate of revascularisation of BMSs in the total population of stented patients and noted that the Assessment Group used 7.43% for patients in its base case in the assessment report. The Committee heard testimony from the clinical specialists that the rate of revascularisation of BMSs was around 12% in the published literature. It noted that some of these published trials included protocol-driven angiography and revascularisation and therefore were likely to be an overestimate of actual revascularisation rates in clinical practice in the UK. The Committee noted that the Liverpool Cardiothoracic Centre audit data revascularisation rates were lower than those from other data sets including the BASKET trial (11%), which had not included protocol-driven angiography, and the Scottish Registry (11.5%). The Committee discussed the range of possible values for revascularisation and their relevance to UK practice and concluded that a rate of 11% for the absolute rate of revascularisation was a reasonable estimate for UK practice.\n\nThe Committee considered the relative reduction in the risk of target lesion revascularisation with DESs. The Committee noted that the trial data typically gave a relative risk reduction of 75%, but considered that this figure might over-estimate the real-life benefit of DESs because it is derived from the trials that included protocol-driven angiography and revascularisation. The Committee heard that the BASKET trial, which had not included protocol-driven angiography, had a relative risk reduction with DESs of 41% at 12\xa0months. The Committee looked at the adjusted relative risk reduction with DESs used by the Assessment Group, and acknowledged that their approach reflected the number of patients, and not the target lesions, that would benefit from DESs. The Committee noted that the Assessment Group's figure was in line with the BASKET trial. The Committee heard from the clinical specialists that the most plausible relative risk reduction with DESs from the clinical evidence was likely to be in the range 50% to 60% for the base case and 61% to 70% for high-risk groups. Given the variation in data the Committee considered a relative risk reduction with DESs over BMSs of 55% in the base case, and of 65% in a sensitivity analysis for the higher risk groups were the most plausible.\n\nThe Committee considered the mean number of stents used for each of the risk groups from the Liverpool Cardiothoracic Centre audit data and concluded that the estimate of mean number of stents per patient (1.6 for elective patients, 1.5 for non-elective patients) was likely to be a representative figure of the number used in all patients in the UK and could be used as a base case for consideration of the benefits of DESs.\n\nThe Committee was mindful of data in the literature on the mortality and morbidity of CABG and repeat angiography. After reviewing the utility values in the Assessment Group's model the Committee acknowledged the possibility that there could be an additional disutility associated with CABG during the initial 6\xa0weeks following the procedure compared with PCI. The Committee accepted the Assessment Group's revisions for this parameter.\n\nThe Committee noted the current UK recommendation that clopidogrel should be given for an additional 9\xa0months in patients receiving a DES and it therefore considered it appropriate that this should be taken account of in the cost-effectiveness analysis. The Committee also accepted the consultation suggestions that patients with acute coronary syndrome would already be receiving 12\xa0months' treatment with clopidogrel and that no additional costs would be incurred in this population.\n\nThe Committee heard testimony from the clinical specialists and received information during the consultation period that in some areas procurement arrangements had resulted in a price difference of £300 for DESs over BMSs. The Committee also received information that although no nationally procured price currently existed for DESs, price differences that were less than £300 did exist in some regions. The Committee agreed that as this price difference existed in some regions, it was reasonable to assume that DESs could be procured in this way across all regions within the NHS and, therefore, it could be considered as an appropriate costing option in its considerations.\n\nAfter agreeing on the parameters to use in the Assessment Group's model, the Committee discussed the resulting ICERs for the base case and risk groups, assuming:\n\nthe absolute risk of revascularisation with BMSs for the total population is 11%, with resulting risks of revascularisation for small vessels of 19% and for long lesions of 11.7%\n\nthe mean number of stents per patient is 1.571\n\nthe relative risk reduction with DESs for the base case is 55% for the total population, and 65% for patients with small vessels and long lesions\n\nprice differences of DESs over BMSs of £600 and £300. At a relative risk reduction of 55% with DESs, the resulting ICER for the total population of patients was associated with a cost per QALY of approximately £171,000 at a price difference of £600 and £74,000 at a price difference of £300. For the higher risk groups of patients (that is, those with long lesions and those with small vessels) using a DES, with a relative risk reduction of 65%, the resulting ICERs were associated with costs per QALYs of £126,000 and £95,000, respectively, at a price difference of £600 and £47,000 and £25,000, respectively, at a price difference of £300.\n\nReflecting the testimony of the clinical specialists and the comments received during consultation, the Committee noted the small differences in the key parameters between those that the Committee had previously agreed and those suggested by BCIS. The Committee noted that the ICERs resulting from using the parameter values suggested by the BCIS into the Assessment Group's model for a price difference of £600 were associated with costs per QALYs of approximately: £111,000 for all patients; £51,000 for long lesions; £53,000 for diabetes; and £59,000 for small vessels. For a price difference of £300 the resulting ICERs were associated with costs per QALYs below £5000 for patients with small vessels and long lesions. The Committee was not, however, persuaded that all of the parameter values suggested by BCIS were plausible, but it agreed that the percentages of elective and non-elective patients at presentation should be 57% elective to 43% non-elective. The Committee noted that taking account of this assumption would decrease the ICERs seen in the updated analysis for long lesions and small vessels (see 4.3.12), which means that, at a price difference of £300, the plausible ICERs would be much lower than cost per QALYs of £47,000 and £25,000, respectively.\n\nThe Committee agreed that DESs could not be considered a cost-effective use of NHS resources at a price difference of £600. After considering the alternative parameter values presented by the Assessment Group and BCIS, the Committee concluded that on balance at a price difference between DESs and BMSs of not more than £300, DESs could be considered a cost effective option in patients with small vessels and long lesions, and should be recommended for use in these patient groups. The Committee's decision was based on a price difference of £300 between BMSs and DESs. The Committee noted that procurement arrangements for DESs at a price difference of £300 was already in place within many NHS regions and achievable across the NHS as a whole. The Committee understood that the mean absolute price of a BMS, to the NHS, was £131.", 'Recommendations for further research': 'The Committee noted that there are a number of trials under way comparing the clinical effectiveness of DESs with their equivalent BMS and/or with other DESs at longer follow-up periods.'}
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https://www.nice.org.uk/guidance/ta152
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Evidence-based recommendations on using drug-eluting stents in adults.
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bf00d233b9bb877247727dd7a4c9e5f55c33c535
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nice
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Swallowable gastric balloon capsule for weight loss
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Swallowable gastric balloon capsule for weight loss
Evidence-based recommendations on swallowable gastric balloon capsules for weight loss in adults. This involves swallowing a capsule containing a balloon that is then filled with liquid to inflate it in the stomach. It stays in the stomach for around 4 months to give a feeling of fullness and temporarily restrict the size of the stomach.
# Recommendations
Evidence on the safety of the swallowable gastric balloon capsule for weight loss shows infrequent but potentially serious adverse events:
For people who need to lose weight in the short term for medical reasons, the evidence of efficacy is adequate to support the use of this procedure provided that special arrangements are in place for clinical governance, consent and audit. Find out what special arrangements mean on the NICE interventional procedures guidance page.
For people who are aiming for long-term weight loss, the evidence on efficacy is inadequate in quantity and quality, so the procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.
Clinicians wishing to use a swallowable gastric balloon capsule for weight loss should:
Inform the clinical governance leads in their healthcare organisation.
Give patients (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public.
Ensure that patients (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.
Audit and review clinical outcomes of all patients having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).
Discuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.
Further research could be in the form of randomised controlled trials comparing the procedure with current standard therapies, or an observational cohort study, including using registry data. Studies should include details of patient selection such as body mass index and other treatments such as diet and lifestyle changes. They should also report:
short- and long-term weight loss
quality of life
metabolic parameters
the need for later surgery.# The condition, current treatments and procedure
# The condition
Overweight is defined as a body mass index (BMI) of 25 kg/m2 to 29.9 kg/m2 and obesity as a BMI of 30 kg/m2 or more. Overweight and obesity increase people's risk of type 2 diabetes, coronary heart disease and hypertension. Weight loss reduces these risks and improves life expectancy.
# Current treatments
Obesity is managed by dietary advice, physical activity and exercise, lifestyle and behavioural changes, and medication. Bariatric surgery is considered for people:
whose BMI is over 40 kg/m2, or over 35 kg/m2 if they have other significant comorbidities, and
who have not been able to reach or maintain a clinically beneficial weight using non‑surgical measures.Surgical procedures include gastric banding, sleeve gastrectomy, or Roux‑en‑Y gastric bypass or other diversion procedures.
People unable to lose weight by non-surgical measures who do not want invasive surgery can have less invasive bariatric procedures. Examples are endoscopic intragastric balloons, gastrointestinal bypass sleeves, endoscopic sleeve gastroplasty and endoluminal restrictive surgical techniques.
# The procedure
A swallowable gastric balloon capsule for weight loss must be used with a nutrition and behaviour modification programme supervised by a suitably qualified and registered healthcare professional.
The procedure is usually done in an outpatient setting without endoscopy or sedation. The patient swallows a capsule containing the deflated balloon, which is attached to a fine delivery catheter, with water. If they have difficulty swallowing the capsule, a stylet can be fed through the catheter to stiffen it. This allows the doctor to help push the catheter during swallowing. After the capsule reaches the stomach this stylet is removed. The position in the stomach is confirmed by X‑ray using guide marks on the catheter. The capsule disintegrates and the balloon is inflated with a fixed amount of fluid (for example, distilled water and citric acid) through the connected catheter. After the balloon is inflated, the catheter is detached by pulling it firmly from the patient's mouth. Imaging is done to recheck position and inflation. After a short wait to make sure the patient can tolerate the balloon, they are discharged with medication including anti-emetics, antispasmodics and proton pump inhibitors. About 4 months later, a resorbable material element of the balloon degrades, which then allows a release valve to open and expel the fluid into the stomach gradually. The deflated balloon then passes through the gastrointestinal tract to be excreted through the bowel.
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{'Recommendations': "Evidence on the safety of the swallowable gastric balloon capsule for weight loss shows infrequent but potentially serious adverse events:\n\nFor people who need to lose weight in the short term for medical reasons, the evidence of efficacy is adequate to support the use of this procedure provided that special arrangements are in place for clinical governance, consent and audit. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nFor people who are aiming for long-term weight loss, the evidence on efficacy is inadequate in quantity and quality, so the procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nClinicians wishing to use a swallowable gastric balloon capsule for weight loss should:\n\nInform the clinical governance leads in their healthcare organisation.\n\nGive patients (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public.\n\nEnsure that patients (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.\n\nAudit and review clinical outcomes of all patients having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).\n\nDiscuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.\n\nFurther research could be in the form of randomised controlled trials comparing the procedure with current standard therapies, or an observational cohort study, including using registry data. Studies should include details of patient selection such as body mass index and other treatments such as diet and lifestyle changes. They should also report:\n\nshort- and long-term weight loss\n\nquality of life\n\nmetabolic parameters\n\nthe need for later surgery.", 'The condition, current treatments and procedure': "# The condition\n\nOverweight is defined as a body mass index (BMI) of 25\xa0kg/m2 to 29.9\xa0kg/m2 and obesity as a BMI of 30\xa0kg/m2 or more. Overweight and obesity increase people's risk of type\xa02 diabetes, coronary heart disease and hypertension. Weight loss reduces these risks and improves life expectancy.\n\n# Current treatments\n\nObesity is managed by dietary advice, physical activity and exercise, lifestyle and behavioural changes, and medication. Bariatric surgery is considered for people:\n\nwhose BMI is over 40\xa0kg/m2, or over 35\xa0kg/m2 if they have other significant comorbidities, and\n\nwho have not been able to reach or maintain a clinically beneficial weight using non‑surgical measures.Surgical procedures include gastric banding, sleeve gastrectomy, or Roux‑en‑Y gastric bypass or other diversion procedures.\n\nPeople unable to lose weight by non-surgical measures who do not want invasive surgery can have less invasive bariatric procedures. Examples are endoscopic intragastric balloons, gastrointestinal bypass sleeves, endoscopic sleeve gastroplasty and endoluminal restrictive surgical techniques.\n\n# The procedure\n\nA swallowable gastric balloon capsule for weight loss must be used with a nutrition and behaviour modification programme supervised by a suitably qualified and registered healthcare professional.\n\nThe procedure is usually done in an outpatient setting without endoscopy or sedation. The patient swallows a capsule containing the deflated balloon, which is attached to a fine delivery catheter, with water. If they have difficulty swallowing the capsule, a stylet can be fed through the catheter to stiffen it. This allows the doctor to help push the catheter during swallowing. After the capsule reaches the stomach this stylet is removed. The position in the stomach is confirmed by X‑ray using guide marks on the catheter. The capsule disintegrates and the balloon is inflated with a fixed amount of fluid (for example, distilled water and citric acid) through the connected catheter. After the balloon is inflated, the catheter is detached by pulling it firmly from the patient's mouth. Imaging is done to recheck position and inflation. After a short wait to make sure the patient can tolerate the balloon, they are discharged with medication including anti-emetics, antispasmodics and proton pump inhibitors. About 4\xa0months later, a resorbable material element of the balloon degrades, which then allows a release valve to open and expel the fluid into the stomach gradually. The deflated balloon then passes through the gastrointestinal tract to be excreted through the bowel."}
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https://www.nice.org.uk/guidance/ipg684
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Evidence-based recommendations on swallowable gastric balloon capsules for weight loss in adults. This involves swallowing a capsule containing a balloon that is then filled with liquid to inflate it in the stomach. It stays in the stomach for around 4 months to give a feeling of fullness and temporarily restrict the size of the stomach.
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3dd47077f99df5a1d3b43371e2691719ba199199
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nice
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Acute coronary syndromes
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Acute coronary syndromes
This guideline covers the early and longer-term (rehabilitation) management of acute coronary syndromes. These include ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI) and unstable angina. The guideline aims to improve survival and quality of life for people who have a heart attack or unstable angina.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# STEMI – early management
NICE has produced a visual summary of the recommendations on the early management of STEMI.
## Assessment
Immediately assess eligibility (irrespective of age, ethnicity or sex) for coronary reperfusion therapy (either primary percutaneous coronary intervention or fibrinolysis) in people with acute ST‑segment elevation myocardial infarction (STEMI).
Do not use level of consciousness after cardiac arrest caused by suspected acute STEMI to determine whether a person is eligible for coronary angiography (with follow‑on primary PCI if indicated).
Deliver coronary reperfusion therapy (either primary PCI or fibrinolysis) as quickly as possible for eligible people with acute STEMI.
## Initial drug therapy
Offer people with acute STEMI a single loading dose of 300-mg aspirin as soon as possible unless there is clear evidence that they are allergic to it.
Do not offer routine glycoprotein IIb/IIIa inhibitors or fibrinolytic drugs before arrival at the catheter laboratory to people with acute STEMI for whom primary PCI is planned.
## Coronary angiography with follow-on primary PCI
Offer coronary angiography, with follow‑on primary PCI if indicated, as the preferred coronary reperfusion strategy for people with acute STEMI, if:
presentation is within 12 hours of onset of symptoms and
primary PCI can be delivered within 120 minutes of the time when fibrinolysis could have been given.
Offer coronary angiography, with follow‑on primary PCI if indicated, to people with acute STEMI and cardiogenic shock who present within 12 hours of the onset of symptoms of STEMI.
Consider coronary angiography, with follow‑on primary PCI if indicated, for people with acute STEMI presenting more than 12 hours after the onset of symptoms if there is evidence of continuing myocardial ischaemia.
Consider coronary angiography, with a view to coronary revascularisation if indicated, for people with acute STEMI who present more than 12 hours after the onset of symptoms and who have cardiogenic shock or go on to develop it.
Consider radial (in preference to femoral) arterial access for people undergoing coronary angiography (with follow‑on primary PCI if indicated).
## Dual antiplatelet therapy for people with acute STEMI having primary PCI
For people with acute STEMI who are having primary PCI, offer:
Prasugrel, as part of dual antiplatelet therapy with aspirin, if they are not already taking an oral anticoagulant (use the maintenance dose in the prasugrel summary of product characteristics; for people aged 75 and over, think about whether the person's risk of bleeding with prasugrel outweighs its effectiveness, in which case offer ticagrelor or clopidogrel as alternatives)
Clopidogrel, as part of dual antiplatelet therapy with aspirin, if they are already taking an oral anticoagulant. Also see the NICE technology appraisal guidance on ticagrelor for the treatment of acute coronary syndromes.
For a short explanation of why the committee made the 2020 recommendation and how it might affect practice, see the rationale and impact section on dual antiplatelet therapy for people with acute STEMI having primary PCI .
Full details of the evidence and the committee's discussion are in evidence review A: antiplatelet therapy.
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## Antithrombin therapy during primary PCI
Offer unfractionated heparin with bailout glycoprotein IIb/IIIa inhibitor in combination with dual antiplatelet therapy to people with acute STEMI undergoing primary PCI with radial access.
Consider bivalirudin with bailout glycoprotein IIb/IIIa inhibitor in combination with dual antiplatelet therapy for people with acute STEMI undergoing primary PCI when femoral access is needed.In November 2020, use of bivalirudin with prasugrel and aspirin was off label. See NICE's information on prescribing medicines.
For a short explanation of why the committee made the 2020 recommendations and how they might affect practice, see the rationale and impact section on antithrombin therapy during primary PCI .
Full details of the evidence and the committee's discussion are in evidence review D: antithrombin therapy in adults with STEMI intended for primary PCI.
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## Thrombus extraction during primary PCI
Consider thrombus aspiration during primary PCI for people with acute STEMI.
Do not routinely use mechanical thrombus extraction during primary PCI for people with acute STEMI.
## Complete or culprit vessel only revascularisation with PCI in people with acute STEMI treated by primary PCI
Offer complete revascularisation with PCI for people with acute STEMI and multivessel coronary artery disease without cardiogenic shock. Consider doing this during the index hospital admission.
Consider culprit vessel only revascularisation with PCI rather than complete revascularisation during the index procedure for people with acute STEMI and multivessel coronary artery disease with cardiogenic shock.
For a short explanation of why the committee made the 2020 recommendations and how they might affect practice, see the rationale and impact section on complete revascularisation with PCI or culprit vessel only PCI .
Full details of the evidence and the committee's discussion are in evidence review E: culprit versus complete revascularisation.
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## Drug-eluting stents in primary PCI
If stenting is indicated, offer a drug-eluting stent to people with acute STEMI undergoing revascularisation by primary PCI.
For a short explanation of why the committee made the 2020 recommendation and how it might affect practice, see the rationale and impact section on drug-eluting stents in primary PCI .
Full details of the evidence and the committee's discussion are in evidence review F: drug-eluting stents.
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## Fibrinolysis
Offer fibrinolysis to people with acute STEMI presenting within 12 hours of onset of symptoms if primary PCI cannot be delivered within 120 minutes of the time when fibrinolysis could have been given.
When treating people with fibrinolysis, give an antithrombin at the same time.
Offer an electrocardiogram (ECG) to people with acute STEMI treated with fibrinolysis, 60 to 90 minutes after administration. For those who have residual ST‑segment elevation suggesting failed coronary reperfusion:
-ffer immediate coronary angiography, with follow‑on PCI if indicated
do not repeat fibrinolytic therapy.
If a person with acute STEMI has recurrent myocardial ischaemia after fibrinolysis, seek immediate specialist cardiological advice and, if appropriate, offer coronary angiography, with follow‑on PCI if indicated.
Consider coronary angiography during the same hospital admission for people with acute STEMI who are clinically stable after successful fibrinolysis.
## Management for people with STEMI not treated with PCI
Offer ticagrelor, as part of dual antiplatelet therapy with aspirin, to people with acute STEMI not treated with PCI, unless they have a high bleeding risk.
Consider clopidogrel, as part of dual antiplatelet therapy with aspirin, or aspirin alone, for people with acute STEMI not treated with PCI, if they have a high bleeding risk.
Also see the NICE technology appraisal guidance on rivaroxaban for preventing adverse outcomes after management of acute coronary syndromes.
For a short explanation of why the committee made the 2020 recommendations and how they might affect practice, see the rationale and impact section on dual antiplatelet therapy for people with STEMI not treated with PCI .
Full details of the evidence and the committee's discussion are in evidence review A: antiplatelet therapy.
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Offer medical management to people with acute STEMI who are ineligible for any reperfusion therapy.
## Tests before discharge
Assess left ventricular function in all people who have had a STEMI.
# NSTEMI and unstable angina – early management
NICE has produced a visual summary of the recommendations on the early management of NSTEMI and unstable angina.
## Initial drug therapy
Offer aspirin as soon as possible to all people with unstable angina or non‑ST‑segment elevation myocardial infarction (NSTEMI) and continue indefinitely unless contraindicated by bleeding risk or aspirin hypersensitivity.
Offer people with unstable angina or NSTEMI a single loading dose of 300-mg aspirin as soon as possible unless there is clear evidence that they are allergic to it.
Offer fondaparinux to people with unstable angina or NSTEMI who do not have a high bleeding risk, unless they are undergoing immediate coronary angiography.
See the recommendation on unfractionated heparin in the section on coronary angiography with follow-on PCI for advice about people with unstable angina or NSTEMI who are undergoing immediate coronary angiography.
For a short explanation of why the committee made the 2020 recommendation and how it might affect practice, see the rationale and impact section on initial antithrombin therapy for people with unstable angina or NSTEMI .
Full details of the evidence and the committee's discussion are in evidence review C: antithrombin for unstable angina and NSTEMI.
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Consider unfractionated heparin, with dose adjustment guided by monitoring of clotting function, as an alternative to fondaparinux for people with unstable angina or NSTEMI and significant renal impairment (creatinine above 265 micromoles per litre).
Carefully consider the choice and dose of antithrombin for people with unstable angina or NSTEMI who have a high risk of bleeding associated with any of the following:
advancing age
known bleeding complications
renal impairment
low body weight.
Do not offer dual antiplatelet therapy to people with chest pain before a diagnosis of unstable angina or NSTEMI is made.
For a short explanation of why the committee made the 2020 recommendation and how it might affect practice, see the rationale and impact section on dual antiplatelet therapy for people with unstable angina or NSTEMI .
Full details of the evidence and the committee's discussion are in evidence review A: antiplatelet therapy.
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## Risk assessment
As soon as the diagnosis of unstable angina or NSTEMI is made, and aspirin and antithrombin therapy have been offered, formally assess individual risk of future adverse cardiovascular events using an established risk scoring system that predicts 6‑month mortality (for example, Global Registry of Acute Cardiac Events ).
Include in the formal risk assessment:
a full clinical history (including age, previous myocardial infarction and previous PCI or coronary artery bypass grafting )
a physical examination (including measurement of blood pressure and heart rate)
a resting 12‑lead ECG, looking particularly for dynamic or unstable patterns that indicate myocardial ischaemia
blood tests (such as troponin I or T, creatinine, glucose and haemoglobin).
Record the results of the risk assessment in the person's care record.
Use risk assessment to guide clinical management, and balance the benefit of a treatment against any risk of related adverse events in the light of this assessment.
Use predicted 6‑month mortality to categorise the risk of future adverse cardiovascular events as shown in table 1.
Predicted 6‑month mortality
Risk of future adverse cardiovascular events
% or below
Lowest
1.5% to 3.0%
Low
3.0% to 6.0%
Intermediate
6.0% to 9.0%
High
-ver 9.0%
Highest
Categories of risk are derived from the Myocardial Ischaemia National Audit Project (MINAP) database.
## Coronary angiography with follow-on PCI
Offer immediate coronary angiography to people with unstable angina or NSTEMI if their clinical condition is unstable.
Consider coronary angiography (with follow‑on PCI if indicated) within 72 hours of first admission for people with unstable angina or NSTEMI who have an intermediate or higher risk of adverse cardiovascular events (predicted 6‑month mortality above 3.0%) and no contraindications to angiography (such as active bleeding or comorbidity).See table 2 for information on the benefits and risks of early invasive treatment compared with conservative management.
Consider coronary angiography (with follow‑on PCI if indicated) for people with unstable angina or NSTEMI who are initially assessed to be at low risk of adverse cardiovascular events (predicted 6‑month mortality 3.0% or less) if ischaemia is subsequently experienced or is demonstrated by ischaemia testing.See table 2 for information on the benefits and risks of early invasive treatment compared with conservative management.
Be aware that some younger people with low risk scores for mortality at 6 months may still be at high risk of adverse cardiovascular events and may benefit from early angiography.
Benefits/risks/other factors
Coronary angiography and possible percutaneous coronary intervention (PCI) within 72 hours
Conservative management with later coronary angiography if problems continue or develop
Benefits (advantages)
Reduced deaths from all causes at 6 to 12 months and at 2 years. Reduced deaths from heart problems at 1 and 2 years.
Reduced incidence of myocardial infarction (MI) at 30 days, 6 to 12 months and 2 years.
Reduced incidence of stroke at 1 year, particularly in people at high risk of future adverse events.
Reduced readmission to hospital and difficult-to-treat angina in the medium term, particularly in people at high risk of future adverse events.
Psychological benefits – people are not anxious about delaying angiography.
Avoid the immediate risks of invasive treatment, including:
death within 4 months related to the procedure from causes other than MI
procedure-related MI
major bleeding in hospital and up to 2 years after the procedure.
These are particularly relevant for people at low risk of future adverse events.
Psychological benefits – people are not anxious about having an invasive procedure.
Risks (disadvantages)
Increased risk of death during the first 4 months, particularly for people at low risk of future adverse events.
Risk of procedure-related MI.
Increased risk of major bleeding during the index admission, at 30 days and 2 years.
Emergency treatment leaves little time for shared decision making.
Increased risk of MI after 6 months.
Increased risk of stroke at 1 year, particularly in the people at high risk of future adverse events.
Psychological factors – people may be anxious about delaying angiography.
Other factors
Recent advances in PCI might increase early benefit, particularly reducing bleeding.
Coronary angiography within 72 hours ensures speedy intervention while allowing time for the correct diagnosis, identifying other conditions and treating symptoms.
For a short explanation of why the committee made the 2020 recommendations and how they might affect practice, see the rationale and impact section on early invasive versus conservative management for people with unstable angina or NSTEMI .
Full details of the evidence and the committee's discussion are in evidence review B: early invasive versus conservative management for unstable angina and NSTEMI.
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Offer systemic unfractionated heparin in the cardiac catheter laboratory to people with unstable angina or NSTEMI who are undergoing PCI whether or not they have already received fondaparinux.In November 2020, this was an off‑label use of unfractionated heparin. See NICE's information on prescribing medicines.
For a short explanation of why the committee made the 2020 recommendation and how it might affect practice, see the rationale and impact section on antithrombin therapy for people with unstable angina or NSTEMI .
Full details of the evidence and the committee's discussion are in evidence review C: antithrombin for unstable angina and NSTEMI.
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For people with unstable angina or NSTEMI who are having coronary angiography, offer:
prasugrel or ticagrelor, as part of dual antiplatelet therapy with aspirin, if they have no separate indication for ongoing oral anticoagulation (if using prasugrel, only give it once coronary anatomy has been defined and PCI is intended, and use the maintenance dose in the prasugrel summary of product characteristics; for people aged 75 and over, think about whether the person's risk of bleeding with prasugrel outweighs its effectiveness)
clopidogrel, as part of dual antiplatelet therapy with aspirin, if they have a separate indication for ongoing oral anticoagulation.
For a short explanation of why the committee made the 2020 recommendation and how it might affect practice, see the rationale and impact section on dual antiplatelet therapy for people with unstable angina or NSTEMI .
Full details of the evidence and the committee's discussion are in evidence review A: antiplatelet therapy.
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If stenting is indicated, offer a drug-eluting stent to people with unstable angina or NSTEMI undergoing revascularisation by PCI.
For a short explanation of why the committee made the 2020 recommendation and how it might affect practice, see the rationale and impact section on drug-eluting stents .
Full details of the evidence and the committee's discussion are in evidence review F: drug-eluting stents.
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## Management when PCI is not indicated
Consider conservative management without early coronary angiography for people with unstable angina or NSTEMI who have a low risk of adverse cardiovascular events (predicted 6‑month mortality 3.0% or less).
For a short explanation of why the committee made the 2020 recommendation and how it might affect practice, see the rationale and impact section on early invasive versus conservative management for people with unstable angina or NSTEMI .
Full details of the evidence and the committee's discussion are in evidence review B: early invasive versus conservative management for unstable angina and NSTEMI.
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Offer ticagrelor, as part of dual antiplatelet therapy with aspirin, to people with unstable angina or NSTEMI when PCI is not indicated, unless they have a high bleeding risk.
Consider clopidogrel, as part of dual antiplatelet therapy with aspirin, or aspirin alone, for people with unstable angina or NSTEMI when PCI is not indicated, if they have a high bleeding risk.
Also see the NICE technology appraisal guidance on rivaroxaban for preventing adverse outcomes after management of acute coronary syndromes.
For a short explanation of why the committee made the 2020 recommendations and how they might affect practice, see the rationale and impact section on antiplatelet therapy for people with unstable angina or NSTEMI .
Full details of the evidence and the committee's discussion are in evidence review A: antiplatelet therapy.
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## Advice on management strategies
Offer people with unstable angina or NSTEMI clear information about the risks and benefits of the treatments offered so that they can make informed choices about management strategies. Information should be appropriate to the person's underlying risk of a future adverse cardiovascular event and any comorbidities.
When advising people with unstable angina or NSTEMI about the choice of revascularisation strategy (PCI or CABG), take account of coronary angiographic findings, comorbidities, and the benefits and risks of each intervention.
When the role of revascularisation or the revascularisation strategy is unclear, resolve this by discussion involving an interventional cardiologist, cardiac surgeon and other healthcare professionals relevant to the needs of the person. Discuss the choice of revascularisation strategy with the person.
## Tests before discharge
To detect and quantify inducible ischaemia, consider ischaemia testing before discharge for people whose condition has been managed conservatively and who have not had coronary angiography.
Assess left ventricular function in all people who have had an NSTEMI.
Consider assessing left ventricular function in all people with unstable angina.
Record measures of left ventricular function in the person's care record and in correspondence with the primary healthcare team and the person.
# Hyperglycaemia in acute coronary syndromes
## Managing hyperglycaemia in inpatients within 48 hours of acute coronary syndrome
Manage hyperglycaemia in people admitted to hospital for an acute coronary syndrome by keeping blood glucose levels below 11.0 mmol/litre while avoiding hypoglycaemia. In the first instance, consider a dose-adjusted insulin infusion with regular monitoring of blood glucose levels.
Do not routinely offer intensive insulin therapy (an intravenous infusion of insulin and glucose with or without potassium) to manage hyperglycaemia (blood glucose above 11.0 mmol/litre) in people admitted to hospital for an acute coronary syndrome unless clinically indicated.
## Identifying people with hyperglycaemia after acute coronary syndrome who are at high risk of developing diabetes
Offer all people with hyperglycaemia after acute coronary syndrome and without known diabetes tests for:
HbA1c levels before discharge
fasting blood glucose levels no earlier than 4 days after the onset of acute coronary syndrome.These tests should not delay discharge.
Do not routinely offer oral glucose tolerance tests to people with hyperglycaemia after acute coronary syndrome and without known diabetes if HbA1c and fasting blood glucose levels are within the normal range.
## Advice and ongoing monitoring for people with hyperglycaemia after acute coronary syndrome and without known diabetes
Offer people with hyperglycaemia after acute coronary syndrome and without known diabetes lifestyle advice on the following:
healthy eating
physical exercise
weight management
smoking cessation
alcohol consumption. See the section on lifestyle changes after an MI for more information.
Advise people without known diabetes that if they have had hyperglycaemia after an acute coronary syndrome, they:
are at increased risk of developing type 2 diabetes
should consult their GP if they experience the following symptoms:
frequent urination
excessive thirst
weight loss
fatigue
should be offered tests for diabetes at least annually.
Inform GPs that they should offer at least annual monitoring of HbA1c or fasting blood glucose levels to people without known diabetes who have had hyperglycaemia after an acute coronary syndrome.
# Drug therapy for secondary prevention
NICE has produced a visual summary of the recommendations on cardiac rehabilitation and secondary prevention.
For secondary prevention, offer people who have had MI treatment with the following drugs:
angiotensin-converting enzyme (ACE) inhibitor
dual antiplatelet therapy (aspirin plus a second antiplatelet) unless they have a separate indication for anticoagulation (see the section on antiplatelet therapy for people with an ongoing separate indication for anticoagulation)
beta-blocker
statin.
Ensure that a clear management plan is available to the person who has had an MI and is also sent to the GP, including:
details and timing of any further drug titration
monitoring of blood pressure
monitoring of renal function.
Offer all people who have had an MI an assessment of bleeding risk at their follow‑up appointment.
Also see the:
NICE guideline on medicines adherence
NICE guideline on cardiovascular disease: risk assessment and risk reduction, including lipid modification
NICE technology appraisal guidance on alirocumab for treating primary hypercholesterolaemia and mixed dyslipidaemia
NICE technology appraisal guidance on evolocumab for treating primary hypercholesterolaemia and mixed dyslipidaemia
NICE technology appraisal guidance on rivaroxaban for preventing atherothrombotic events in people with coronary or peripheral artery disease.
## ACE inhibitors
Offer people who present acutely with an MI, an ACE inhibitor as soon as they are haemodynamically stable. Continue the ACE inhibitor indefinitely.
Titrate the ACE inhibitor dose upwards at short intervals (for example, every 12 to 24 hours) before the person leaves hospital until the maximum tolerated or target dose is reached. If it is not possible to complete the titration during this time, it should be completed within 4 to 6 weeks of hospital discharge.
Do not offer combined treatment with an ACE inhibitor and an angiotensin II receptor blocker (ARB) to people after an MI, unless there are other reasons to use this combination.
After an MI, offer people who are intolerant to ACE inhibitors, an ARB instead of an ACE inhibitor.
Renal function, serum electrolytes and blood pressure should be measured before starting an ACE inhibitor or ARB and again within 1 or 2 weeks of starting treatment. People should have appropriate monitoring as the dose is titrated upwards, until the maximum tolerated or target dose is reached, and then at least annually. More frequent monitoring may be needed in people who are at increased risk of deterioration in renal function. People with chronic heart failure should be monitored in line with the NICE guideline on chronic heart failure in adults.
Offer an ACE inhibitor to people who have had an MI more than 12 months ago. Titrate to the maximum tolerated or target dose (over a 4‑ to 6‑week period) and continue indefinitely.
Offer people who have had an MI more than 12 months ago and who are intolerant to ACE inhibitors an ARB instead of an ACE inhibitor.
## Antiplatelet therapy
Offer aspirin to all people after an MI and continue it indefinitely, unless they are aspirin intolerant or have an indication for anticoagulation (see the section on antiplatelet therapy for people with an ongoing separate indication for anticoagulation).
Offer aspirin to people who have had an MI more than 12 months ago and continue it indefinitely.
Continue dual antiplatelet therapy for up to 12 months after an MI unless contraindicated (see recommendations 1.1.11, 1.1.24, 1.1.25, 1.2.17, 1.2.20 and 1.2.21 for more information about dual antiplatelet therapy).
For people with aspirin hypersensitivity who have had an MI, clopidogrel monotherapy should be considered as an alternative treatment.
People with a history of dyspepsia should be considered for treatment in line with the NICE guideline on gastro-oesophageal reflux disease and dyspepsia in adults.
After appropriate treatment, people with a history of aspirin-induced ulcer bleeding whose ulcers have healed and who are negative for Helicobacter pylori should be considered for treatment in line with the NICE guideline on gastro-oesophageal reflux disease and dyspepsia in adults.
Offer clopidogrel instead of aspirin to people who also have other clinical vascular disease, in line with the NICE technology appraisal guidance on clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events, and who have:
had an MI and stopped dual antiplatelet therapy or
had an MI more than 12 months ago.
For people who have a separate indication for anticoagulation, take into account all of the following when thinking about the duration and type (dual or single) of antiplatelet therapy in the 12 months after an acute coronary syndrome:
bleeding risk
thromboembolic risk
cardiovascular risk
person's wishes.Be aware that the optimal duration of aspirin therapy has not been established, and that long-term continuation of aspirin, clopidogrel and oral anticoagulation (triple therapy) significantly increases bleeding risk.
For people already on anticoagulation who have had PCI, continue anticoagulation and clopidogrel for up to 12 months. If the person is taking a direct oral anticoagulant, adjust the dose according to bleeding risk, thromboembolic risk and cardiovascular risk.
For people with a new indication for anticoagulation who have had PCI, offer clopidogrel (to replace prasugrel or ticagrelor) for up to 12 months and an oral anticoagulant licensed for the indication, which best matches the person's:
bleeding risk
thromboembolic risk
cardiovascular risk
wishes.
For people already on anticoagulation, or those with a new indication, who have not had PCI (medical management, CABG), continue anticoagulation and, unless there is a high risk of bleeding, consider continuing aspirin (or clopidogrel for people with contraindication for aspirin) for up to 12 months.
Do not routinely offer prasugrel or ticagrelor in combination with an anticoagulant that is needed for an ongoing separate indication for anticoagulation.
For people with an ongoing indication for anticoagulation 12 months after an MI, take into consideration all of the following when thinking about the need for continuing antiplatelet therapy:
indication for anticoagulation
bleeding risk
thromboembolic risk
cardiovascular risk
person's wishes.
For a short explanation of why the committee made the 2020 recommendations and how they might affect practice, see the rationale and impact section on antiplatelet therapy for people with an indication for anticoagulation .
Full details of the evidence and the committee's discussion are in evidence review G: combination therapy.
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## Beta-blockers
Offer people a beta-blocker as soon as possible after an MI, when the person is haemodynamically stable.
Communicate plans for titrating beta-blockers up to the maximum tolerated or target dose – for example, in the discharge summary.
Consider continuing a beta-blocker for 12 months after an MI for people without reduced left ventricular ejection fraction.
Discuss the potential benefits and risks of stopping or continuing beta-blockers beyond 12 months after an MI for people without reduced left ventricular ejection fraction. Include in the discussion:
the lack of evidence on the relative benefits and harms of continuing beyond 12 months
the person's experience of adverse effects.
For a short explanation of why the committee made the 2020 recommendations and how they might affect practice, see the rationale and impact section on duration of beta-blocker treatment after an MI .
Full details of the evidence and the committee's discussion are in evidence review H: beta-blockers.
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Continue a beta-blocker indefinitely in people with reduced left ventricular ejection fraction.
Offer all people who have had an MI more than 12 months ago, who have reduced left ventricular ejection fraction, a beta-blocker whether or not they have symptoms. For people with heart failure plus reduced left ventricular ejection fraction, manage the condition in line with the NICE guideline on chronic heart failure in adults.
Do not offer people without reduced left ventricular ejection fraction or heart failure, who have had an MI more than 12 months ago, treatment with a beta-blocker unless there is an additional clinical indication for a beta-blocker.
## Calcium channel blockers
Do not routinely offer calcium channel blockers to reduce cardiovascular risk after an MI.
If beta-blockers are contraindicated or need to be discontinued, diltiazem or verapamil may be considered for secondary prevention in people without pulmonary congestion or reduced left ventricular ejection fraction.
For people whose condition is stable after an MI, calcium channel blockers may be used to treat hypertension and/or angina. For people with heart failure with reduced ejection fraction, use amlodipine, and avoid verapamil, diltiazem and short-acting dihydropyridine agents in line with the NICE guideline on chronic heart failure in adults.
## Potassium channel activators
Do not offer nicorandil to reduce cardiovascular risk after an MI.
## Aldosterone antagonists in people with heart failure and reduced left ventricular ejection fraction
For people who have had an acute MI and who have symptoms and/or signs of heart failure and reduced left ventricular ejection fraction, initiate treatment with an aldosterone antagonist licensed for post‑MI treatment within 3 to 14 days of the MI, preferably after ACE inhibitor therapy.
People who have recently had an acute MI and have clinical heart failure and reduced left ventricular ejection fraction, but who are already being treated with an aldosterone antagonist for a concomitant condition (for example, chronic heart failure), should continue with the aldosterone antagonist or an alternative, licensed for early post‑MI treatment.
For people who have had a proven MI in the past and heart failure due to reduced left ventricular ejection fraction, treatment with an aldosterone antagonist should be in line with the NICE guideline on chronic heart failure in adults.
Monitor renal function and serum potassium before and during treatment with an aldosterone antagonist. If hyperkalaemia is a problem, halve the dose of the aldosterone antagonist or stop the drug.
## Statins and other lipid-lowering agents
Statin therapy is recommended for adults with clinical evidence of cardiovascular disease in line with the NICE guideline on cardiovascular disease.
# Coronary revascularisation after an MI
Offer a cardiological assessment to everyone who has had a previous MI, but not had coronary revascularisation to consider whether coronary revascularisation is appropriate. This should take into account comorbidity.
# Selected patient subgroups
## People with reduced left ventricular ejection fraction
People who have reduced left ventricular ejection fraction should be considered for an implantable cardioverter defibrillator in line with NICE technology appraisal guidance on implantable cardioverter defibrillators and cardiac resynchronisation therapy for arrhythmias and heart failure.
## People with hypertension
Treat hypertension in line with the NICE guideline on hypertension in adults.
# Communication of diagnosis and advice
After an acute MI, ensure that the following are part of every discharge summary:
confirmation of the diagnosis of acute MI
results of investigations
incomplete drug titrations
future management plans
advice on secondary prevention.
Offer a copy of the discharge summary to the person.
# Cardiac rehabilitation after an MI
All people (regardless of their age) should be given advice about and offered a cardiac rehabilitation programme with an exercise component.
Cardiac rehabilitation programmes should provide a range of options, and people should be encouraged to attend all those appropriate to their clinical needs. People should not be excluded from the entire programme if they choose not to attend certain components.
If a person has cardiac or other clinical conditions that may worsen during exercise, these should be treated if possible before they are offered the exercise component of cardiac rehabilitation. For some people, the exercise component may be adapted by an appropriately qualified healthcare professional.
People with reduced left ventricular ejection fraction who are stable can safely be offered the exercise component of cardiac rehabilitation.
## Encouraging people to attend
Deliver cardiac rehabilitation in a non-judgemental, respectful and culturally sensitive manner. Consider employing bilingual peer educators or cardiac rehabilitation assistants who reflect the diversity of the local population.
Establish people's health beliefs and their specific illness perceptions before offering appropriate lifestyle advice and to encourage attendance to a cardiac rehabilitation programme.
Offer cardiac rehabilitation programmes designed to motivate people to attend and complete the programme. Explain the benefits of attending.
Discuss with the person any factors that might stop them attending a cardiac rehabilitation programme, such as transport difficulties.
Offer cardiac rehabilitation programmes in a choice of venues (including at the person's home, in hospital and in the community) and at a choice of times of day, for example, sessions outside of working hours. Explain the options available.
Provide a range of different types of exercise, as part of the cardiac rehabilitation programme, to meet the needs of people of all ages, or those with significant comorbidity. Do not exclude people from the whole programme if they choose not to attend specific components.
Offer single-sex cardiac rehabilitation programme classes if there is sufficient demand.
Enrol people who have had an MI in a system of structured care, ensuring that there are clear lines of responsibility for arranging the early initiation of cardiac rehabilitation.
Begin cardiac rehabilitation as soon as possible after admission before discharge from hospital, and invite the person to a cardiac rehabilitation session. This should start within 10 days of their discharge from hospital.
Contact people who do not start or do not continue to attend the cardiac rehabilitation programme with a further reminder, such as:
a motivational letter
a prearranged visit from a member of the cardiac rehabilitation team
a telephone call
a combination of the above.
Seek feedback from cardiac rehabilitation programme users and aim to use this feedback to increase the number of people starting and attending the programme.
Be aware of the wider health and social care needs of a person who has had an MI. Offer information and sources of help on:
economic issues
welfare rights
housing and social support issues.
Make cardiac rehabilitation equally accessible and relevant to all people after an MI, particularly people from groups that are less likely to access this service. These include people from black, Asian and minority ethnic groups, older people, people from lower socioeconomic groups, women, people from rural communities, people with a learning disability and people with mental and physical health conditions.
Encourage all staff, including senior medical staff, involved in providing care for people after an MI, to actively promote cardiac rehabilitation.
## Health education and information needs
Comprehensive cardiac rehabilitation programmes should include health education and stress management components.
A home-based programme validated for people who have had an MI (such as NHS Lothian's heart manual) that incorporates education, exercise and stress management components with follow ups by a trained facilitator may be used to provide comprehensive cardiac rehabilitation.
Take into account the physical and psychological status of the patient, the nature of their work and their work environment when giving advice on returning to work.
Be up to date with the latest Driver and Vehicle Licensing Agency (DVLA) guidelines. Regular updates are published by the DVLA.
After an MI without complications, people who wish to travel by air should seek advice from the Civil Aviation Authority. People who have had a complicated MI need expert individual advice.
People who have had an MI who hold a pilot's licence should seek advice from the Civil Aviation Authority.
Take into account the person's physical and psychological status, as well as the type of activity planned when offering advice about the timing of returning to normal activities.
An estimate of the physical demand of a particular activity, and a comparison between activities, can be made using tables of metabolic equivalents (METS) of different activities (for further information, please refer to the information from the Centers for Disease Control and Prevention). Advise people how to use a perceived exertion scale to help monitor physiological demand. People who have had a complicated MI may need expert advice.
Advice on competitive sport may need expert assessment of function and risk, and is dependent on what sport is being discussed and the level of competitiveness.
## Psychological and social support
Offer stress management in the context of comprehensive cardiac rehabilitation.
Do not routinely offer complex psychological interventions such as cognitive behavioural therapy.
Involve partners or carers in the cardiac rehabilitation programme if the person wishes.
For recommendations on managing clinical anxiety or depression, refer to the NICE guidelines on anxiety, depression in adults and depression in adults with a chronic physical health problem.
## Sexual activity
Reassure people that after recovery from an MI, sexual activity presents no greater risk of triggering a subsequent MI than if they had never had an MI.
Advise people who have made an uncomplicated recovery after their MI that they can resume sexual activity when they feel comfortable to do so, usually after about 4 weeks.
Raise the subject of sexual activity within the context of cardiac rehabilitation and aftercare for people who have had an MI.
# Lifestyle changes after an MI
## Changing diet
Advise people to eat a Mediterranean-style diet (more bread, fruit, vegetables and fish; less meat; and replace butter and cheese with products based on plant oils).
Do not routinely recommend eating oily fish for the sole purpose of preventing another MI. If people choose to consume oily fish after an MI, be aware that there is no evidence of harm, and fish may form part of a Mediterranean-style diet.
Do not offer or advise people to use the following to prevent another MI:
-mega-3 fatty acid capsules
-mega-3 fatty acid supplemented foods.
If people choose to take omega‑3 fatty acid capsules or eat omega‑3 fatty acid supplemented foods, be aware that there is no evidence of harm.
Advise people not to take supplements containing beta-carotene. Do not recommend antioxidant supplements (vitamin E and/or C) or folic acid to reduce cardiovascular risk.
Offer people an individual consultation to discuss diet, including their current eating habits, and advice on improving their diet.
Give people consistent dietary advice tailored to their needs.
Give people healthy eating advice that can be extended to the whole family.
## Alcohol consumption
For advice on alcohol consumption, see the UK government drinking guidelines.
## Regular physical activity
Advise people to undertake regular physical activity sufficient to increase exercise capacity.
Advise people to be physically active for 20 to 30 minutes a day to the point of slight breathlessness. Advise people who are not active to this level to increase their activity in a gradual, step-by-step way, aiming to increase their exercise capacity. They should start at a level that is comfortable, and increase the duration and intensity of activity as they gain fitness.
Advice on physical activity should involve a discussion about current and past activity levels and preferences. The benefit of exercise may be enhanced by tailored advice from a suitably qualified professional.
## Smoking cessation
Advise all people who smoke to stop and offer assistance from a smoking cessation service in line with the NICE guideline on stop smoking interventions and services.
If a person is unable or unwilling to accept a referral to a stop smoking service, they should be offered pharmacotherapy in line with the NICE guideline on stop smoking interventions and services.
## Weight management
After an MI, offer all people who are overweight or obese advice and support to achieve and maintain a healthy weight in line with the NICE guideline on obesity.
# Terms used in this guideline
## Bailout glycoprotein IIb/IIIa inhibitor
Bailout glycoprotein inhibitor (GPI) refers to the use of GPI when the PCI operator has not intended to use GPI from the outset, but considers that clinical or angiographic features (such as worsening or persistent thrombus burden) have changed during the course of the procedure, such that there may be benefit to giving the patient GPI.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Key recommendations for research
## Dual antiplatelet therapy for people aged 75 and over
What is the most clinically and cost-effective dual antiplatelet therapy for people aged 75 and over with an acute coronary syndrome, who are having percutaneous coronary intervention (PCI)?
The evidence reviewed for this guideline found that prasugrel is the most clinically and cost-effective antiplatelet therapy when used with aspirin for the general acute coronary syndrome population having PCI, particularly for people with ST‑segment elevation myocardial infarction (STEMI). However, the summary of product characteristics for prasugrel states that its use in people aged 75 and over 'is generally not recommended and should only be undertaken with caution after a careful individual benefit/risk evaluation by the prescribing physician indicates that benefits in terms of prevention of ischaemic events outweigh the risk of serious bleedings'. There were not enough data available for this guideline to determine whether prasugrel is less effective, or even harmful, in people aged 75 and over. Further research is needed to determine the optimal dual antiplatelet therapy for this group of older people.
## Primary PCI and fibrinolysis in people with acute STEMI who have a long anticipated transfer time for primary PCI
In people with acute STEMI who present more than 1 hour after the onset of symptoms, is a primary PCI-related delay of 120 to 180 minutes associated with outcomes similar to, better or worse than pre-hospital administered fibrinolysis?
Primary PCI is the preferred coronary reperfusion therapy provided it can be delivered 'in a timely fashion'. It is suggested that primary PCI is the preferred reperfusion strategy for primary PCI-related delays of at least up to 2 hours. However, there is inadequate evidence to conclude whether primary PCI is still preferable at primary PCI-related time delays of more than 2 hours.
No specifically designed randomised controlled trial (RCT) or observational study has addressed the issue of the extent to which primary PCI-related time delay (and other factors such as presentation delay and a person's risk profile) diminishes the advantages of primary PCI over fibrinolysis. For example, in more geographically remote areas, a short presentation delay together with an anticipated long primary PCI-related delay could favour a strategy of pre-hospital fibrinolysis.
To answer this question, an RCT of pre-hospital fibrinolysis versus primary PCI in people with acute STEMI who have a primary PCI-related time delay of 2 hours or more is needed. Primary endpoints would include cardiovascular and all-cause mortality and other major adverse cardiovascular events.
## Ischaemia testing
What is the role of ischaemia testing in people after an acute coronary syndrome and what is the comparative efficacy and cost effectiveness of the different non-invasive tests (for example, stress electrocardiogram , echocardiography, radionuclide scanning and MRI)?
An increasing number of non-invasive tests are now available for the investigation of suspected myocardial ischaemia. These tests need different equipment, different clinical expertise, come at different costs and may differ in their ability to detect and quantify myocardial ischaemia. Their place in the routine investigation of patients admitted with unstable angina and non-ST‑segment elevation myocardial infarction (NSTEMI) (particularly those who have not undergone angiography), as opposed to their selective use, is not clear. Management of unstable angina and NSTEMI would be enhanced if the relative place of these investigations were better understood and an assessment of their cost effectiveness made.
## Relationship between volume of procedures and clinical outcomes
What is the relationship between hospital volume of primary PCI procedures and optimal outcomes in people with acute STEMI?
There is a suggestion that outcomes may be better in larger-volume primary PCI units, and some retrospective registries have reported data to support this. However, the quality of the data is poor and still leaves the question open. In the UK, primary PCI is provided by units that vary greatly in the number of cases per year. The development of services has been ad hoc and not designed specifically around the provision of primary PCI. If it was possible to conclusively show that people were or were not better off having treatment in larger-volume units, then it would have important implications for the national provision of primary PCI.
## Risk assessment – risk scoring systems
What is the clinical and cost effectiveness of the systematic use of risk scoring systems (in addition to clinical assessment) for ischaemic outcomes and bleeding complications in the management of unstable angina and NSTEMI (at all levels of risk) compared with clinical assessment alone?
Most risk scoring systems currently predict the likelihood of mortality or ischaemic cardiovascular events at various times after a patient's admission to hospital with an acute coronary syndrome. A number of interventions (such as drugs and revascularisation procedures) have been shown to reduce these adverse outcomes. This effect tends to be greatest in patients at highest risk. However, as a broad generalisation, patients who are at highest ischaemic risk are also those who are at higher risk of bleeding complications associated with the use of multiple antiplatelet and antithrombin agents. There are fewer scoring systems that predict bleeding risk, but we know that bleeding complications are associated with a significantly worse outcome. Using a combination of scoring systems assessing ischaemic and bleeding risk when evaluating data from randomised trials and registries may help to determine where the net clinical benefit (reduction in ischaemic risk minus any increase in bleeding risk) lies.
## Risk assessment – data from cardiac registries
For patients with unstable angina and NSTEMI (at differing levels of risk), how do clinical outcome data (adverse cardiovascular events and bleeding complications) collected in cardiac registries compare with data derived from RCTs?
Patients recruited to participate in clinical trials are often highly selected; trials tend not to include patients who are very elderly, are at high risk, or have significant comorbidity. On the other hand, good registry data include information on all patients, but are observational and not randomised. Often there is uncertainty about how the outcome data from RCTs can be applied to the much larger unselected population of patients admitted to UK hospitals with unstable angina or NSTEMI. A greater understanding of the differences between RCT and registry populations, and their levels of ischaemic and bleeding risk would help inform future management. Collection of well-validated registry data is essential if conclusions from RCTs are to be applied appropriately to all patients with unstable angina and NSTEMI, not just to patients who are comparable to trial populations.
## Management of hyperglycaemia
What is the optimal management of hyperglycaemia in people with acute coronary syndrome who have diagnosed or previously undiagnosed diabetes?
Existing studies on the optimal management of hyperglycaemia in people who have acute coronary syndrome and diagnosed or previously undiagnosed diabetes are generally of poor quality.
It is recommended that a large RCT is conducted for people with acute coronary syndrome and hyperglycaemia (blood glucose 11 mmol/litre and over) stratified by NSTEMI and STEMI and by known diabetes and without a previous diagnosis of diabetes.
The interventions for the trial should be intravenous insulin or subcutaneous insulin administered within 4 hours of presentation to hospital. The aim is to achieve blood glucose between 6 and 11 mmol/litre for at least 24 hours. The comparator should be standard care.
## Beta-blockers
Does continuing beta-blocker treatment beyond 1 year after a myocardial infarction (MI) improve outcomes for people with normal left ventricular systolic function?
Recent cohort studies have suggested that continuing treatment with a beta-blocker beyond a year after an acute MI may not confer any benefit to the person in terms of reduced morbidity or mortality. This is particularly relevant given recent changes in acute management strategies. While beta-blockers are valuable in reducing mortality and morbidity for up to a year after an MI, they have side effects and represent an additional treatment burden to people who are already taking many other medications. However, there is also some suggestion that there are risks associated with withdrawal of beta-blockers in this population. The balance of risks and benefits of long-term beta blockade has not been clearly determined, particularly in the context of modern acute treatment of MI.# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice.
# Dual antiplatelet therapy for acute STEMI intended for primary PCI
Recommendation 1.1.11
## Why the committee made the recommendation
Evidence was reviewed comparing the clinical effectiveness of clopidogrel, prasugrel and ticagrelor, each in combination with aspirin, at time-points of 30 days and 1 year. Prasugrel and ticagrelor were more effective than clopidogrel at both time-points. In a network meta-analysis of the 30‑day data, prasugrel was more effective than ticagrelor, although with some uncertainty around this conclusion. Prasugrel was more effective than ticagrelor at 1 year with noteworthy differences in all-cause mortality and re‑infarction. A detailed cost-effectiveness analysis was also performed incorporating data at both time-points with either prasugrel or ticagrelor being most cost effective in different scenarios using different clinical data. The results favouring prasugrel were driven by the ISAR‑REACT 5 trial that directly compared ticagrelor and prasugrel and these were considered the most relevant. The committee agreed that clinical evidence and cost-effectiveness results are directly applicable to the treatment of ST‑segment elevation myocardial infarction (STEMI) in the NHS, and recommended prasugrel for people with STEMI undergoing percutaneous coronary intervention (PCI).
The final wording of the recommendation reflects the wording of the summary of product characteristics for prasugrel. If there is particular concern about bleeding risk from prasugrel in a person aged 75 or over, either ticagrelor or clopidogrel might be used instead; although ticagrelor is the more cost effective of the two, it also carries a higher bleeding risk.
An exception was added for people needing anticoagulation for a separate reason (for example, ongoing atrial fibrillation). For these people, clopidogrel is preferred because of the high bleeding risk of full anticoagulation plus prasugrel.
## How the recommendation might affect practice
In the UK, prasugrel is currently used less than ticagrelor or clopidogrel. The recommendation will therefore require a change in prescribing for most centres, but should be easily achievable. Prasugrel costs less than ticagrelor, but considerably more than clopidogrel, and although some areas will see a cost saving from switching to prasugrel from ticagrelor, the overall effect of this recommendation will be an increase in cost to the NHS.
Return to recommendations
# Antithrombin therapy during primary PCI for acute STEMI
Recommendations 1.1.12 and 1.1.13
## Why the committee made the recommendations
When considering the evidence on the effectiveness of bivalirudin for people with acute STEMI undergoing primary PCI, the committee gave more weight to studies that were closest to current UK practice. These included studies that used bailout or selective, rather than routine, glycoprotein inhibitors (GPIs) and radial artery rather than femoral artery access. The committee concluded that there was no convincing difference between bivalirudin and the main alternative, heparin, in terms of mortality, and that bivalirudin is inferior to heparin in reducing the need for subsequent unplanned revascularisation. The committee discussed data on bleeding risk and agreed that there is no clinically significant difference between bivalirudin and heparin when radial access is used, but bivalirudin probably lowers the bleeding risk when access via the femoral artery is needed. The committee noted that heparin is cheaper than bivalirudin and easier to administer.
## How the recommendations might affect practice
The committee agreed that the recommendations generally reflect current practice and are not expected to result in a substantial resource impact to the NHS in England.
Return to recommendations
# Complete revascularisation with PCI or culprit vessel only PCI for acute STEMI
Recommendations 1.1.16 and 1.1.17
## Why the committee made the recommendations
Evidence showed that complete revascularisation with multivessel PCI reduced cardiovascular mortality, myocardial infarction (MI) and repeat revascularisation at 1 year, compared with culprit vessel only PCI for people with acute STEMI without cardiogenic shock. It was also associated with lower overall costs.
Although the evidence clearly favoured complete revascularisation, there was less certainty about the timing of the non-culprit procedure. There are a number of different possible approaches to multivessel PCI: undertaking multivessel revascularisation at the time of primary PCI; treating the culprit vessel during the primary procedure and then bringing the person back to the catheter laboratory for revascularisation of other vessels later in the index admission; or treating the culprit vessel during primary PCI, discharging the person and then electively readmitting them for further revascularisation. The committee agreed that multivessel PCI during the index admission should be considered, either at the time of primary PCI or later during the same admission. They were concerned that the clinical benefits may be lower and costs may be higher when people are discharged and readmitted, and noted that delaying treatment of the non-culprit lesions is worrying for patients. However, they agreed that the optimal timing within the index admission will depend on a number of variables and is best left to the discretion of the clinical team.
People with cardiogenic shock were excluded from these studies of multivessel PCI and the committee agreed that, in view of the results from the separate CULPRIT-SHOCK trial, it was not appropriate to recommend multivessel PCI for this group during the index admission.
## How the recommendations might affect practice
Current practice is variable across centres and also within centres. Some offer multivessel PCI during the first procedure for acute STEMI but others may postpone this (either to later within the index admission or to a later readmission). Some operate on the culprit vessel only. The recommendations are therefore likely to result in a change in practice, but not for all centres or all professionals performing PCI. Because the recommendations allow for multivessel PCI to be either at the time of primary PCI or later within the index admission, they offer flexibility to accommodate situations in which there are a number of other people waiting for primary PCI. Healthcare professionals can move on to treat the next person after completing revascularisation of the culprit vessel, minimising the overall impact on primary PCI services.
There will be a resource impact for centres not currently undertaking multivessel PCI, because multivessel PCI has higher costs than culprit vessel only PCI. Audit data reported by MINAP (the Myocardial Ischaemia National Audit Project) between April 2016 and March 2017 show there were 33,797 cases of STEMI reported in England, Wales, Northern Ireland and the Isle of Man. It is estimated that around 30% will present with multivessel disease, which would be around 10,000 people. However, it is unclear for how many of these people multivessel PCI would be suitable. The change from current practice is likely to be cost saving overall because of the reduction in later revascularisation procedures.
Return to recommendations
# Drug-eluting stents
Recommendations 1.1.18 and 1.2.18
## Why the committee made the recommendations
Evidence from angiography studies showed that drug-eluting stents are less likely to fail than bare metal stents in terms of both recurrence of obstruction to the target vessel and the need for further revascularisation. The evidence also shows that drug-eluting stents may be beneficial in reducing deaths (all-cause and cardiac) and there is a reduced incidence of MI in the 3 years after revascularisation when drug-eluting stents are used. Costs of drug-eluting stents are higher than bare metal stents, but analyses using current cost and benefit data suggest that they are a cost-effective use of resources.
## How the recommendations might affect practice
The use of drug-eluting stents has been slowly increasing over recent years in the UK and the most recent national audit data show that 91% of PCIs for acute coronary syndromes used stents and 97% of these used drug-eluting stents. The recommendation will therefore involve little change from current practice and will not have a substantial resource impact for the NHS in England.
Return to recommendations
# Antiplatelet therapy for STEMI not treated with PCI
Recommendations 1.1.24 and 1.1.25
## Why the committee made the recommendations
The UK licence for prasugrel is for people with acute coronary syndrome who are proceeding to coronary angiography with a view to PCI. Although this is usual practice for most people with STEMI, for some people, either medical management without coronary revascularisation or coronary artery surgery are better options. Direct evidence in these patient groups was lacking; the evidence comparing the clinical effectiveness of clopidogrel and ticagrelor was largely for people receiving PCI. This showed convincing superiority of ticagrelor in reducing mortality (cardiac and all-cause) and in preventing re‑infarction and the need for future revascularisation procedures, although there was some evidence of an increased risk of bleeding complications. The committee agreed to recommend ticagrelor for people with STEMI having medical management unless they are at high risk of bleeding when clopidogrel or no second antiplatelet may be the safer option. However, the committee were aware that some of the excess bleeding risk comes from complications of a PCI procedure, which is not relevant to this particular group of people with acute coronary syndrome. They therefore made a recommendation to offer ticagrelor in most cases but to consider clopidogrel as an alternative when the bleeding risk is high.
## How the recommendations might affect practice
In the UK, both ticagrelor and clopidogrel are currently used for STEMI that is managed without PCI. The recommendations require a change in practice for most, but not all, people who would otherwise receive clopidogrel. Ticagrelor costs considerably more than clopidogrel, and although the recommendations apply to a minority of people with STEMI, the effect will be an increase in cost to the NHS.
Return to recommendations
# Initial antithrombin therapy for unstable angina and NSTEMI
Recommendations 1.2.3 and 1.2.16
## Why the committee made the recommendations
The 2010 NICE guideline on unstable angina and NSTEMI recommended fondaparinux rather than low molecular weight heparin for initial management. The recommendation was based mainly on evidence from a single large study (the OASIS‑5 study). This study showed a small risk of catheter thrombosis when fondaparinux was the only antithrombin used before angiography, and therefore the 2010 guideline recommended not to use fondaparinux when angiography is planned within 24 hours. The thrombosis risk was noted by the OASIS‑5 investigators before the study ended, and in the later phase of the study, people were given intravenous unfractionated heparin with fondaparinux during angiography; this appeared to remove the excess risk of catheter thrombosis. Two further small studies published after 2010 have confirmed that giving unfractionated heparin during angiography to people already receiving fondaparinux removed the excess risk of catheter thrombosis. The committee considered that unfractionated heparin is already used in this way in many centres, agreed with the 2010 guideline that fondaparinux is the most cost-effective option, and were able to remove the caveat about avoiding fondaparinux if catheterisation is planned within 24 hours. They recommended that fondaparinux should be given to people who are not at high risk of bleeding unless they are having immediate angiography. People receiving fondaparinux should be given additional systemic unfractionated heparin in the catheter laboratory.
## How the recommendations might affect practice
Fondaparinux is already used before angiography in many centres in the UK, with additional unfractionated heparin given during the procedure. The recommendations will affect those centres currently withholding fondaparinux from people having angiography in the next 24 hours. Fondaparinux is a cheaper option than low molecular weight heparin so the recommendation could be cost saving in these centres.
Return to recommendations
# Early invasive versus conservative management for unstable angina and NSTEMI
Recommendations 1.2.12 to 1.2.15 and 1.2.19
## Why the committee made the recommendations
The 2010 guideline on unstable angina and non-ST-segment elevation MI (NSTEMI) recommended a comprehensive assessment of baseline risk of adverse events. The committee agreed that this should influence the choice between early invasive intervention (coronary angiography, with PCI if indicated) and conservative management (initial medical management, proceeding to coronary angiography and PCI if there is evidence of recurrent ischaemia). Studies comparing these options show a short-term harm with an invasive strategy, but this is offset by the clinical benefits in the months following the procedure. A cost-effectiveness analysis found that routine early invasive intervention was cost effective in people at higher risk of adverse events, but conservative management was the most cost-effective option for people at lower risk. This was because overall health gains were greater in those at higher baseline risk.
Most of the evidence was already available at the time of the 2010 guideline, and the committee recognised that the data may be less applicable to modern practice than had been the case in 2010. Nonetheless, they agreed that early angiography should be the default recommendation for most people at intermediate or higher baseline risk of adverse outcomes. They accepted the previous committee's interpretation of the appropriate risk cut‑offs based on their detailed work mapping of the evidence to real-world UK risk data. However, the committee also recognised that the risk prediction models might be less applicable to the youngest people with unstable angina and NSTEMI who are relatively under-represented in the dataset, and therefore added a cautionary recommendation to this effect.
The committee noted that the 2010 guideline had recommended that angiography should be done within 96 hours of admission for those who are likely to benefit from an early invasive strategy. However, they considered this a conservative target and knew that angiography within 72 hours is now common practice. This allows time for a correct diagnosis, immediate stabilisation and treatment of symptoms, and transfer to a centre with PCI facilities if necessary. The available evidence does not permit a definitive statement about the optimal timing, but a recommendation to consider angiography within 72 hours was agreed.
## How the recommendations might affect practice
The recommendations largely reflect current NHS practice. Although the timeframe for early invasive management has been reduced from 96 hours, 72 hours has been specified in the NICE quality standard for a number of years and a best practice tariff on the same basis was introduced in 2017. Audit data are only currently available from the same year as the introduction of the tariff and report that, of people who are admitted to a hospital that can perform angiography, 56% received angiography within 72 hours and 69% within 96 hours. The proportion receiving angiography within 72 hours is likely to be higher since the introduction of the best practice tariff. Performing angiography earlier is likely to result in a shorter hospital stay. The recommendations are unlikely to result in a substantial resource impact for the NHS.
Return to recommendations
# Antiplatelet therapy for unstable angina and NSTEMI
Recommendations 1.2.6, 1.2.17, 1.2.20 and 1.2.21
## Why the committee made the recommendations
The committee agreed that dual antiplatelet therapy should not be offered to people with chest pain before a diagnosis of unstable angina or NSTEMI is made. In their experience, dual antiplatelet therapy had caused harm (bleeding) in some people presenting with chest pain not caused by an acute coronary syndrome.
Evidence was reviewed comparing the clinical effectiveness of clopidogrel, prasugrel and ticagrelor, each in combination with aspirin, at time-points of 30 days and 1 year. A detailed cost-effectiveness analysis for people with unstable angina or NSTEMI undergoing PCI was performed incorporating these data. Although the overall conclusion was that prasugrel is a more effective agent than ticagrelor, which in turn is more effective than clopidogrel, there was considerable uncertainty around the cost-effectiveness results, with either prasugrel or ticagrelor being most cost effective in different scenarios using different clinical data. The results favouring prasugrel were driven by the ISAR‑REACT 5 trial, in which time to angiography was much shorter than is currently achieved in the UK for people with unstable angina or NSTEMI. This could cause practical difficulty in using prasugrel because its licence effectively prevents its use before angiography, and this could leave people with unstable angina or NSTEMI without dual antiplatelet therapy for several days. The committee therefore recommended either prasugrel or ticagrelor for people with unstable angina or NSTEMI intended for PCI, depending on individual circumstances. The final wording of the recommendation reflects the wording of the summary of product characteristics for prasugrel.
Although many people with unstable angina or NSTEMI proceed to PCI, for some medical management without coronary revascularisation or coronary artery surgery are better options. Prasugrel is not licensed in these circumstances. The evidence available for medical management shows better outcomes with ticagrelor than clopidogrel. This is consistent with results from the larger datasets for people having PCI. The committee therefore recommended ticagrelor for people with unstable angina or NSTEMI having either medical management without coronary revascularisation or coronary artery surgery. However, the committee also noted that clopidogrel may be the safer agent for people who are at high risk of bleeding but still need dual antiplatelet therapy, although this is based on evidence of higher bleeding risk with ticagrelor in people with an acute coronary syndrome generally rather than specific evidence from those at higher risk. They therefore made a recommendation to consider using clopidogrel in this situation.
## How the recommendations might affect practice
In the UK, prasugrel is currently used less than ticagrelor or clopidogrel. The recommendations may therefore involve a change in practice for some centres. Prasugrel costs less than ticagrelor, but considerably more than clopidogrel, and although some areas will see a cost saving from switching to prasugrel from ticagrelor, others will see an increase where either prasugrel or ticagrelor is used instead of clopidogrel. The overall effect of these recommendations will be an increase in cost to the NHS.
Return to recommendations
# Antiplatelet therapy for people with an indication for anticoagulation
Recommendations 1.4.18 to 1.4.23
## Why the committee made the recommendations
The committee noted that current practice is to use dual antiplatelet therapy at the time of PCI, and found no evidence to recommend changing this practice for people who are on an anticoagulant at the time of admission. In practice, the anticoagulant will often be suspended for a short period (perhaps using heparin cover). The evidence available showed that continuing dual antiplatelet therapy plus an anticoagulant after the acute PCI phase increases the risk of bleeding complications, and so a recommendation raising awareness of this issue was included. The committee therefore agreed that either aspirin or the second antiplatelet agent should be stopped, but unfortunately there was no evidence to show at what point this should happen.
In the absence of any conclusive data, recommendations for treatment after the initial phase were based on the knowledge and experience of the committee. For people who have had PCI and stent insertion, they agreed that it would be safest to combine an anticoagulant with a potent antiplatelet agent (clopidogrel), whereas for those who have had medical management or had angioplasty without stenting, the anticoagulant should be combined with aspirin. There was not enough evidence for the committee to recommend a particular anticoagulant.
## How the recommendations might affect practice
Current practice is variable, with people taking different combinations of antiplatelets and anticoagulants. The number of people affected is small. It is estimated that between 5% and 15% of people with an acute coronary syndrome will have an indication for oral anticoagulation. The recommendations are mostly unchanged from the 2013 guideline and the minor changes that have been made are unlikely to result in a substantial resource impact for the NHS in England.
Return to recommendations
# Duration of beta-blocker treatment after an MI
Recommendations 1.4.26 and 1.4.27
## Why the committee made the recommendations
There was no direct evidence on the optimal duration of beta-blocker treatment for people who have had an MI but do not have reduced left ventricular ejection fraction. The 2013 guideline recommended beta-blocker treatment for at least 12 months. In the absence of any conclusive evidence, the committee agreed that they could not recommend a definite time for stopping treatment. However, they agreed that healthcare professionals should discuss the absence of clear evidence for benefit of continuing beyond 12 months with people taking beta-blockers after an MI who have normal left ventricular function. This should prompt a personalised approach to stopping or continuing beta-blockers based on the person's attitude to risk and experience of side effects.
## How the recommendations might affect practice
Beta-blockers are currently offered for at least 12 months after an MI to people without reduced left ventricular ejection fraction. Audit data show that around 97% of people with MI are discharged on beta-blockers. A discussion of the absence of clear evidence for benefit of continuing treatment beyond 12 months is likely to lead to more people deciding to stop treatment at this point. Any reduction in prescriptions for beta-blockers will be cost saving.
Return to recommendations# Context
Acute coronary syndromes due to ischaemic heart disease remain a significant cause of morbidity and mortality. In 2015, heart disease remained the leading cause of death in men and the second most common cause of death in women in England. In 2015/16, more than 58,000 people were admitted to hospital in England with a heart attack. Although many more people now survive than in the past, there remains considerable scope to reduce their future risk of death, angina, heart failure and further heart attack.
National audits continue to show variation in practice across the UK in the treatments offered for acute coronary syndromes. This, combined with evidence of novel ways of treating acute coronary syndromes and updates to existing treatments, indicates a need for an updated guideline that will help deliver best practice to the large number of people receiving treatment for acute coronary syndromes in the NHS.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# STEMI – early management\n\nNICE has produced a visual summary of the recommendations on the early management of STEMI.\n\n## Assessment\n\nImmediately assess eligibility (irrespective of age, ethnicity or sex) for coronary reperfusion therapy (either primary percutaneous coronary intervention [PCI] or fibrinolysis) in people with acute ST‑segment elevation myocardial infarction (STEMI). \n\nDo not use level of consciousness after cardiac arrest caused by suspected acute STEMI to determine whether a person is eligible for coronary angiography (with follow‑on primary PCI if indicated). \n\nDeliver coronary reperfusion therapy (either primary PCI or fibrinolysis) as quickly as possible for eligible people with acute STEMI. \n\n## Initial drug therapy\n\nOffer people with acute STEMI a single loading dose of 300-mg aspirin as soon as possible unless there is clear evidence that they are allergic to it. \n\nDo not offer routine glycoprotein\xa0IIb/IIIa inhibitors or fibrinolytic drugs before arrival at the catheter laboratory to people with acute STEMI for whom primary PCI is planned. \n\n## Coronary angiography with follow-on primary PCI\n\nOffer coronary angiography, with follow‑on primary PCI if indicated, as the preferred coronary reperfusion strategy for people with acute STEMI, if:\n\npresentation is within 12\xa0hours of onset of symptoms and\n\nprimary PCI can be delivered within 120\xa0minutes of the time when fibrinolysis could have been given. \n\nOffer coronary angiography, with follow‑on primary PCI if indicated, to people with acute STEMI and cardiogenic shock who present within 12\xa0hours of the onset of symptoms of STEMI. \n\nConsider coronary angiography, with follow‑on primary PCI if indicated, for people with acute STEMI presenting more than 12\xa0hours after the onset of symptoms if there is evidence of continuing myocardial ischaemia. \n\nConsider coronary angiography, with a view to coronary revascularisation if indicated, for people with acute STEMI who present more than 12\xa0hours after the onset of symptoms and who have cardiogenic shock or go on to develop it. \n\nConsider radial (in preference to femoral) arterial access for people undergoing coronary angiography (with follow‑on primary PCI if indicated). \n\n## Dual antiplatelet therapy for people with acute STEMI having primary PCI\n\nFor people with acute STEMI who are having primary PCI, offer:\n\nPrasugrel, as part of dual antiplatelet therapy with aspirin, if they are not already taking an oral anticoagulant (use the maintenance dose in the prasugrel summary of product characteristics; for people aged 75\xa0and over, think about whether the person's risk of bleeding with prasugrel outweighs its effectiveness, in which case offer ticagrelor or clopidogrel as alternatives)\n\nClopidogrel, as part of dual antiplatelet therapy with aspirin, if they are already taking an oral anticoagulant. Also see the NICE technology appraisal guidance on ticagrelor for the treatment of acute coronary syndromes.\n\nFor a short explanation of why the committee made the 2020 recommendation and how it might affect practice, see the rationale and impact section on dual antiplatelet therapy for people with acute STEMI having primary PCI\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: antiplatelet therapy.\n\nLoading. Please wait.\n\n## Antithrombin therapy during primary PCI\n\nOffer unfractionated heparin with bailout glycoprotein IIb/IIIa inhibitor in combination with dual antiplatelet therapy to people with acute STEMI undergoing primary PCI with radial access. \n\nConsider bivalirudin with bailout glycoprotein IIb/IIIa inhibitor in combination with dual antiplatelet therapy for people with acute STEMI undergoing primary PCI when femoral access is needed.In November 2020, use of bivalirudin with prasugrel and aspirin was off label. See NICE's information on prescribing medicines. \n\nFor a short explanation of why the committee made the 2020 recommendations and how they might affect practice, see the rationale and impact section on antithrombin therapy during primary PCI\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: antithrombin therapy in adults with STEMI intended for primary PCI.\n\nLoading. Please wait.\n\n## Thrombus extraction during primary PCI\n\nConsider thrombus aspiration during primary PCI for people with acute STEMI. \n\nDo not routinely use mechanical thrombus extraction during primary PCI for people with acute STEMI. \n\n## Complete or culprit vessel only revascularisation with PCI in people with acute STEMI treated by primary PCI\n\nOffer complete revascularisation with PCI for people with acute STEMI and multivessel coronary artery disease without cardiogenic shock. Consider doing this during the index hospital admission. \n\nConsider culprit vessel only revascularisation with PCI rather than complete revascularisation during the index procedure for people with acute STEMI and multivessel coronary artery disease with cardiogenic shock. \n\nFor a short explanation of why the committee made the 2020 recommendations and how they might affect practice, see the rationale and impact section on complete revascularisation with PCI or culprit vessel only PCI\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: culprit versus complete revascularisation.\n\nLoading. Please wait.\n\n## Drug-eluting stents in primary PCI\n\nIf stenting is indicated, offer a drug-eluting stent to people with acute STEMI undergoing revascularisation by primary PCI. \n\nFor a short explanation of why the committee made the 2020 recommendation and how it might affect practice, see the rationale and impact section on drug-eluting stents in primary PCI\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: drug-eluting stents.\n\nLoading. Please wait.\n\n## Fibrinolysis\n\nOffer fibrinolysis to people with acute STEMI presenting within 12\xa0hours of onset of symptoms if primary PCI cannot be delivered within 120\xa0minutes of the time when fibrinolysis could have been given. \n\nWhen treating people with fibrinolysis, give an antithrombin at the same time. \n\nOffer an electrocardiogram (ECG) to people with acute STEMI treated with fibrinolysis, 60\xa0to 90\xa0minutes after administration. For those who have residual ST‑segment elevation suggesting failed coronary reperfusion:\n\noffer immediate coronary angiography, with follow‑on PCI if indicated\n\ndo not repeat fibrinolytic therapy. \n\nIf a person with acute STEMI has recurrent myocardial ischaemia after fibrinolysis, seek immediate specialist cardiological advice and, if appropriate, offer coronary angiography, with follow‑on PCI if indicated. \n\nConsider coronary angiography during the same hospital admission for people with acute STEMI who are clinically stable after successful fibrinolysis. \n\n## Management for people with STEMI not treated with PCI\n\nOffer ticagrelor, as part of dual antiplatelet therapy with aspirin, to people with acute STEMI not treated with PCI, unless they have a high bleeding risk. \n\nConsider clopidogrel, as part of dual antiplatelet therapy with aspirin, or aspirin alone, for people with acute STEMI not treated with PCI, if they have a high bleeding risk. \n\nAlso see the NICE technology appraisal guidance on rivaroxaban for preventing adverse outcomes after management of acute coronary syndromes.\n\nFor a short explanation of why the committee made the 2020 recommendations and how they might affect practice, see the rationale and impact section on dual antiplatelet therapy for people with STEMI not treated with PCI\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: antiplatelet therapy.\n\nLoading. Please wait.\n\nOffer medical management to people with acute STEMI who are ineligible for any reperfusion therapy. \n\n## Tests before discharge\n\nAssess left ventricular function in all people who have had a STEMI. \n\n# NSTEMI and unstable angina – early management\n\nNICE has produced a visual summary of the recommendations on the early management of NSTEMI and unstable angina.\n\n## Initial drug therapy\n\nOffer aspirin as soon as possible to all people with unstable angina or non‑ST‑segment elevation myocardial infarction (NSTEMI) and continue indefinitely unless contraindicated by bleeding risk or aspirin hypersensitivity. \n\nOffer people with unstable angina or NSTEMI a single loading dose of 300-mg aspirin as soon as possible unless there is clear evidence that they are allergic to it. \n\nOffer fondaparinux to people with unstable angina or NSTEMI who do not have a high bleeding risk, unless they are undergoing immediate coronary angiography. \n\nSee the recommendation on unfractionated heparin in the section on coronary angiography with follow-on PCI for advice about people with unstable angina or NSTEMI who are undergoing immediate coronary angiography.\n\nFor a short explanation of why the committee made the 2020 recommendation and how it might affect practice, see the rationale and impact section on initial antithrombin therapy for people with unstable angina or NSTEMI\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: antithrombin for unstable angina and NSTEMI.\n\nLoading. Please wait.\n\nConsider unfractionated heparin, with dose adjustment guided by monitoring of clotting function, as an alternative to fondaparinux for people with unstable angina or NSTEMI and significant renal impairment (creatinine above 265\xa0micromoles per litre). \n\nCarefully consider the choice and dose of antithrombin for people with unstable angina or NSTEMI who have a high risk of bleeding associated with any of the following:\n\nadvancing age\n\nknown bleeding complications\n\nrenal impairment\n\nlow body weight. \n\nDo not offer dual antiplatelet therapy to people with chest pain before a diagnosis of unstable angina or NSTEMI is made. \n\nFor a short explanation of why the committee made the 2020 recommendation and how it might affect practice, see the rationale and impact section on dual antiplatelet therapy for people with unstable angina or NSTEMI\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: antiplatelet therapy.\n\nLoading. Please wait.\n\n## Risk assessment\n\nAs soon as the diagnosis of unstable angina or NSTEMI is made, and aspirin and antithrombin therapy have been offered, formally assess individual risk of future adverse cardiovascular events using an established risk scoring system that predicts 6‑month mortality (for example, Global Registry of Acute Cardiac Events [GRACE]). \n\nInclude in the formal risk assessment:\n\na full clinical history (including age, previous myocardial infarction [MI] and previous PCI or coronary artery bypass grafting [CABG])\n\na physical examination (including measurement of blood pressure and heart rate)\n\na resting 12‑lead ECG, looking particularly for dynamic or unstable patterns that indicate myocardial ischaemia\n\nblood tests (such as troponin\xa0I or\xa0T, creatinine, glucose and haemoglobin). \n\nRecord the results of the risk assessment in the person's care record. \n\nUse risk assessment to guide clinical management, and balance the benefit of a treatment against any risk of related adverse events in the light of this assessment. \n\nUse predicted 6‑month mortality to categorise the risk of future adverse cardiovascular events as shown in table\xa01. \n\nPredicted 6‑month mortality\n\nRisk of future adverse cardiovascular events\n\n% or below\n\nLowest\n\n>1.5% to 3.0%\n\nLow\n\n>3.0% to 6.0%\n\nIntermediate\n\n>6.0% to 9.0%\n\nHigh\n\nover 9.0%\n\nHighest\n\nCategories of risk are derived from the Myocardial Ischaemia National Audit Project (MINAP) database.\n\n## Coronary angiography with follow-on PCI\n\nOffer immediate coronary angiography to people with unstable angina or NSTEMI if their clinical condition is unstable. \n\nConsider coronary angiography (with follow‑on PCI if indicated) within 72\xa0hours of first admission for people with unstable angina or NSTEMI who have an intermediate or higher risk of adverse cardiovascular events (predicted 6‑month mortality above 3.0%) and no contraindications to angiography (such as active bleeding or comorbidity).See table\xa02 for information on the benefits and risks of early invasive treatment compared with conservative management. \n\nConsider coronary angiography (with follow‑on PCI if indicated) for people with unstable angina or NSTEMI who are initially assessed to be at low risk of adverse cardiovascular events (predicted 6‑month mortality 3.0% or less) if ischaemia is subsequently experienced or is demonstrated by ischaemia testing.See table\xa02 for information on the benefits and risks of early invasive treatment compared with conservative management. \n\nBe aware that some younger people with low risk scores for mortality at 6\xa0months may still be at high risk of adverse cardiovascular events and may benefit from early angiography. \n\nBenefits/risks/other factors\n\nCoronary angiography and possible percutaneous coronary intervention (PCI) within 72\xa0hours\n\nConservative management with later coronary angiography if problems continue or develop\n\nBenefits (advantages)\n\nReduced deaths from all causes at 6\xa0to 12\xa0months and at 2\xa0years. Reduced deaths from heart problems at 1\xa0and 2\xa0years.\n\nReduced incidence of myocardial infarction (MI) at 30\xa0days, 6\xa0to 12\xa0months and 2\xa0years.\n\nReduced incidence of stroke at 1\xa0year, particularly in people at high risk of future adverse events.\n\nReduced readmission to hospital and difficult-to-treat angina in the medium term, particularly in people at high risk of future adverse events.\n\nPsychological benefits – people are not anxious about delaying angiography.\n\nAvoid the immediate risks of invasive treatment, including:\n\ndeath within 4\xa0months related to the procedure from causes other than MI\n\nprocedure-related MI\n\nmajor bleeding in hospital and up to 2\xa0years after the procedure.\n\nThese are particularly relevant for people at low risk of future adverse events.\n\nPsychological benefits – people are not anxious about having an invasive procedure.\n\nRisks (disadvantages)\n\nIncreased risk of death during the first 4\xa0months, particularly for people at low risk of future adverse events.\n\nRisk of procedure-related MI.\n\nIncreased risk of major bleeding during the index admission, at 30\xa0days and 2\xa0years.\n\nEmergency treatment leaves little time for shared decision making.\n\nIncreased risk of MI after 6\xa0months.\n\nIncreased risk of stroke at 1\xa0year, particularly in the people at high risk of future adverse events.\n\nPsychological factors – people may be anxious about delaying angiography.\n\nOther factors\n\nRecent advances in PCI might increase early benefit, particularly reducing bleeding.\n\nCoronary angiography within 72\xa0hours ensures speedy intervention while allowing time for the correct diagnosis, identifying other conditions and treating symptoms.\n\n–\n\nFor a short explanation of why the committee made the 2020 recommendations and how they might affect practice, see the rationale and impact section on early invasive versus conservative management for people with unstable angina or NSTEMI\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: early invasive versus conservative management for unstable angina and NSTEMI.\n\nLoading. Please wait.\n\nOffer systemic unfractionated heparin in the cardiac catheter laboratory to people with unstable angina or NSTEMI who are undergoing PCI whether or not they have already received fondaparinux.In November 2020, this was an off‑label use of unfractionated heparin. See NICE's information on prescribing medicines. \n\nFor a short explanation of why the committee made the 2020 recommendation and how it might affect practice, see the rationale and impact section on antithrombin therapy for people with unstable angina or NSTEMI\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: antithrombin for unstable angina and NSTEMI.\n\nLoading. Please wait.\n\nFor people with unstable angina or NSTEMI who are having coronary angiography, offer:\n\nprasugrel or ticagrelor, as part of dual antiplatelet therapy with aspirin, if they have no separate indication for ongoing oral anticoagulation (if using prasugrel, only give it once coronary anatomy has been defined and PCI is intended, and use the maintenance dose in the prasugrel summary of product characteristics; for people aged 75\xa0and over, think about whether the person's risk of bleeding with prasugrel outweighs its effectiveness)\n\nclopidogrel, as part of dual antiplatelet therapy with aspirin, if they have a separate indication for ongoing oral anticoagulation. \n\nFor a short explanation of why the committee made the 2020 recommendation and how it might affect practice, see the rationale and impact section on dual antiplatelet therapy for people with unstable angina or NSTEMI\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: antiplatelet therapy.\n\nLoading. Please wait.\n\nIf stenting is indicated, offer a drug-eluting stent to people with unstable angina or NSTEMI undergoing revascularisation by PCI. \n\nFor a short explanation of why the committee made the 2020 recommendation and how it might affect practice, see the rationale and impact section on drug-eluting stents\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: drug-eluting stents.\n\nLoading. Please wait.\n\n## Management when PCI is not indicated\n\nConsider conservative management without early coronary angiography for people with unstable angina or NSTEMI who have a low risk of adverse cardiovascular events (predicted 6‑month mortality 3.0% or less). \n\nFor a short explanation of why the committee made the 2020 recommendation and how it might affect practice, see the rationale and impact section on early invasive versus conservative management for people with unstable angina or NSTEMI\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: early invasive versus conservative management for unstable angina and NSTEMI.\n\nLoading. Please wait.\n\nOffer ticagrelor, as part of dual antiplatelet therapy with aspirin, to people with unstable angina or NSTEMI when PCI is not indicated, unless they have a high bleeding risk. \n\nConsider clopidogrel, as part of dual antiplatelet therapy with aspirin, or aspirin alone, for people with unstable angina or NSTEMI when PCI is not indicated, if they have a high bleeding risk. \n\nAlso see the NICE technology appraisal guidance on rivaroxaban for preventing adverse outcomes after management of acute coronary syndromes.\n\nFor a short explanation of why the committee made the 2020 recommendations and how they might affect practice, see the rationale and impact section on antiplatelet therapy for people with unstable angina or NSTEMI\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: antiplatelet therapy.\n\nLoading. Please wait.\n\n## Advice on management strategies\n\nOffer people with unstable angina or NSTEMI clear information about the risks and benefits of the treatments offered so that they can make informed choices about management strategies. Information should be appropriate to the person's underlying risk of a future adverse cardiovascular event and any comorbidities. \n\nWhen advising people with unstable angina or NSTEMI about the choice of revascularisation strategy (PCI or CABG), take account of coronary angiographic findings, comorbidities, and the benefits and risks of each intervention. \n\nWhen the role of revascularisation or the revascularisation strategy is unclear, resolve this by discussion involving an interventional cardiologist, cardiac surgeon and other healthcare professionals relevant to the needs of the person. Discuss the choice of revascularisation strategy with the person. \n\n## Tests before discharge\n\nTo detect and quantify inducible ischaemia, consider ischaemia testing before discharge for people whose condition has been managed conservatively and who have not had coronary angiography. \n\nAssess left ventricular function in all people who have had an NSTEMI. \n\nConsider assessing left ventricular function in all people with unstable angina. \n\nRecord measures of left ventricular function in the person's care record and in correspondence with the primary healthcare team and the person. \n\n# Hyperglycaemia in acute coronary syndromes\n\n## Managing hyperglycaemia in inpatients within 48\xa0hours of acute coronary syndrome\n\nManage hyperglycaemia in people admitted to hospital for an acute coronary syndrome by keeping blood glucose levels below 11.0\xa0mmol/litre while avoiding hypoglycaemia. In the first instance, consider a dose-adjusted insulin infusion with regular monitoring of blood glucose levels. \n\nDo not routinely offer intensive insulin therapy (an intravenous infusion of insulin and glucose with or without potassium) to manage hyperglycaemia (blood glucose above 11.0\xa0mmol/litre) in people admitted to hospital for an acute coronary syndrome unless clinically indicated. \n\n## Identifying people with hyperglycaemia after acute coronary syndrome who are at high risk of developing diabetes\n\nOffer all people with hyperglycaemia after acute coronary syndrome and without known diabetes tests for:\n\nHbA1c levels before discharge\n\nfasting blood glucose levels no earlier than 4\xa0days after the onset of acute coronary syndrome.These tests should not delay discharge. \n\nDo not routinely offer oral glucose tolerance tests to people with hyperglycaemia after acute coronary syndrome and without known diabetes if HbA1c and fasting blood glucose levels are within the normal range. \n\n## Advice and ongoing monitoring for people with hyperglycaemia after acute coronary syndrome and without known diabetes\n\nOffer people with hyperglycaemia after acute coronary syndrome and without known diabetes lifestyle advice on the following:\n\nhealthy eating\n\nphysical exercise\n\nweight management\n\nsmoking cessation\n\nalcohol consumption. See the section on lifestyle changes after an MI for more information. \n\nAdvise people without known diabetes that if they have had hyperglycaemia after an acute coronary syndrome, they:\n\nare at increased risk of developing type\xa02 diabetes\n\nshould consult their GP if they experience the following symptoms:\n\n\n\nfrequent urination\n\nexcessive thirst\n\nweight loss\n\nfatigue\n\n\n\nshould be offered tests for diabetes at least annually. \n\nInform GPs that they should offer at least annual monitoring of HbA1c or fasting blood glucose levels to people without known diabetes who have had hyperglycaemia after an acute coronary syndrome. \n\n# Drug therapy for secondary prevention\n\nNICE has produced a visual summary of the recommendations on cardiac rehabilitation and secondary prevention.\n\nFor secondary prevention, offer people who have had MI treatment with the following drugs:\n\nangiotensin-converting enzyme (ACE) inhibitor\n\ndual antiplatelet therapy (aspirin plus a second antiplatelet) unless they have a separate indication for anticoagulation (see the section on antiplatelet therapy for people with an ongoing separate indication for anticoagulation)\n\nbeta-blocker\n\nstatin. [2007, amended 2020]\n\nEnsure that a clear management plan is available to the person who has had an MI and is also sent to the GP, including:\n\ndetails and timing of any further drug titration\n\nmonitoring of blood pressure\n\nmonitoring of renal function. \n\nOffer all people who have had an MI an assessment of bleeding risk at their follow‑up appointment. \n\nAlso see the:\n\nNICE guideline on medicines adherence\n\nNICE guideline on cardiovascular disease: risk assessment and risk reduction, including lipid modification\n\nNICE technology appraisal guidance on alirocumab for treating primary hypercholesterolaemia and mixed dyslipidaemia\n\nNICE technology appraisal guidance on evolocumab for treating primary hypercholesterolaemia and mixed dyslipidaemia\n\nNICE technology appraisal guidance on rivaroxaban for preventing atherothrombotic events in people with coronary or peripheral artery disease.\n\n## ACE inhibitors\n\nOffer people who present acutely with an MI, an ACE inhibitor as soon as they are haemodynamically stable. Continue the ACE inhibitor indefinitely. \n\nTitrate the ACE inhibitor dose upwards at short intervals (for example, every 12\xa0to\xa024\xa0hours) before the person leaves hospital until the maximum tolerated or target dose is reached. If it is not possible to complete the titration during this time, it should be completed within 4\xa0to\xa06\xa0weeks of hospital discharge. \n\nDo not offer combined treatment with an ACE inhibitor and an angiotensin\xa0II receptor blocker (ARB) to people after an MI, unless there are other reasons to use this combination. \n\nAfter an MI, offer people who are intolerant to ACE inhibitors, an ARB instead of an ACE inhibitor. \n\nRenal function, serum electrolytes and blood pressure should be measured before starting an ACE inhibitor or ARB and again within 1\xa0or\xa02\xa0weeks of starting treatment. People should have appropriate monitoring as the dose is titrated upwards, until the maximum tolerated or target dose is reached, and then at least annually. More frequent monitoring may be needed in people who are at increased risk of deterioration in renal function. People with chronic heart failure should be monitored in line with the NICE guideline on chronic heart failure in adults. \n\nOffer an ACE inhibitor to people who have had an MI more than 12\xa0months ago. Titrate to the maximum tolerated or target dose (over a 4‑ to 6‑week period) and continue indefinitely. \n\nOffer people who have had an MI more than 12\xa0months ago and who are intolerant to ACE inhibitors an ARB instead of an ACE inhibitor. \n\n## Antiplatelet therapy\n\nOffer aspirin to all people after an MI and continue it indefinitely, unless they are aspirin intolerant or have an indication for anticoagulation (see the section on antiplatelet therapy for people with an ongoing separate indication for anticoagulation). [2007, amended 2013]\n\nOffer aspirin to people who have had an MI more than 12\xa0months ago and continue it indefinitely. \n\nContinue dual antiplatelet therapy for up to 12\xa0months after an MI unless contraindicated (see recommendations 1.1.11, 1.1.24, 1.1.25, 1.2.17, 1.2.20 and 1.2.21 for more information about dual antiplatelet therapy). \n\nFor people with aspirin hypersensitivity who have had an MI, clopidogrel monotherapy should be considered as an alternative treatment. \n\nPeople with a history of dyspepsia should be considered for treatment in line with the NICE guideline on gastro-oesophageal reflux disease and dyspepsia in adults. [2007, amended 2013]\n\nAfter appropriate treatment, people with a history of aspirin-induced ulcer bleeding whose ulcers have healed and who are negative for Helicobacter pylori should be considered for treatment in line with the NICE guideline on gastro-oesophageal reflux disease and dyspepsia in adults. [2007, amended 2013]\n\nOffer clopidogrel instead of aspirin to people who also have other clinical vascular disease, in line with the NICE technology appraisal guidance on clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events, and who have:\n\nhad an MI and stopped dual antiplatelet therapy or\n\nhad an MI more than 12\xa0months ago. \n\nFor people who have a separate indication for anticoagulation, take into account all of the following when thinking about the duration and type (dual or single) of antiplatelet therapy in the 12\xa0months after an acute coronary syndrome:\n\nbleeding risk\n\nthromboembolic risk\n\ncardiovascular risk\n\nperson's wishes.Be aware that the optimal duration of aspirin therapy has not been established, and that long-term continuation of aspirin, clopidogrel and oral anticoagulation (triple therapy) significantly increases bleeding risk. \n\nFor people already on anticoagulation who have had PCI, continue anticoagulation and clopidogrel for up to 12\xa0months. If the person is taking a direct oral anticoagulant, adjust the dose according to bleeding risk, thromboembolic risk and cardiovascular risk. \n\nFor people with a new indication for anticoagulation who have had PCI, offer clopidogrel (to replace prasugrel or ticagrelor) for up to 12\xa0months and an oral anticoagulant licensed for the indication, which best matches the person's:\n\nbleeding risk\n\nthromboembolic risk\n\ncardiovascular risk\n\nwishes. \n\nFor people already on anticoagulation, or those with a new indication, who have not had PCI (medical management, CABG), continue anticoagulation and, unless there is a high risk of bleeding, consider continuing aspirin (or clopidogrel for people with contraindication for aspirin) for up to 12\xa0months. \n\nDo not routinely offer prasugrel or ticagrelor in combination with an anticoagulant that is needed for an ongoing separate indication for anticoagulation. \n\nFor people with an ongoing indication for anticoagulation 12\xa0months after an MI, take into consideration all of the following when thinking about the need for continuing antiplatelet therapy:\n\nindication for anticoagulation\n\nbleeding risk\n\nthromboembolic risk\n\ncardiovascular risk\n\nperson's wishes. \n\nFor a short explanation of why the committee made the 2020 recommendations and how they might affect practice, see the rationale and impact section on antiplatelet therapy for people with an indication for anticoagulation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: combination therapy.\n\nLoading. Please wait.\n\n## Beta-blockers\n\nOffer people a beta-blocker as soon as possible after an MI, when the person is haemodynamically stable. \n\nCommunicate plans for titrating beta-blockers up to the maximum tolerated or target dose – for example, in the discharge summary. \n\nConsider continuing a beta-blocker for 12\xa0months after an MI for people without reduced left ventricular ejection fraction. \n\nDiscuss the potential benefits and risks of stopping or continuing beta-blockers beyond 12\xa0months after an MI for people without reduced left ventricular ejection fraction. Include in the discussion:\n\nthe lack of evidence on the relative benefits and harms of continuing beyond 12\xa0months\n\nthe person's experience of adverse effects. \n\nFor a short explanation of why the committee made the 2020 recommendations and how they might affect practice, see the rationale and impact section on duration of beta-blocker treatment after an MI\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: beta-blockers.\n\nLoading. Please wait.\n\nContinue a beta-blocker indefinitely in people with reduced left ventricular ejection fraction. \n\nOffer all people who have had an MI more than 12\xa0months ago, who have reduced left ventricular ejection fraction, a beta-blocker whether or not they have symptoms. For people with heart failure plus reduced left ventricular ejection fraction, manage the condition in line with the NICE guideline on chronic heart failure in adults. \n\nDo not offer people without reduced left ventricular ejection fraction or heart failure, who have had an MI more than 12\xa0months ago, treatment with a beta-blocker unless there is an additional clinical indication for a beta-blocker. \n\n## Calcium channel blockers\n\nDo not routinely offer calcium channel blockers to reduce cardiovascular risk after an MI. \n\nIf beta-blockers are contraindicated or need to be discontinued, diltiazem or verapamil may be considered for secondary prevention in people without pulmonary congestion or reduced left ventricular ejection fraction. \n\nFor people whose condition is stable after an MI, calcium channel blockers may be used to treat hypertension and/or angina. For people with heart failure with reduced ejection fraction, use amlodipine, and avoid verapamil, diltiazem and short-acting dihydropyridine agents in line with the NICE guideline on chronic heart failure in adults. [2007, amended 2020]\n\n## Potassium channel activators\n\nDo not offer nicorandil to reduce cardiovascular risk after an MI. \n\n## Aldosterone antagonists in people with heart failure and reduced left ventricular ejection fraction\n\nFor people who have had an acute MI and who have symptoms and/or signs of heart failure and reduced left ventricular ejection fraction, initiate treatment with an aldosterone antagonist licensed for post‑MI treatment within 3\xa0to\xa014\xa0days of the MI, preferably after ACE inhibitor therapy. \n\nPeople who have recently had an acute MI and have clinical heart failure and reduced left ventricular ejection fraction, but who are already being treated with an aldosterone antagonist for a concomitant condition (for example, chronic heart failure), should continue with the aldosterone antagonist or an alternative, licensed for early post‑MI treatment. \n\nFor people who have had a proven MI in the past and heart failure due to reduced left ventricular ejection fraction, treatment with an aldosterone antagonist should be in line with the NICE guideline on chronic heart failure in adults. \n\nMonitor renal function and serum potassium before and during treatment with an aldosterone antagonist. If hyperkalaemia is a problem, halve the dose of the aldosterone antagonist or stop the drug. \n\n## Statins and other lipid-lowering agents\n\nStatin therapy is recommended for adults with clinical evidence of cardiovascular disease in line with the NICE guideline on cardiovascular disease. \n\n# Coronary revascularisation after an MI\n\nOffer a cardiological assessment to everyone who has had a previous MI, but not had coronary revascularisation to consider whether coronary revascularisation is appropriate. This should take into account comorbidity. [2007, amended 2020]\n\n# Selected patient subgroups\n\n## People with reduced left ventricular ejection fraction\n\nPeople who have reduced left ventricular ejection fraction should be considered for an implantable cardioverter defibrillator in line with NICE technology appraisal guidance on implantable cardioverter defibrillators and cardiac resynchronisation therapy for arrhythmias and heart failure. \n\n## People with hypertension\n\nTreat hypertension in line with the NICE guideline on hypertension in adults. [2007, amended 2013]\n\n# Communication of diagnosis and advice\n\nAfter an acute MI, ensure that the following are part of every discharge summary:\n\nconfirmation of the diagnosis of acute MI\n\nresults of investigations\n\nincomplete drug titrations\n\nfuture management plans\n\nadvice on secondary prevention. [2007, amended 2013]\n\nOffer a copy of the discharge summary to the person. \n\n# Cardiac rehabilitation after an MI\n\nAll people (regardless of their age) should be given advice about and offered a cardiac rehabilitation programme with an exercise component. \n\nCardiac rehabilitation programmes should provide a range of options, and people should be encouraged to attend all those appropriate to their clinical needs. People should not be excluded from the entire programme if they choose not to attend certain components. \n\nIf a person has cardiac or other clinical conditions that may worsen during exercise, these should be treated if possible before they are offered the exercise component of cardiac rehabilitation. For some people, the exercise component may be adapted by an appropriately qualified healthcare professional. \n\nPeople with reduced left ventricular ejection fraction who are stable can safely be offered the exercise component of cardiac rehabilitation. \n\n## Encouraging people to attend\n\nDeliver cardiac rehabilitation in a non-judgemental, respectful and culturally sensitive manner. Consider employing bilingual peer educators or cardiac rehabilitation assistants who reflect the diversity of the local population. \n\nEstablish people's health beliefs and their specific illness perceptions before offering appropriate lifestyle advice and to encourage attendance to a cardiac rehabilitation programme. \n\nOffer cardiac rehabilitation programmes designed to motivate people to attend and complete the programme. Explain the benefits of attending. \n\nDiscuss with the person any factors that might stop them attending a cardiac rehabilitation programme, such as transport difficulties. \n\nOffer cardiac rehabilitation programmes in a choice of venues (including at the person's home, in hospital and in the community) and at a choice of times of day, for example, sessions outside of working hours. Explain the options available. \n\nProvide a range of different types of exercise, as part of the cardiac rehabilitation programme, to meet the needs of people of all ages, or those with significant comorbidity. Do not exclude people from the whole programme if they choose not to attend specific components. \n\nOffer single-sex cardiac rehabilitation programme classes if there is sufficient demand. \n\nEnrol people who have had an MI in a system of structured care, ensuring that there are clear lines of responsibility for arranging the early initiation of cardiac rehabilitation. \n\nBegin cardiac rehabilitation as soon as possible after admission before discharge from hospital, and invite the person to a cardiac rehabilitation session. This should start within 10\xa0days of their discharge from hospital. \n\nContact people who do not start or do not continue to attend the cardiac rehabilitation programme with a further reminder, such as:\n\na motivational letter\n\na prearranged visit from a member of the cardiac rehabilitation team\n\na telephone call\n\na combination of the above. \n\nSeek feedback from cardiac rehabilitation programme users and aim to use this feedback to increase the number of people starting and attending the programme. \n\nBe aware of the wider health and social care needs of a person who has had an MI. Offer information and sources of help on:\n\neconomic issues\n\nwelfare rights\n\nhousing and social support issues. \n\nMake cardiac rehabilitation equally accessible and relevant to all people after an MI, particularly people from groups that are less likely to access this service. These include people from black, Asian and minority ethnic groups, older people, people from lower socioeconomic groups, women, people from rural communities, people with a learning disability and people with mental and physical health conditions. [2007, amended 2013]\n\nEncourage all staff, including senior medical staff, involved in providing care for people after an MI, to actively promote cardiac rehabilitation. \n\n## Health education and information needs\n\nComprehensive cardiac rehabilitation programmes should include health education and stress management components. \n\nA home-based programme validated for people who have had an MI (such as NHS Lothian's heart manual) that incorporates education, exercise and stress management components with follow ups by a trained facilitator may be used to provide comprehensive cardiac rehabilitation. \n\nTake into account the physical and psychological status of the patient, the nature of their work and their work environment when giving advice on returning to work. \n\nBe up to date with the latest Driver and Vehicle Licensing Agency (DVLA) guidelines. Regular updates are published by the DVLA. \n\nAfter an MI without complications, people who wish to travel by air should seek advice from the Civil Aviation Authority. People who have had a complicated MI need expert individual advice. [2007, amended 2013]\n\nPeople who have had an MI who hold a pilot's licence should seek advice from the Civil Aviation Authority. \n\nTake into account the person's physical and psychological status, as well as the type of activity planned when offering advice about the timing of returning to normal activities. \n\nAn estimate of the physical demand of a particular activity, and a comparison between activities, can be made using tables of metabolic equivalents (METS) of different activities (for further information, please refer to the information from the Centers for Disease Control and Prevention). Advise people how to use a perceived exertion scale to help monitor physiological demand. People who have had a complicated MI may need expert advice. \n\nAdvice on competitive sport may need expert assessment of function and risk, and is dependent on what sport is being discussed and the level of competitiveness. \n\n## Psychological and social support\n\nOffer stress management in the context of comprehensive cardiac rehabilitation. \n\nDo not routinely offer complex psychological interventions such as cognitive behavioural therapy. \n\nInvolve partners or carers in the cardiac rehabilitation programme if the person wishes. \n\nFor recommendations on managing clinical anxiety or depression, refer to the NICE guidelines on anxiety, depression in adults and depression in adults with a chronic physical health problem. \n\n## Sexual activity\n\nReassure people that after recovery from an MI, sexual activity presents no greater risk of triggering a subsequent MI than if they had never had an MI. \n\nAdvise people who have made an uncomplicated recovery after their MI that they can resume sexual activity when they feel comfortable to do so, usually after about 4\xa0weeks. \n\nRaise the subject of sexual activity within the context of cardiac rehabilitation and aftercare for people who have had an MI. \n\n# Lifestyle changes after an MI\n\n## Changing diet\n\nAdvise people to eat a Mediterranean-style diet (more bread, fruit, vegetables and fish; less meat; and replace butter and cheese with products based on plant oils). \n\nDo not routinely recommend eating oily fish for the sole purpose of preventing another MI. If people choose to consume oily fish after an MI, be aware that there is no evidence of harm, and fish may form part of a Mediterranean-style diet. \n\nDo not offer or advise people to use the following to prevent another MI:\n\nomega-3 fatty acid capsules\n\nomega-3 fatty acid supplemented foods. \n\nIf people choose to take omega‑3 fatty acid capsules or eat omega‑3 fatty acid supplemented foods, be aware that there is no evidence of harm. \n\nAdvise people not to take supplements containing beta-carotene. Do not recommend antioxidant supplements (vitamin\xa0E and/or\xa0C) or folic acid to reduce cardiovascular risk. \n\nOffer people an individual consultation to discuss diet, including their current eating habits, and advice on improving their diet. \n\nGive people consistent dietary advice tailored to their needs. \n\nGive people healthy eating advice that can be extended to the whole family. \n\n## Alcohol consumption\n\nFor advice on alcohol consumption, see the UK government drinking guidelines. \n\n## Regular physical activity\n\nAdvise people to undertake regular physical activity sufficient to increase exercise capacity. \n\nAdvise people to be physically active for 20\xa0to 30\xa0minutes a day to the point of slight breathlessness. Advise people who are not active to this level to increase their activity in a gradual, step-by-step way, aiming to increase their exercise capacity. They should start at a level that is comfortable, and increase the duration and intensity of activity as they gain fitness. \n\nAdvice on physical activity should involve a discussion about current and past activity levels and preferences. The benefit of exercise may be enhanced by tailored advice from a suitably qualified professional. \n\n## Smoking cessation\n\nAdvise all people who smoke to stop and offer assistance from a smoking cessation service in line with the NICE guideline on stop smoking interventions and services. \n\nIf a person is unable or unwilling to accept a referral to a stop smoking service, they should be offered pharmacotherapy in line with the NICE guideline on stop smoking interventions and services. [2007, amended 2020]\n\n## Weight management\n\nAfter an MI, offer all people who are overweight or obese advice and support to achieve and maintain a healthy weight in line with the NICE guideline on obesity. \n\n# Terms used in this guideline\n\n## Bailout glycoprotein IIb/IIIa inhibitor\n\nBailout glycoprotein inhibitor (GPI) refers to the use of GPI when the PCI operator has not intended to use GPI from the outset, but considers that clinical or angiographic features (such as worsening or persistent thrombus burden) have changed during the course of the procedure, such that there may be benefit to giving the patient GPI.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Dual antiplatelet therapy for people aged 75\xa0and over\n\nWhat is the most clinically and cost-effective dual antiplatelet therapy for people aged 75\xa0and over with an acute coronary syndrome, who are having percutaneous coronary intervention (PCI)? \n\nThe evidence reviewed for this guideline found that prasugrel is the most clinically and cost-effective antiplatelet therapy when used with aspirin for the general acute coronary syndrome population having PCI, particularly for people with ST‑segment elevation myocardial infarction (STEMI). However, the summary of product characteristics for prasugrel states that its use in people aged 75\xa0and over 'is generally not recommended and should only be undertaken with caution after a careful individual benefit/risk evaluation by the prescribing physician indicates that benefits in terms of prevention of ischaemic events outweigh the risk of serious bleedings'. There were not enough data available for this guideline to determine whether prasugrel is less effective, or even harmful, in people aged 75\xa0and over. Further research is needed to determine the optimal dual antiplatelet therapy for this group of older people.\n\n## Primary PCI and fibrinolysis in people with acute STEMI who have a long anticipated transfer time for primary PCI\n\nIn people with acute STEMI who present more than 1\xa0hour after the onset of symptoms, is a primary PCI-related delay of 120\xa0to 180\xa0minutes associated with outcomes similar to, better or worse than pre-hospital administered fibrinolysis? \n\nPrimary PCI is the preferred coronary reperfusion therapy provided it can be delivered 'in a timely fashion'. It is suggested that primary PCI is the preferred reperfusion strategy for primary PCI-related delays of at least up to 2\xa0hours. However, there is inadequate evidence to conclude whether primary PCI is still preferable at primary PCI-related time delays of more than 2\xa0hours.\n\nNo specifically designed randomised controlled trial (RCT) or observational study has addressed the issue of the extent to which primary PCI-related time delay (and other factors such as presentation delay and a person's risk profile) diminishes the advantages of primary PCI over fibrinolysis. For example, in more geographically remote areas, a short presentation delay together with an anticipated long primary PCI-related delay could favour a strategy of pre-hospital fibrinolysis.\n\nTo answer this question, an RCT of pre-hospital fibrinolysis versus primary PCI in people with acute STEMI who have a primary PCI-related time delay of 2\xa0hours or more is needed. Primary endpoints would include cardiovascular and all-cause mortality and other major adverse cardiovascular events.\n\n## Ischaemia testing\n\nWhat is the role of ischaemia testing in people after an acute coronary syndrome and what is the comparative efficacy and cost effectiveness of the different non-invasive tests (for example, stress electrocardiogram [ECG], echocardiography, radionuclide scanning and MRI)? \n\nAn increasing number of non-invasive tests are now available for the investigation of suspected myocardial ischaemia. These tests need different equipment, different clinical expertise, come at different costs and may differ in their ability to detect and quantify myocardial ischaemia. Their place in the routine investigation of patients admitted with unstable angina and non-ST‑segment elevation myocardial infarction (NSTEMI) (particularly those who have not undergone angiography), as opposed to their selective use, is not clear. Management of unstable angina and NSTEMI would be enhanced if the relative place of these investigations were better understood and an assessment of their cost effectiveness made.\n\n## Relationship between volume of procedures and clinical outcomes\n\nWhat is the relationship between hospital volume of primary PCI procedures and optimal outcomes in people with acute STEMI? \n\nThere is a suggestion that outcomes may be better in larger-volume primary PCI units, and some retrospective registries have reported data to support this. However, the quality of the data is poor and still leaves the question open. In the UK, primary PCI is provided by units that vary greatly in the number of cases per year. The development of services has been ad\xa0hoc and not designed specifically around the provision of primary PCI. If it was possible to conclusively show that people were or were not better off having treatment in larger-volume units, then it would have important implications for the national provision of primary PCI.\n\n## Risk assessment – risk scoring systems\n\nWhat is the clinical and cost effectiveness of the systematic use of risk scoring systems (in addition to clinical assessment) for ischaemic outcomes and bleeding complications in the management of unstable angina and NSTEMI (at all levels of risk) compared with clinical assessment alone? \n\nMost risk scoring systems currently predict the likelihood of mortality or ischaemic cardiovascular events at various times after a patient's admission to hospital with an acute coronary syndrome. A number of interventions (such as drugs and revascularisation procedures) have been shown to reduce these adverse outcomes. This effect tends to be greatest in patients at highest risk. However, as a broad generalisation, patients who are at highest ischaemic risk are also those who are at higher risk of bleeding complications associated with the use of multiple antiplatelet and antithrombin agents. There are fewer scoring systems that predict bleeding risk, but we know that bleeding complications are associated with a significantly worse outcome. Using a combination of scoring systems assessing ischaemic and bleeding risk when evaluating data from randomised trials and registries may help to determine where the net clinical benefit (reduction in ischaemic risk minus any increase in bleeding risk) lies.\n\n## Risk assessment – data from cardiac registries\n\nFor patients with unstable angina and NSTEMI (at differing levels of risk), how do clinical outcome data (adverse cardiovascular events and bleeding complications) collected in cardiac registries compare with data derived from RCTs? \n\nPatients recruited to participate in clinical trials are often highly selected; trials tend not to include patients who are very elderly, are at high risk, or have significant comorbidity. On the other hand, good registry data include information on all patients, but are observational and not randomised. Often there is uncertainty about how the outcome data from RCTs can be applied to the much larger unselected population of patients admitted to UK hospitals with unstable angina or NSTEMI. A greater understanding of the differences between RCT and registry populations, and their levels of ischaemic and bleeding risk would help inform future management. Collection of well-validated registry data is essential if conclusions from RCTs are to be applied appropriately to all patients with unstable angina and NSTEMI, not just to patients who are comparable to trial populations.\n\n## Management of hyperglycaemia\n\nWhat is the optimal management of hyperglycaemia in people with acute coronary syndrome who have diagnosed or previously undiagnosed diabetes? \n\nExisting studies on the optimal management of hyperglycaemia in people who have acute coronary syndrome and diagnosed or previously undiagnosed diabetes are generally of poor quality.\n\nIt is recommended that a large RCT is conducted for people with acute coronary syndrome and hyperglycaemia (blood glucose 11\xa0mmol/litre and over) stratified by NSTEMI and STEMI and by known diabetes and without a previous diagnosis of diabetes.\n\nThe interventions for the trial should be intravenous insulin or subcutaneous insulin administered within 4\xa0hours of presentation to hospital. The aim is to achieve blood glucose between 6\xa0and 11\xa0mmol/litre for at least 24\xa0hours. The comparator should be standard care.\n\n## Beta-blockers\n\nDoes continuing beta-blocker treatment beyond 1\xa0year after a myocardial infarction (MI) improve outcomes for people with normal left ventricular systolic function? \n\nRecent cohort studies have suggested that continuing treatment with a beta-blocker beyond a year after an acute MI may not confer any benefit to the person in terms of reduced morbidity or mortality. This is particularly relevant given recent changes in acute management strategies. While beta-blockers are valuable in reducing mortality and morbidity for up to a year after an MI, they have side effects and represent an additional treatment burden to people who are already taking many other medications. However, there is also some suggestion that there are risks associated with withdrawal of beta-blockers in this population. The balance of risks and benefits of long-term beta blockade has not been clearly determined, particularly in the context of modern acute treatment of MI.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice.\n\n# Dual antiplatelet therapy for acute STEMI intended for primary PCI\n\nRecommendation 1.1.11\n\n## Why the committee made the recommendation\n\nEvidence was reviewed comparing the clinical effectiveness of clopidogrel, prasugrel and ticagrelor, each in combination with aspirin, at time-points of 30\xa0days and 1\xa0year. Prasugrel and ticagrelor were more effective than clopidogrel at both time-points. In a network meta-analysis of the 30‑day data, prasugrel was more effective than ticagrelor, although with some uncertainty around this conclusion. Prasugrel was more effective than ticagrelor at 1\xa0year with noteworthy differences in all-cause mortality and re‑infarction. A detailed cost-effectiveness analysis was also performed incorporating data at both time-points with either prasugrel or ticagrelor being most cost effective in different scenarios using different clinical data. The results favouring prasugrel were driven by the ISAR‑REACT\xa05 trial that directly compared ticagrelor and prasugrel and these were considered the most relevant. The committee agreed that clinical evidence and cost-effectiveness results are directly applicable to the treatment of ST‑segment elevation myocardial infarction (STEMI) in the NHS, and recommended prasugrel for people with STEMI undergoing percutaneous coronary intervention (PCI).\n\nThe final wording of the recommendation reflects the wording of the summary of product characteristics for prasugrel. If there is particular concern about bleeding risk from prasugrel in a person aged 75\xa0or over, either ticagrelor or clopidogrel might be used instead; although ticagrelor is the more cost effective of the two, it also carries a higher bleeding risk.\n\nAn exception was added for people needing anticoagulation for a separate reason (for example, ongoing atrial fibrillation). For these people, clopidogrel is preferred because of the high bleeding risk of full anticoagulation plus prasugrel.\n\n## How the recommendation might affect practice\n\nIn the UK, prasugrel is currently used less than ticagrelor or clopidogrel. The recommendation will therefore require a change in prescribing for most centres, but should be easily achievable. Prasugrel costs less than ticagrelor, but considerably more than clopidogrel, and although some areas will see a cost saving from switching to prasugrel from ticagrelor, the overall effect of this recommendation will be an increase in cost to the NHS.\n\nReturn to recommendations\n\n# Antithrombin therapy during primary PCI for acute STEMI\n\nRecommendations 1.1.12 and 1.1.13\n\n## Why the committee made the recommendations\n\nWhen considering the evidence on the effectiveness of bivalirudin for people with acute STEMI undergoing primary PCI, the committee gave more weight to studies that were closest to current UK practice. These included studies that used bailout or selective, rather than routine, glycoprotein inhibitors (GPIs) and radial artery rather than femoral artery access. The committee concluded that there was no convincing difference between bivalirudin and the main alternative, heparin, in terms of mortality, and that bivalirudin is inferior to heparin in reducing the need for subsequent unplanned revascularisation. The committee discussed data on bleeding risk and agreed that there is no clinically significant difference between bivalirudin and heparin when radial access is used, but bivalirudin probably lowers the bleeding risk when access via the femoral artery is needed. The committee noted that heparin is cheaper than bivalirudin and easier to administer.\n\n## How the recommendations might affect practice\n\nThe committee agreed that the recommendations generally reflect current practice and are not expected to result in a substantial resource impact to the NHS in England.\n\nReturn to recommendations\n\n# Complete revascularisation with PCI or culprit vessel only PCI for acute STEMI\n\nRecommendations 1.1.16 and 1.1.17\n\n## Why the committee made the recommendations\n\nEvidence showed that complete revascularisation with multivessel PCI reduced cardiovascular mortality, myocardial infarction (MI) and repeat revascularisation at 1\xa0year, compared with culprit vessel only PCI for people with acute STEMI without cardiogenic shock. It was also associated with lower overall costs.\n\nAlthough the evidence clearly favoured complete revascularisation, there was less certainty about the timing of the non-culprit procedure. There are a number of different possible approaches to multivessel PCI: undertaking multivessel revascularisation at the time of primary PCI; treating the culprit vessel during the primary procedure and then bringing the person back to the catheter laboratory for revascularisation of other vessels later in the index admission; or treating the culprit vessel during primary PCI, discharging the person and then electively readmitting them for further revascularisation. The committee agreed that multivessel PCI during the index admission should be considered, either at the time of primary PCI or later during the same admission. They were concerned that the clinical benefits may be lower and costs may be higher when people are discharged and readmitted, and noted that delaying treatment of the non-culprit lesions is worrying for patients. However, they agreed that the optimal timing within the index admission will depend on a number of variables and is best left to the discretion of the clinical team.\n\nPeople with cardiogenic shock were excluded from these studies of multivessel PCI and the committee agreed that, in view of the results from the separate CULPRIT-SHOCK trial, it was not appropriate to recommend multivessel PCI for this group during the index admission.\n\n## How the recommendations might affect practice\n\nCurrent practice is variable across centres and also within centres. Some offer multivessel PCI during the first procedure for acute STEMI but others may postpone this (either to later within the index admission or to a later readmission). Some operate on the culprit vessel only. The recommendations are therefore likely to result in a change in practice, but not for all centres or all professionals performing PCI. Because the recommendations allow for multivessel PCI to be either at the time of primary PCI or later within the index admission, they offer flexibility to accommodate situations in which there are a number of other people waiting for primary PCI. Healthcare professionals can move on to treat the next person after completing revascularisation of the culprit vessel, minimising the overall impact on primary PCI services.\n\nThere will be a resource impact for centres not currently undertaking multivessel PCI, because multivessel PCI has higher costs than culprit vessel only PCI. Audit data reported by MINAP (the Myocardial Ischaemia National Audit Project) between April 2016 and March 2017 show there were 33,797\xa0cases of STEMI reported in England, Wales, Northern Ireland and the Isle of Man. It is estimated that around 30% will present with multivessel disease, which would be around 10,000\xa0people. However, it is unclear for how many of these people multivessel PCI would be suitable. The change from current practice is likely to be cost saving overall because of the reduction in later revascularisation procedures.\n\nReturn to recommendations\n\n# Drug-eluting stents\n\nRecommendations 1.1.18 and 1.2.18\n\n## Why the committee made the recommendations\n\nEvidence from angiography studies showed that drug-eluting stents are less likely to fail than bare metal stents in terms of both recurrence of obstruction to the target vessel and the need for further revascularisation. The evidence also shows that drug-eluting stents may be beneficial in reducing deaths (all-cause and cardiac) and there is a reduced incidence of MI in the 3\xa0years after revascularisation when drug-eluting stents are used. Costs of drug-eluting stents are higher than bare metal stents, but analyses using current cost and benefit data suggest that they are a cost-effective use of resources.\n\n## How the recommendations might affect practice\n\nThe use of drug-eluting stents has been slowly increasing over recent years in the UK and the most recent national audit data show that 91% of PCIs for acute coronary syndromes used stents and 97% of these used drug-eluting stents. The recommendation will therefore involve little change from current practice and will not have a substantial resource impact for the NHS in England.\n\nReturn to recommendations\n\n# Antiplatelet therapy for STEMI not treated with PCI\n\nRecommendations 1.1.24 and 1.1.25\n\n## Why the committee made the recommendations\n\nThe UK licence for prasugrel is for people with acute coronary syndrome who are proceeding to coronary angiography with a view to PCI. Although this is usual practice for most people with STEMI, for some people, either medical management without coronary revascularisation or coronary artery surgery are better options. Direct evidence in these patient groups was lacking; the evidence comparing the clinical effectiveness of clopidogrel and ticagrelor was largely for people receiving PCI. This showed convincing superiority of ticagrelor in reducing mortality (cardiac and all-cause) and in preventing re‑infarction and the need for future revascularisation procedures, although there was some evidence of an increased risk of bleeding complications. The committee agreed to recommend ticagrelor for people with STEMI having medical management unless they are at high risk of bleeding when clopidogrel or no second antiplatelet may be the safer option. However, the committee were aware that some of the excess bleeding risk comes from complications of a PCI procedure, which is not relevant to this particular group of people with acute coronary syndrome. They therefore made a recommendation to offer ticagrelor in most cases but to consider clopidogrel as an alternative when the bleeding risk is high.\n\n## How the recommendations might affect practice\n\nIn the UK, both ticagrelor and clopidogrel are currently used for STEMI that is managed without PCI. The recommendations require a change in practice for most, but not all, people who would otherwise receive clopidogrel. Ticagrelor costs considerably more than clopidogrel, and although the recommendations apply to a minority of people with STEMI, the effect will be an increase in cost to the NHS.\n\nReturn to recommendations\n\n# Initial antithrombin therapy for unstable angina and NSTEMI\n\nRecommendations 1.2.3 and 1.2.16\n\n## Why the committee made the recommendations\n\nThe 2010 NICE guideline on unstable angina and NSTEMI recommended fondaparinux rather than low molecular weight heparin for initial management. The recommendation was based mainly on evidence from a single large study (the OASIS‑5 study). This study showed a small risk of catheter thrombosis when fondaparinux was the only antithrombin used before angiography, and therefore the 2010 guideline recommended not to use fondaparinux when angiography is planned within 24\xa0hours. The thrombosis risk was noted by the OASIS‑5 investigators before the study ended, and in the later phase of the study, people were given intravenous unfractionated heparin with fondaparinux during angiography; this appeared to remove the excess risk of catheter thrombosis. Two further small studies published after 2010 have confirmed that giving unfractionated heparin during angiography to people already receiving fondaparinux removed the excess risk of catheter thrombosis. The committee considered that unfractionated heparin is already used in this way in many centres, agreed with the 2010 guideline that fondaparinux is the most cost-effective option, and were able to remove the caveat about avoiding fondaparinux if catheterisation is planned within 24\xa0hours. They recommended that fondaparinux should be given to people who are not at high risk of bleeding unless they are having immediate angiography. People receiving fondaparinux should be given additional systemic unfractionated heparin in the catheter laboratory.\n\n## How the recommendations might affect practice\n\nFondaparinux is already used before angiography in many centres in the UK, with additional unfractionated heparin given during the procedure. The recommendations will affect those centres currently withholding fondaparinux from people having angiography in the next 24\xa0hours. Fondaparinux is a cheaper option than low molecular weight heparin so the recommendation could be cost saving in these centres.\n\nReturn to recommendations\n\n# Early invasive versus conservative management for unstable angina and NSTEMI\n\nRecommendations 1.2.12 to 1.2.15 and 1.2.19\n\n## Why the committee made the recommendations\n\nThe 2010 guideline on unstable angina and non-ST-segment elevation MI (NSTEMI) recommended a comprehensive assessment of baseline risk of adverse events. The committee agreed that this should influence the choice between early invasive intervention (coronary angiography, with PCI if indicated) and conservative management (initial medical management, proceeding to coronary angiography and PCI if there is evidence of recurrent ischaemia). Studies comparing these options show a short-term harm with an invasive strategy, but this is offset by the clinical benefits in the months following the procedure. A cost-effectiveness analysis found that routine early invasive intervention was cost effective in people at higher risk of adverse events, but conservative management was the most cost-effective option for people at lower risk. This was because overall health gains were greater in those at higher baseline risk.\n\nMost of the evidence was already available at the time of the 2010 guideline, and the committee recognised that the data may be less applicable to modern practice than had been the case in 2010. Nonetheless, they agreed that early angiography should be the default recommendation for most people at intermediate or higher baseline risk of adverse outcomes. They accepted the previous committee's interpretation of the appropriate risk cut‑offs based on their detailed work mapping of the evidence to real-world UK risk data. However, the committee also recognised that the risk prediction models might be less applicable to the youngest people with unstable angina and NSTEMI who are relatively under-represented in the dataset, and therefore added a cautionary recommendation to this effect.\n\nThe committee noted that the 2010 guideline had recommended that angiography should be done within 96\xa0hours of admission for those who are likely to benefit from an early invasive strategy. However, they considered this a conservative target and knew that angiography within 72\xa0hours is now common practice. This allows time for a correct diagnosis, immediate stabilisation and treatment of symptoms, and transfer to a centre with PCI facilities if necessary. The available evidence does not permit a definitive statement about the optimal timing, but a recommendation to consider angiography within 72\xa0hours was agreed.\n\n## How the recommendations might affect practice\n\nThe recommendations largely reflect current NHS practice. Although the timeframe for early invasive management has been reduced from 96\xa0hours, 72\xa0hours has been specified in the NICE quality standard for a number of years and a best practice tariff on the same basis was introduced in 2017. Audit data are only currently available from the same year as the introduction of the tariff and report that, of people who are admitted to a hospital that can perform angiography, 56% received angiography within 72\xa0hours and 69% within 96\xa0hours. The proportion receiving angiography within 72\xa0hours is likely to be higher since the introduction of the best practice tariff. Performing angiography earlier is likely to result in a shorter hospital stay. The recommendations are unlikely to result in a substantial resource impact for the NHS.\n\nReturn to recommendations\n\n# Antiplatelet therapy for unstable angina and NSTEMI\n\nRecommendations 1.2.6, 1.2.17, 1.2.20 and 1.2.21\n\n## Why the committee made the recommendations\n\nThe committee agreed that dual antiplatelet therapy should not be offered to people with chest pain before a diagnosis of unstable angina or NSTEMI is made. In their experience, dual antiplatelet therapy had caused harm (bleeding) in some people presenting with chest pain not caused by an acute coronary syndrome.\n\nEvidence was reviewed comparing the clinical effectiveness of clopidogrel, prasugrel and ticagrelor, each in combination with aspirin, at time-points of 30\xa0days and 1\xa0year. A detailed cost-effectiveness analysis for people with unstable angina or NSTEMI undergoing PCI was performed incorporating these data. Although the overall conclusion was that prasugrel is a more effective agent than ticagrelor, which in turn is more effective than clopidogrel, there was considerable uncertainty around the cost-effectiveness results, with either prasugrel or ticagrelor being most cost effective in different scenarios using different clinical data. The results favouring prasugrel were driven by the ISAR‑REACT\xa05 trial, in which time to angiography was much shorter than is currently achieved in the UK for people with unstable angina or NSTEMI. This could cause practical difficulty in using prasugrel because its licence effectively prevents its use before angiography, and this could leave people with unstable angina or NSTEMI without dual antiplatelet therapy for several days. The committee therefore recommended either prasugrel or ticagrelor for people with unstable angina or NSTEMI intended for PCI, depending on individual circumstances. The final wording of the recommendation reflects the wording of the summary of product characteristics for prasugrel.\n\nAlthough many people with unstable angina or NSTEMI proceed to PCI, for some medical management without coronary revascularisation or coronary artery surgery are better options. Prasugrel is not licensed in these circumstances. The evidence available for medical management shows better outcomes with ticagrelor than clopidogrel. This is consistent with results from the larger datasets for people having PCI. The committee therefore recommended ticagrelor for people with unstable angina or NSTEMI having either medical management without coronary revascularisation or coronary artery surgery. However, the committee also noted that clopidogrel may be the safer agent for people who are at high risk of bleeding but still need dual antiplatelet therapy, although this is based on evidence of higher bleeding risk with ticagrelor in people with an acute coronary syndrome generally rather than specific evidence from those at higher risk. They therefore made a recommendation to consider using clopidogrel in this situation.\n\n## How the recommendations might affect practice\n\nIn the UK, prasugrel is currently used less than ticagrelor or clopidogrel. The recommendations may therefore involve a change in practice for some centres. Prasugrel costs less than ticagrelor, but considerably more than clopidogrel, and although some areas will see a cost saving from switching to prasugrel from ticagrelor, others will see an increase where either prasugrel or ticagrelor is used instead of clopidogrel. The overall effect of these recommendations will be an increase in cost to the NHS.\n\nReturn to recommendations\n\n# Antiplatelet therapy for people with an indication for anticoagulation\n\nRecommendations 1.4.18 to 1.4.23\n\n## Why the committee made the recommendations\n\nThe committee noted that current practice is to use dual antiplatelet therapy at the time of PCI, and found no evidence to recommend changing this practice for people who are on an anticoagulant at the time of admission. In practice, the anticoagulant will often be suspended for a short period (perhaps using heparin cover). The evidence available showed that continuing dual antiplatelet therapy plus an anticoagulant after the acute PCI phase increases the risk of bleeding complications, and so a recommendation raising awareness of this issue was included. The committee therefore agreed that either aspirin or the second antiplatelet agent should be stopped, but unfortunately there was no evidence to show at what point this should happen.\n\nIn the absence of any conclusive data, recommendations for treatment after the initial phase were based on the knowledge and experience of the committee. For people who have had PCI and stent insertion, they agreed that it would be safest to combine an anticoagulant with a potent antiplatelet agent (clopidogrel), whereas for those who have had medical management or had angioplasty without stenting, the anticoagulant should be combined with aspirin. There was not enough evidence for the committee to recommend a particular anticoagulant.\n\n## How the recommendations might affect practice\n\nCurrent practice is variable, with people taking different combinations of antiplatelets and anticoagulants. The number of people affected is small. It is estimated that between 5% and 15% of people with an acute coronary syndrome will have an indication for oral anticoagulation. The recommendations are mostly unchanged from the 2013 guideline and the minor changes that have been made are unlikely to result in a substantial resource impact for the NHS in England.\n\nReturn to recommendations\n\n# Duration of beta-blocker treatment after an MI\n\nRecommendations 1.4.26 and 1.4.27\n\n## Why the committee made the recommendations\n\nThere was no direct evidence on the optimal duration of beta-blocker treatment for people who have had an MI but do not have reduced left ventricular ejection fraction. The 2013 guideline recommended beta-blocker treatment for at least 12\xa0months. In the absence of any conclusive evidence, the committee agreed that they could not recommend a definite time for stopping treatment. However, they agreed that healthcare professionals should discuss the absence of clear evidence for benefit of continuing beyond 12\xa0months with people taking beta-blockers after an MI who have normal left ventricular function. This should prompt a personalised approach to stopping or continuing beta-blockers based on the person's attitude to risk and experience of side effects.\n\n## How the recommendations might affect practice\n\nBeta-blockers are currently offered for at least 12\xa0months after an MI to people without reduced left ventricular ejection fraction. Audit data show that around 97% of people with MI are discharged on beta-blockers. A discussion of the absence of clear evidence for benefit of continuing treatment beyond 12\xa0months is likely to lead to more people deciding to stop treatment at this point. Any reduction in prescriptions for beta-blockers will be cost saving.\n\nReturn to recommendations", 'Context': 'Acute coronary syndromes due to ischaemic heart disease remain a significant cause of morbidity and mortality. In 2015, heart disease remained the leading cause of death in men and the second most common cause of death in women in England. In 2015/16, more than 58,000\xa0people were admitted to hospital in England with a heart attack. Although many more people now survive than in the past, there remains considerable scope to reduce their future risk of death, angina, heart failure and further heart attack.\n\nNational audits continue to show variation in practice across the UK in the treatments offered for acute coronary syndromes. This, combined with evidence of novel ways of treating acute coronary syndromes and updates to existing treatments, indicates a need for an updated guideline that will help deliver best practice to the large number of people receiving treatment for acute coronary syndromes in the NHS.'}
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https://www.nice.org.uk/guidance/ng185
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This guideline covers the early and longer-term (rehabilitation) management of acute coronary syndromes. These include ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI) and unstable angina. The guideline aims to improve survival and quality of life for people who have a heart attack or unstable angina.
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014b35bd81661a58375723732a6161dc5937829a
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nice
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Guidance on the use of coronary artery stents
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Guidance on the use of coronary artery stents
Evidence-based recommendations on using coronary artery stents in adults.
# Guidance
Stents should be used routinely when percutaneous coronary intervention (PCI) is the clinically appropriate procedure for people with stable angina. For recommendations on drug-eluting stents for people with unstable angina, non-ST-segment-elevation myocardial infarction (NSTEMI) or ST-segment-elevation myocardial infarction (STEMI), see recommendation 1.1.18 and recommendation 1.2.18 in NICE's guideline on acute coronary syndromes.
This recommendation has been replaced by NICE's technology appraisal guidance on drug-eluting stents for the treatment of coronary artery disease.
This recommendation has been replaced by NICE's technology appraisal guidance on drug-eluting stents for the treatment of coronary artery disease.
This recommendation has been replaced by NICE's technology appraisal guidance on drug-eluting stents for the treatment of coronary artery disease.
This guidance specifically relates to the present clinical indications for PCI and excludes conditions (such as many cases of stable angina) that are adequately managed with standard drug therapy. # Clinical need and practice
CAD is by far the most common cause of heart disease, resulting from the narrowing of coronary arteries ('stenosis') caused by deposition of atherosclerotic plaque. Coronary artery stenosis may be asymptomatic or may lead to angina, a chest pain that may be severe enough to restrict or prevent exertion. A critical reduction of the blood supply to the heart may result in MI or death.
CAD causes about 2100 deaths annually per million of the population in England and Wales (about 110,000 deaths in total), one of the highest rates in the world. CAD is also the cause of considerable morbidity and loss of ability to lead a normal life. Approximately 1.4 million people in England and Wales suffer from angina, the most common form of such morbidity.
Stenotic lesions are categorised as A, B1, B2 and C. A denotes a relatively short (less than 10 mm) and easily accessible lesion. C denotes lesions that: are relatively long (greater than 20 mm); may be less accessible, tortuous and/or have side branches; and may be totally occluded.
CAD may affect one or more arteries, which may be of different calibres. Occlusion may be partial or total.
The symptoms and health risks that are associated with a stenosed artery may be treated medically – by modification of risk factors (for example, smoking, hyperlipidaemia, obesity and hyperglycaemia) and/or by drug treatment (for example, beta-adrenergic blockers, nitrates, calcium channel blockers, antiplatelet agents and statins).
If these medical treatments fail or are inappropriate, two invasive therapies are available. The first, coronary artery bypass grafting (CABG), involves major cardiac surgery. The second, so-called balloon angioplasty, or percutaneous transluminal coronary angioplasty (PTCA), involves a non-surgical widening from within the artery using a balloon catheter. When inflated, the balloon increases the calibre of the artery.
Recently, most PTCA procedures have involved the use of stents. Stents are thin wire-mesh structures that act as permanent prosthetic linings to keep the artery inflated and maintain its patency. PCI is a generic term to encompass PTCA with or without adjunct techniques such as stenting.
For disease in a single artery, PCI with a stent has been the more frequent treatment; for disease in two arteries, patient numbers for PCI with a stent and CABG have been similar; and for more than two affected arteries, CABG has been used much more frequently.
The major problem with PCI is restenosis of the artery, which has three main causes. The first, recoil of the artery, happens when the balloon is deflated. It usually occurs immediately or within 24 hours of completion of the procedure, and may require emergency CABG. Stents essentially eliminate recoil of the artery. The two subsequent problems, mostly arising during the first 6 months, are contraction of the adventitia secondary to an injury reaction (3–6 months), and proliferation of smooth muscle cells within the arterial wall (4–6 months). A repeat procedure is consequently required in approximately 20% of patients with simple lesions. This rate of reintervention is much higher (up to 50%) for arteries of small calibre, saphenous vein grafts, long lesions, total occlusions and in people with diabetes.
Recent advances in stent technology have reduced some of the problems of restenosis, as well as lowering the cost of stents. In addition, the use of antiplatelet drugs and other therapeutic strategies to prevent thrombosis have improved long-term outcomes.
One of the main criteria for assessing the clinical effectiveness of PTCA with stents compared with standard PTCA (without stents) is the ability to reduce the incidence of subsequent attacks of angina as well as major adverse coronary events (MACE), which include death, MI and the need for further revascularisation procedures (CABG or repeat PCI).
Patients for whom both a CABG and a PCI involving stenting are appropriate techniques would, other things being equal, choose PCI in almost all cases, even though the chances of restenosis are greater. This is because the procedure is less invasive, has a lower chance of death during the operation, and involves a much shorter and less painful recuperation time.
Approximately 39,000 PCI procedures were undertaken in the UK in 2001, equating to 663 per million of the population – a rate that had increased at an average of 14% per year over the previous 10 years. The rate for the UK remains below that of the European Union (EU) average, which exceeds 1000 per million of the population.
In the UK, the proportion of PCI procedures using stents rose steeply between 1993 and 1999, from below 10% to nearly 80%. It has continued to increase, although more slowly, to about 85% in 2001.
The number of CABG procedures performed each year in the UK has increased from 15,700 in 1991 to 24,700 in 1999/2000, or from 292 to 464 per million of the population. The rate of increase has slowed since the first half of the 1990s.
The National Service Framework for Coronary heart Disease target, set in March 2000 for revascularisations (PCIs and CABGs), is at least 1500 per million of the population (750 for each type of intervention). At current growth rates, the combined target will be reached by about 2005.# The technology
This appraisal is both a review of earlier NICE guidance (NICE Technology Appraisal Guidance No. 4; see Section 8) covering BMS, and a new appraisal of DES. BMS have already been described in Section 2 as part of existing practice. The rest of this section is devoted to methods of reducing restenosis and, in particular, to the use of DES as a means of achieving this.
Methods of reducing restenosis include: coating the stent with an appropriate drug; introducing an emitter of radioactive particles at the stenting site (brachytherapy); and creating the slow release of a drug from the stent, making the stent 'drug-eluting'. For DES, the drug is held temporarily in place within a polymer 'painted' onto the metallic stent. Other than one trial (the ELUTES trial), there is little evidence in favour of coating the stent directly with an active drug (without a polymer); this technology, and brachytherapy, are outside the scope of this appraisal.
Although a number of drugs have been tested in the context of DES, only three have been granted CE (Conformite Europeene) marking for use within EU countries: paclitaxel, which inhibits cell division, elutes from the Taxus stent; sirolimus (previously known as rapamycin), an immunosuppressive agent that reduces inflammation, elutes from the Cypher stent; and dexamethasone, a synthetic adrenocortical steroid that reduces inflammation, elutes from the BiodivYsio stent. These drugs may elute at different rates, depending on the presence or absence of additional polymer coatings on the stent. Because the performance of a DES depends critically on the particular drug being used, each DES should be regarded as a separate technology. However, as yet, studies directly comparing different DES have not been performed.
Both types of stent (BMS and DES) require the use of an antiplatelet drug in addition to aspirin. Such drugs should be used after the implantation of a stent, in accordance with the device-specific instructions for use (IFU).
List prices for both BMS and DES differ between manufacturers, and some manufacturers produce more than one stent in each class, at different prices. Prices for BMS range from about £600 to £900 and for DES from about £1300 to £1500 per stent. For bare-metal and drug-eluting stents that are the same apart from their drug-eluting properties, the difference in cost is about £500 to £600. Costs may vary in different settings because of negotiated procurement discounts.# Evidence and interpretation
The Appraisal Committee (Appendix A) considered evidence from a number of sources (Appendix B).
# Clinical effectiveness
The Assessment Report presents three sets of comparison: PCI without stents versus PCI with BMS; PCI with BMS versus CABG; and BMS versus DES.
Assessment of the relative clinical effectiveness of stents considers the likelihood of restenosis discovered on follow-up and the requirement for repeat intervention (revascularisation). Repeat intervention may occur: (i) because of a requirement of the trial protocol, specifying a repeat angiographic examination at a predetermined interval (so-called 'protocol-driven' reintervention); or (ii) following a recurrence of symptomatic angina in the patient (that is, 'clinically-driven' reintervention). The frequency of protocol-driven reinterventions is higher than that of clinically driven reinterventions, because angiography is usually mandatory at 6 months in the trial protocol whereas in clinical practice it is carried out only after recurrence of symptoms. Accordingly, the absolute differences observed between the treatment and control arms of clinical trials are likely to be higher than would be expected to occur in clinical practice.
## PCI with BMS versus PCI (without stents)
Fifty randomised controlled trials (RCTs) were analysed comparing the use of PCI with BMS versus PCI without stents. Because of differences in, and completeness of, the reporting of these trials, the number of trials on which meta-analyses are based is a subset of these 50 trials. In a meta-analysis comprising 12 trials involving 5700 patients with non-specified ischaemic heart disease, where a composite endpoint of revascularisation, MI or death (MACE) was reported, the MACE rate was statistically significantly different at 6 months' follow-up: 23.0% for the PCI without stents group versus 15.4% for the PCI with BMS group, with an odds ratio (OR) of 1.66 (95% confidence interval , 1.45 to 1.90). The difference was smaller after 12 months' follow-up but still statistically significant. Of the above 12 trials, seven, involving 3500 patients, reported data for 12-months' follow-up: the MACE rate was 22.0% for the PCI without stents group versus 18.9% for the PCI with stents group (OR 1.33; 95% CI, 1.12 to 1.58).
Differences in MACE rates were due almost entirely to differences in the rate of restenosis. For the outcomes of acute MI and deaths, for which individual trials were not powered to detect statistically significant differences, meta-analyses showed that while both of these sets of events occurred less frequently in those treated with PCI using BMS than in PCI without stents, in neither case was the result statistically significant.
Overall, the results of the RCTs showed that the use of PCI with BMS has significant advantages over the use of PCI without stents, in terms of lower rates of restenosis at 6 and 12 months.
According to the joint professional submission, the likelihood of restenosis is greater in small vessels, because a given tissue regrowth will have a greater proportionate effect in a vessel of smaller calibre. In eight out of nine studies that looked at vessels of a small calibre (less than 3 mm), restenosis rates were lower in the BMS arm than in the PCI without stent arm, and in two of these studies, the difference was statistically significant. A meta-analysis showed a statistically significant advantage for PCI with BMS. However, restenosis rates were still high in this group.
According to the joint professional submission, the restenosis rate increased by an estimated 8 to 13 percentage points with every 10-mm increase in the length of BMS required.
## PCI with BMS versus CABG
There were six RCTs in the meta-analysis. None of the trials involved a DES.
For single-vessel disease, the MACE rate was statistically significantly different at 6 months' follow-up in two trials involving a total of 300 patients: 12.6% for CABG versus 25.8% for PCI with BMS (OR 0.41; 95% CI, 0.22 to 0.74). The higher MACE rate for PCI with BMS reflects the higher rate of restenosis following this procedure.
For multiple-vessel disease, the MACE rate was statistically significantly different at 12 months' follow-up in two trials involving a total of 2300 patients: 12.3% for CABG versus 24.5% for PCI with BMS (OR 0.43; 95% CI, 0.34 to 0.54).
At 36 days' follow-up, the rate of acute MIs was statistically significantly lower following PCI with BMS, but the difference between the two procedures was not statistically significant at 6 and 12 months.
No statistically significant differences were reported for deaths, because the trials were not powered to detect differences in these uncommon events.
## BMS versus DES
There were 12 RCTs comparing BMS with DES. Of these, seven involved paclitaxel, four sirolimus, one everolimus and one actinomycin stents. The first two sets of trials (paclitaxel and sirolimus) are considered separately below, and the last two trials have not been considered here because they involved products that have not been granted CE marking. No RCT for the third DES with a CE mark (eluting dexamethasone) has yet been reported.
## Paclitaxel-eluting stents
Based on four trials with a paclitaxel DES (Taxus and non-CE-marked stents), involving almost 1000 patients, the MACE rate for PCIs using a paclitaxel DES was not statistically significantly lower at 36 days or at 1 year, but it was statistically significantly lower at 6 months: 7.4% for DES versus 15.4% for BMS (OR 0.48; 95% CI, 0.31 to 0.73). From a random effects model (which takes account of heterogeneity of results between trials), the 6-month data for the MACE rate were not statistically significant (OR 0.58; 95% CI, 0.24 to 1.43). Most of the MACE events refer to restenosis. However, the two trials of the Taxus DES stent (which has a CE mark), involving 583 patients, yielded a statistically significantly lower MACE rate at 6 months: 7.2% for DES versus 18.4% for BMS (OR 0.35; 95% CI, 0.21 to 0.59); and at 12 months: 9.7% for DES versus 20.5% for BMS (OR 0.41; 95% CI, 0.25 to 0.67).
Paclitaxel DES have not been demonstrated to show an advantage over BMS in either mortality or prevention of MI. However, in a series of trials of the Taxus stent (the TAXUS trials), the MI rate for PCIs using a paclitaxel DES was statistically significantly lower at 6 months: 1.7% for DES versus 5.9% for BMS (OR 0.35; 95% CI, 0.12 to 0.99). The statistical significance of this result was not maintained at 12 months: 2.8% for DES versus 5.8% for BMS (OR 0.56; 95% CI, 0.23 to 1.37).
Multivariate analysis of data from the TAXUS trials shows that once the effect of small-calibre arteries and long lesions has been allowed for, the difference in performance between DES and BMS for people with diabetes is not statistically significantly different from that of people without diabetes.
## Sirolimus-eluting stents
The MACE rate for PCIs using a sirolimus DES (Cypher and non-CE-marked stents) was not statistically significantly lower at 36 days, but it was lower at 9 months and at 1 year; at 9 months the rate was 7.4% for DES versus 18.9% for BMS (OR 0.34; 95% CI, 0.23 to 0.47), and at 1 year it was 7.8% for DES versus 21.8% for BMS (OR 0.30; 95% CI, 0.22 to 0.43). Most of the MACE events refer to restenosis. The trials of the Cypher sirolimus DES (which has a CE mark) showed a statistically significantly lower MACE rate compared with trials of BMS at 9 months (OR 0.32; 95% CI, 0.16 to 0.45), 12 months (OR 0.31; 95% CI, 0.22 to 0.43), and 24 months (OR 0.46; 95% CI, 0.22 to 0.97).
Sirolimus-eluting stents in general have not been shown to have either a mortality or acute MI advantage over BMS in trials, and neither do the DES within the subset of Cypher stent trials.
According to the joint professional submission, in larger arteries, PCIs using a sirolimus DES have shown very low rates of restenosis, approaching zero. In small-calibre arteries, PCIs using a sirolimus DES have shown lower rates of restenosis than PCIs using a BMS (for example, 7% versus 20% restenosis at 9 months in the SIRIUS trial for vessels of mean calibre 2.3 mm).
In patients with diabetes and those with longer lesions, rates of restenosis following PCIs using a sirolimus DES have been higher than those of the 'average' patient, but still much lower than following PCIs using the BMS control. Subsequent post hoc subgroup analysis from one of the manufacturers from a trial involving patients who received a DES was considered by the Committee. The analysis compared the restenosis rate for people with diabetes with that for people without diabetes. It showed that the restenosis rate for those with diabetes as a whole was higher than for the non-diabetes group, but the difference was not statistically significant. In addition, the analysis did not control for artery calibre or length.
According to the joint professional submission, for every 10 mm increase in the length of the stent, the difference in restenosis rate between a Cypher DES and Cypher BMS increased by between 1 and 1.6 percentage points.
# Cost effectiveness
The most recent evidence of cost effectiveness comes from models supplied by four manufacturers and one from the Assessment Group, including an addendum. The manufacturer models show that PCIs with a BMS are cost effective compared with PCIs without stents and also compared with CABG. However, these models are relatively short-run, ranging from 6 months to 2 years. The manufacturers of the Cypher and of the Taxus stents each provided a model which examined the cost effectiveness of their own DES compared with the corresponding BMS. Each of these models showed that the DES is cost effective compared with the corresponding BMS. The Assessment Group's model showed that the Cypher and Taxus stents, as a group, are cost effective compared with BMS.
## PCI with BMS versus PCI without stents
For patients with moderate or severe angina, PCI has been shown to be a cost-effective alternative to conventional medical treatment. Since the previous appraisal (by the Institute in 2000) of PCI with BMS versus PCI without stents, several further studies have demonstrated the cost effectiveness of stents in a number of patient populations and clinical settings, including elective stenting and stenting immediately following an acute MI.
## PCI with BMS versus CABG
Comparative data on PCI using BMS versus CABG are available for only 3 years of follow-up. There are no data beyond 3 years and little data from years 2 to 3. The best available data are up to 2 years. Long-term models are needed to determine cost effectiveness because most patients who have stents fitted live longer than 5 years, and it is impossible to give a proper answer to the question of cost effectiveness by taking a short-term perspective.
The Assessment Group's model extrapolates the results to 5 years based on the currently available 3-year data. However, the extrapolation is very sensitive to the functional form chosen for the survival curve of patients who have undergone either stenting or CABG.
The benefits/disadvantages of PCIs using BMS compared with CABG, in terms of quality-of-life differences, derive from stents being a less invasive procedure on one hand but having higher rates of restenosis on the other. Neither of these two effects, in terms of quality-adjusted life years (QALYs), has been estimated to be very great, which means that if there was any appreciable difference in mortality between the two therapies, this factor would determine which of the therapies had the greater benefits. However, none of the meta-analyses from the trials shows any mortality benefit from PCI with either BMS or DES compared with CABG in the first 2 years. Hence, all the measurable benefits from using stents rather than CABG derive from an increase in the quality of life. Since stenting is considerably cheaper than CABG, under the 2-year models, it is therefore more cost effective, and indeed, dominates CABG.
The Assessment Group's model, however, estimated a survival benefit for CABG over PCI using BMS of the order of 0.05 QALYs per patient, after the model was extrapolated to 5 years. This benefit would be enough to make CABG the preferred technology (in terms of both clinical and cost effectiveness) for patients who were candidates for both stents and CABG. The clinician consultees to the appraisal process, however, vigorously challenged this, stating that previous studies had not reached this conclusion.
## BMS versus DES
The quality-of-life component of the QALY differences between BMS and DES is small, because it relates only to the extent of the differences in restenosis rates. No differences in mortality have been demonstrated. Thus, the greatest benefits of DES over BMS will occur for categories of patients for whom the absolute differences in restenosis rates are greatest.
The addendum to the Assessment Report showed that, for single-vessel disease, PCI using a DES was estimated to be cost-saving compared with PCI using a BMS at 12 months for patients with diabetes and long lesions; the estimated cost per QALY for patients without diabetes and long lesions was £15,000 and, for all patients with narrow vessels, it was £16,000. These estimates were derived from patient-level data derived from the TAXUS II trial. For the total population of patients with single-vessel disease, the cost per QALY was £94,000. This estimate was derived from registry data.
These estimates are sensitive to five factors:
the percentage point reduction in the risk of revascularisation
the price differential between BMS and DES
the proportion of repeat interventions needing CABG
the disutility caused by recurrent symptoms
the average waiting time for repeat intervention.
There are no RCT data for two-vessel disease. The estimated incremental cost per QALY for two-vessel disease gained from PCI using a DES compared with PCI using a BMS for all non-diabetic patients is £195,000. This estimate is derived from registry data.
# Consideration of the evidence
The Committee reviewed the evidence available on the clinical and cost effectiveness of PCIs using a BMS and DES, having considered evidence on the nature of the condition and the value placed by users on the benefits of BMS and DES from clinical experts and those who represent patients with angina. It was also mindful of the need to ensure that its advice took account of the efficient use of NHS resources.
## PCI with BMS versus PCI without stents
The Committee considered that no new evidence had been found since the previous appraisal to change its view that where PCI is being undertaken, the use of stents is likely to be both clinically and cost effective.
## BMS versus DES
The Committee noted that there were no head-to-head trials of the sirolimus-eluting Cypher stent and the paclitaxel-eluting Taxus stent, and the clinical experts advised that there was no evidence that would allow them to favour one of these drug-eluting agents over the other.
The Committee considered that, for single-vessel disease, restenosis rates were in general low using a BMS in the majority of patients requiring PCI, and that, therefore, the routine use of a DES was not justified. However, this was not the case for patients presenting with either small-calibre arteries ( 15 mm); in these patients, the risk of restenosis using a BMS was considerably higher, and the absolute reduction in restenosis rates would justify the use of a DES.
The Committee considered the risk factors predicting the likelihood of higher rates of restenosis after the use of a BMS. It was persuaded that the main determinants of risk were the target vessel calibre and the complexity of the arterial lesion, in particular the length of the stenosis. It recognised that the combination of small-vessel disease and long lesions was particularly prevalent in patients with CAD who also had diabetes. Whilst, in general, patients with diabetes have higher restenosis rates than those without diabetes following PCI with a BMS, the Review Group's analysis indicated that these higher rates arise predominantly from the fact that a much higher proportion of patients with diabetes needing PCI have disease of small-calibre arteries and long lesions than is true for the general population of patients requiring PCI.
The Committee discussed how the RCTs comparing BMS with DES relate to current clinical practice. In particular, in the trials, the decision to reintervene following an initial PCI with stent procedure was often made on the basis of protocol-driven angiographic examinations at certain fixed times (for example at 6 months), rather than in response to the recurrence of clinical symptoms. It is likely that the trials would encourage reintervention that might not be required in clinical practice, where routine re-angiography is not usual. Thus, the Committee was aware that the difference in restenosis rates between BMS and DES identified in the trials could overestimate the extent of the difference that would actually be seen in clinical practice. The addendum to the Assessment Report attempted to correct for this potential overestimate of the benefit of DES versus BMS. The Committee decided that, whether or not the correction factor was applied, the guidance in Section 1 would not be materially affected.
The Committee considered PCI with a DES for more than one target vessel in a person with symptomatic coronary disease. It was aware that the evidence from the RCTs relates to the use of DES in single-vessel disease. However, the experts indicated that treatment of more than one vessel in an individual patient during PCI might be required. This is because, despite additional investigations, it is frequently difficult to determine which of several vessels identified at angiography is the most likely cause of the patient's symptoms. The Committee considered that the risk of a need for future intervention following an initial PCI is likely to be dependent on the degree of stenosis of any of the affected vessels. The appropriateness of a DES or BMS for each diseased artery in turn would therefore depend on considering the artery's characteristics in isolation from those of other diseased arteries. It was therefore persuaded that planned treatment of more than one vessel in a single patient should be based on the requirements laid out in the guidance for a single vessel.
The Committee discussed the use of DES with regard to coronary artery vein grafts and for more complex situations such as bifurcation lesions, but noted that there was no robust evidence in this area at present.
The Committee noted statements from some manufacturers that restenosis rates using a BMS of recent design were low compared with those of other BMS, and were comparable with those of the CE-marked DES. The cost-effectiveness calculations were not based on evidence comparing these stents with other BMS or with DES in head-to-head trials. The Committee considered that this evidence was not sufficient to affect its recommendations for guidance in Section 1. It would, however, wish to include further evidence on new developments in BMS design as part of the next review of the use of coronary stents.
## PCI with BMS versus CABG
Having reviewed the Assessment Group's model and the submissions from manufacturers, together with the views of cardiologist consultees, the Committee concluded that the guidance offered in 2000 should be maintained. While it was clear that models with outcomes up to 2 years favoured stents in terms of cost effectiveness, the conclusions to be drawn from longer-term models depended critically on whether a survival advantage accrues to CABG. The Committee concluded that no convincing case had been made on this matter. Its considerations ranged over what may happen to patients requiring one or other of these procedures in different age ranges, and whether the conclusions about the most appropriate procedure would be the same for younger patients (who are more likely to need a repeat procedure) as for older ones. In none of the cases considered was there sufficient evidence of effect to be able to reach any conclusion.# Recommendations for further research
Ongoing trials for paclitaxel-eluting stents include TAXUS I (follow-up of a small initial study of slow-release formulation versus BMS in patients with either previously-untreated lesions or restenosis), TAXUS II (follow-up of a larger study of both slow- and moderate-release formulations versus BMS in patients with previously-untreated lesions), TAXUS IV (a large trial of slow-release formulation versus BMS stratified by presence or absence of diabetes and by vessel diameter), TAXUS V (focussing on small vessels, long lesions, bifurcations and in-stent restenosis) and TAXUS VI (moderate release for long lesions). For sirolimus-eluting stents, on-going trials include RAVEL (small-diameter vessels), SIRIUS (high risk for cardiovascular disease progression and restenosis due to the diabetes, exposure to multiple stent implantation and use of overlapping stents) and E-SIRIUS (previously-untreated single vessels of diameter 2.5 to 3 mm and for lesions between 15 and 32 mm in length); and FUTURE (previously-untreated vessels between 2.75 and 4 mm, less than 28 mm long ) for everolimus-eluting stents. REALITY, a head-to-head trial of the Cypher sirolimus DES and Taxus paclitaxel DES, is under way.
Until now, trials have been restricted to single-artery studies for the sake of simplicity and ease of interpretation. Extrapolation of results to more than one artery critically depends on untested assumptions. Randomised controlled trials (RCTs) of the use of DES in more than one artery concurrently are therefore required, in order to confirm or refute the appropriateness of the extrapolations used in the modelling.
To compare long-term outcomes, particularly with respect to stents against CABG, much longer trial follow-ups are required.
New BMS designs should be tested against current BMS and DES designs.
Head-to-head RCTs of those DES that have been CE marked and have been shown to be clinically superior to the corresponding BMS are required.
Studies to determine whether diabetes is a risk factor for increased rate of restenosis following PCI, independent of lesion length and artery calibre, are required. Much of this work could be performed by an analysis of patient-level data taken from trials already conducted.# Implications for the NHS
The financial impact of using DES depends on the proportion of stented arteries that are narrow or contain long lesions offset against the increased capacity of the system resulting from a decrease in procedures to manage restenosis. Although the total number of arteries requiring a DES in the UK is unknown, it could be as high as one-third of all stents. Based on this proportion, the additional cost of DES without offsets would be between £6 and £7.2 million per year, assuming the use of about 12,000 DES stents costing an additional £500 to £600 each.
If the use of drug-eluting stents reduced the restenosis rate by about 10 percentage points then the additional capacity generated could be used to increase the number of new stent procedures. This would have the effect of offsetting the cost of the BMS by about £4 million per year. Such cost savings, however, will often only be realised in the form of additional capacity.# Appendix C. Detail on criteria for audit of the use of coronary artery stents
# Possible objectives for an audit
An audit could be carried out to ensure that stents are being used appropriately in patients undergoing PCIs. Local clinical audits could also confirm that PCI is the clinically appropriate procedure for patients included in the audit.
# Possible patients to be included in the audit
An audit could include all patients having a PCI for stable or unstable angina, acute MI or symptomatic CAD in a suitable time period, for example, 3 months.
# Measures that could be used as a basis for audit
Criterion
Standard
Exception
Definition of terms
. Stents are used when a PCI is performed in an individual having any of the following:
a. stable angina or
b. unstable angina or
c. acute MI
% of individuals having a PCI for stable or unstable angina or acute MI
None
Clinicians will need to agree locally on any exceptions for audit purposes.
. A Cypher or a Taxus stent is used in a PCI for an individual with symptomatic CAD when either of the following occurs:
a. the target artery is < 3 mm in calibre or
b. the lesion to be stented is longer than 15 mm
% of individuals having a PCI for symptomatic CAD
A. The individual has had an MI in the preceding 24 hours
B. The individual has angiographic evidence of thrombus in the target artery
Clinicians will need to agree locally on any other exceptions for audit purposes.
# Calculation of compliance
Compliance (%) with each measure described in table 1 is calculated as follows.
divided by x 100
Clinicians should review the findings of measurement, identify whether practice can be improved, agree on a plan to achieve any desired improvement and repeat the measurement of actual practice to confirm that the desired improvement is being achieved.
|
{'Guidance': "Stents should be used routinely when percutaneous coronary intervention (PCI) is the clinically appropriate procedure for people with stable angina. For recommendations on drug-eluting stents for people with unstable angina, non-ST-segment-elevation myocardial infarction (NSTEMI) or ST-segment-elevation myocardial infarction (STEMI), see recommendation\xa01.1.18 and recommendation\xa01.2.18 in NICE's guideline on acute coronary syndromes. \n\nThis recommendation has been replaced by NICE's technology appraisal guidance on drug-eluting stents for the treatment of coronary artery disease. \n\nThis recommendation has been replaced by NICE's technology appraisal guidance on drug-eluting stents for the treatment of coronary artery disease. \n\nThis recommendation has been replaced by NICE's technology appraisal guidance on drug-eluting stents for the treatment of coronary artery disease. \n\nThis guidance specifically relates to the present clinical indications for PCI and excludes conditions (such as many cases of stable angina) that are adequately managed with standard drug therapy. ", 'Clinical need and practice': "CAD is by far the most common cause of heart disease, resulting from the narrowing of coronary arteries ('stenosis') caused by deposition of atherosclerotic plaque. Coronary artery stenosis may be asymptomatic or may lead to angina, a chest pain that may be severe enough to restrict or prevent exertion. A critical reduction of the blood supply to the heart may result in MI or death.\n\nCAD causes about 2100 deaths annually per million of the population in England and Wales (about 110,000 deaths in total), one of the highest rates in the world. CAD is also the cause of considerable morbidity and loss of ability to lead a normal life. Approximately 1.4 million people in England and Wales suffer from angina, the most common form of such morbidity.\n\nStenotic lesions are categorised as A, B1, B2 and C. A denotes a relatively short (less than 10 mm) and easily accessible lesion. C denotes lesions that: are relatively long (greater than 20 mm); may be less accessible, tortuous and/or have side branches; and may be totally occluded.\n\nCAD may affect one or more arteries, which may be of different calibres. Occlusion may be partial or total.\n\nThe symptoms and health risks that are associated with a stenosed artery may be treated medically – by modification of risk factors (for example, smoking, hyperlipidaemia, obesity and hyperglycaemia) and/or by drug treatment (for example, beta-adrenergic blockers, nitrates, calcium channel blockers, antiplatelet agents and statins).\n\nIf these medical treatments fail or are inappropriate, two invasive therapies are available. The first, coronary artery bypass grafting (CABG), involves major cardiac surgery. The second, so-called balloon angioplasty, or percutaneous transluminal coronary angioplasty (PTCA), involves a non-surgical widening from within the artery using a balloon catheter. When inflated, the balloon increases the calibre of the artery.\n\nRecently, most PTCA procedures have involved the use of stents. Stents are thin wire-mesh structures that act as permanent prosthetic linings to keep the artery inflated and maintain its patency. PCI is a generic term to encompass PTCA with or without adjunct techniques such as stenting.\n\nFor disease in a single artery, PCI with a stent has been the more frequent treatment; for disease in two arteries, patient numbers for PCI with a stent and CABG have been similar; and for more than two affected arteries, CABG has been used much more frequently.\n\nThe major problem with PCI is restenosis of the artery, which has three main causes. The first, recoil of the artery, happens when the balloon is deflated. It usually occurs immediately or within 24 hours of completion of the procedure, and may require emergency CABG. Stents essentially eliminate recoil of the artery. The two subsequent problems, mostly arising during the first 6 months, are contraction of the adventitia secondary to an injury reaction (3–6 months), and proliferation of smooth muscle cells within the arterial wall (4–6 months). A repeat procedure is consequently required in approximately 20% of patients with simple lesions. This rate of reintervention is much higher (up to 50%) for arteries of small calibre, saphenous vein grafts, long lesions, total occlusions and in people with diabetes.\n\nRecent advances in stent technology have reduced some of the problems of restenosis, as well as lowering the cost of stents. In addition, the use of antiplatelet drugs and other therapeutic strategies to prevent thrombosis have improved long-term outcomes.\n\nOne of the main criteria for assessing the clinical effectiveness of PTCA with stents compared with standard PTCA (without stents) is the ability to reduce the incidence of subsequent attacks of angina as well as major adverse coronary events (MACE), which include death, MI and the need for further revascularisation procedures (CABG or repeat PCI).\n\nPatients for whom both a CABG and a PCI involving stenting are appropriate techniques would, other things being equal, choose PCI in almost all cases, even though the chances of restenosis are greater. This is because the procedure is less invasive, has a lower chance of death during the operation, and involves a much shorter and less painful recuperation time.\n\nApproximately 39,000 PCI procedures were undertaken in the UK in 2001, equating to 663 per million of the population – a rate that had increased at an average of 14% per year over the previous 10 years. The rate for the UK remains below that of the European Union (EU) average, which exceeds 1000 per million of the population.\n\nIn the UK, the proportion of PCI procedures using stents rose steeply between 1993 and 1999, from below 10% to nearly 80%. It has continued to increase, although more slowly, to about 85% in 2001.\n\nThe number of CABG procedures performed each year in the UK has increased from 15,700 in 1991 to 24,700 in 1999/2000, or from 292 to 464 per million of the population. The rate of increase has slowed since the first half of the 1990s.\n\nThe National Service Framework for Coronary heart Disease target, set in March 2000 for revascularisations (PCIs and CABGs), is at least 1500 per million of the population (750 for each type of intervention). At current growth rates, the combined target will be reached by about 2005.", 'The technology': "This appraisal is both a review of earlier NICE guidance (NICE Technology Appraisal Guidance No. 4; see Section 8) covering BMS, and a new appraisal of DES. BMS have already been described in Section 2 as part of existing practice. The rest of this section is devoted to methods of reducing restenosis and, in particular, to the use of DES as a means of achieving this.\n\nMethods of reducing restenosis include: coating the stent with an appropriate drug; introducing an emitter of radioactive particles at the stenting site (brachytherapy); and creating the slow release of a drug from the stent, making the stent 'drug-eluting'. For DES, the drug is held temporarily in place within a polymer 'painted' onto the metallic stent. Other than one trial (the ELUTES trial), there is little evidence in favour of coating the stent directly with an active drug (without a polymer); this technology, and brachytherapy, are outside the scope of this appraisal.\n\nAlthough a number of drugs have been tested in the context of DES, only three have been granted CE (Conformite Europeene) marking for use within EU countries: paclitaxel, which inhibits cell division, elutes from the Taxus stent; sirolimus (previously known as rapamycin), an immunosuppressive agent that reduces inflammation, elutes from the Cypher stent; and dexamethasone, a synthetic adrenocortical steroid that reduces inflammation, elutes from the BiodivYsio stent. These drugs may elute at different rates, depending on the presence or absence of additional polymer coatings on the stent. Because the performance of a DES depends critically on the particular drug being used, each DES should be regarded as a separate technology. However, as yet, studies directly comparing different DES have not been performed.\n\nBoth types of stent (BMS and DES) require the use of an antiplatelet drug in addition to aspirin. Such drugs should be used after the implantation of a stent, in accordance with the device-specific instructions for use (IFU).\n\nList prices for both BMS and DES differ between manufacturers, and some manufacturers produce more than one stent in each class, at different prices. Prices for BMS range from about £600 to £900 and for DES from about £1300 to £1500 per stent. For bare-metal and drug-eluting stents that are the same apart from their drug-eluting properties, the difference in cost is about £500 to £600. Costs may vary in different settings because of negotiated procurement discounts.", 'Evidence and interpretation': "The Appraisal Committee (Appendix A) considered evidence from a number of sources (Appendix B).\n\n# Clinical effectiveness\n\nThe Assessment Report presents three sets of comparison: PCI without stents versus PCI with BMS; PCI with BMS versus CABG; and BMS versus DES.\n\nAssessment of the relative clinical effectiveness of stents considers the likelihood of restenosis discovered on follow-up and the requirement for repeat intervention (revascularisation). Repeat intervention may occur: (i) because of a requirement of the trial protocol, specifying a repeat angiographic examination at a predetermined interval (so-called 'protocol-driven' reintervention); or (ii) following a recurrence of symptomatic angina in the patient (that is, 'clinically-driven' reintervention). The frequency of protocol-driven reinterventions is higher than that of clinically driven reinterventions, because angiography is usually mandatory at 6 months in the trial protocol whereas in clinical practice it is carried out only after recurrence of symptoms. Accordingly, the absolute differences observed between the treatment and control arms of clinical trials are likely to be higher than would be expected to occur in clinical practice.\n\n## PCI with BMS versus PCI (without stents)\n\nFifty randomised controlled trials (RCTs) were analysed comparing the use of PCI with BMS versus PCI without stents. Because of differences in, and completeness of, the reporting of these trials, the number of trials on which meta-analyses are based is a subset of these 50 trials. In a meta-analysis comprising 12 trials involving 5700 patients with non-specified ischaemic heart disease, where a composite endpoint of revascularisation, MI or death (MACE) was reported, the MACE rate was statistically significantly different at 6 months' follow-up: 23.0% for the PCI without stents group versus 15.4% for the PCI with BMS group, with an odds ratio (OR) of 1.66 (95% confidence interval [CI], 1.45 to 1.90). The difference was smaller after 12 months' follow-up but still statistically significant. Of the above 12 trials, seven, involving 3500 patients, reported data for 12-months' follow-up: the MACE rate was 22.0% for the PCI without stents group versus 18.9% for the PCI with stents group (OR 1.33; 95% CI, 1.12 to 1.58).\n\nDifferences in MACE rates were due almost entirely to differences in the rate of restenosis. For the outcomes of acute MI and deaths, for which individual trials were not powered to detect statistically significant differences, meta-analyses showed that while both of these sets of events occurred less frequently in those treated with PCI using BMS than in PCI without stents, in neither case was the result statistically significant.\n\nOverall, the results of the RCTs showed that the use of PCI with BMS has significant advantages over the use of PCI without stents, in terms of lower rates of restenosis at 6 and 12 months.\n\nAccording to the joint professional submission, the likelihood of restenosis is greater in small vessels, because a given tissue regrowth will have a greater proportionate effect in a vessel of smaller calibre. In eight out of nine studies that looked at vessels of a small calibre (less than 3 mm), restenosis rates were lower in the BMS arm than in the PCI without stent arm, and in two of these studies, the difference was statistically significant. A meta-analysis showed a statistically significant advantage for PCI with BMS. However, restenosis rates were still high in this group.\n\nAccording to the joint professional submission, the restenosis rate increased by an estimated 8 to 13 percentage points with every 10-mm increase in the length of BMS required.\n\n## PCI with BMS versus CABG\n\nThere were six RCTs in the meta-analysis. None of the trials involved a DES.\n\nFor single-vessel disease, the MACE rate was statistically significantly different at 6 months' follow-up in two trials involving a total of 300 patients: 12.6% for CABG versus 25.8% for PCI with BMS (OR 0.41; 95% CI, 0.22 to 0.74). The higher MACE rate for PCI with BMS reflects the higher rate of restenosis following this procedure.\n\nFor multiple-vessel disease, the MACE rate was statistically significantly different at 12 months' follow-up in two trials involving a total of 2300 patients: 12.3% for CABG versus 24.5% for PCI with BMS (OR 0.43; 95% CI, 0.34 to 0.54).\n\nAt 36 days' follow-up, the rate of acute MIs was statistically significantly lower following PCI with BMS, but the difference between the two procedures was not statistically significant at 6 and 12 months.\n\nNo statistically significant differences were reported for deaths, because the trials were not powered to detect differences in these uncommon events.\n\n## BMS versus DES\n\nThere were 12 RCTs comparing BMS with DES. Of these, seven involved paclitaxel, four sirolimus, one everolimus and one actinomycin stents. The first two sets of trials (paclitaxel and sirolimus) are considered separately below, and the last two trials have not been considered here because they involved products that have not been granted CE marking. No RCT for the third DES with a CE mark (eluting dexamethasone) has yet been reported.\n\n## Paclitaxel-eluting stents\n\nBased on four trials with a paclitaxel DES (Taxus and non-CE-marked stents), involving almost 1000 patients, the MACE rate for PCIs using a paclitaxel DES was not statistically significantly lower at 36 days or at 1 year, but it was statistically significantly lower at 6 months: 7.4% for DES versus 15.4% for BMS (OR 0.48; 95% CI, 0.31 to 0.73). From a random effects model (which takes account of heterogeneity of results between trials), the 6-month data for the MACE rate were not statistically significant (OR 0.58; 95% CI, 0.24 to 1.43). Most of the MACE events refer to restenosis. However, the two trials of the Taxus DES stent (which has a CE mark), involving 583 patients, yielded a statistically significantly lower MACE rate at 6 months: 7.2% for DES versus 18.4% for BMS (OR 0.35; 95% CI, 0.21 to 0.59); and at 12 months: 9.7% for DES versus 20.5% for BMS (OR 0.41; 95% CI, 0.25 to 0.67).\n\nPaclitaxel DES have not been demonstrated to show an advantage over BMS in either mortality or prevention of MI. However, in a series of trials of the Taxus stent (the TAXUS trials), the MI rate for PCIs using a paclitaxel DES was statistically significantly lower at 6 months: 1.7% for DES versus 5.9% for BMS (OR 0.35; 95% CI, 0.12 to 0.99). The statistical significance of this result was not maintained at 12 months: 2.8% for DES versus 5.8% for BMS (OR 0.56; 95% CI, 0.23 to 1.37).\n\nMultivariate analysis of data from the TAXUS trials shows that once the effect of small-calibre arteries and long lesions has been allowed for, the difference in performance between DES and BMS for people with diabetes is not statistically significantly different from that of people without diabetes.\n\n## Sirolimus-eluting stents\n\nThe MACE rate for PCIs using a sirolimus DES (Cypher and non-CE-marked stents) was not statistically significantly lower at 36 days, but it was lower at 9 months and at 1 year; at 9 months the rate was 7.4% for DES versus 18.9% for BMS (OR 0.34; 95% CI, 0.23 to 0.47), and at 1 year it was 7.8% for DES versus 21.8% for BMS (OR 0.30; 95% CI, 0.22 to 0.43). Most of the MACE events refer to restenosis. The trials of the Cypher sirolimus DES (which has a CE mark) showed a statistically significantly lower MACE rate compared with trials of BMS at 9 months (OR 0.32; 95% CI, 0.16 to 0.45), 12 months (OR 0.31; 95% CI, 0.22 to 0.43), and 24 months (OR 0.46; 95% CI, 0.22 to 0.97).\n\nSirolimus-eluting stents in general have not been shown to have either a mortality or acute MI advantage over BMS in trials, and neither do the DES within the subset of Cypher stent trials.\n\nAccording to the joint professional submission, in larger arteries, PCIs using a sirolimus DES have shown very low rates of restenosis, approaching zero. In small-calibre arteries, PCIs using a sirolimus DES have shown lower rates of restenosis than PCIs using a BMS (for example, 7% versus 20% restenosis at 9 months in the SIRIUS trial for vessels of mean calibre 2.3 mm).\n\nIn patients with diabetes and those with longer lesions, rates of restenosis following PCIs using a sirolimus DES have been higher than those of the 'average' patient, but still much lower than following PCIs using the BMS control. Subsequent post hoc subgroup analysis from one of the manufacturers from a trial involving patients who received a DES was considered by the Committee. The analysis compared the restenosis rate for people with diabetes with that for people without diabetes. It showed that the restenosis rate for those with diabetes as a whole was higher than for the non-diabetes group, but the difference was not statistically significant. In addition, the analysis did not control for artery calibre or length.\n\nAccording to the joint professional submission, for every 10 mm increase in the length of the stent, the difference in restenosis rate between a Cypher DES and Cypher BMS increased by between 1 and 1.6 percentage points.\n\n# Cost effectiveness\n\nThe most recent evidence of cost effectiveness comes from models supplied by four manufacturers and one from the Assessment Group, including an addendum. The manufacturer models show that PCIs with a BMS are cost effective compared with PCIs without stents and also compared with CABG. However, these models are relatively short-run, ranging from 6 months to 2 years. The manufacturers of the Cypher and of the Taxus stents each provided a model which examined the cost effectiveness of their own DES compared with the corresponding BMS. Each of these models showed that the DES is cost effective compared with the corresponding BMS. The Assessment Group's model showed that the Cypher and Taxus stents, as a group, are cost effective compared with BMS.\n\n## PCI with BMS versus PCI without stents\n\nFor patients with moderate or severe angina, PCI has been shown to be a cost-effective alternative to conventional medical treatment. Since the previous appraisal (by the Institute in 2000) of PCI with BMS versus PCI without stents, several further studies have demonstrated the cost effectiveness of stents in a number of patient populations and clinical settings, including elective stenting and stenting immediately following an acute MI.\n\n## PCI with BMS versus CABG\n\nComparative data on PCI using BMS versus CABG are available for only 3 years of follow-up. There are no data beyond 3 years and little data from years 2 to 3. The best available data are up to 2 years. Long-term models are needed to determine cost effectiveness because most patients who have stents fitted live longer than 5 years, and it is impossible to give a proper answer to the question of cost effectiveness by taking a short-term perspective.\n\nThe Assessment Group's model extrapolates the results to 5 years based on the currently available 3-year data. However, the extrapolation is very sensitive to the functional form chosen for the survival curve of patients who have undergone either stenting or CABG.\n\nThe benefits/disadvantages of PCIs using BMS compared with CABG, in terms of quality-of-life differences, derive from stents being a less invasive procedure on one hand but having higher rates of restenosis on the other. Neither of these two effects, in terms of quality-adjusted life years (QALYs), has been estimated to be very great, which means that if there was any appreciable difference in mortality between the two therapies, this factor would determine which of the therapies had the greater benefits. However, none of the meta-analyses from the trials shows any mortality benefit from PCI with either BMS or DES compared with CABG in the first 2 years. Hence, all the measurable benefits from using stents rather than CABG derive from an increase in the quality of life. Since stenting is considerably cheaper than CABG, under the 2-year models, it is therefore more cost effective, and indeed, dominates CABG.\n\nThe Assessment Group's model, however, estimated a survival benefit for CABG over PCI using BMS of the order of 0.05 QALYs per patient, after the model was extrapolated to 5 years. This benefit would be enough to make CABG the preferred technology (in terms of both clinical and cost effectiveness) for patients who were candidates for both stents and CABG. The clinician consultees to the appraisal process, however, vigorously challenged this, stating that previous studies had not reached this conclusion.\n\n## BMS versus DES\n\nThe quality-of-life component of the QALY differences between BMS and DES is small, because it relates only to the extent of the differences in restenosis rates. No differences in mortality have been demonstrated. Thus, the greatest benefits of DES over BMS will occur for categories of patients for whom the absolute differences in restenosis rates are greatest.\n\nThe addendum to the Assessment Report showed that, for single-vessel disease, PCI using a DES was estimated to be cost-saving compared with PCI using a BMS at 12 months for patients with diabetes and long lesions; the estimated cost per QALY for patients without diabetes and long lesions was £15,000 and, for all patients with narrow vessels, it was £16,000. These estimates were derived from patient-level data derived from the TAXUS II trial. For the total population of patients with single-vessel disease, the cost per QALY was £94,000. This estimate was derived from registry data.\n\nThese estimates are sensitive to five factors:\n\nthe percentage point reduction in the risk of revascularisation\n\nthe price differential between BMS and DES\n\nthe proportion of repeat interventions needing CABG\n\nthe disutility caused by recurrent symptoms\n\nthe average waiting time for repeat intervention.\n\nThere are no RCT data for two-vessel disease. The estimated incremental cost per QALY for two-vessel disease gained from PCI using a DES compared with PCI using a BMS for all non-diabetic patients is £195,000. This estimate is derived from registry data.\n\n# Consideration of the evidence\n\nThe Committee reviewed the evidence available on the clinical and cost effectiveness of PCIs using a BMS and DES, having considered evidence on the nature of the condition and the value placed by users on the benefits of BMS and DES from clinical experts and those who represent patients with angina. It was also mindful of the need to ensure that its advice took account of the efficient use of NHS resources.\n\n## PCI with BMS versus PCI without stents\n\nThe Committee considered that no new evidence had been found since the previous appraisal to change its view that where PCI is being undertaken, the use of stents is likely to be both clinically and cost effective.\n\n## BMS versus DES\n\nThe Committee noted that there were no head-to-head trials of the sirolimus-eluting Cypher stent and the paclitaxel-eluting Taxus stent, and the clinical experts advised that there was no evidence that would allow them to favour one of these drug-eluting agents over the other.\n\nThe Committee considered that, for single-vessel disease, restenosis rates were in general low using a BMS in the majority of patients requiring PCI, and that, therefore, the routine use of a DES was not justified. However, this was not the case for patients presenting with either small-calibre arteries (< 3 mm) or long lesions (> 15 mm); in these patients, the risk of restenosis using a BMS was considerably higher, and the absolute reduction in restenosis rates would justify the use of a DES.\n\nThe Committee considered the risk factors predicting the likelihood of higher rates of restenosis after the use of a BMS. It was persuaded that the main determinants of risk were the target vessel calibre and the complexity of the arterial lesion, in particular the length of the stenosis. It recognised that the combination of small-vessel disease and long lesions was particularly prevalent in patients with CAD who also had diabetes. Whilst, in general, patients with diabetes have higher restenosis rates than those without diabetes following PCI with a BMS, the Review Group's analysis indicated that these higher rates arise predominantly from the fact that a much higher proportion of patients with diabetes needing PCI have disease of small-calibre arteries and long lesions than is true for the general population of patients requiring PCI.\n\nThe Committee discussed how the RCTs comparing BMS with DES relate to current clinical practice. In particular, in the trials, the decision to reintervene following an initial PCI with stent procedure was often made on the basis of protocol-driven angiographic examinations at certain fixed times (for example at 6 months), rather than in response to the recurrence of clinical symptoms. It is likely that the trials would encourage reintervention that might not be required in clinical practice, where routine re-angiography is not usual. Thus, the Committee was aware that the difference in restenosis rates between BMS and DES identified in the trials could overestimate the extent of the difference that would actually be seen in clinical practice. The addendum to the Assessment Report attempted to correct for this potential overestimate of the benefit of DES versus BMS. The Committee decided that, whether or not the correction factor was applied, the guidance in Section 1 would not be materially affected.\n\nThe Committee considered PCI with a DES for more than one target vessel in a person with symptomatic coronary disease. It was aware that the evidence from the RCTs relates to the use of DES in single-vessel disease. However, the experts indicated that treatment of more than one vessel in an individual patient during PCI might be required. This is because, despite additional investigations, it is frequently difficult to determine which of several vessels identified at angiography is the most likely cause of the patient's symptoms. The Committee considered that the risk of a need for future intervention following an initial PCI is likely to be dependent on the degree of stenosis of any of the affected vessels. The appropriateness of a DES or BMS for each diseased artery in turn would therefore depend on considering the artery's characteristics in isolation from those of other diseased arteries. It was therefore persuaded that planned treatment of more than one vessel in a single patient should be based on the requirements laid out in the guidance for a single vessel.\n\nThe Committee discussed the use of DES with regard to coronary artery vein grafts and for more complex situations such as bifurcation lesions, but noted that there was no robust evidence in this area at present.\n\nThe Committee noted statements from some manufacturers that restenosis rates using a BMS of recent design were low compared with those of other BMS, and were comparable with those of the CE-marked DES. The cost-effectiveness calculations were not based on evidence comparing these stents with other BMS or with DES in head-to-head trials. The Committee considered that this evidence was not sufficient to affect its recommendations for guidance in Section 1. It would, however, wish to include further evidence on new developments in BMS design as part of the next review of the use of coronary stents.\n\n## PCI with BMS versus CABG\n\nHaving reviewed the Assessment Group's model and the submissions from manufacturers, together with the views of cardiologist consultees, the Committee concluded that the guidance offered in 2000 should be maintained. While it was clear that models with outcomes up to 2 years favoured stents in terms of cost effectiveness, the conclusions to be drawn from longer-term models depended critically on whether a survival advantage accrues to CABG. The Committee concluded that no convincing case had been made on this matter. Its considerations ranged over what may happen to patients requiring one or other of these procedures in different age ranges, and whether the conclusions about the most appropriate procedure would be the same for younger patients (who are more likely to need a repeat procedure) as for older ones. In none of the cases considered was there sufficient evidence of effect to be able to reach any conclusion.", 'Recommendations for further research': 'Ongoing trials for paclitaxel-eluting stents include TAXUS I (follow-up of a small initial study of slow-release formulation versus BMS in patients with either previously-untreated lesions or restenosis), TAXUS II (follow-up of a larger study of both slow- and moderate-release formulations versus BMS in patients with previously-untreated lesions), TAXUS IV (a large trial of slow-release formulation versus BMS stratified by presence or absence of diabetes and by vessel diameter), TAXUS V (focussing on small vessels, long lesions, bifurcations and in-stent restenosis) and TAXUS VI (moderate release for long lesions). For sirolimus-eluting stents, on-going trials include RAVEL (small-diameter vessels), SIRIUS (high risk for cardiovascular disease progression and restenosis due to the diabetes, exposure to multiple stent implantation and use of overlapping stents) and E-SIRIUS (previously-untreated single vessels of diameter 2.5 to 3 mm and for lesions between 15 and 32 mm in length); and FUTURE (previously-untreated vessels between 2.75 and 4 mm, less than 28 mm long ) for everolimus-eluting stents. REALITY, a head-to-head trial of the Cypher sirolimus DES and Taxus paclitaxel DES, is under way.\n\nUntil now, trials have been restricted to single-artery studies for the sake of simplicity and ease of interpretation. Extrapolation of results to more than one artery critically depends on untested assumptions. Randomised controlled trials (RCTs) of the use of DES in more than one artery concurrently are therefore required, in order to confirm or refute the appropriateness of the extrapolations used in the modelling.\n\nTo compare long-term outcomes, particularly with respect to stents against CABG, much longer trial follow-ups are required.\n\nNew BMS designs should be tested against current BMS and DES designs.\n\nHead-to-head RCTs of those DES that have been CE marked and have been shown to be clinically superior to the corresponding BMS are required.\n\nStudies to determine whether diabetes is a risk factor for increased rate of restenosis following PCI, independent of lesion length and artery calibre, are required. Much of this work could be performed by an analysis of patient-level data taken from trials already conducted.', 'Implications for the NHS': 'The financial impact of using DES depends on the proportion of stented arteries that are narrow or contain long lesions offset against the increased capacity of the system resulting from a decrease in procedures to manage restenosis. Although the total number of arteries requiring a DES in the UK is unknown, it could be as high as one-third of all stents. Based on this proportion, the additional cost of DES without offsets would be between £6 and £7.2 million per year, assuming the use of about 12,000 DES stents costing an additional £500 to £600 each.\n\nIf the use of drug-eluting stents reduced the restenosis rate by about 10 percentage points then the additional capacity generated could be used to increase the number of new stent procedures. This would have the effect of offsetting the cost of the BMS by about £4 million per year. Such cost savings, however, will often only be realised in the form of additional capacity.', 'Appendix C. Detail on criteria for audit of the use of coronary artery stents': '# Possible objectives for an audit\n\nAn audit could be carried out to ensure that stents are being used appropriately in patients undergoing PCIs. Local clinical audits could also confirm that PCI is the clinically appropriate procedure for patients included in the audit.\n\n# Possible patients to be included in the audit\n\nAn audit could include all patients having a PCI for stable or unstable angina, acute MI or symptomatic CAD in a suitable time period, for example, 3 months.\n\n# Measures that could be used as a basis for audit\n\nCriterion\n\nStandard\n\nException\n\nDefinition of terms\n\n. Stents are used when a PCI is performed in an individual having any of the following:\n\na. stable angina or\n\nb. unstable angina or\n\nc. acute MI\n\n% of individuals having a PCI for stable or unstable angina or acute MI\n\nNone\n\nClinicians will need to agree locally on any exceptions for audit purposes.\n\n. A Cypher or a Taxus stent is used in a PCI for an individual with symptomatic CAD when either of the following occurs:\n\na. the target artery is < 3\xa0mm in calibre or\n\nb. the lesion to be stented is longer than 15\xa0mm\n\n% of individuals having a PCI for symptomatic CAD\n\nA. The individual has had an MI in the preceding 24 hours\n\nB. The individual has angiographic evidence of thrombus in the target artery\n\nClinicians will need to agree locally on any other exceptions for audit purposes.\n\n# Calculation of compliance\n\nCompliance (%) with each measure described in table\xa01 is calculated as follows.\n\n[Number of patients whose care is consistent with the criterion plus number of patients who meet any exception listed] divided by [Number of patients to whom the measure applies] x 100\n\nClinicians should review the findings of measurement, identify whether practice can be improved, agree on a plan to achieve any desired improvement and repeat the measurement of actual practice to confirm that the desired improvement is being achieved.'}
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https://www.nice.org.uk/guidance/ta71
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Evidence-based recommendations on using coronary artery stents in adults.
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f0558b617622c6793163766425b189223ba4e615
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nice
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Siponimod for treating secondary progressive multiple sclerosis
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Siponimod for treating secondary progressive multiple sclerosis
Evidence-based recommendations on siponimod (Mayzent) for treating secondary progressive multiple sclerosis in adults.
# Recommendations
Siponimod is recommended, within its marketing authorisation, as an option for treating secondary progressive multiple sclerosis with evidence of active disease (that is, relapses or imaging features of inflammatory activity) in adults. It is recommended only if the company provides siponimod according to the commercial arrangement.
Why the committee made these recommendations
Interferon beta‑1b is the only disease-modifying treatment available for people with active secondary progressive multiple sclerosis. However, few people have it. Most people do not have any disease-modifying treatments. Effective treatment options are therefore very limited.
Clinical trial results show that siponimod reduces the number of relapses and slows disability progression compared with placebo. It is uncertain how effective siponimod is compared with interferon beta‑1b because there is no evidence directly comparing them.
The most plausible cost-effectiveness estimates for siponimod compared with no disease-modifying treatment and with interferon beta‑1b (Extavia) are in the range that NICE normally considers an acceptable use of NHS resources. Therefore, siponimod is recommended.# Information about siponimod
# Marketing authorisation indication
Siponimod (Mayzent, Novartis) is indicated for 'the treatment of adult patients with secondary progressive multiple sclerosis with active disease evidenced by relapses or imaging features of inflammatory activity'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price for siponimod is £1,643.72 per pack of 28×2‑mg tablets (excluding VAT; BNF online, September 2020).
The company has a commercial arrangement with the NHS. This makes siponimod available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Novartis, a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.
# Treatment pathway
## Secondary progressive multiple sclerosis is a continuum of relapsing–remitting multiple sclerosis
Relapsing–remitting multiple sclerosis progresses to secondary progressive multiple sclerosis in many people. The patient and clinical experts, company and ERG all indicated that there is a period of transition in which people with relapsing–remitting multiple sclerosis may be suspected of having secondary progressive disease but are not formally diagnosed. This is especially the case for the population in this appraisal (that is, people with active secondary progressive disease) because they may still have relapses. The clinical experts confirmed that multiple sclerosis is a spectrum and does not consist of distinct phenotypic subtypes. The patient and clinical experts acknowledged that, historically, there has been reluctance to diagnose secondary progressive multiple sclerosis. This is because there is only 1 licensed treatment, interferon beta‑1b, which people may have already had. Also, disease-modifying treatments for relapsing–remitting multiple sclerosis are no longer indicated once someone is diagnosed with secondary progressive multiple sclerosis, so treatment usually stops. The clinical experts explained that many factors influence disease progression in multiple sclerosis, including inflammation and age. However, there is a lack of clinical understanding in this area. The committee concluded that secondary progressive multiple sclerosis is a continuum of relapsing–remitting multiple sclerosis, and that various factors contribute to the progression of disease.
## Siponimod could change the timing of diagnosis of secondary progressive multiple sclerosis and involve doing an MRI scan
In its submission, the company explained that the availability of a new treatment option for active secondary progressive multiple sclerosis could lead to diagnosing secondary progressive multiple sclerosis earlier. This is because neurologists are reluctant to make the diagnosis without an effective treatment being available (see section 3.1). The clinical experts explained that, if siponimod becomes available, somebody who would usually be diagnosed with secondary progressive multiple sclerosis at an Expanded Disability Status Scale (EDSS) score of 6 may instead be diagnosed at EDSS 4. They explained that diagnosis is currently based on signs and symptoms rather than biochemical or radiological testing. The committee was aware that siponimod's marketing authorisation limits its use to people with 'active' disease, and that the company defined active disease by either relapses or imaging features of inflammatory activity. The clinical experts explained that, if siponimod becomes available, more people would have an MRI scan to assess whether they have secondary progressive disease and identify whether they are eligible for siponimod. They explained that people already diagnosed with secondary progressive disease would have to have MRI scans and visit a neurologist to assess if siponimod is a suitable treatment option. The committee was aware that this additional activity could have a substantial resource impact for the NHS. It concluded that people may be formally diagnosed earlier with secondary progressive multiple sclerosis if siponimod becomes available, and that diagnosis would involve an MRI scan.
# Comparators
## Interferon beta‑1b and best supportive care are the relevant comparators
Interferon beta‑1b is the only treatment licensed for secondary progressive multiple sclerosis with active disease evidenced by relapses. One brand, Extavia, is recommended in NICE's technology appraisal guidance on beta interferons for multiple sclerosis. The patient and clinical experts explained that many people have difficulty tolerating interferon beta‑1b because it can cause adverse effects such as flu-like symptoms, and involves having subcutaneous injections every other day. Also, the clinical experts reported that healthcare professionals query the efficacy of interferon beta‑1b, so few people with secondary progressive multiple sclerosis have it. An NHS commissioning expert estimated that only about 75 people with secondary progressive multiple sclerosis in England have interferon beta‑1b. So, most people do not have any disease-modifying treatment. In its original base-case analysis, the company compared siponimod with interferon beta‑1b. It also provided scenario analyses comparing siponimod with a range of disease-modifying treatments licensed for relapsing–remitting multiple sclerosis. In its updated base case, the company compared siponimod with best supportive care and with interferon beta‑1b, but not with other disease-modifying treatments. This was in line with the committee conclusions from its first meeting. The company also presented a scenario using a weighted comparator. This included some people who were assumed to be having disease-modifying treatments licensed for relapsing–remitting multiple sclerosis and others who were not. The clinical experts explained that disease-modifying treatments are sometimes used outside of their licensed indications in people with secondary progressive multiple sclerosis during the transition period from relapsing–remitting disease. However, the NHS commissioning expert clarified that the NHS does not commission these drugs for secondary progressive multiple sclerosis, so they should not be considered relevant comparators. The committee concluded that some people diagnosed with active secondary progressive multiple sclerosis have interferon beta‑1b, but that most people have no disease-modifying treatment. This means that patients and their clinicians have limited treatment options, and best supportive care or interferon beta‑1b are the only relevant comparators. The committee further concluded not to consider the weighted comparator in its decision making.
# EXPAND clinical trial
## Characteristics of people in the subgroup with active disease from EXPAND reflect the population with active disease in NHS clinical practice
The main clinical evidence for siponimod came from EXPAND, a double-blind, randomised, placebo-controlled trial in adults with secondary progressive multiple sclerosis. The randomised part of the trial was followed by an observational period in which everyone was switched to open-label (unblinded) siponimod and followed for up to 10 years. This part of the trial is ongoing. The committee was aware that the marketing authorisation, being limited to active disease, reflected only a portion of the overall trial population. EXPAND enrolled people in 31 countries, including the UK. The primary outcome was the percentage of people with sustained disability lasting at least 3 months, defined as a 1‑point increase in EDSS if the baseline score was 3.0 to 5.0 or a 0.5‑point increase if the baseline score was 5.5 to 6.5. Health-related quality of life data were collected using EQ‑5D. The company suggested that EXPAND was generalisable to the secondary progressive multiple sclerosis population seen in NHS clinical practice because the study had UK sites. However, the committee noted that most sites were not in the UK. The ERG was concerned that outcomes and clinical practice may vary across the countries in the trial. The clinical experts advised that the baseline characteristics reflected people with the condition seen in the NHS. The committee concluded that the baseline characteristics of the subgroup with active disease in EXPAND were similar to the NHS population with active secondary progressive multiple sclerosis, and that the trial results are likely to be generalisable to the NHS population.
## Siponimod is an effective treatment compared with placebo for active secondary progressive multiple sclerosis
In the subgroup of people with active disease in EXPAND, both time to 3‑month (the primary endpoint) and 6‑month confirmed disability progression (defined by the same EDSS changes as for the primary endpoint, but lasting at least 6 months) were longer with siponimod than with placebo. The annualised relapse rate was lower with siponimod than with placebo. The full results cannot be reported here because the company considers them confidential. The patient experts explained that the endpoints of 6‑month confirmed disability progression and annualised relapse rate are important to patients, and the clinical experts considered the improvements seen in these endpoints to be clinically meaningful. The committee concluded that siponimod is an effective treatment for active secondary progressive multiple sclerosis compared with placebo.
## It is uncertain whether siponimod has the same effect in disease with and without imaging features of inflammatory activity
Based on the possibility that it could not recommend siponimod for use in all patients covered in the marketing authorisation, in its first meeting, the committee was interested in whether siponimod is of more benefit in disease with imaging features of inflammatory activity than without. The clinical experts advised that it is possible to have active disease without any changes in imaging features, and that it is possible to progress in terms of changes on MRI without evidence of clinical progression. For the committee's second meeting, the company provided results for subgroups of the EXPAND active population according to whether the disease was relapsing and whether there were imaging features of inflammatory activity. Based on these results, the company considered siponimod to be an effective treatment regardless of whether or not people have imaging features of inflammatory activity. However, it did not provide a test for interaction. The committee concluded that it remains uncertain whether siponimod compared with placebo has the same effect on disease with and without imaging features of inflammatory activity.
# Indirect treatment comparisons
## All of the company's and ERG's indirect treatment comparisons have limitations
There is no trial comparing siponimod with interferon beta‑1b. Therefore, the company did an indirect comparison using data from EXPAND and 2 trials of interferon beta‑1b, which reported relevant efficacy outcomes. One trial by the European Study Group, known as the 'European trial', reported annualised relapse rate and 3‑month confirmed disability progression. The other, a North American trial, reported annualised relapse rate and 6‑month confirmed disability progression. The company chose a matching-adjusted indirect comparison as its base case because it considered that differences between EXPAND and the 2 interferon beta‑1b trials made a network meta-analysis unfeasible. The company stated that its analysis used the full trial populations because the trials did not report relevant results separately for people with active disease. The company highlighted differences in the inclusion and exclusion criteria, placebo regimens and response in the placebo arms. The ERG stated that the company did not match for all relevant confounders and effect modifiers in its matching-adjusted indirect comparison. It noted that matching to the data for interferon beta‑1b reduced the EXPAND effective sample size, which increased uncertainty. The ERG did its own network meta-analysis because it did not consider the company's reasons for doing a matching-adjusted indirect comparison instead of a network meta-analysis reasonable. Both the company's and the ERG's analyses favoured siponimod over interferon beta‑1b for the outcome of 6‑month confirmed disability progression, but the wide confidence interval around the ERG's estimate included the possibility of no effect. For annualised relapse rate, both the company's and the ERG's analyses favoured siponimod over interferon beta‑1b, but the confidence intervals for both analyses included the possibility of no effect. The company considered that any network meta-analysis should be based on the population in the marketing authorisation (that is, people with active disease), whereas the ERG used the full EXPAND population. At technical engagement, the company provided an additional network meta-analysis based on the active-disease population from EXPAND. The point estimate of effectiveness for 6‑month confirmed disability progression favoured siponimod compared with interferon beta‑1b, but the confidence interval included the possibility of no benefit. The results cannot be reported here because they are considered confidential by the company. The committee was concerned that, although this network meta-analysis used the active-disease population from EXPAND, it used the full trial populations for the trials of interferon beta‑1b. The committee noted that, in the European trial, about 70% of people had relapses, indicating probable active disease. It questioned whether a matching-adjusted indirect comparison using only this trial data may provide a more reliable result than any of the indirect comparisons it had been presented with so far. However, the committee was aware that the European trial collected only 3‑month rather than 6‑month confirmed disability progression data, which it would normally prefer. In response to consultation, the company explained that the point estimate of effectiveness for 3‑month confirmed disability progression favoured siponimod compared with interferon beta‑1b, but the confidence interval included the possibility of no benefit. The company also expressed concerns that the population in the European trial was younger than in the EXPAND and North American trials, and the effective sample size was lower when using European trial data. The committee concluded that there were substantial uncertainties associated with all of the indirect comparisons.
# The company's economic model
## Data from the placebo arm of EXPAND and the London Ontario registry should be used to model untreated secondary progressive multiple sclerosis
The company modelled disease progression using 11 health states, 10 defined by EDSS scores ranging from 0 to 9 (with a higher score indicating worse disease) and a death state. It assumed that an effective treatment for secondary progressive multiple sclerosis improves quality of life by delaying the progression of disease to higher EDSS states, and by reducing the frequency of relapses. The company also assumed that treatment improves a carer's quality of life, and that an effective treatment prolongs life by delaying progression to higher EDSS states that are associated with higher rates of death. To model untreated disease (best supportive care), the company used the placebo group from EXPAND supplemented with data from the London Ontario registry. In each cycle, people could move to a higher or lower EDSS state (that is, their disability could worsen or improve) or remain in the same state. The ERG, in discussion with its clinical adviser, highlighted that, over the long term, people with secondary progressive multiple sclerosis will progress to (or sometimes plateau at) higher EDSS states. But, in the short term, if people have a relapse from which they recover, they could improve before they worsen again. The ERG assumed that this short timeframe may be about 2 to 3 months and pointed out that transitions in the model were yearly, so improvements were likely to be very rare. Because the London Ontario data do not allow improvements in the EDSS, the ERG considered it to be more appropriate than the trial data. It also highlighted that these data were collected over 25 years compared with the 2‑year duration of EXPAND. The committee was aware that previous appraisals for relapsing–remitting multiple sclerosis had used both the London Ontario data alone and the trial placebo data supplemented by registry data. The committee considered that, because improvements in EDSS had been seen in the trial, it was reasonable for the model to capture them. The committee concluded that it was appropriate for the company to model untreated disease using data from the placebo arm of EXPAND supplemented by the London Ontario registry.
## The modelled population should have active disease to reflect the marketing authorisation
In its base case, the company used baseline characteristics reflecting the subgroup of people with active disease in EXPAND. The ERG considered that the characteristics from the full (intention-to-treat) population should have been used instead because this is the population in whom the treatment effect estimates were derived in both the company's and the ERG's preferred indirect comparison (see section 3.7). The committee was aware that it could appraise treatments only within the marketing authorisation. It considered that the modelled population should match the marketing authorisation for siponimod, which covers people with active secondary progressive multiple sclerosis. The committee concluded that the modelled population should have active disease at baseline.
## Treatment discontinuation rather than study discontinuation provides a better estimate of the number of people stopping siponimod in clinical practice
The committee noted that it was unclear whether the company had used study discontinuation or treatment discontinuation from EXPAND to model stopping treatment with siponimod for any reason in its original model. The committee considered that treatment discontinuation rather than study discontinuation would provide a better estimate of the number of people stopping siponimod in clinical practice. The company clarified that its original model used study discontinuation. It agreed with the committee's suggested change and in response to consultation used treatment discontinuation instead in its updated base case.
# Utility values in the economic model
## The model should include utility values from the active subgroup of EXPAND supplemented by Orme et al. (2007)
To estimate health-related quality of life, the company used EQ‑5D‑3L utility values from EXPAND. It supplemented these with values from a published paper, Orme et al. (2007), for EDSS states 0, 1, 2, 8 and 9 because there were few people with these EDSS values in the EXPAND trial. The ERG considered that there was uncertainty about the EQ‑5D values from EXPAND and that they might not be generalisable to people in the NHS. The ERG preferred to use the data from Orme et al. because they were based on more people than EXPAND. The committee noted that the utility value for EDSS 3 (0.529) from Orme et al. was lower than the value for EDSS 4 (0.565), which the committee considered to lack face validity. The clinical experts explained that the EXPAND data were more recent than the Orme data, so may better reflect advances in supportive care. The committee considered that the model should have included utility values from the subgroup of people with active disease, rather than the full EXPAND population. The company updated its base case in response to consultation to reflect the committee's preferences.
# Costs in the economic model
## Costs associated with starting siponimod are appropriately included in the company's model
The committee was aware that the company estimated costs for each EDSS state using data from the UK Multiple Sclerosis Survey, which was used in NICE's technology appraisal guidance on dimethyl fumarate for relapsing–remitting multiple sclerosis. The company inflated the prices to 2017/2018 values. The patient and clinical experts explained that many people with secondary progressive multiple sclerosis do not regularly attend a specialist service, especially if they are not having disease-modifying treatments. The clinical and commissioning experts agreed that, if siponimod was offered in the NHS, it would be prescribed by healthcare professionals in a specialist service. Before starting treatment, people being considered for siponimod would attend a neurology clinic and have an MRI scan that they may not previously have been offered (see section 3.2). The clinical experts highlighted that these costs would apply only to people who had already been diagnosed with secondary progressive multiple sclerosis. It would not apply to people who are transitioning from relapsing–remitting to secondary progressive disease, who would generally have regular MRI scans. The company clarified that its original model already included 2 neurology appointments for siponimod each year, including a higher cost of a first appointment as well as a follow-up appointment in the first year. In response to consultation, it also presented a scenario in which it included a third annual neurology appointment and explained that its updated base case included the cost of an additional MRI scan for people starting siponimod. The committee concluded that the company had appropriately modelled costs associated with additional neurology visits and scans in its updated base case.
# Waning of siponimod treatment effect
## It is appropriate to model waning of the effect of treatment with siponimod
The company presented an analysis of 6‑year data from the open-label extension of EXPAND. It argued that this shows the effect of siponimod treatment does not diminish over time. The committee considered this analysis to be highly uncertain because everyone in the open-label extension had siponimod. Also, there was no comparator arm that could be used to confidently estimate siponimod's relative treatment effect. In its original analysis, the company considered the rate at which people stop treatment for any reason to be a suitable proxy for the waning of treatment effect with siponimod in the model. This was because, if siponimod stops working, people are likely to stop taking it. The committee considered that the company's original approach may have overestimated the benefits of siponimod if people remain on treatment even if its efficacy decreases over time. Including a waning of the treatment effect in the model would help to address this possibility. The clinical experts explained that it is difficult to comment on whether the effect of treatment with siponimod is likely to wane over time. The committee noted NICE's technology appraisal guidance for fingolimod, which has a related mechanism of action to siponimod. In that appraisal, the committee concluded that the treatment effect was likely to wane. In response to consultation, the company updated its base case to include a 50% decrease in siponimod's effectiveness from year 11 of treatment onwards. It also presented a scenario with a 25% decrease in effectiveness from year 7 to year 10 of treatment, then a 50% decrease from year 10 onwards. The committee concluded that the company appropriately included waning of siponimod's treatment effect in its updated model.
# Innovation
## The company's model may not capture all the benefits of treatment with siponimod
The company explained that it considered siponimod to be innovative because it is taken orally, whereas interferon beta‑1b is a powder that must be mixed with solvent and injected subcutaneously. Therefore, people are likely to find siponimod easier to take. Consultees noted that people with impaired motor function are likely to find it particularly difficult to self-administer interferon beta‑1b, so this is a potential equality issue. The company also suggested that the beneficial effects of siponimod on cognitive processing have not been captured in the modelling. It presented results from EXPAND showing improvements in the symbol digit modalities test score (a test for assessing cognitive processing in multiple sclerosis) with siponimod compared with placebo. The ERG agreed with the company that there was some evidence suggesting that siponimod benefits cognitive processing speed and that the EQ‑5D may not have fully captured this. The committee agreed that such benefits could be important. However, the symbol digit modalities test score was only 1 exploratory endpoint of the EXPAND trial, and the committee did not see the other exploratory endpoints, so it was difficult to draw conclusions using this score alone. However, the committee concluded that the benefits related to ease of administration had likely not been captured in the model.
# Cost-effectiveness estimate
## The company's updated base case reflects the committee's preferred assumptions
Following changes made in response to consultation, the company's updated analysis reflected the committee's preferences as follows:
a comparison of siponimod with interferon beta‑1b and best supportive care in a probabilistic fully incremental analysis
treatment discontinuation rather than study discontinuation used to estimate the numbers stopping siponimod in clinical practice
utility values from the subgroup of people with active disease from EXPAND supplemented by Orme et al. (2007)
costs of neurology appointments and MRI scans for people starting siponimod
a waning of the effect of treatment for siponimod.Because of confidential commercial arrangements for siponimod and interferon beta‑1b, the cost-effectiveness results cannot be reported here.
## Siponimod is likely to be a cost-effective use of NHS resources
The committee considered the company's base-case cost-effectiveness results based on its matching-adjusted indirect treatment comparison, and a scenario analysis based on its network meta-analysis using the active population from EXPAND. For the comparison with best supportive care, the committee noted that the EXPAND trial compared siponimod with placebo directly. Therefore, the company could have used the trial results as a source of effectiveness evidence in the model without the need for an indirect comparison. This analysis was not available. However, the committee noted that the hazard ratio for 6‑month confirmed disability progression was more favourable for siponimod in EXPAND than in the company's network meta-analysis. It was therefore satisfied that the incremental cost-effectiveness ratio would decrease if the EXPAND results were used instead of the network meta-analysis. The committee noted that some uncertainty remained about the cost-effectiveness results because of uncertainties associated with the indirect comparisons. However, the committee appreciated the steps taken by the company to resolve some of this uncertainty, including presenting an updated analysis that was in line with its preferences. The committee also noted that there were limited alternative treatment options for this population (see section 3.3). Taking this into account, the committee was satisfied that the cost-effectiveness estimates were within the range that NICE normally considers an acceptable use of NHS resources.
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{'Recommendations': 'Siponimod is recommended, within its marketing authorisation, as an option for treating secondary progressive multiple sclerosis with evidence of active disease (that is, relapses or imaging features of inflammatory activity) in adults. It is recommended only if the company provides siponimod according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nInterferon beta‑1b is the only disease-modifying treatment available for people with active secondary progressive multiple sclerosis. However, few people have it. Most people do not have any disease-modifying treatments. Effective treatment options are therefore very limited.\n\nClinical trial results show that siponimod reduces the number of relapses and slows disability progression compared with placebo. It is uncertain how effective siponimod is compared with interferon beta‑1b because there is no evidence directly comparing them.\n\nThe most plausible cost-effectiveness estimates for siponimod compared with no disease-modifying treatment and with interferon beta‑1b (Extavia) are in the range that NICE normally considers an acceptable use of NHS resources. Therefore, siponimod is recommended.', 'Information about siponimod': "# Marketing authorisation indication\n\nSiponimod (Mayzent, Novartis) is indicated for 'the treatment of adult patients with secondary progressive multiple sclerosis with active disease evidenced by relapses or imaging features of inflammatory activity'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price for siponimod is £1,643.72 per pack of 28×2‑mg tablets (excluding VAT; BNF online, September 2020).\n\nThe company has a commercial arrangement with the NHS. This makes siponimod available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Novartis, a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.\n\n# Treatment pathway\n\n## Secondary progressive multiple sclerosis is a continuum of relapsing–remitting multiple sclerosis\n\nRelapsing–remitting multiple sclerosis progresses to secondary progressive multiple sclerosis in many people. The patient and clinical experts, company and ERG all indicated that there is a period of transition in which people with relapsing–remitting multiple sclerosis may be suspected of having secondary progressive disease but are not formally diagnosed. This is especially the case for the population in this appraisal (that is, people with active secondary progressive disease) because they may still have relapses. The clinical experts confirmed that multiple sclerosis is a spectrum and does not consist of distinct phenotypic subtypes. The patient and clinical experts acknowledged that, historically, there has been reluctance to diagnose secondary progressive multiple sclerosis. This is because there is only 1\xa0licensed treatment, interferon beta‑1b, which people may have already had. Also, disease-modifying treatments for relapsing–remitting multiple sclerosis are no longer indicated once someone is diagnosed with secondary progressive multiple sclerosis, so treatment usually stops. The clinical experts explained that many factors influence disease progression in multiple sclerosis, including inflammation and age. However, there is a lack of clinical understanding in this area. The committee concluded that secondary progressive multiple sclerosis is a continuum of relapsing–remitting multiple sclerosis, and that various factors contribute to the progression of disease.\n\n## Siponimod could change the timing of diagnosis of secondary progressive multiple sclerosis and involve doing an MRI scan\n\nIn its submission, the company explained that the availability of a new treatment option for active secondary progressive multiple sclerosis could lead to diagnosing secondary progressive multiple sclerosis earlier. This is because neurologists are reluctant to make the diagnosis without an effective treatment being available (see section\xa03.1). The clinical experts explained that, if siponimod becomes available, somebody who would usually be diagnosed with secondary progressive multiple sclerosis at an Expanded Disability Status Scale (EDSS) score of\xa06 may instead be diagnosed at EDSS\xa04. They explained that diagnosis is currently based on signs and symptoms rather than biochemical or radiological testing. The committee was aware that siponimod's marketing authorisation limits its use to people with 'active' disease, and that the company defined active disease by either relapses or imaging features of inflammatory activity. The clinical experts explained that, if siponimod becomes available, more people would have an MRI scan to assess whether they have secondary progressive disease and identify whether they are eligible for siponimod. They explained that people already diagnosed with secondary progressive disease would have to have MRI scans and visit a neurologist to assess if siponimod is a suitable treatment option. The committee was aware that this additional activity could have a substantial resource impact for the NHS. It concluded that people may be formally diagnosed earlier with secondary progressive multiple sclerosis if siponimod becomes available, and that diagnosis would involve an MRI scan.\n\n# Comparators\n\n## Interferon beta‑1b and best supportive care are the relevant comparators\n\nInterferon beta‑1b is the only treatment licensed for secondary progressive multiple sclerosis with active disease evidenced by relapses. One brand, Extavia, is recommended in NICE's technology appraisal guidance on beta interferons for multiple sclerosis. The patient and clinical experts explained that many people have difficulty tolerating interferon beta‑1b because it can cause adverse effects such as flu-like symptoms, and involves having subcutaneous injections every other day. Also, the clinical experts reported that healthcare professionals query the efficacy of interferon beta‑1b, so few people with secondary progressive multiple sclerosis have it. An NHS commissioning expert estimated that only about 75\xa0people with secondary progressive multiple sclerosis in England have interferon beta‑1b. So, most people do not have any disease-modifying treatment. In its original base-case analysis, the company compared siponimod with interferon beta‑1b. It also provided scenario analyses comparing siponimod with a range of disease-modifying treatments licensed for relapsing–remitting multiple sclerosis. In its updated base case, the company compared siponimod with best supportive care and with interferon beta‑1b, but not with other disease-modifying treatments. This was in line with the committee conclusions from its first meeting. The company also presented a scenario using a weighted comparator. This included some people who were assumed to be having disease-modifying treatments licensed for relapsing–remitting multiple sclerosis and others who were not. The clinical experts explained that disease-modifying treatments are sometimes used outside of their licensed indications in people with secondary progressive multiple sclerosis during the transition period from relapsing–remitting disease. However, the NHS commissioning expert clarified that the NHS does not commission these drugs for secondary progressive multiple sclerosis, so they should not be considered relevant comparators. The committee concluded that some people diagnosed with active secondary progressive multiple sclerosis have interferon beta‑1b, but that most people have no disease-modifying treatment. This means that patients and their clinicians have limited treatment options, and best supportive care or interferon beta‑1b are the only relevant comparators. The committee further concluded not to consider the weighted comparator in its decision making.\n\n# EXPAND clinical trial\n\n## Characteristics of people in the subgroup with active disease from EXPAND reflect the population with active disease in NHS clinical practice\n\nThe main clinical evidence for siponimod came from EXPAND, a double-blind, randomised, placebo-controlled trial in adults with secondary progressive multiple sclerosis. The randomised part of the trial was followed by an observational period in which everyone was switched to open-label (unblinded) siponimod and followed for up to 10\xa0years. This part of the trial is ongoing. The committee was aware that the marketing authorisation, being limited to active disease, reflected only a portion of the overall trial population. EXPAND enrolled people in 31\xa0countries, including the UK. The primary outcome was the percentage of people with sustained disability lasting at least 3\xa0months, defined as a 1‑point increase in EDSS if the baseline score was 3.0\xa0to\xa05.0 or a 0.5‑point increase if the baseline score was 5.5\xa0to\xa06.5. Health-related quality of life data were collected using EQ‑5D. The company suggested that EXPAND was generalisable to the secondary progressive multiple sclerosis population seen in NHS clinical practice because the study had UK sites. However, the committee noted that most sites were not in the UK. The ERG was concerned that outcomes and clinical practice may vary across the countries in the trial. The clinical experts advised that the baseline characteristics reflected people with the condition seen in the NHS. The committee concluded that the baseline characteristics of the subgroup with active disease in EXPAND were similar to the NHS population with active secondary progressive multiple sclerosis, and that the trial results are likely to be generalisable to the NHS population.\n\n## Siponimod is an effective treatment compared with placebo for active secondary progressive multiple sclerosis\n\nIn the subgroup of people with active disease in EXPAND, both time to 3‑month (the primary endpoint) and 6‑month confirmed disability progression (defined by the same EDSS changes as for the primary endpoint, but lasting at least 6\xa0months) were longer with siponimod than with placebo. The annualised relapse rate was lower with siponimod than with placebo. The full results cannot be reported here because the company considers them confidential. The patient experts explained that the endpoints of 6‑month confirmed disability progression and annualised relapse rate are important to patients, and the clinical experts considered the improvements seen in these endpoints to be clinically meaningful. The committee concluded that siponimod is an effective treatment for active secondary progressive multiple sclerosis compared with placebo.\n\n## It is uncertain whether siponimod has the same effect in disease with and without imaging features of inflammatory activity\n\nBased on the possibility that it could not recommend siponimod for use in all patients covered in the marketing authorisation, in its first meeting, the committee was interested in whether siponimod is of more benefit in disease with imaging features of inflammatory activity than without. The clinical experts advised that it is possible to have active disease without any changes in imaging features, and that it is possible to progress in terms of changes on MRI without evidence of clinical progression. For the committee's second meeting, the company provided results for subgroups of the EXPAND active population according to whether the disease was relapsing and whether there were imaging features of inflammatory activity. Based on these results, the company considered siponimod to be an effective treatment regardless of whether or not people have imaging features of inflammatory activity. However, it did not provide a test for interaction. The committee concluded that it remains uncertain whether siponimod compared with placebo has the same effect on disease with and without imaging features of inflammatory activity.\n\n# Indirect treatment comparisons\n\n## All of the company's and ERG's indirect treatment comparisons have limitations\n\nThere is no trial comparing siponimod with interferon beta‑1b. Therefore, the company did an indirect comparison using data from EXPAND and 2\xa0trials of interferon beta‑1b, which reported relevant efficacy outcomes. One trial by the European Study Group, known as the 'European trial', reported annualised relapse rate and 3‑month confirmed disability progression. The other, a North American trial, reported annualised relapse rate and 6‑month confirmed disability progression. The company chose a matching-adjusted indirect comparison as its base case because it considered that differences between EXPAND and the 2\xa0interferon beta‑1b trials made a network meta-analysis unfeasible. The company stated that its analysis used the full trial populations because the trials did not report relevant results separately for people with active disease. The company highlighted differences in the inclusion and exclusion criteria, placebo regimens and response in the placebo arms. The ERG stated that the company did not match for all relevant confounders and effect modifiers in its matching-adjusted indirect comparison. It noted that matching to the data for interferon beta‑1b reduced the EXPAND effective sample size, which increased uncertainty. The ERG did its own network meta-analysis because it did not consider the company's reasons for doing a matching-adjusted indirect comparison instead of a network meta-analysis reasonable. Both the company's and the ERG's analyses favoured siponimod over interferon beta‑1b for the outcome of 6‑month confirmed disability progression, but the wide confidence interval around the ERG's estimate included the possibility of no effect. For annualised relapse rate, both the company's and the ERG's analyses favoured siponimod over interferon beta‑1b, but the confidence intervals for both analyses included the possibility of no effect. The company considered that any network meta-analysis should be based on the population in the marketing authorisation (that is, people with active disease), whereas the ERG used the full EXPAND population. At technical engagement, the company provided an additional network meta-analysis based on the active-disease population from EXPAND. The point estimate of effectiveness for 6‑month confirmed disability progression favoured siponimod compared with interferon beta‑1b, but the confidence interval included the possibility of no benefit. The results cannot be reported here because they are considered confidential by the company. The committee was concerned that, although this network meta-analysis used the active-disease population from EXPAND, it used the full trial populations for the trials of interferon beta‑1b. The committee noted that, in the European trial, about 70% of people had relapses, indicating probable active disease. It questioned whether a matching-adjusted indirect comparison using only this trial data may provide a more reliable result than any of the indirect comparisons it had been presented with so far. However, the committee was aware that the European trial collected only 3‑month rather than 6‑month confirmed disability progression data, which it would normally prefer. In response to consultation, the company explained that the point estimate of effectiveness for 3‑month confirmed disability progression favoured siponimod compared with interferon beta‑1b, but the confidence interval included the possibility of no benefit. The company also expressed concerns that the population in the European trial was younger than in the EXPAND and North American trials, and the effective sample size was lower when using European trial data. The committee concluded that there were substantial uncertainties associated with all of the indirect comparisons.\n\n# The company's economic model\n\n## Data from the placebo arm of EXPAND and the London Ontario registry should be used to model untreated secondary progressive multiple sclerosis\n\nThe company modelled disease progression using 11\xa0health states, 10\xa0defined by EDSS scores ranging from 0\xa0to\xa09 (with a higher score indicating worse disease) and a death state. It assumed that an effective treatment for secondary progressive multiple sclerosis improves quality of life by delaying the progression of disease to higher EDSS states, and by reducing the frequency of relapses. The company also assumed that treatment improves a carer's quality of life, and that an effective treatment prolongs life by delaying progression to higher EDSS states that are associated with higher rates of death. To model untreated disease (best supportive care), the company used the placebo group from EXPAND supplemented with data from the London Ontario registry. In each cycle, people could move to a higher or lower EDSS state (that is, their disability could worsen or improve) or remain in the same state. The ERG, in discussion with its clinical adviser, highlighted that, over the long term, people with secondary progressive multiple sclerosis will progress to (or sometimes plateau at) higher EDSS states. But, in the short term, if people have a relapse from which they recover, they could improve before they worsen again. The ERG assumed that this short timeframe may be about 2\xa0to 3\xa0months and pointed out that transitions in the model were yearly, so improvements were likely to be very rare. Because the London Ontario data do not allow improvements in the EDSS, the ERG considered it to be more appropriate than the trial data. It also highlighted that these data were collected over 25\xa0years compared with the 2‑year duration of EXPAND. The committee was aware that previous appraisals for relapsing–remitting multiple sclerosis had used both the London Ontario data alone and the trial placebo data supplemented by registry data. The committee considered that, because improvements in EDSS had been seen in the trial, it was reasonable for the model to capture them. The committee concluded that it was appropriate for the company to model untreated disease using data from the placebo arm of EXPAND supplemented by the London Ontario registry.\n\n## The modelled population should have active disease to reflect the marketing authorisation\n\nIn its base case, the company used baseline characteristics reflecting the subgroup of people with active disease in EXPAND. The ERG considered that the characteristics from the full (intention-to-treat) population should have been used instead because this is the population in whom the treatment effect estimates were derived in both the company's and the ERG's preferred indirect comparison (see section\xa03.7). The committee was aware that it could appraise treatments only within the marketing authorisation. It considered that the modelled population should match the marketing authorisation for siponimod, which covers people with active secondary progressive multiple sclerosis. The committee concluded that the modelled population should have active disease at baseline.\n\n## Treatment discontinuation rather than study discontinuation provides a better estimate of the number of people stopping siponimod in clinical practice\n\nThe committee noted that it was unclear whether the company had used study discontinuation or treatment discontinuation from EXPAND to model stopping treatment with siponimod for any reason in its original model. The committee considered that treatment discontinuation rather than study discontinuation would provide a better estimate of the number of people stopping siponimod in clinical practice. The company clarified that its original model used study discontinuation. It agreed with the committee's suggested change and in response to consultation used treatment discontinuation instead in its updated base case.\n\n# Utility values in the economic model\n\n## The model should include utility values from the active subgroup of EXPAND supplemented by Orme et al. (2007)\n\nTo estimate health-related quality of life, the company used EQ‑5D‑3L utility values from EXPAND. It supplemented these with values from a published paper, Orme et al. (2007), for EDSS states 0,\xa01,\xa02,\xa08 and\xa09 because there were few people with these EDSS values in the EXPAND trial. The ERG considered that there was uncertainty about the EQ‑5D values from EXPAND and that they might not be generalisable to people in the NHS. The ERG preferred to use the data from Orme et al. because they were based on more people than EXPAND. The committee noted that the utility value for EDSS\xa03 (0.529) from Orme et al. was lower than the value for EDSS\xa04 (0.565), which the committee considered to lack face validity. The clinical experts explained that the EXPAND data were more recent than the Orme data, so may better reflect advances in supportive care. The committee considered that the model should have included utility values from the subgroup of people with active disease, rather than the full EXPAND population. The company updated its base case in response to consultation to reflect the committee's preferences.\n\n# Costs in the economic model\n\n## Costs associated with starting siponimod are appropriately included in the company's model\n\nThe committee was aware that the company estimated costs for each EDSS state using data from the UK Multiple Sclerosis Survey, which was used in NICE's technology appraisal guidance on dimethyl fumarate for relapsing–remitting multiple sclerosis. The company inflated the prices to 2017/2018 values. The patient and clinical experts explained that many people with secondary progressive multiple sclerosis do not regularly attend a specialist service, especially if they are not having disease-modifying treatments. The clinical and commissioning experts agreed that, if siponimod was offered in the NHS, it would be prescribed by healthcare professionals in a specialist service. Before starting treatment, people being considered for siponimod would attend a neurology clinic and have an MRI scan that they may not previously have been offered (see section\xa03.2). The clinical experts highlighted that these costs would apply only to people who had already been diagnosed with secondary progressive multiple sclerosis. It would not apply to people who are transitioning from relapsing–remitting to secondary progressive disease, who would generally have regular MRI scans. The company clarified that its original model already included 2\xa0neurology appointments for siponimod each year, including a higher cost of a first appointment as well as a follow-up appointment in the first year. In response to consultation, it also presented a scenario in which it included a third annual neurology appointment and explained that its updated base case included the cost of an additional MRI scan for people starting siponimod. The committee concluded that the company had appropriately modelled costs associated with additional neurology visits and scans in its updated base case.\n\n# Waning of siponimod treatment effect\n\n## It is appropriate to model waning of the effect of treatment with siponimod\n\nThe company presented an analysis of 6‑year data from the open-label extension of EXPAND. It argued that this shows the effect of siponimod treatment does not diminish over time. The committee considered this analysis to be highly uncertain because everyone in the open-label extension had siponimod. Also, there was no comparator arm that could be used to confidently estimate siponimod's relative treatment effect. In its original analysis, the company considered the rate at which people stop treatment for any reason to be a suitable proxy for the waning of treatment effect with siponimod in the model. This was because, if siponimod stops working, people are likely to stop taking it. The committee considered that the company's original approach may have overestimated the benefits of siponimod if people remain on treatment even if its efficacy decreases over time. Including a waning of the treatment effect in the model would help to address this possibility. The clinical experts explained that it is difficult to comment on whether the effect of treatment with siponimod is likely to wane over time. The committee noted NICE's technology appraisal guidance for fingolimod, which has a related mechanism of action to siponimod. In that appraisal, the committee concluded that the treatment effect was likely to wane. In response to consultation, the company updated its base case to include a 50% decrease in siponimod's effectiveness from year\xa011 of treatment onwards. It also presented a scenario with a 25% decrease in effectiveness from year\xa07\xa0to year\xa010 of treatment, then a 50% decrease from year\xa010 onwards. The committee concluded that the company appropriately included waning of siponimod's treatment effect in its updated model.\n\n# Innovation\n\n## The company's model may not capture all the benefits of treatment with siponimod\n\nThe company explained that it considered siponimod to be innovative because it is taken orally, whereas interferon beta‑1b is a powder that must be mixed with solvent and injected subcutaneously. Therefore, people are likely to find siponimod easier to take. Consultees noted that people with impaired motor function are likely to find it particularly difficult to self-administer interferon beta‑1b, so this is a potential equality issue. The company also suggested that the beneficial effects of siponimod on cognitive processing have not been captured in the modelling. It presented results from EXPAND showing improvements in the symbol digit modalities test score (a test for assessing cognitive processing in multiple sclerosis) with siponimod compared with placebo. The ERG agreed with the company that there was some evidence suggesting that siponimod benefits cognitive processing speed and that the EQ‑5D may not have fully captured this. The committee agreed that such benefits could be important. However, the symbol digit modalities test score was only 1\xa0exploratory endpoint of the EXPAND trial, and the committee did not see the other exploratory endpoints, so it was difficult to draw conclusions using this score alone. However, the committee concluded that the benefits related to ease of administration had likely not been captured in the model.\n\n# Cost-effectiveness estimate\n\n## The company's updated base case reflects the committee's preferred assumptions\n\nFollowing changes made in response to consultation, the company's updated analysis reflected the committee's preferences as follows:\n\na comparison of siponimod with interferon beta‑1b and best supportive care in a probabilistic fully incremental analysis\n\ntreatment discontinuation rather than study discontinuation used to estimate the numbers stopping siponimod in clinical practice\n\nutility values from the subgroup of people with active disease from EXPAND supplemented by Orme et al. (2007)\n\ncosts of neurology appointments and MRI scans for people starting siponimod\n\na waning of the effect of treatment for siponimod.Because of confidential commercial arrangements for siponimod and interferon beta‑1b, the cost-effectiveness results cannot be reported here.\n\n## Siponimod is likely to be a cost-effective use of NHS resources\n\nThe committee considered the company's base-case cost-effectiveness results based on its matching-adjusted indirect treatment comparison, and a scenario analysis based on its network meta-analysis using the active population from EXPAND. For the comparison with best supportive care, the committee noted that the EXPAND trial compared siponimod with placebo directly. Therefore, the company could have used the trial results as a source of effectiveness evidence in the model without the need for an indirect comparison. This analysis was not available. However, the committee noted that the hazard ratio for 6‑month confirmed disability progression was more favourable for siponimod in EXPAND than in the company's network meta-analysis. It was therefore satisfied that the incremental cost-effectiveness ratio would decrease if the EXPAND results were used instead of the network meta-analysis. The committee noted that some uncertainty remained about the cost-effectiveness results because of uncertainties associated with the indirect comparisons. However, the committee appreciated the steps taken by the company to resolve some of this uncertainty, including presenting an updated analysis that was in line with its preferences. The committee also noted that there were limited alternative treatment options for this population (see section\xa03.3). Taking this into account, the committee was satisfied that the cost-effectiveness estimates were within the range that NICE normally considers an acceptable use of NHS resources."}
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https://www.nice.org.uk/guidance/ta656
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Evidence-based recommendations on siponimod (Mayzent) for treating secondary progressive multiple sclerosis in adults.
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9d5aea5174009cb156b49de623f14c06ad4cf7e5
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nice
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Carfilzomib for previously treated multiple myeloma
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Carfilzomib for previously treated multiple myeloma
Evidence-based recommendations on carfilzomib (Kyprolis) for previously treated multiple myeloma in adults.
# Recommendations
Carfilzomib with dexamethasone is recommended as an option for treating multiple myeloma in adults, only if:
they have had only 1 previous therapy and
the company provides carfilzomib according to the commercial arrangement.
These recommendations are not intended to affect treatment with carfilzomib that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. # The technology
# Marketing authorisation indication
Kyprolis 'in combination with either lenalidomide and dexamethasone or dexamethasone alone, is indicated for the treatment of adult patients with multiple myeloma who have had at least 1 prior therapy'.
# Adverse reactions
The most common adverse reactions (in more than 20% of patients) were: anaemia, fatigue, diarrhoea, thrombocytopenia, nausea, pyrexia, dyspnoea, respiratory tract infection, cough and peripheral oedema. For full details of adverse reactions and contraindications, see the summary of product characteristics.
# Dosage in the marketing authorisation
One cycle of carfilzomib is 28 days.
## In combination with lenalidomide and dexamethasone
Carfilzomib is given on 2 consecutive days each week for 3 weeks (days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period (days 17 to 28) for the first 12 cycles.
From cycle 13, the day 8 and 9 doses of carfilzomib are omitted.
Carfilzomib is administered at a starting dose of 20 mg/m2 (maximum dose 44 mg) in cycle 1 on days 1 and 2.
If tolerated, the dose should be increased to 27 mg/m2 (maximum dose 60 mg) from day 8 of cycle 1.
## In combination with dexamethasone alone
Carfilzomib is given on 2 consecutive days each week for 3 weeks (days 1, 2, 8, 9, 15, and 16) followed by a 12-day rest period (days 17 to 28).
Carfilzomib is administered at a starting dose of 20 mg/m2 (maximum dose 44 mg) in cycle 1 on days 1 and 2.
If tolerated, the dose should be increased to 56 mg/m2 (maximum dose 123 mg) from day 8 of cycle 1.For further details, see the summary of product characteristics.
# Price
The list price of carfilzomib is £1,056 for a 60-mg vial (excluding VAT; Monthly Index of Monthly Specialties online, accessed October 2016).
## In combination with lenalidomide and dexamethasone
From cycle 1 to 12: £5,127 (no wastage), £6,336 (wastage).
From cycle 13: £3,418 (no wastage), £4,220 (wastage).
## In combination with dexamethasone alone
£10,644 (no wastage), £12,627 (wastage).The company has a commercial arrangement. This makes carfilzomib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount. # Evidence
The appraisal committee considered evidence submitted by Amgen, including new evidence submitted after responses to the consultation document and suspension of the initial final appraisal determination, and a review of these submissions by the evidence review group (ERG). See the committee papers for full details of the evidence. # Committee discussion
The appraisal committee reviewed the data available on the clinical and cost effectiveness of carfilzomib, having considered evidence on the nature of multiple myeloma and the value placed on the benefits of carfilzomib by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.
# Clinical need
The committee noted the emotional impact and burden of disease on people with multiple myeloma, their families and carers, and the value of carfilzomib because it provides an additional treatment option that is well tolerated. The committee understood that there are effective treatments at earlier stages of the disease but there is a need for novel chemotherapeutic agents at later stages of the disease. The clinical experts emphasised the problem of emergent cells that are resistant to current treatment options; because of this, double and triple therapies are often used at later stages of the treatment pathway because a combination of different mechanisms is needed to control the resistant cells. The committee heard from the patient expert that although carfilzomib is given intravenously, which often deters patients, it offers important benefits over existing treatments. In particular, carfilzomib does not appear to be associated with neuropathic adverse reactions to the same extent as standard treatment and offers an increased remission time so patients are willing to have an intravenous administration. The committee concluded that patients and clinicians would welcome carfilzomib because there is a need for effective treatments after relapse and because it offers a number of quality-of-life improvements over current treatment options.
# Decision problem and treatment pathway
The committee considered the current treatment pathway for people whose disease has relapsed after having 1 therapy, including current NICE-recommended treatments and other agents used in practice.
The NICE scope specified comparator treatments that are currently used at second, third and fourth line (see figure 1). The committee noted that the marketing authorisation for carfilzomib is for people who have had at least 1 previous therapy (and therefore includes fourth-line treatment). However the company's comparisons restricted placement to second and third line only, based on the previous treatments received (taking account of current NICE guidance and the most commonly used treatment regimens in practice; see figure 2). The committee heard from the clinical expert that the company's approach was clinically rational and carfilzomib would mainly be used at second and third line. Clinicians prefer to use a combination of chemotherapeutic agents, alternating between agents with different mechanisms of action (immunomodulators and proteasome inhibitors, such as thalidomide and bortezomib). The clinical expert also explained that there are several treatments newly recommended in NICE technology appraisals, which are not yet used routinely in practice (pomalidomide for treating multiple myeloma after 3 previous treatments which included both lenalidomide and bortezomib, panobinostat for treating multiple myeloma after at least 2 previous therapies and lenalidomide for treating multiple myeloma after at least 2 previous therapies). The committee accepted this opinion and concluded that the positioning and comparison rationale provided by the company for carfilzomib is appropriate, that is:
carfilzomib and dexamethasone compared with bortezomib and dexamethasone at second line
carfilzomib, lenalidomide and dexamethasone compared with lenalidomide and dexamethasone at third line.
The company also provided a scenario analysis in which carfilzomib plus lenalidomide and dexamethasone was proposed at second line, as an alternative to lenalidomide plus dexamethasone for people who have had bortezomib first line.
The committee was aware that carfilzomib could theoretically be considered, within its marketing authorisation, in other positions within the treatment pathway (for example, as an alternative to lenalidomide plus dexamethasone at second line, for which the company provided a scenario analysis, and at subsequent lines after third line). However, it was not able to consider carfilzomib in these positions because not enough evidence was received from the company. The committee therefore focused its recommendations on the second and third-line positions.
# Clinical effectiveness
The committee noted that the company presented data from 2 trials:
ENDEAVOR: carfilzomib plus dexamethasone, compared with bortezomib plus dexamethasone
ASPIRE: carfilzomib plus lenalidomide and dexamethasone, compared with lenalidomide plus dexamethasone.The committee noted that these trials were of good quality and included active comparators that are relevant to the appraisal, thereby providing direct head-to-head evidence. It noted the overall survival data had not yet matured, so considered in detail the progression-free survival estimates for the overall population. It agreed that the estimates were compelling in favour of carfilzomib over the comparator treatments. It noted that, compared with bortezomib and dexamethasone, carfilzomib and dexamethasone doubled the progression-free survival to 18.7 months. When compared with lenalidomide and dexamethasone, carfilzomib with lenalidomide and dexamethasone increased the progression-free survival to 26.3 months (a gain of 8.7 months). The committee concluded the trial evidence showed a progression-free survival benefit for carfilzomib combinations over the comparators in the overall population.
The committee understood that to estimate the efficacy of carfilzomib at second and third line, the company specified post hoc subgroups for:
people who had 1 previous therapy, not bortezomib (second line compared with bortezomib and dexamethasone)
people who had 2 previous therapies, not lenalidomide (or carfilzomib; third line compared with lenalidomide and dexamethasone).The committee was aware of the limitations and the uncertain outcomes associated with subgroups that were not prespecified. It recognised the company's attempt to counter the uncertainties by adjusting for imbalances in the baseline characteristics with additional covariates by using a Cox proportional hazards model to estimate efficacy (as hazard ratios) of carfilzomib and its comparators. But the committee heard from the evidence review group (ERG) that the choice of these covariates was unclear without sufficient justification. The committee noted that the choice of variables to adjust the model should be those that are prognostic of the outcome. In response to the appraisal consultation document the company presented a range of methods to adjust for covariates, including stepwise-selection and least absolute shrinkage and selection operator (LASSO) methods, to explore the plausibility of different combinations of covariates. The committee noted that the company preferred the stepwise-selection method, whereas the ERG considered that the LASSO method was more appropriate. The committee was satisfied that the company had sufficiently explored uncertainty around the choice of covariates and that the comparative efficacy estimates were reasonable to consider for decision making for both comparisons of carfilzomib at second and third line.
The committee noted that the median age of people in ENDEAVOR (comparing carfilzomib and dexamethasone with bortezomib and dexamethasone) and ASPIRE (comparing carfilzomib, lenalidomide and dexamethasone with lenalidomide and dexamethasone) was 64 and 65 respectively. Patients had an average Eastern Cooperative Oncology Group (ECOG) status of 0 to 2. In comparison, data collected in the UK by the Haematological Malignancy Research Network (HMRN) from 2001 to 2012 showed that the median age at diagnosis was 73. The committee was therefore concerned that the results of the trials may not be generalisable to clinical practice in England. The committee understood from the clinical expert that patients in myeloma trials are generally younger because they are more willing and able to travel to the treatment centre. It also understood that patients are being diagnosed earlier and, as a result, the average age at diagnosis in England is younger than that recorded by the HMRN. The committee concluded that the patient characteristics in the trials could be generalised to UK clinical practice.
The committee noted a discrepancy between the length of carfilzomib treatment stipulated in the marketing authorisation and the stopping rule applied in ASPIRE. It understood that in ASPIRE, carfilzomib was stopped after 18 cycles whereas the marketing authorisation allows for treatment until progression or unacceptable toxicity. The committee heard from the company that no stopping rule was applied in ENDEAVOR and the average length of treatment was 16.5 cycles, which the clinical experts stated would be reflective of clinical practice. The committee concluded that the length of treatment in the trials was reflective of clinical practice in the UK.
The committee noted the adverse reactions listed in the summary of product characteristics. It heard that in practice, serious adverse reactions and toxicity are managed through dose reduction and concomitant medication. It also heard that people taking carfilzomib find it tolerable and that neuropathic adverse reactions are less evident than with bortezomib. The committee was satisfied that although carfilzomib is associated with serious adverse reactions, these are not any more significant than those experienced with other chemotherapeutic agents and are manageable in practice.
# Cost effectiveness
The committee had concerns about the company's initial approach to survival modelling. It stated in the appraisal consultation document that it would have liked to see the effect of fitting different covariate-adjusted parametric models, using different extrapolation techniques and assessing the plausibility of the resulting predictions. The committee recognised that the company provided revised analyses to address these concerns in response to the appraisal consultation document but was still uncertain on the cost-effectiveness results due to immature survival data. The committee was subsequently made aware that more mature overall survival data was available from the ENDEAVOR trial after the meeting had concluded. Therefore, the initial final appraisal determination was suspended to allow the committee to consider the new data and analysis. It considered in detail the most appropriate extrapolation function and the validity of the proportional hazards assumption.
The committee considered the validity of the proportional hazards assumption and noted that this assumes the hazards are constant over time (that is, the benefits of treatment continue until the end of the time horizon or death). The committee was aware that the company presented a model with jointly fitted survival curves in its revised base case, which requires the assumption of proportional hazards. The company also presented a detailed exploration of the appropriateness of the proportional hazards assumption, including a scenario analysis comparing the effect of using jointly or independently fitted curves (no proportional hazards assumption required) on the cost-effectiveness results. The committee heard from the ERG that in the extrapolation of overall survival for carfilzomib plus lenalidomide and dexamethasone compared with lenalidomide plus dexamethasone (third line), the convergence of curves in the log-log plots suggested that the proportional hazards assumption was not valid. The committee recognised that the company had thoroughly explored the proportional hazards assumption in response to the appraisal consultation document but it was not convinced by the company's interpretation that the proportional hazards assumption was valid for the comparison of carfilzomib at third line. The independently fitted model had a substantially higher incremental cost-effectiveness ratio (ICER) for carfilzomib plus lenalidomide and dexamethasone compared with lenalidomide plus dexamethasone (third line). The committee acknowledged that when comparing joint and independently fitted models in the company's revised scenario analysis there was very little difference in the cost-effectiveness results for carfilzomib plus dexamethasone compared with bortezomib plus dexamethasone at second line. For these reasons, the committee concluded that the proportional hazards assumption was acceptable for consideration in decision making for the comparison of carfilzomib at second line but not third line.
The committee considered the survival model used in the company's revised base case in response to the appraisal consultation document. It noted that the company used a Weibull distribution to estimate long-term survival whereas the ERG's exploratory base case used a Gompertz distribution. The committee also considered the company's revised scenario analysis to assess the effect of several different parametric distributions on the cost-effectiveness results. The company justified its choice of parametric curve by analysis of statistical fit, eliciting expert opinion and validating the curves externally. The committee considered the validation, plausibility and maturity of the overall survival data used to inform the Weibull and Gompertz parametric curves. It noted that the company presented new data in which the ENDEAVOR trial had reached its clinical end point for overall survival and the data were more mature than the ASPIRE trial, but it recalled its earlier conclusion on the lack of reliability of the proportional hazards assumptions for the comparison of carfilzomib at third line (see section 4.11). Therefore the committee focused on the comparison of carfilzomib at second line from the ENDEAVOR trial. The committee noted that the use of the Weibull or Gompertz distribution had a considerable effect on the ICER estimates, and that they had similar statistical fits. It also considered the external validity of both extrapolations; the company presented evidence that further validated the Weibull curve using data from Orlowski et al. (2016) trial (which compared bortezomib monotherapy to bortezomib combination therapy up to 9 years). The committee noted that the Kaplan–Meier curve for the bortezomib monotherapy arm from Orlowski et al. showed a greater percentage of people surviving with multiple myeloma at 9 years than predicted by the Gompertz curve. It also heard from the ERG that it agreed with the validation evidence presented by the company. The committee concluded that the new overall survival data and external validation supported the Weibull distribution for extrapolation for the comparison of carfilzomib at second line. It further concluded that the trial data was too immature to inform on the most appropriate parametric curve for extrapolation for the comparison of carfilzomib at third line.
For comparison of carfilzomib at second line, the committee noted that there were discrepancies between the company's initial model and clinical practice in the dosing schedule and length of treatment for bortezomib. It noted that the marketing authorisation for bortezomib states that it can be given twice weekly for 8 cycles (21-day cycles equal to a total of 32 doses), whereas the model assumed bortezomib would be given twice weekly as an intravenous infusion until progression (consistent with the duration of treatment in ENDEAVOR). The clinical experts clarified that in practice they prefer to give bortezomib once weekly and subcutaneously, because this is associated with fewer adverse reactions, and to give the full 32 doses. In response to the appraisal consultation document, the company provided a scenario analysis in which the duration of bortezomib was limited to 8 cycles and its efficacy adjusted accordingly. The committee noted that the company estimated this reduction in efficacy using a matched-adjusted indirect comparison (MAIC). The committee heard that the ERG agreed with this approach in principle. However, the ERG noted that key adjustments in the MAIC may have been missed and it considered that the results may be unreliable. It therefore presented an exploratory analysis in which it assumed no reduction in efficacy for bortezomib, while capping the costs to 8 cycles. The committee considered that it was appropriate to limit the duration of bortezomib therapy to 8 cycles in the model, consistent with NHS clinical practice, and that it was plausible that this approach would reduce the efficacy of bortezomib compared with continuing treatment until progression. The committee therefore concluded that the ERG's assumption was very conservative. In the absence of a more robust analysis the committee accepted that the company's approach was suitable for decision making.
For the comparison of carfilzomib at second line, the committee noted that bortezomib has a complex patient access scheme (PAS), in which the price paid for bortezomib is reimbursed by the company if there is not at least a partial response after a maximum of 4 cycles. It noted that this PAS was not included in the company's new base case received in response to the appraisal consultation document, although it was included in a scenario analysis. The committee was aware that the company had approximated the price of bortezomib to be equivalent to a 15% discount and heard from the ERG that this was a reasonable approximation. The committee concluded that this was an appropriate approximation and that it was appropriate for it to be included in the analysis.
The committee was aware that the company presented a scenario analysis in response to the appraisal consultation document, in which it made a case for excluding the extra costs of lenalidomide and dexamethasone associated with long-term carfilzomib therapy. The committee acknowledged that treatments that extend the use of other high costs drugs (such as lenalidomide) can lead to additional cost associated with those other drugs. However, it was not convinced that the company's approach is valid because lenalidomide is part of the regimen in which carfilzomib is given. The committee concluded that the costs of lenalidomide are relevant because the NHS would incur those costs in practice, so they should be included in the model.
The committee discussed how the company had derived the health state utility values used in the model. It noted that the company had used a mixed method, using published utility values from Agthoven et al. (2004) and mapped utility values from the trials. The committee heard that the ERG considered it more appropriate to derive utility values straight from trial data, using a mapping algorithm from Proskorovsky et al. (2014). In response to the appraisal consultation document, the company presented a revised base case using utility estimates mapped straight from trial data. The committee considered that the approach in the revised base case was appropriate and consistent with its preferred assumptions.
# Most plausible ICER
Having considered the key issues in the economic modelling, the committee considered the most plausible estimates for the cost-effective results. It considered separately the ICERs for carfilzomib in the 2 treatment-pathway positions proposed by the company (see section 4.4) and the new overall survival evidence submitted after the initial final appraisal determination was suspended (see section 4.10).
Carfilzomib in combination with lenalidomide and dexamethasone, compared with lenalidomide in combination with dexamethasone (third line): The committee considered the range of ICERs presented by the company in its base case and scenario analyses where they explored the effect of different parametric distributions for extrapolation and the effect of non-proportional hazards on the cost-effective results. It noted the company's revised base-case ICER, presented in response to the appraisal consultation document, was £41,429 per quality-adjusted life year (QALY) gained (with the Weibull distribution and proportional hazards) and the ERG's exploratory analysis ICER was £52,439 per QALY gained (Gompertz distribution and proportional hazards). The committee noted that this difference was driven by the choice of parametric extrapolation curve, which was highly uncertain due to immature overall survival data (see section 4.12). It also recalled there was doubt over the proportional hazards assumption in the model (see section 4.11), and that using the independent-fit model (non-proportional hazards) further increases the ICER above £52,439. Therefore the committee reasoned that there was uncertainty in the cost-effective estimate for the comparison of carfilzomib at third line but the most plausible ICER is very likely to be in a range above the company's estimate of £41,429 per QALY gained and one that could be substantially higher.
Carfilzomib in combination with dexamethasone, compared with bortezomib in combination with dexamethasone (second line): The committee noted that the company's new analysis, received after the initial final appraisal determination was suspended, included the committee's preferred assumptions (with the new overall survival data, Weibull extrapolation, including the PAS for bortezomib, and capping the cost of bortezomib to 8 cycles and reducing its efficacy) and resulted in an ICER of £27,629 per QALY gained. The committee also noted that the ERG's exploratory analysis in response to the new evidence (which used the Weibull extrapolation, included the PAS for bortezomib and capped the cost to 8 cycles without adjusting bortezomib's efficacy) resulted in an ICER of £40,744 per QALY gained. The committee recalled its earlier decisions on adjusting for bortezomib efficacy, if capping its cost to 8 cycles (see section 4.13) and concluded that the most plausible ICER is the company's estimate of £27,629 per QALY gained and that carfilzomib with dexamethasone is a cost-effective use of NHS resources for people with multiple myeloma who have had only 1 previous therapy, which did not include bortezomib.
# End-of-life considerations
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods.
The committee considered whether survival after a second relapse (third line) was less than 24 months while on current treatment. It noted that the company presented data from the HMRN showing that median survival on lenalidomide and dexamethasone at third line is 1.3 years. The committee concluded that it is preferable to have mean estimates for survival over the entire expected lifetime horizon. It noted that the modelled mean overall survival for lenalidomide and dexamethasone was 4.93 years. In considering the overall survival with bortezomib after first relapse (second line) the committee noted the modelled survival was 4.26 years. The committee was aware this was contradictory as survival is expected to be lower at second relapse than after first relapse, but recalled that the overall survival data was immature (see section 4.5). Therefore, the committee concluded that even though the mean estimates for the model were uncertain, carfilzomib most likely did not meet the first end-of-life criterion for the comparison of carfilzomib at second and third line.
The committee discussed whether carfilzomib with lenalidomide and dexamethasone increases survival by 3 months compared with lenalidomide and dexamethasone. It noted the mean estimates from the model were uncertain and that the trial data was immature but reasoned that in the overall trial population there was a median gain in progression-free survival of more than 3 months (see section 4.5) and therefore it was highly likely that overall survival would also be greater than 3 months. The committee therefore concluded carfilzomib therapy meets the second end-of-life criterion for the comparison of carfilzomib at second and third line.
# Conclusion
The committee concluded that the end-of-life criteria were not met for the comparison of carfilzomib at third line. Therefore, recalling that the most plausible ICERs were very likely above a range of £41,429 (and one that is substantially higher) and the important remaining uncertainties over proportional hazards and the parametric distribution for extrapolation (see section 4.18), the committee concluded that carfilzomib in combination with lenalidomide and dexamethasone at third line is not recommended as a cost-effective use of NHS resources.
The committee also concluded that the end-of-life criteria was not met for the comparison of carfilzomib at second line but recalling its conclusion on the most plausible ICER (see section 4.19), the committee concluded that carfilzomib in combination with dexamethasone at second line was a cost-effective use of NHS resources.
# update to guidance
Since this guidance was first published in 2017, there have been some changes to the treatments for multiple myeloma in the NHS. Specifically, during development of the original guidance, the committee understood that patients could have thalidomide or bortezomib plus dexamethasone as their first treatment for multiple myeloma. The next treatment for those who had thalidomide was bortezomib plus dexamethasone. The next treatment for those who had bortezomib plus dexamethasone first was chemotherapy, but this has since changed to bortezomib plus dexamethasone (that is, re-treatment with bortezomib).
This change to the treatment pathway means that the comparator relevant to current NHS practice is bortezomib plus dexamethasone, regardless of what people have as their first treatment. The committee was aware that a post-hoc subgroup analysis from the ENDEAVOR trial was based on whether patients had previously had bortezomib (Mateos et al. 2017). The results suggested that the gain in progression-free survival and the overall response rate with carfilzomib plus dexamethasone compared with bortezomib plus dexamethasone was similar whether patients had previous bortezomib or not. A clinical expert explained that when bortezomib is used as the first treatment, it is often limited to 4 to 6 cycles. They added that they did not expect that using bortezomib first would have a treatment modifying effect on carfilzomib. They acknowledged that although the data supporting this were from a post-hoc subgroup, the clinical community felt that this was based on a sufficiently large number of patients to be able to draw a robust conclusion. The committee therefore concluded that it could broaden the original recommendation to allow carfilzomib to be used after either thalidomide or bortezomib.
TA657
Appraisal title: carfilzomib for previously treated multiple myeloma
Section
Key conclusion
Carfilzomib in combination with dexamethasone is recommended as an option for treating multiple myeloma in adults, only if they have had only 1 previous therapy.
The committee concluded that:
there is a progression-free survival benefit for carfilzomib combinations over the comparators
there is uncertainty in the choice of parametric distribution for extrapolation of survival benefit in the economic model. Comparisons to external data confirmed that the company's survival model with the Weibull distribution was more plausible than the ERG's Gompertz distribution
the most plausible ICER is likely to be £27,629 per QALY gained
carfilzomib with dexamethasone is a cost-effective use of NHS resources.
Carfilzomib in combination with lenalidomide and dexamethasone is not recommended for treating multiple myeloma.
The committee concluded that:
there is a progression-free survival benefit for carfilzomib combinations over the comparators
there was uncertainty in the proportional hazards assumption being met and choice of parametric distribution for extrapolation
the most plausible ICER is uncertain but likely to be above the range from £41,400 per QALY gained and could be substantially higher
the end-of-life criteria were not met
carfilzomib with lenalidomide and dexamethasone is not recommended as a cost-effective use of NHS resources.
The committee was aware that carfilzomib could theoretically be considered, within its marketing authorisation, in other positions within the treatment pathway (for example, as an alternative to lenalidomide plus dexamethasone at second line, for which the company provided a scenario analysis, and at subsequent lines after third line). However, it was not able to consider carfilzomib in these positions because not enough evidence was received from the company. The committee therefore focused its recommendations on the second and third line positions.
Current practice
Clinical need of patients, including the availability of alternative treatments
The committee noted the emotional impact and burden of disease on patients, their families and carers and the value of carfilzomib because it provides an additional treatment option that is well tolerated. The clinical experts emphasised the problem of emergent cells that are resistant to current treatment options. Double and triple therapies are often used at later stages of the treatment pathway, because a combination of different mechanisms is needed to control the resistant cells. The committee concluded that there is a need for effective treatment options after relapse.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
The committee heard from the patient expert that although carfilzomib is given intravenously, which often deters patients, it offers important benefits over existing treatments. In particular, carfilzomib does not appear to be associated with neuropathic adverse reactions to the same extent as standard treatment. The committee concluded that patients and clinicians would like to have access to carfilzomib because it offers quality-of-life improvements over current treatment options.
What is the position of the treatment in the pathway of care for the condition?
Carfilzomib therapy would be used at second and third line (after first and second relapse).
Adverse reactions
The committee noted the adverse reactions listed in the summary of product characteristics. It heard that serious adverse reactions and toxicity are managed through dose reduction and concomitant medication. People taking carfilzomib find it tolerable and neuropathic adverse reactions are less evident than with other chemotherapeutic agents. The committee was satisfied that although carfilzomib is associated with serious adverse reactions these are not more significant than those experienced with other chemotherapeutic agents and are manageable in practice.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
Evidence was from 2 trials: ENDEAVOR (carfilzomib plus dexamethasone compared with bortezomib plus dexamethasone) and ASPIRE (carfilzomib plus lenalidomide and dexamethasone compared with lenalidomide plus dexamethasone).
Relevance to general clinical practice in the NHS
The trials had a lower median age than data collected on people in a UK registry, the HMRN. But the committee understood from the clinical expert that patients in myeloma trials are generally younger than the clinical population, and that patients are being diagnosed earlier in the UK. The committee concluded that the patient characteristics in the trials could be generalised to UK clinical practice.
Uncertainties generated by the evidence
The committee was aware of the limitations and the uncertain outcomes associated with subgroups that were not prespecified. It recognised the company's attempt to counter the uncertainties by adjusting for imbalances in the baseline characteristics, using a Cox proportional hazards model to estimate the efficacy of carfilzomib and its comparators. But it heard from the ERG that the choice for these covariates was unclear and without sufficient justification. In response to the appraisal consultation document the company presented a range of methods to adjust for covariates. The committee was satisfied that the company had sufficiently explored the uncertainty and the estimates were reasonable for decision-making.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
The committee was aware of the limitations and the uncertain outcomes associated with subgroups that were not prespecified.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The committee noted that the choice of variables to adjust the model should be those that are prognostic of the outcome, including an adjustment for treatment effect. It concluded that the company's new estimates in response to the appraisal consultation document were reasonable for decision-making.
Evidence for cost effectiveness
Availability and nature of evidence
The committee noted that the company provided evidence to address uncertainties in the effect of fitting different covariate-adjusted parametric models, using different extrapolation techniques and assessing the plausibility of the resulting predictions, in response to the appraisal consultation document. Further new evidence for overall survival from the ENDEAVOR trial was considered by the committee following suspension of the initial final appraisal determination.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The committee acknowledged that the company presented a revised analysis exploring the effect of using different parametric distributions to estimate long-term survival, in the response to the appraisal consultation document. The committee noted that the use of the Weibull or Gompertz distribution had a considerable effect on the ICER estimates. Following submission of new overall survival data from the ENDEAVOR trial the committee accepted that the Weibull was the most plausible choice because it was validated by other trials that had longer follow-ups for the comparison of carfilzomib at second line but was still uncertain on the most appropriate choice for the comparison of carfilzomib at third line.
The committee discussed whether the proportional hazard assumption was valid and acknowledged that the company had explored the validity of this assumption in the response to the appraisal consultation document, by fitting both joint and independent models. The committee noted that the proportional hazards assumption had a substantial effect on the comparison at third line, and was not convinced it was valid, but was acceptable for consideration in decision-making for the comparison of carfilzomib at second line.
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The company's model used a mixed method, using published utility values from Agthoven et al. (2004) and mapped utility values from the trials. In response to the appraisal consultation document, the company presented a revised base case using utility estimates mapped straight from trial data. The committee considered that the approach in the revised base case was appropriate and consistent with its preferred assumptions.
Are there specific groups of people for whom the technology is particularly cost effective?
No specific considerations.
What are the key drivers of cost effectiveness?
The committee agreed that the proportional hazards assumption and choice of parametric distribution for extrapolation were key drivers for the model for the comparison of carfilzomib at third line and second line.
Most likely cost-effectiveness estimate (given as an ICER)
For the comparison of carfilzomib at third line the most plausible ICER was uncertain but very likely to be in a range above the company's estimate of £41,429 per QALY gained and could be substantially higher.
For the comparison of carfilzomib at second line, the most plausible ICER depended on the choice of parametric distribution used for extrapolation of survival. After considering the new evidence presented by the company on overall survival, following suspension of the initial final appraisal determination, the committee agreed the most appropriate extrapolation curve was likely to be the Weibull distribution. It concluded that the most plausible ICER is £27,629 per QALY gained.
Additional factors taken into account
Patient access schemes (PPRS)
The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism is not relevant in considering the cost effectiveness of any of the technologies in this appraisal.
End-of-life considerations
The committee concluded that carfilzomib therapy, after first or second relapse, does not meet the end-of-life criteria. It agreed that the trial data showed a gain in progression-free survival of more than 3 months for carfilzomib compared to lenalidomide plus dexamethasone. But the modelled overall survival estimates for lenalidomide plus dexamethasone were longer than 24 months. The committee concluded that for the comparison of carfilzomib at first or second line does not meet the end-of-life criteria.
Equalities considerations and social value judgements
No equality issues raised.
|
{'Recommendations': 'Carfilzomib with dexamethasone is recommended as an option for treating multiple myeloma in adults, only if:\n\nthey have had only 1\xa0previous therapy and\n\nthe company provides carfilzomib according to the commercial arrangement. \n\nThese recommendations are not intended to affect treatment with carfilzomib that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. ', 'The technology': "# Marketing authorisation indication\n\nKyprolis 'in combination with either lenalidomide and dexamethasone or dexamethasone alone, is indicated for the treatment of adult patients with multiple myeloma who have had at least 1\xa0prior therapy'. \n\n# Adverse reactions\n\nThe most common adverse reactions (in more than 20% of patients) were: anaemia, fatigue, diarrhoea, thrombocytopenia, nausea, pyrexia, dyspnoea, respiratory tract infection, cough and peripheral oedema. For full details of adverse reactions and contraindications, see the summary of product characteristics. \n\n# Dosage in the marketing authorisation\n\nOne cycle of carfilzomib is 28\xa0days. \n\n## In combination with lenalidomide and dexamethasone\n\nCarfilzomib is given on 2\xa0consecutive days each week for 3\xa0weeks (days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period (days\xa017 to\xa028) for the first 12\xa0cycles.\n\nFrom cycle\xa013, the day\xa08 and 9 doses of carfilzomib are omitted.\n\nCarfilzomib is administered at a starting dose of 20\xa0mg/m2 (maximum dose 44\xa0mg) in cycle\xa01 on days\xa01 and 2.\n\nIf tolerated, the dose should be increased to 27\xa0mg/m2 (maximum dose 60\xa0mg) from day\xa08 of cycle\xa01. \n\n## In combination with dexamethasone alone\n\nCarfilzomib is given on 2\xa0consecutive days each week for 3\xa0weeks (days 1, 2, 8, 9, 15, and 16) followed by a 12-day rest period (days\xa017 to\xa028).\n\nCarfilzomib is administered at a starting dose of 20\xa0mg/m2 (maximum dose 44\xa0mg) in cycle\xa01 on days\xa01 and\xa02.\n\nIf tolerated, the dose should be increased to 56\xa0mg/m2 (maximum dose 123\xa0mg) from day\xa08 of cycle\xa01.For further details, see the summary of product characteristics. \n\n# Price\n\nThe list price of carfilzomib is £1,056 for a 60-mg vial (excluding VAT; Monthly Index of Monthly Specialties online, accessed October 2016). \n\n## In combination with lenalidomide and dexamethasone\n\nFrom cycle 1 to 12: £5,127 (no wastage), £6,336 (wastage).\n\nFrom cycle 13: £3,418 (no wastage), £4,220 (wastage). \n\n## In combination with dexamethasone alone\n\n£10,644 (no wastage), £12,627 (wastage).The company has a commercial arrangement. This makes carfilzomib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount. ", 'Evidence': 'The appraisal committee considered evidence submitted by Amgen, including new evidence submitted after responses to the consultation document and suspension of the initial final appraisal determination, and a review of these submissions by the evidence review group (ERG). See the committee papers for full details of the evidence. ', 'Committee discussion': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of carfilzomib, having considered evidence on the nature of multiple myeloma and the value placed on the benefits of carfilzomib by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\n# Clinical need\n\nThe committee noted the emotional impact and burden of disease on people with multiple myeloma, their families and carers, and the value of carfilzomib because it provides an additional treatment option that is well tolerated. The committee understood that there are effective treatments at earlier stages of the disease but there is a need for novel chemotherapeutic agents at later stages of the disease. The clinical experts emphasised the problem of emergent cells that are resistant to current treatment options; because of this, double and triple therapies are often used at later stages of the treatment pathway because a combination of different mechanisms is needed to control the resistant cells. The committee heard from the patient expert that although carfilzomib is given intravenously, which often deters patients, it offers important benefits over existing treatments. In particular, carfilzomib does not appear to be associated with neuropathic adverse reactions to the same extent as standard treatment and offers an increased remission time so patients are willing to have an intravenous administration. The committee concluded that patients and clinicians would welcome carfilzomib because there is a need for effective treatments after relapse and because it offers a number of quality-of-life improvements over current treatment options. \n\n# Decision problem and treatment pathway\n\nThe committee considered the current treatment pathway for people whose disease has relapsed after having 1\xa0therapy, including current NICE-recommended treatments and other agents used in practice. \n\nThe NICE scope specified comparator treatments that are currently used at second, third and fourth line (see figure\xa01). The committee noted that the marketing authorisation for carfilzomib is for people who have had at least 1\xa0previous therapy (and therefore includes fourth-line treatment). However the company's comparisons restricted placement to second and third line only, based on the previous treatments received (taking account of current NICE guidance and the most commonly used treatment regimens in practice; see figure\xa02). The committee heard from the clinical expert that the company's approach was clinically rational and carfilzomib would mainly be used at second and third line. Clinicians prefer to use a combination of chemotherapeutic agents, alternating between agents with different mechanisms of action (immunomodulators and proteasome inhibitors, such as thalidomide and bortezomib). The clinical expert also explained that there are several treatments newly recommended in NICE technology appraisals, which are not yet used routinely in practice (pomalidomide for treating multiple myeloma after 3\xa0previous treatments which included both lenalidomide and bortezomib, panobinostat for treating multiple myeloma after at least 2\xa0previous therapies and lenalidomide for treating multiple myeloma after at least 2\xa0previous therapies). The committee accepted this opinion and concluded that the positioning and comparison rationale provided by the company for carfilzomib is appropriate, that is:\n\ncarfilzomib and dexamethasone compared with bortezomib and dexamethasone at second line\n\ncarfilzomib, lenalidomide and dexamethasone compared with lenalidomide and dexamethasone at third line. \n\nThe company also provided a scenario analysis in which carfilzomib plus lenalidomide and dexamethasone was proposed at second line, as an alternative to lenalidomide plus dexamethasone for people who have had bortezomib first line.\n\nThe committee was aware that carfilzomib could theoretically be considered, within its marketing authorisation, in other positions within the treatment pathway (for example, as an alternative to lenalidomide plus dexamethasone at second line, for which the company provided a scenario analysis, and at subsequent lines after third line). However, it was not able to consider carfilzomib in these positions because not enough evidence was received from the company. The committee therefore focused its recommendations on the second and third-line positions. \n\n# Clinical effectiveness\n\nThe committee noted that the company presented data from 2 trials:\n\nENDEAVOR: carfilzomib plus dexamethasone, compared with bortezomib plus dexamethasone\n\nASPIRE: carfilzomib plus lenalidomide and dexamethasone, compared with lenalidomide plus dexamethasone.The committee noted that these trials were of good quality and included active comparators that are relevant to the appraisal, thereby providing direct head-to-head evidence. It noted the overall survival data had not yet matured, so considered in detail the progression-free survival estimates for the overall population. It agreed that the estimates were compelling in favour of carfilzomib over the comparator treatments. It noted that, compared with bortezomib and dexamethasone, carfilzomib and dexamethasone doubled the progression-free survival to 18.7\xa0months. When compared with lenalidomide and dexamethasone, carfilzomib with lenalidomide and dexamethasone increased the progression-free survival to 26.3\xa0months (a gain of 8.7\xa0months). The committee concluded the trial evidence showed a progression-free survival benefit for carfilzomib combinations over the comparators in the overall population. \n\nThe committee understood that to estimate the efficacy of carfilzomib at second and third line, the company specified post hoc subgroups for:\n\npeople who had 1\xa0previous therapy, not bortezomib (second line compared with bortezomib and dexamethasone)\n\npeople who had 2\xa0previous therapies, not lenalidomide (or carfilzomib; third line compared with lenalidomide and dexamethasone).The committee was aware of the limitations and the uncertain outcomes associated with subgroups that were not prespecified. It recognised the company's attempt to counter the uncertainties by adjusting for imbalances in the baseline characteristics with additional covariates by using a Cox proportional hazards model to estimate efficacy (as hazard ratios) of carfilzomib and its comparators. But the committee heard from the evidence review group (ERG) that the choice of these covariates was unclear without sufficient justification. The committee noted that the choice of variables to adjust the model should be those that are prognostic of the outcome. In response to the appraisal consultation document the company presented a range of methods to adjust for covariates, including stepwise-selection and least absolute shrinkage and selection operator (LASSO) methods, to explore the plausibility of different combinations of covariates. The committee noted that the company preferred the stepwise-selection method, whereas the ERG considered that the LASSO method was more appropriate. The committee was satisfied that the company had sufficiently explored uncertainty around the choice of covariates and that the comparative efficacy estimates were reasonable to consider for decision making for both comparisons of carfilzomib at second and third line. \n\nThe committee noted that the median age of people in ENDEAVOR (comparing carfilzomib and dexamethasone with bortezomib and dexamethasone) and ASPIRE (comparing carfilzomib, lenalidomide and dexamethasone with lenalidomide and dexamethasone) was 64 and 65 respectively. Patients had an average Eastern Cooperative Oncology Group (ECOG) status of 0 to 2. In comparison, data collected in the UK by the Haematological Malignancy Research Network (HMRN) from 2001 to 2012 showed that the median age at diagnosis was 73. The committee was therefore concerned that the results of the trials may not be generalisable to clinical practice in England. The committee understood from the clinical expert that patients in myeloma trials are generally younger because they are more willing and able to travel to the treatment centre. It also understood that patients are being diagnosed earlier and, as a result, the average age at diagnosis in England is younger than that recorded by the HMRN. The committee concluded that the patient characteristics in the trials could be generalised to UK clinical practice. \n\nThe committee noted a discrepancy between the length of carfilzomib treatment stipulated in the marketing authorisation and the stopping rule applied in ASPIRE. It understood that in ASPIRE, carfilzomib was stopped after 18\xa0cycles whereas the marketing authorisation allows for treatment until progression or unacceptable toxicity. The committee heard from the company that no stopping rule was applied in ENDEAVOR and the average length of treatment was 16.5\xa0cycles, which the clinical experts stated would be reflective of clinical practice. The committee concluded that the length of treatment in the trials was reflective of clinical practice in the UK. \n\nThe committee noted the adverse reactions listed in the summary of product characteristics. It heard that in practice, serious adverse reactions and toxicity are managed through dose reduction and concomitant medication. It also heard that people taking carfilzomib find it tolerable and that neuropathic adverse reactions are less evident than with bortezomib. The committee was satisfied that although carfilzomib is associated with serious adverse reactions, these are not any more significant than those experienced with other chemotherapeutic agents and are manageable in practice. \n\n# Cost effectiveness\n\nThe committee had concerns about the company's initial approach to survival modelling. It stated in the appraisal consultation document that it would have liked to see the effect of fitting different covariate-adjusted parametric models, using different extrapolation techniques and assessing the plausibility of the resulting predictions. The committee recognised that the company provided revised analyses to address these concerns in response to the appraisal consultation document but was still uncertain on the cost-effectiveness results due to immature survival data. The committee was subsequently made aware that more mature overall survival data was available from the ENDEAVOR trial after the meeting had concluded. Therefore, the initial final appraisal determination was suspended to allow the committee to consider the new data and analysis. It considered in detail the most appropriate extrapolation function and the validity of the proportional hazards assumption. \n\nThe committee considered the validity of the proportional hazards assumption and noted that this assumes the hazards are constant over time (that is, the benefits of treatment continue until the end of the time horizon or death). The committee was aware that the company presented a model with jointly fitted survival curves in its revised base case, which requires the assumption of proportional hazards. The company also presented a detailed exploration of the appropriateness of the proportional hazards assumption, including a scenario analysis comparing the effect of using jointly or independently fitted curves (no proportional hazards assumption required) on the cost-effectiveness results. The committee heard from the ERG that in the extrapolation of overall survival for carfilzomib plus lenalidomide and dexamethasone compared with lenalidomide plus dexamethasone (third line), the convergence of curves in the log-log plots suggested that the proportional hazards assumption was not valid. The committee recognised that the company had thoroughly explored the proportional hazards assumption in response to the appraisal consultation document but it was not convinced by the company's interpretation that the proportional hazards assumption was valid for the comparison of carfilzomib at third line. The independently fitted model had a substantially higher incremental cost-effectiveness ratio (ICER) for carfilzomib plus lenalidomide and dexamethasone compared with lenalidomide plus dexamethasone (third line). The committee acknowledged that when comparing joint and independently fitted models in the company's revised scenario analysis there was very little difference in the cost-effectiveness results for carfilzomib plus dexamethasone compared with bortezomib plus dexamethasone at second line. For these reasons, the committee concluded that the proportional hazards assumption was acceptable for consideration in decision making for the comparison of carfilzomib at second line but not third line. \n\nThe committee considered the survival model used in the company's revised base case in response to the appraisal consultation document. It noted that the company used a Weibull distribution to estimate long-term survival whereas the ERG's exploratory base case used a Gompertz distribution. The committee also considered the company's revised scenario analysis to assess the effect of several different parametric distributions on the cost-effectiveness results. The company justified its choice of parametric curve by analysis of statistical fit, eliciting expert opinion and validating the curves externally. The committee considered the validation, plausibility and maturity of the overall survival data used to inform the Weibull and Gompertz parametric curves. It noted that the company presented new data in which the ENDEAVOR trial had reached its clinical end point for overall survival and the data were more mature than the ASPIRE trial, but it recalled its earlier conclusion on the lack of reliability of the proportional hazards assumptions for the comparison of carfilzomib at third line (see section\xa04.11). Therefore the committee focused on the comparison of carfilzomib at second line from the ENDEAVOR trial. The committee noted that the use of the Weibull or Gompertz distribution had a considerable effect on the ICER estimates, and that they had similar statistical fits. It also considered the external validity of both extrapolations; the company presented evidence that further validated the Weibull curve using data from Orlowski et al. (2016) trial (which compared bortezomib monotherapy to bortezomib combination therapy up to 9\xa0years). The committee noted that the Kaplan–Meier curve for the bortezomib monotherapy arm from Orlowski et al. showed a greater percentage of people surviving with multiple myeloma at 9\xa0years than predicted by the Gompertz curve. It also heard from the ERG that it agreed with the validation evidence presented by the company. The committee concluded that the new overall survival data and external validation supported the Weibull distribution for extrapolation for the comparison of carfilzomib at second line. It further concluded that the trial data was too immature to inform on the most appropriate parametric curve for extrapolation for the comparison of carfilzomib at third line. \n\nFor comparison of carfilzomib at second line, the committee noted that there were discrepancies between the company's initial model and clinical practice in the dosing schedule and length of treatment for bortezomib. It noted that the marketing authorisation for bortezomib states that it can be given twice weekly for 8\xa0cycles (21-day cycles equal to a total of 32\xa0doses), whereas the model assumed bortezomib would be given twice weekly as an intravenous infusion until progression (consistent with the duration of treatment in ENDEAVOR). The clinical experts clarified that in practice they prefer to give bortezomib once weekly and subcutaneously, because this is associated with fewer adverse reactions, and to give the full 32\xa0doses. In response to the appraisal consultation document, the company provided a scenario analysis in which the duration of bortezomib was limited to 8\xa0cycles and its efficacy adjusted accordingly. The committee noted that the company estimated this reduction in efficacy using a matched-adjusted indirect comparison (MAIC). The committee heard that the ERG agreed with this approach in principle. However, the ERG noted that key adjustments in the MAIC may have been missed and it considered that the results may be unreliable. It therefore presented an exploratory analysis in which it assumed no reduction in efficacy for bortezomib, while capping the costs to 8\xa0cycles. The committee considered that it was appropriate to limit the duration of bortezomib therapy to 8\xa0cycles in the model, consistent with NHS clinical practice, and that it was plausible that this approach would reduce the efficacy of bortezomib compared with continuing treatment until progression. The committee therefore concluded that the ERG's assumption was very conservative. In the absence of a more robust analysis the committee accepted that the company's approach was suitable for decision making. \n\nFor the comparison of carfilzomib at second line, the committee noted that bortezomib has a complex patient access scheme (PAS), in which the price paid for bortezomib is reimbursed by the company if there is not at least a partial response after a maximum of 4\xa0cycles. It noted that this PAS was not included in the company's new base case received in response to the appraisal consultation document, although it was included in a scenario analysis. The committee was aware that the company had approximated the price of bortezomib to be equivalent to a 15% discount and heard from the ERG that this was a reasonable approximation. The committee concluded that this was an appropriate approximation and that it was appropriate for it to be included in the analysis. \n\nThe committee was aware that the company presented a scenario analysis in response to the appraisal consultation document, in which it made a case for excluding the extra costs of lenalidomide and dexamethasone associated with long-term carfilzomib therapy. The committee acknowledged that treatments that extend the use of other high costs drugs (such as lenalidomide) can lead to additional cost associated with those other drugs. However, it was not convinced that the company's approach is valid because lenalidomide is part of the regimen in which carfilzomib is given. The committee concluded that the costs of lenalidomide are relevant because the NHS would incur those costs in practice, so they should be included in the model. \n\nThe committee discussed how the company had derived the health state utility values used in the model. It noted that the company had used a mixed method, using published utility values from Agthoven et al. (2004) and mapped utility values from the trials. The committee heard that the ERG considered it more appropriate to derive utility values straight from trial data, using a mapping algorithm from Proskorovsky et al. (2014). In response to the appraisal consultation document, the company presented a revised base case using utility estimates mapped straight from trial data. The committee considered that the approach in the revised base case was appropriate and consistent with its preferred assumptions. \n\n# Most plausible ICER\n\nHaving considered the key issues in the economic modelling, the committee considered the most plausible estimates for the cost-effective results. It considered separately the ICERs for carfilzomib in the 2\xa0treatment-pathway positions proposed by the company (see section 4.4) and the new overall survival evidence submitted after the initial final appraisal determination was suspended (see section 4.10). \n\nCarfilzomib in combination with lenalidomide and dexamethasone, compared with lenalidomide in combination with dexamethasone (third line): The committee considered the range of ICERs presented by the company in its base case and scenario analyses where they explored the effect of different parametric distributions for extrapolation and the effect of non-proportional hazards on the cost-effective results. It noted the company's revised base-case ICER, presented in response to the appraisal consultation document, was £41,429 per quality-adjusted life year (QALY) gained (with the Weibull distribution and proportional hazards) and the ERG's exploratory analysis ICER was £52,439 per QALY gained (Gompertz distribution and proportional hazards). The committee noted that this difference was driven by the choice of parametric extrapolation curve, which was highly uncertain due to immature overall survival data (see section\xa04.12). It also recalled there was doubt over the proportional hazards assumption in the model (see section\xa04.11), and that using the independent-fit model (non-proportional hazards) further increases the ICER above £52,439. Therefore the committee reasoned that there was uncertainty in the cost-effective estimate for the comparison of carfilzomib at third line but the most plausible ICER is very likely to be in a range above the company's estimate of £41,429 per QALY gained and one that could be substantially higher. \n\nCarfilzomib in combination with dexamethasone, compared with bortezomib in combination with dexamethasone (second line): The committee noted that the company's new analysis, received after the initial final appraisal determination was suspended, included the committee's preferred assumptions (with the new overall survival data, Weibull extrapolation, including the PAS for bortezomib, and capping the cost of bortezomib to 8\xa0cycles and reducing its efficacy) and resulted in an ICER of £27,629 per QALY gained. The committee also noted that the ERG's exploratory analysis in response to the new evidence (which used the Weibull extrapolation, included the PAS for bortezomib and capped the cost to 8\xa0cycles without adjusting bortezomib's efficacy) resulted in an ICER of £40,744 per QALY gained. The committee recalled its earlier decisions on adjusting for bortezomib efficacy, if capping its cost to 8\xa0cycles (see section\xa04.13) and concluded that the most plausible ICER is the company's estimate of £27,629 per QALY gained and that carfilzomib with dexamethasone is a cost-effective use of NHS resources for people with multiple myeloma who have had only 1\xa0previous therapy, which did not include bortezomib. \n\n# End-of-life considerations\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods. \n\nThe committee considered whether survival after a second relapse (third line) was less than 24\xa0months while on current treatment. It noted that the company presented data from the HMRN showing that median survival on lenalidomide and dexamethasone at third line is 1.3\xa0years. The committee concluded that it is preferable to have mean estimates for survival over the entire expected lifetime horizon. It noted that the modelled mean overall survival for lenalidomide and dexamethasone was 4.93\xa0years. In considering the overall survival with bortezomib after first relapse (second line) the committee noted the modelled survival was 4.26\xa0years. The committee was aware this was contradictory as survival is expected to be lower at second relapse than after first relapse, but recalled that the overall survival data was immature (see section\xa04.5). Therefore, the committee concluded that even though the mean estimates for the model were uncertain, carfilzomib most likely did not meet the first end-of-life criterion for the comparison of carfilzomib at second and third line. \n\nThe committee discussed whether carfilzomib with lenalidomide and dexamethasone increases survival by 3\xa0months compared with lenalidomide and dexamethasone. It noted the mean estimates from the model were uncertain and that the trial data was immature but reasoned that in the overall trial population there was a median gain in progression-free survival of more than 3\xa0months (see section\xa04.5) and therefore it was highly likely that overall survival would also be greater than 3\xa0months. The committee therefore concluded carfilzomib therapy meets the second end-of-life criterion for the comparison of carfilzomib at second and third line. \n\n# Conclusion\n\nThe committee concluded that the end-of-life criteria were not met for the comparison of carfilzomib at third line. Therefore, recalling that the most plausible ICERs were very likely above a range of £41,429 (and one that is substantially higher) and the important remaining uncertainties over proportional hazards and the parametric distribution for extrapolation (see section\xa04.18), the committee concluded that carfilzomib in combination with lenalidomide and dexamethasone at third line is not recommended as a cost-effective use of NHS resources. \n\nThe committee also concluded that the end-of-life criteria was not met for the comparison of carfilzomib at second line but recalling its conclusion on the most plausible ICER (see section\xa04.19), the committee concluded that carfilzomib in combination with dexamethasone at second line was a cost-effective use of NHS resources. \n\n# update to guidance\n\nSince this guidance was first published in 2017, there have been some changes to the treatments for multiple myeloma in the NHS. Specifically, during development of the original guidance, the committee understood that patients could have thalidomide or bortezomib plus dexamethasone as their first treatment for multiple myeloma. The next treatment for those who had thalidomide was bortezomib plus dexamethasone. The next treatment for those who had bortezomib plus dexamethasone first was chemotherapy, but this has since changed to bortezomib plus dexamethasone (that is, re-treatment with bortezomib). \n\nThis change to the treatment pathway means that the comparator relevant to current NHS practice is bortezomib plus dexamethasone, regardless of what people have as their first treatment. The committee was aware that a post-hoc subgroup analysis from the ENDEAVOR trial was based on whether patients had previously had bortezomib (Mateos et al. 2017). The results suggested that the gain in progression-free survival and the overall response rate with carfilzomib plus dexamethasone compared with bortezomib plus dexamethasone was similar whether patients had previous bortezomib or not. A clinical expert explained that when bortezomib is used as the first treatment, it is often limited to 4\xa0to 6\xa0cycles. They added that they did not expect that using bortezomib first would have a treatment modifying effect on carfilzomib. They acknowledged that although the data supporting this were from a post-hoc subgroup, the clinical community felt that this was based on a sufficiently large number of patients to be able to draw a robust conclusion. The committee therefore concluded that it could broaden the original recommendation to allow carfilzomib to be used after either thalidomide or bortezomib. \n\nTA657\n\nAppraisal title: carfilzomib for previously treated multiple myeloma\n\nSection\n\nKey conclusion\n\nCarfilzomib in combination with dexamethasone is recommended as an option for treating multiple myeloma in adults, only if they have had only 1\xa0previous therapy.\n\nThe committee concluded that:\n\nthere is a progression-free survival benefit for carfilzomib combinations over the comparators\n\nthere is uncertainty in the choice of parametric distribution for extrapolation of survival benefit in the economic model. Comparisons to external data confirmed that the company's survival model with the Weibull distribution was more plausible than the ERG's Gompertz distribution\n\nthe most plausible ICER is likely to be £27,629 per QALY gained\n\ncarfilzomib with dexamethasone is a cost-effective use of NHS resources.\n\n, 4.1 4.19, 4.24\n\nCarfilzomib in combination with lenalidomide and dexamethasone is not recommended for treating multiple myeloma.\n\nThe committee concluded that:\n\nthere is a progression-free survival benefit for carfilzomib combinations over the comparators\n\nthere was uncertainty in the proportional hazards assumption being met and choice of parametric distribution for extrapolation\n\nthe most plausible ICER is uncertain but likely to be above the range from £41,400 per QALY gained and could be substantially higher\n\nthe end-of-life criteria were not met\n\ncarfilzomib with lenalidomide and dexamethasone is not recommended as a cost-effective use of NHS resources.\n\n, 4.1, 4.18, 4.23\n\nThe committee was aware that carfilzomib could theoretically be considered, within its marketing authorisation, in other positions within the treatment pathway (for example, as an alternative to lenalidomide plus dexamethasone at second line, for which the company provided a scenario analysis, and at subsequent lines after third line). However, it was not able to consider carfilzomib in these positions because not enough evidence was received from the company. The committee therefore focused its recommendations on the second and third line positions.\n\n\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe committee noted the emotional impact and burden of disease on patients, their families and carers and the value of carfilzomib because it provides an additional treatment option that is well tolerated. The clinical experts emphasised the problem of emergent cells that are resistant to current treatment options. Double and triple therapies are often used at later stages of the treatment pathway, because a combination of different mechanisms is needed to control the resistant cells. The committee concluded that there is a need for effective treatment options after relapse.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe committee heard from the patient expert that although carfilzomib is given intravenously, which often deters patients, it offers important benefits over existing treatments. In particular, carfilzomib does not appear to be associated with neuropathic adverse reactions to the same extent as standard treatment. The committee concluded that patients and clinicians would like to have access to carfilzomib because it offers quality-of-life improvements over current treatment options.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nCarfilzomib therapy would be used at second and third line (after first and second relapse).\n\n\n\nAdverse reactions\n\nThe committee noted the adverse reactions listed in the summary of product characteristics. It heard that serious adverse reactions and toxicity are managed through dose reduction and concomitant medication. People taking carfilzomib find it tolerable and neuropathic adverse reactions are less evident than with other chemotherapeutic agents. The committee was satisfied that although carfilzomib is associated with serious adverse reactions these are not more significant than those experienced with other chemotherapeutic agents and are manageable in practice.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nEvidence was from 2 trials: ENDEAVOR (carfilzomib plus dexamethasone compared with bortezomib plus dexamethasone) and ASPIRE (carfilzomib plus lenalidomide and dexamethasone compared with lenalidomide plus dexamethasone).\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe trials had a lower median age than data collected on people in a UK registry, the HMRN. But the committee understood from the clinical expert that patients in myeloma trials are generally younger than the clinical population, and that patients are being diagnosed earlier in the UK. The committee concluded that the patient characteristics in the trials could be generalised to UK clinical practice.\n\n\n\nUncertainties generated by the evidence\n\nThe committee was aware of the limitations and the uncertain outcomes associated with subgroups that were not prespecified. It recognised the company's attempt to counter the uncertainties by adjusting for imbalances in the baseline characteristics, using a Cox proportional hazards model to estimate the efficacy of carfilzomib and its comparators. But it heard from the ERG that the choice for these covariates was unclear and without sufficient justification. In response to the appraisal consultation document the company presented a range of methods to adjust for covariates. The committee was satisfied that the company had sufficiently explored the uncertainty and the estimates were reasonable for decision-making.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe committee was aware of the limitations and the uncertain outcomes associated with subgroups that were not prespecified.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe committee noted that the choice of variables to adjust the model should be those that are prognostic of the outcome, including an adjustment for treatment effect. It concluded that the company's new estimates in response to the appraisal consultation document were reasonable for decision-making.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe committee noted that the company provided evidence to address uncertainties in the effect of fitting different covariate-adjusted parametric models, using different extrapolation techniques and assessing the plausibility of the resulting predictions, in response to the appraisal consultation document. Further new evidence for overall survival from the ENDEAVOR trial was considered by the committee following suspension of the initial final appraisal determination.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe committee acknowledged that the company presented a revised analysis exploring the effect of using different parametric distributions to estimate long-term survival, in the response to the appraisal consultation document. The committee noted that the use of the Weibull or Gompertz distribution had a considerable effect on the ICER estimates. Following submission of new overall survival data from the ENDEAVOR trial the committee accepted that the Weibull was the most plausible choice because it was validated by other trials that had longer follow-ups for the comparison of carfilzomib at second line but was still uncertain on the most appropriate choice for the comparison of carfilzomib at third line.\n\nThe committee discussed whether the proportional hazard assumption was valid and acknowledged that the company had explored the validity of this assumption in the response to the appraisal consultation document, by fitting both joint and independent models. The committee noted that the proportional hazards assumption had a substantial effect on the comparison at third line, and was not convinced it was valid, but was acceptable for consideration in decision-making for the comparison of carfilzomib at second line.\n\n, 4.11\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe company's model used a mixed method, using published utility values from Agthoven et al. (2004) and mapped utility values from the trials. In response to the appraisal consultation document, the company presented a revised base case using utility estimates mapped straight from trial data. The committee considered that the approach in the revised base case was appropriate and consistent with its preferred assumptions.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNo specific considerations.\n\n–\n\nWhat are the key drivers of cost effectiveness?\n\nThe committee agreed that the proportional hazards assumption and choice of parametric distribution for extrapolation were key drivers for the model for the comparison of carfilzomib at third line and second line.\n\n, 4.12\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nFor the comparison of carfilzomib at third line the most plausible ICER was uncertain but very likely to be in a range above the company's estimate of £41,429 per QALY gained and could be substantially higher.\n\n\n\nFor the comparison of carfilzomib at second line, the most plausible ICER depended on the choice of parametric distribution used for extrapolation of survival. After considering the new evidence presented by the company on overall survival, following suspension of the initial final appraisal determination, the committee agreed the most appropriate extrapolation curve was likely to be the Weibull distribution. It concluded that the most plausible ICER is £27,629 per QALY gained.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nThe committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism is not relevant in considering the cost effectiveness of any of the technologies in this appraisal.\n\n–\n\nEnd-of-life considerations\n\nThe committee concluded that carfilzomib therapy, after first or second relapse, does not meet the end-of-life criteria. It agreed that the trial data showed a gain in progression-free survival of more than 3\xa0months for carfilzomib compared to lenalidomide plus dexamethasone. But the modelled overall survival estimates for lenalidomide plus dexamethasone were longer than 24\xa0months. The committee concluded that for the comparison of carfilzomib at first or second line does not meet the end-of-life criteria.\n\n, 4.22, 4.23\n\nEqualities considerations and social value judgements\n\nNo equality issues raised.\n\n–"}
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https://www.nice.org.uk/guidance/ta657
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Evidence-based recommendations on carfilzomib (Kyprolis) for previously treated multiple myeloma in adults.
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b790c79e8847b279c5c682093e613b4b9d403a43
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nice
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Isatuximab with pomalidomide and dexamethasone for treating relapsed and refractory multiple myeloma
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Isatuximab with pomalidomide and dexamethasone for treating relapsed and refractory multiple myeloma
Evidence-based recommendations on isatuximab (Sarclisa) with pomalidomide and dexamethasone for treating relapsed and refractory multiple myeloma in adults.
# Recommendations
Isatuximab, plus pomalidomide and dexamethasone, is recommended for use within the Cancer Drugs Fund as an option for treating relapsed and refractory multiple myeloma in adults who have had lenalidomide and a proteasome inhibitor, and whose disease has progressed on their last treatment, only if:
they have had 3 previous lines of treatment
the conditions in the managed access agreement for isatuximab plus pomalidomide and dexamethasone are followed.
This recommendation is not intended to affect treatment with isatuximab plus pomalidomide and dexamethasone that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
The company proposes that isatuximab plus pomalidomide and dexamethasone is used only for people who have already had 3 lines of treatment. Although effective options after 2 lines of treatment are also needed, the clinical- and cost-effectiveness data for isatuximab plus pomalidomide and dexamethasone at this point in the treatment pathway are not suitable for decision making.
After 3 lines of treatment, people usually have pomalidomide plus dexamethasone, or daratumumab alone (in the Cancer Drugs Fund). Clinical trial evidence suggests that isatuximab plus pomalidomide and dexamethasone delays the disease progressing and increases how long people live compared with pomalidomide plus dexamethasone. But, the trial is not finished so the benefit in the longer term is uncertain.
The cost-effectiveness estimates for isatuximab plus pomalidomide and dexamethasone after 3 previous lines of treatment are uncertain because of limitations in the clinical data. The estimates are higher than what NICE normally considers an acceptable use of NHS resources. So isatuximab plus pomalidomide and dexamethasone cannot be recommended for routine use in the NHS.
Collecting more data from the ongoing trial and from NHS practice would help to address some of the uncertainties. Isatuximab plus pomalidomide and dexamethasone could be cost effective after 3 previous lines of treatment when the company's commercial offer as part of a managed access agreement is used. Therefore, isatuximab plus pomalidomide and dexamethasone is recommended for use in the Cancer Drugs Fund.# Information about isatuximab
# Marketing authorisation indication
Isatuximab (Sarclisa, Sanofi) in combination with pomalidomide and dexamethasone has a marketing authorisation 'for the treatment of adult patients with relapsed and refractory multiple myeloma who have received at least 2 prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on the last therapy'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The proposed list price for isatuximab in the company submission is £506.94 for a 100‑mg vial or £2,534.70 for a 500‑mg vial. The company has a commercial arrangement. This makes isatuximab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Sanofi, a review of this submission by the evidence review group (ERG), the technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:
The model time horizon should be 20 years to capture all benefits and costs of the intervention and the comparators.
The company's amendment to the probabilistic sampling of health utility data, which ensures that the utility value for the progressed disease health state does not exceed the utility value for the progression-free disease health state, is appropriate.
The company's amendment to its model, which applies drug costs at the start of each cycle, is appropriate.
The committee recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, table 4, page 40), and took these into account in its decision making. It discussed the issues that were outstanding after the technical engagement stage.
# The condition
## People with relapsed and refractory multiple myeloma would welcome a new effective treatment option
Multiple myeloma is an incurable and progressive condition that affects survival and quality of life. The patient experts explained that it causes severe symptoms, which have a significant impact on patients' quality of life and are also challenging for carers. They highlighted the psychological impact for patients approaching the end of the treatment pathway, where further treatment options are limited. The committee was aware that clinicians value having a range of different treatment options for patients. One patient expert noted that although some treatments are oral and people can take them at home, some people prefer to have their treatment in hospital. He also highlighted that patients value treatments that delay the disease progressing, which outweighs the negative impact of their side effects. The committee recognised the need for effective treatment options for previously treated multiple myeloma, and concluded that people would welcome a new treatment option.
# Treatment pathway
## The treatment pathway for multiple myeloma is rapidly evolving
Treatment options for multiple myeloma depend on how many previous lines of treatment a person has had, the specific treatments, their response to these treatments, and their preferences. If a stem cell transplant is suitable:
Induction treatment is bortezomib, given before the transplant.
After 1 previous line of treatment, people may have bortezomib again, along with a second stem cell transplant.If a stem cell transplant is not suitable:
For untreated disease, treatments include thalidomide or bortezomib plus an alkylating agent, for example, melphalan or cyclophosphamide, and a corticosteroid, for example, dexamethasone. Lenalidomide plus dexamethasone is also an option when thalidomide is not appropriate.
After 1 previous line of treatment, options include lenalidomide plus dexamethasone if the person has had bortezomib before, or carfilzomib plus dexamethasone if they have not had bortezomib before. Also, daratumumab plus bortezomib and dexamethasone is available in the Cancer Drugs Fund.After this, the options do not depend on whether a stem cell transplant is suitable:
After 2 previous lines of treatment, options include lenalidomide plus dexamethasone or panobinostat plus bortezomib and dexamethasone. Also, ixazomib plus lenalidomide and dexamethasone is available in the Cancer Drugs Fund.
After 3 previous lines of treatment, options include pomalidomide plus dexamethasone or panobinostat plus bortezomib and dexamethasone. Daratumumab alone or ixazomib plus lenalidomide and dexamethasone are available in the Cancer Drugs Fund.Isatuximab plus pomalidomide and dexamethasone can be used whether or not people have had a stem cell transplant. The clinical experts explained that, following recent NICE guidance, the use of lenalidomide plus dexamethasone for untreated disease and the use of daratumumab plus bortezomib and dexamethasone after 1 previous line of treatment is increasing. The committee understood that the multiple myeloma pathway is rapidly evolving.
## The company positions isatuximab plus pomalidomide and dexamethasone after 3 previous lines of treatment
The marketing authorisation for isatuximab plus pomalidomide and dexamethasone states that it must be used after lenalidomide and a proteasome inhibitor, which means after 2 previous lines of treatment or later. Proteasome inhibitors include bortezomib, carfilzomib and ixazomib. But the marketing authorisation does not specify the position in the treatment pathway. The company chose to position isatuximab plus pomalidomide and dexamethasone after 3 previous lines of treatment. It did this based on unmet clinical need and advice from clinical experts. The committee noted that the company's positioning meant that the population was narrower than defined by both the marketing authorisation and NICE's final scope. The clinical expert explained that to have isatuximab plus pomalidomide and dexamethasone, a person must have had lenalidomide. But currently many clinicians use lenalidomide after 2 previous lines of treatment, with ixazomib and dexamethasone in the Cancer Drugs Fund, or with dexamethasone. Therefore, the clinical experts agreed that the company's positioning was appropriate. The committee concluded at its first meeting that it would focus its discussion on people who have had 3 previous lines of treatment.
## There is unmet need for new effective options after 2 previous lines of treatment
The committee recalled that for isatuximab plus pomalidomide and dexamethasone both the marketing authorisation and NICE's final scope included people who have had at least 2 previous lines of treatment, to include lenalidomide and a proteasome inhibitor. It also recalled that lenalidomide and bortezomib are now options for untreated multiple myeloma and after 1 previous line of treatment (see section 3.2). The patient expert explained that patients would prefer any NICE recommendation to include the population covered by the marketing authorisation rather than restrict it to those who have had 3 previous lines of treatment. The Cancer Drugs Fund clinical lead explained at the first meeting that lenalidomide and a proteasome inhibitor is now being used more often at earlier points in the treatment pathway. This has meant that there is an increasing need for new and effective options after 2 previous lines of treatment. In response to the committee's request at the first meeting, the company did a cost-effectiveness analysis for isatuximab plus pomalidomide and dexamethasone after 2 previous lines of treatment compared with the comparator in NICE's final scope (see section 3.24). The committee concluded that there is unmet need for new effective treatment options for people who have had 2 previous lines of treatment.
# Comparators
## After 3 previous lines of treatment, pomalidomide plus dexamethasone is the only relevant comparator
NICE guidance recommends both pomalidomide plus dexamethasone and panobinostat plus bortezomib and dexamethasone after 3 previous lines of treatment for multiple myeloma. NICE's final scope for this appraisal lists these as the comparators. The committee recalled that treatments recommended in the Cancer Drugs Fund are not considered to be comparators. The company did not consider panobinostat plus bortezomib and dexamethasone to be a relevant comparator to isatuximab plus pomalidomide and dexamethasone after 3 previous lines of treatment. It explained that this was because of toxic adverse effects and the lack of perceived efficacy noted by clinicians it consulted, which means it is usually used after 4 previous lines of treatment. To comply with NICE's final scope, the company compared the clinical and cost effectiveness of isatuximab plus pomalidomide and dexamethasone with panobinostat plus bortezomib and dexamethasone and pomalidomide plus dexamethasone. The comparison with panobinostat plus bortezomib and dexamethasone included an indirect treatment comparison for clinical effectiveness because there was no trial directly comparing the 2 treatments. The ERG noted that 1 of its clinical advisers agreed with the company's position, but 2 other advisers stated that panobinostat plus bortezomib and dexamethasone is used after 3 previous lines of treatment and toxicity is managed by adjusting the dose. The clinical experts at the meeting explained that daratumumab, available in the Cancer Drugs Fund, or pomalidomide plus dexamethasone are the most commonly used options after 3 previous lines of treatment. They stated that panobinostat plus bortezomib and dexamethasone is very rarely used after 3 previous lines of treatment because of toxicity and perceived poor clinical efficacy. The Cancer Drugs Fund clinical lead explained that clinicians can now offer bortezomib again without having to use it with panobinostat and that few clinicians offer panobinostat plus bortezomib and dexamethasone after 3 previous lines of treatment. The committee concluded that after 3 previous lines of treatment, pomalidomide plus dexamethasone is the only relevant comparator.
# Clinical evidence
## The evidence for people who have had 3 previous lines of treatment is acceptable for decision making
ICARIA-MM is an open-label randomised trial, comparing isatuximab plus pomalidomide and dexamethasone with pomalidomide plus dexamethasone. It included people with relapsed and refractory multiple myeloma who have had at least 2 previous lines of treatment, including lenalidomide and a proteasome inhibitor. The primary outcome was progression-free survival. Because the company positioned isatuximab plus pomalidomide and dexamethasone as a treatment option after 3 previous lines of treatment, it provided clinical-effectiveness data from a post hoc subgroup of people from ICARIA-MM who had 3 previous lines of treatment. The committee was aware that this subgroup was not stratified and therefore not a randomised group. The ERG noted that there was more uncertainty associated with the subgroup results than with the randomised population results, indicated by wider confidence intervals. The committee understood the limitations of the subgroup analysis for people who have had 3 previous lines of treatment, but agreed to accept it for decision making.
## Isatuximab plus pomalidomide and dexamethasone likely extends both progression-free and overall survival, but the data are immature
ICARIA-MM is ongoing. At the interim data cut (October 2018), median follow up was 11.6 months in the trial for people who had 3 previous lines of treatment. For progression-free survival, the interim subgroup analysis was based on only about half of patients having events. It showed that isatuximab plus pomalidomide and dexamethasone extended median progression-free survival compared with pomalidomide plus dexamethasone from 7.8 months to 13.3 months (hazard ratio 0.598; 95% confidence interval 0.348 to 1.03, p=0.0611). For time to death, the interim subgroup analysis was based on 11 deaths in the treatment group (which included 52 people) and 23 deaths in the control group (which included 58 people) and heavily censored data. It showed that median overall survival had not yet been reached for the isatuximab plus pomalidomide and dexamethasone arm. The hazard ratio for overall survival compared with pomalidomide plus dexamethasone was 0.494 (95% confidence interval 0.24 to 1.02, p=0.0502). The committee acknowledged the immaturity of the data in this ongoing trial. It concluded that isatuximab plus pomalidomide and dexamethasone was likely to extend progression-free and overall survival compared with pomalidomide plus dexamethasone after 3 previous lines of treatment, but noted that median follow up was short, the subgroup was small and the data were immature.
## It is not appropriate to use isatuximab plus pomalidomide and dexamethasone when disease is refractory to a previous anti-CD38 monoclonal antibody
Isatuximab is an anti-CD38 monoclonal antibody. Daratumumab, another anti‑CD38 monoclonal antibody, is an option after 1 previous line of treatment and 3 previous lines of treatments in the Cancer Drugs Fund. ICARIA-MM included people with multiple myeloma that was not refractory to anti-CD38 antibody treatment, that is, their disease had not progressed on the treatment. But, it excluded people whose disease was refractory to anti-CD38 antibody treatment, that is, their disease progressed while on the treatment. The clinical experts explained that they would consider using isatuximab plus pomalidomide and dexamethasone for people who had previous treatment with an anti‑CD38 antibody such as daratumumab, but only if that treatment was stopped for reasons other than disease progression. They stated that they would not use an anti‑CD38 antibody again if the disease had been refractory to one in a previous line of treatment. The company noted that only 1 person in ICARIA-MM had previous anti-CD38 antibody treatment. The clinical experts explained that in NHS practice many people increasingly have daratumumab after 1 previous line of treatment. This means that many people with relapsed and refractory multiple myeloma after 3 previous lines of treatment would have already had an anti‑CD38 antibody. The Cancer Drugs Fund clinical lead noted that daratumumab is well tolerated and few people would stop it for reasons other than disease progression. The clinical experts and the Cancer Drugs Fund clinical lead also noted that there was high biological plausibility that response to isatuximab would be reduced in people whose disease was refractory to previous daratumumab treatment. The committee acknowledged that clinical-effectiveness evidence for isatuximab plus pomalidomide and dexamethasone in people who had previously had anti-CD38 antibody treatment had not been presented. It recalled that the clinical experts explained that using an anti‑CD38 antibody treatment again later in the treatment pathway would be appropriate if it had been stopped for reasons other than disease progression. The committee concluded that it had not been presented with evidence for people whose disease was refractory to anti-CD38 antibody treatment. Also, it concluded that it was not appropriate to use isatuximab plus pomalidomide and dexamethasone when disease is refractory to a previous anti-CD38 monoclonal antibody.
## Subsequent treatments in ICARIA-MM do not reflect NHS clinical practice
The subgroup of people in ICARIA-MM who had had 3 previous lines of treatment had a range of subsequent treatments after disease progression. The committee was aware that some of these treatments, such as daratumumab and lenalidomide, were not available at this point in the pathway in the NHS, and may prolong life. The clinical experts explained that for people who have had 4 previous lines of treatment, there are no standard treatments in current NHS clinical practice, and treatments at this point in the pathway would likely be ineffective. The clinical experts therefore considered that treatments after 4 or more previous lines of treatment in ICARIA-MM were unlikely to affect the survival results in the ICARIA-MM subgroup. At the second meeting, the Cancer Drugs Fund clinical lead noted that lenalidomide would likely be ineffective after 4 or more previous lines of treatment but daratumumab would give some benefit. The committee recognised that these treatment options improve clinical outcomes when used at other points in the treatment pathway, and it was appropriate to consider that they might also increase survival later in the treatment pathway. The committee also noted that the proportion of people having these treatments varied between arms in ICARIA-MM; more people had daratumumab in the pomalidomide plus dexamethasone arm and more people had lenalidomide in the isatuximab plus pomalidomide and dexamethasone arm. The committee concluded that the subsequent treatments people had in ICARIA-MM did not reflect NHS clinical practice. This made generalising the overall survival results from the trial to NHS practice problematic.
# The company's economic model
## The company's model is appropriate for decision making
The company chose a partitioned survival model to estimate the cost effectiveness of isatuximab plus pomalidomide and dexamethasone. The model included 3 health states: progression-free, progressed, and dead. The probability of being in a given health state was defined by the area under the curves for progression-free survival and overall survival or their difference. The model cycle length was 1 week and the time horizon was 20 years. The committee considered the company's model to be appropriate for decision making.
## Clinical experts prefer using a Weibull distribution to estimate overall survival in each trial arm
Follow up for the interim data from ICARIA-MM was short in relation to the modelled time horizon. So, the company extrapolated the overall survival data for the subgroup who had had 3 previous lines of treatment, choosing an exponential distribution in its base case. The committee understood that the distribution chosen to estimate overall survival affects the incremental cost-effectiveness ratio (ICER). The ERG noted that the exponential distribution provided the best statistical fit to the trial data, but other distributions had similar statistical fits. The committee noted that because there were limited trial data, the statistical fit of a curve is of limited importance when selecting the most appropriate distribution. It heard that 2 of the 3 clinical advisers to the company supported using the Weibull, whereas the other preferred the exponential distribution. The clinical experts at the first meeting also stated that the Weibull distribution produced the most plausible long-term estimates of overall survival in both trial arms. The committee noted that the overall survival estimates were uncertain because of the limited trial data and the clinical experts preferred the Weibull distribution to estimate overall survival in each arm.
## The company updated its base case in response to consultation
At the second meeting, the company updated its base case to use a Weibull distribution to extrapolate the overall survival data for pomalidomide and dexamethasone from ICARIA-MM. It also provided supporting evidence for its original choice of an exponential distribution for estimating overall survival for isatuximab plus pomalidomide and dexamethasone. This evidence included no new survival data from ICARIA-MM, but it did include data documenting the experience of people who had daratumumab monotherapy after 4 previous lines of treatment (see section 3.13). The company also included an analysis using surrogate endpoints such as progression-free survival, depth of response to treatment and attaining minimal residual disease to model overall survival (see section 3.14).
## Clinical data are immature and there is a range of plausible distributions to estimate overall survival in each trial arm
To show potential overall survival beyond the ICARIA-MM trial follow-up period, the company identified a study that pooled overall survival for 2 single-arm trials of the anti-CD38 antibody daratumumab (GEN501 and SIRUS). The pooled data had a median follow up of 36.3 months compared with 11.6 months for the ICARIA-MM trial. The company stated that the exponential and log-normal distributions were the best fit for the longer-term daratumumab data. The ERG noted that it was reasonable to assume that treatments of the same class might follow a similar statistical model. The ERG explained that the hazard function (likelihood of dying) over time for the pooled daratumumab survival data appeared to decrease slightly. This suggested that using the Weibull distribution (which in this case is characterised by increasing hazards) was not appropriate to extrapolate the overall survival data for isatuximab plus pomalidomide and dexamethasone. The ERG preferred the exponential (constant hazards) to the Weibull distribution to estimate survival for isatuximab plus pomalidomide and dexamethasone because it did not consider that the hazard rate increased over time. The ERG also did an analysis using the log-normal distribution, which it considered plausible based on the current evidence because the log-normal function has decreasing hazards. The ERG stated it was reasonable to use a different distribution to extrapolate the overall survival data for isatuximab plus pomalidomide and dexamethasone to that used for pomalidomide and dexamethasone given that isatuximab has a different mechanism of action. But the ERG highlighted that when using separate distributions, it is not appropriate to apply a jointly fitted distribution as the company had done for the Weibull distribution to extrapolate the pomalidomide and dexamethasone data. Instead an independently fitted Weibull should be used. The committee noted that there was a range of plausible distributions to estimate overall survival in each trial arm. It concluded that the most appropriate hazard function to model overall survival for each treatment was uncertain because the clinical data are immature. But the exponential or the log-normal extrapolation for isatuximab plus pomalidomide and dexamethasone and the independently fitted Weibull for pomalidomide plus dexamethasone were plausible.
## The company's alternative survival analysis using surrogates for overall survival is not robust
The company did an alternative survival analysis using other trial outcomes including minimal residual disease, depth of response to treatment, and progression-free survival data. It considered these outcomes to be surrogates for overall survival, because the ICARIA-MM data were immature. The company highlighted that more people had minimum residual disease and disease with a partial response or better with isatuximab plus pomalidomide and dexamethasone than with pomalidomide and dexamethasone. It suggested that those whose disease responded to treatment may live for a considerable length of time. The ERG acknowledged that survival may differ depending on whether there was minimal residual disease or response to treatment but these data from ICARIA-MM were uncertain. The company also did an analysis using an assumed ratio between progression-free and overall survival based on a literature search of meta-analyses of trials. The company identified 3 ratios that differed markedly and considered 1 of them to be the most plausible. The ratios were applied to the log-normal distribution it had used to estimate progression-free survival. This was then used to predict overall survival with the aim of validating the company's choice of the exponential distribution to model overall survival for isatuximab plus pomalidomide and dexamethasone. The company also did a separate analysis. This used overall survival data that the company had generated using progression-free survival data from ICARIA-MM and the ratio it considered most plausible to replace some of the censored overall survival data. The company noted that the overall survival outcomes based on the curves from these alternative analyses appeared to match those predicted by the company's preferred exponential distribution. The ERG highlighted that although progression-free survival correlated with overall survival, the exact relationship between these 2 parameters was uncertain and the company did not account for this. The committee was aware that progression-free survival is important to patients and is accepted by regulatory bodies as evidence of effectiveness, but is not a proxy for overall survival. The committee concluded that the analyses that used progression-free survival as a surrogate for overall survival were not robust. Also, they did not provide information on the most appropriate hazard function to extrapolate overall survival in people who had isatuximab plus pomalidomide and dexamethasone.
## The company's log-normal extrapolation is appropriate to model progression-free survival
The company used a jointly fitted log-normal distribution to estimate progression-free survival in its base case. That is, it fitted a curve to data for both treatment arms and included treatment group as a covariate, implying a constant treatment effect over time. The company stated that the log-normal provided the best statistical fit to the data. The committee was aware that both the ERG and the company used other distributions in sensitivity analyses to estimate progression-free survival, but this had little effect on the economic model results. The committee agreed that the log-normal distribution was appropriate to estimate progression-free survival.
## Adjusting trial data and costs for subsequent treatments is appropriate but the company did not provide the requested analysis
The committee was aware that some of the treatments given after 4 or more previous lines of treatment in ICARIA-MM would not be available in NHS clinical practice and might prolong life (see section 3.9). It was also aware that these subsequent treatments affected total costs in both treatment arms. For the committee's first meeting, the company used the inverse probability of censoring weighting method to adjust for the effect of treatment with daratumumab and lenalidomide after 4 previous lines of treatment. The company considered this analysis exploratory because it included a small number of people and may not have accounted for all the factors associated with subsequent daratumumab or lenalidomide use. The committee considered it reasonable to adjust for subsequent treatments in both arms of the trial, but noted that the company adjusted only 1 arm of the ICARIA-MM data. The committee was also not satisfied that the company had provided enough information about the analysis at the first meeting. At the second meeting, it noted that the company was unable to identify the covariates it had used. The committee could not evaluate the method of adjusting for subsequent treatments without knowing which covariates the company chose. The company stated that the analysis resulted in slightly increased survival estimates for both isatuximab plus pomalidomide and dexamethasone and pomalidomide and dexamethasone when daratumumab and lenalidomide were removed. It considered this implausible and so did not present cost-effectiveness estimates using this adjustment. The committee concluded that adjusting the trial data and costs for subsequent treatments not available in clinical practice was appropriate, but the company did not fully report its methods or present results from the requested analysis.
## It is reasonable to remove costs of daratumumab and lenalidomide, but this approach has limitations
The company's updated base case for the second committee meeting did not adjust for the effects or the costs of treatments given after 4 previous lines of treatment (see section 3.16). That is, the company considered that the overall survival results from a trial that used treatments unavailable in the NHS were generalisable to the NHS, and that the NHS would incur the costs of drugs it does not offer. The company explained that the clinical experts at the first committee meeting stated that these therapies were unlikely to affect survival after 4 or more previous lines of treatment. The ERG highlighted that this approach, that is, to maintain the effects but not remove the costs, was not appropriate. This was because it included high-cost treatments not recommended at this position in the treatment pathway in the NHS. The ERG noted that removing treatments reduced the total costs less in the isatuximab plus pomalidomide and dexamethasone arm than in the pomalidomide plus dexamethasone arm. This was because a higher proportion of people taking pomalidomide plus dexamethasone moved to daratumumab than did people taking isatuximab plus pomalidomide and dexamethasone. The committee recognised that the ERG's analysis that removed the costs of daratumumab and lenalidomide after 4 or more previous lines of treatment did not adjust for effects. The ERG noted that the reported survival hazard ratio from the adjustment analysis was not markedly different to that from the current ICARIA‑MM data. The committee concluded that it would have preferred to have seen analyses adjusting for both effects and costs of daratumumab and lenalidomide given after 4 previous lines of treatment, with the methods fully reported. But without these analyses, it was reasonable to remove the costs of these treatments, particularly because the clinical experts suggested that treatments given after 4 previous lines of treatment would likely have minimal effects on survival.
# Utility values in the economic model
## Utility estimates in the company's model are appropriate
ICARIA-MM included the EQ-5D-5L health questionnaire to measure health-related quality of life. The company mapped the EQ‑5D‑5L data to the EQ‑5D‑3L to estimate mean utility for the pre-progressed and progressed disease health states. This is in line with NICE's guide to the methods of technology appraisal. The utility value used for the progression-free health state in the isatuximab plus pomalidomide and dexamethasone arm was slightly higher than for the pomalidomide plus dexamethasone arm (0.719 compared with 0.717). The company applied a utility value of 0.611 to both arms for the progressed disease state. More adverse events occurred in the isatuximab plus pomalidomide and dexamethasone arm. The company did not apply utility decrements for adverse events. It explained that health utility data were collected at the beginning of every treatment cycle (every 2 weeks) in the trial and it assumed that the EQ‑5D would capture any loss in utility from adverse events. The ERG considered this to be reasonable. The patient expert stated that despite the higher rate of adverse events in the isatuximab plus pomalidomide and dexamethasone arm of the trial, fewer people stopped treatment because of adverse events than in the pomalidomide plus dexamethasone arm (7.8% compared with 17.2%). On balance, the committee concluded that the utility estimates used in the company's model were appropriate.
# Costs in the economic model
## Time on treatment determines cost of treatment, and the company's choice of extrapolation is reasonable
The committee understood that the cost of treatment was a key driver in the cost effectiveness of isatuximab plus pomalidomide and dexamethasone. It also appreciated that time on treatment and price largely determine the cost of treatment. The company collected time on treatment data in ICARIA-MM. The committee was aware that because the trial is ongoing, some people were on treatment at the time of the interim analysis (27.6% in the pomalidomide plus dexamethasone arm and 45.1% in the isatuximab plus pomalidomide and dexamethasone arm). This added uncertainty to any extrapolation. The company chose an exponential model in its base case to estimate time on treatment. The ERG highlighted that alternative models increased the ICER. The committee considered that there was some uncertainty around the most plausible model to use to estimate time on treatment, but concluded that the company's choice was reasonable, given the available data.
## Including drug wastage and treatment costs based on relative dose intensities in ICARIA-MM is appropriate
In its base case, the company assumed drug wastage for isatuximab in line with previous NICE technology appraisal guidance in multiple myeloma. But the company also stated that there was potential for vial sharing, which could reduce drug wastage. The ERG modelled a scenario without drug wastage to highlight the effect on the ICER, while noting this was unlikely in clinical practice. The Cancer Drugs Fund clinical lead confirmed that drug wastage was likely, particularly if treatments are not widely used. The ERG noted that the relative dose intensity, that is, the ratio of the given dose to the planned dose, of pomalidomide was lower in the isatuximab plus pomalidomide and dexamethasone arm than in the pomalidomide plus dexamethasone arm in ICARIA-MM. It modelled a scenario that assumed 100% relative dose intensities in both treatment arms to highlight the effect on the ICER. The company explained that the differences in the relative dose intensities of pomalidomide between trial arms resulted from the trial allowing dose reductions of pomalidomide, but only missed doses of isatuximab. The committee concluded that drug wastage occurs, and the company's base-case drug wastage and relative dose intensity assumptions were appropriate.
## Removing pomalidomide and dexamethasone costs from the isatuximab plus pomalidomide and dexamethasone arm is not appropriate
The company stated that there were challenges in showing the cost effectiveness of isatuximab plus pomalidomide and dexamethasone because of the relatively high cost of pomalidomide. Pomalidomide is made by a different company, and is available with a confidential discount. The company acknowledged at the second meeting that this meant that it did not know the price of its own treatment combination, or the comparator, both of which include pomalidomide (and dexamethasone). The company noted that pomalidomide plus dexamethasone was a NICE recommended treatment option for multiple myeloma after 3 treatments and is part of standard of care. Therefore it proposed 2 alternative scenario analyses, which removed the cost of pomalidomide and dexamethasone from the isatuximab plus pomalidomide and dexamethasone arm when:
those on pomalidomide plus dexamethasone are on treatment
those on pomalidomide plus dexamethasone stop treatment.The committee noted that NICE's guide to the methods of technology appraisal states that all relevant costs should be included in the analysis. It concluded that removing pomalidomide and dexamethasone costs from the isatuximab plus pomalidomide and dexamethasone arm was not appropriate.
# Waning of treatment effect
## An increasing relative treatment effect of isatuximab plus pomalidomide and dexamethasone over time is potentially plausible but uncertain
The company's original base case assumed that the relative survival benefit of isatuximab plus pomalidomide and dexamethasone, compared with pomalidomide plus dexamethasone, was maintained at the same level after treatment stopped, for the rest of a person's life. This means that people who survive long term have a lower risk of death at any point in time if they took isatuximab plus pomalidomide and dexamethasone arm than if they took pomalidomide plus dexamethasone, even long after treatment stops. The company did not include the possibility that the effects of treatment wane over time, but instead tested for proportional hazards, which the trial data supported. However, the ERG noted that the proportional hazards assumption was supported only for the observed trial follow-up period, with no evidence for what happens after this. The clinical experts explained that it was plausible for isatuximab plus pomalidomide and dexamethasone to have some treatment benefit that continues after stopping treatment, although it may not be maintained at the same level for the rest of a person's life. The committee heard that the point at which the relative treatment benefit starts to diminish was unknown and how long the relative benefit lasts after stopping treatment was uncertain. At the second meeting, the company included in its updated base case an exponential distribution (constant hazard rate) to extrapolate overall survival data for isatuximab plus pomalidomide and dexamethasone. It also included a Weibull distribution (increasing hazard rate) to extrapolate overall survival for pomalidomide and dexamethasone (see section 3.12). The company stated that the exponential distribution likely included treatment effect waning because people whose disease responds to isatuximab plus pomalidomide and dexamethasone could be expected to live for a considerable length of time (see section 3.14). The ERG explained that by using an exponential distribution for isatuximab plus pomalidomide and dexamethasone, and a Weibull distribution for pomalidomide and dexamethasone, the relative treatment effect of isatuximab plus pomalidomide and dexamethasone increased over time. The ERG stated that this may be plausible because of the different mechanisms of action of the treatments but also based on the hazards seen in the daratumumab survival data (see section 3.13). The company did an analysis that included treatment effect waning by setting the hazard ratio associated with survival to 1.0 (no effect of treatment) at 3 years in the model, when approximately 90% of people had died. The company stated that this did not give plausible survival estimates for isatuximab plus pomalidomide and dexamethasone. This was because the estimated overall survival was shorter than for daratumumab monotherapy (see section 3.13), which the company considered should be inferior to triple combination therapy. The committee understood that this conclusion, based on an informal and naive comparison, would hold only if the people in ICARIA‑MM and the pooled daratumumab monotherapy trials were similar. The committee considered that an increasing relative treatment effect of isatuximab plus pomalidomide and dexamethasone over time was potentially plausible, but is highly uncertain because of the immaturity of the ICARIA-MM data.
# End of life
## Isatuximab plus pomalidomide and dexamethasone after 3 previous lines of treatment meets NICE's end-of-life criteria
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. Median overall survival in the pomalidomide plus dexamethasone arm of the ICARIA-MM subgroup who had 3 previous lines of treatment was 14.4 months. The ERG noted that the modelled mean survival was higher than the median (these values are commercial in confidence and cannot be reported here). The company referred to epidemiological evidence showing that median overall survival was less than 14 months in people with relapsed or refractory multiple myeloma who had 3 previous lines of treatment. The clinical experts stated that life expectancy for people in this group was less than 2 years. Therefore, the committee concluded that the short life expectancy criterion was met. Median overall survival was not reached in the isatuximab plus pomalidomide and dexamethasone arm of ICARIA‑MM. But both the Weibull (committee's preferred distribution) and the exponential model (company's base case) estimated that it extended life by more than 3 months compared with pomalidomide plus dexamethasone in people who had 3 previous lines of treatment. The committee acknowledged the uncertainty in the life-extending benefits of the treatment. But, on balance, it concluded that isatuximab plus pomalidomide and dexamethasone extended mean overall survival by over 3 months compared with pomalidomide plus dexamethasone. The committee concluded that isatuximab plus pomalidomide and dexamethasone, after 3 previous lines of treatment, met the criteria to be considered a life-extending, end-of-life treatment.
# Cost-effectiveness results
## The cost-effectiveness analysis after 2 previous lines of treatment is not robust enough for decision making
At the second meeting, the company did an analysis using data from people who had had 2 previous lines of treatment. It compared isatuximab plus pomalidomide and dexamethasone with panobinostat plus bortezomib and dexamethasone, the comparator listed in NICE's final scope after 2 previous lines of treatment. This was in response to the committee's request at the first meeting after hearing that there was unmet need at this part of the treatment pathway (see section 3.4). The company explained that it considered this analysis exploratory because the ICARIA-MM data were even less mature for people who had 2 previous lines of treatments than it was for people who had 3 previous lines of treatment. The company did not consider the indirect comparison to be robust and noted that panobinostat plus bortezomib and dexamethasone is not widely used in the NHS at this point in the treatment pathway. The committee agreed that there is unmet need for new effective treatment options for people who have had 2 previous lines of treatment, but concluded that the analysis of isatuximab plus pomalidomide and dexamethasone compared with panobinostat plus bortezomib and dexamethasone after 2 previous lines of treatment was not robust enough for decision making.
## The committee states its preferred assumptions
Because of confidential commercial arrangements for isatuximab, pomalidomide and the comparators, none of the cost-effectiveness results are reported here. The committee recalled its preferred assumptions for analyses that:
estimate overall survival using an exponential or log-normal extrapolation in the isatuximab plus pomalidomide and dexamethasone arm and an independently fitted Weibull extrapolation in the pomalidomide and dexamethasone arm (see section 3.13)
use survival estimates for both treatment arms that are adjusted for daratumumab and lenalidomide, which are not used in NHS clinical practice after 4 or more previous lines of treatment; with or without (depending on the validity of the adjustment analysis) removing the costs of these treatments (see section 3.9 and section 3.17)
apply the drug wastage and relative dose intensity assumptions from the company's base case (see section 3.20).
## Isatuximab plus pomalidomide and dexamethasone is not recommended for routine use in the NHS
The committee considered that the evidence base was immature, which meant that the most plausible ICER range was highly uncertain. The committee agreed that the uncertainty in the current evidence base was too high for it to be confident that the most plausible ICER range was below the range NICE normally considers to be a cost-effective use of NHS resources for a life-extending treatment at the end of life. It therefore concluded that it could not recommend isatuximab plus pomalidomide and dexamethasone for routine use in adults with relapsed and refractory multiple myeloma.
# Cancer Drugs Fund
## Isatuximab plus pomalidomide and dexamethasone meets the Cancer Drugs Fund criteria
Having concluded that isatuximab plus pomalidomide and dexamethasone could not be recommended for routine use, the committee then considered if it could be recommended for treating multiple myeloma within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum). It recalled:
The company expressed an interest in isatuximab plus pomalidomide and dexamethasone being considered for the Cancer Drugs Fund.
Data from ICARIA-MM were immature (data cut was October 2018) and median overall survival was not reached in the isatuximab plus pomalidomide and dexamethasone arm.
ICARIA-MM is due to finish in March 2022. Further data from this trial could help reduce uncertainties in estimating long-term progression-free and overall survival and the time on treatment. The committee was aware that overall survival and time on treatment estimates were key drivers of the cost-effectiveness results (see sections 3.11, 3.12, 3.13 and 3.19).
Data collection through the Systemic Anti-Cancer Therapy dataset could be used to collect evidence on clinical outcomes for people with multiple myeloma who have had 3 previous lines of treatment. It may also provide information on the proportion of people having treatment after progression on 4 previous lines of treatment and the treatments used. However, there may not be enough time for these data to be collected before ICARIA‑MM ends.
The Cancer Drugs Fund clinical lead stated that because daratumumab, an anti‑CD38 monoclonal antibody, is used after 1 previous line of treatment, there are fewer people eligible for isatuximab, another anti‑CD38 monoclonal antibody treatment, after 3 previous lines of treatment. This may further limit the amount of data that would be collected for isatuximab in clinical practice.
The company's price for isatuximab, including a commercial arrangement, means that it has plausible potential to be cost effective after 3 previous lines of treatment.The committee concluded that isatuximab plus pomalidomide and dexamethasone met the criteria to be considered for inclusion in the Cancer Drugs Fund, when the company's commercial offer as part of the managed access agreement is used. It recommended isatuximab plus pomalidomide and dexamethasone for use through the Cancer Drugs Fund as an option for relapsed and refractory multiple myeloma. It is only recommended if people have had 3 previous lines of treatment (including lenalidomide and a proteasome inhibitor), and their disease has progressed on the last treatment. Also, the conditions in the managed access agreement must be followed. When the guidance is next reviewed, the company should use the committee's preferred assumptions (unless new evidence indicates otherwise), as set out in section 3.25.
# Innovation
## The model adequately captures the benefits of isatuximab plus pomalidomide and dexamethasone
The company considered isatuximab plus pomalidomide and dexamethasone to be innovative. This is because it is the first treatment option for relapsed and refractory multiple myeloma to combine an anti‑CD38 monoclonal antibody and an immunomodulatory agent. The company also highlighted that the treatment shows benefit in a population who have had many previous lines of treatment. The Cancer Drugs Fund clinical lead stated that there are currently no anti‑CD38 antibody treatments recommended for NHS routine commissioning to treat multiple myeloma. He also noted that the company supported a recommendation in the Cancer Drugs Fund. But the Cancer Drugs Fund already offers access to anti-CD38 antibody treatment after 1 previous line of treatment (daratumumab plus bortezomib and dexamethasone) and after 3 previous lines of treatment (daratumumab alone). At the second meeting, the company stated that although all relevant health benefits were captured in the model, there were likely to be other benefits that the model did not account for. These additional benefits included hope for people with multiple myeloma at later lines of treatment and improved quality of life for carers. The ERG noted the possibility that hope was captured by the anxiety and depression domain of the EQ‑5D in the clinical trial and that the company did not investigate the impact on caregiver quality of life. The committee considered that the model captured all health-related quality-of-life benefits. It concluded that it had not been presented with any evidence of additional benefits from treatment with isatuximab plus pomalidomide and dexamethasone.
# Other factors
No equality or social value judgement issues were identified.
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{'Recommendations': "Isatuximab, plus pomalidomide and dexamethasone, is recommended for use within the Cancer Drugs Fund as an option for treating relapsed and refractory multiple myeloma in adults who have had lenalidomide and a proteasome inhibitor, and whose disease has progressed on their last treatment, only if:\n\nthey have had 3\xa0previous lines of treatment\n\nthe conditions in the managed access agreement for isatuximab plus pomalidomide and dexamethasone are followed.\n\nThis recommendation is not intended to affect treatment with isatuximab plus pomalidomide and dexamethasone that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nThe company proposes that isatuximab plus pomalidomide and dexamethasone is used only for people who have already had 3\xa0lines of treatment. Although effective options after 2\xa0lines of treatment are also needed, the clinical- and cost-effectiveness data for isatuximab plus pomalidomide and dexamethasone at this point in the treatment pathway are not suitable for decision making.\n\nAfter 3\xa0lines of treatment, people usually have pomalidomide plus dexamethasone, or daratumumab alone (in the Cancer Drugs Fund). Clinical trial evidence suggests that isatuximab plus pomalidomide and dexamethasone delays the disease progressing and increases how long people live compared with pomalidomide plus dexamethasone. But, the trial is not finished so the benefit in the longer term is uncertain.\n\nThe cost-effectiveness estimates for isatuximab plus pomalidomide and dexamethasone after 3\xa0previous lines of treatment are uncertain because of limitations in the clinical data. The estimates are higher than what NICE normally considers an acceptable use of NHS resources. So isatuximab plus pomalidomide and dexamethasone cannot be recommended for routine use in the NHS.\n\nCollecting more data from the ongoing trial and from NHS practice would help to address some of the uncertainties. Isatuximab plus pomalidomide and dexamethasone could be cost effective after 3\xa0previous lines of treatment when the company's commercial offer as part of a managed access agreement is used. Therefore, isatuximab plus pomalidomide and dexamethasone is recommended for use in the Cancer Drugs Fund.", 'Information about isatuximab': "# Marketing authorisation indication\n\nIsatuximab (Sarclisa, Sanofi) in combination with pomalidomide and dexamethasone has a marketing authorisation 'for the treatment of adult patients with relapsed and refractory multiple myeloma who have received at least 2\xa0prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on the last therapy'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe proposed list price for isatuximab in the company submission is £506.94 for a 100‑mg vial or £2,534.70 for a 500‑mg vial. The company has a commercial arrangement. This makes isatuximab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Sanofi, a review of this submission by the evidence review group (ERG), the technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:\n\nThe model time horizon should be 20\xa0years to capture all benefits and costs of the intervention and the comparators.\n\nThe company's amendment to the probabilistic sampling of health utility data, which ensures that the utility value for the progressed disease health state does not exceed the utility value for the progression-free disease health state, is appropriate.\n\nThe company's amendment to its model, which applies drug costs at the start of each cycle, is appropriate.\n\nThe committee recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, table\xa04, page 40), and took these into account in its decision making. It discussed the issues that were outstanding after the technical engagement stage.\n\n# The condition\n\n## People with relapsed and refractory multiple myeloma would welcome a new effective treatment option\n\nMultiple myeloma is an incurable and progressive condition that affects survival and quality of life. The patient experts explained that it causes severe symptoms, which have a significant impact on patients' quality of life and are also challenging for carers. They highlighted the psychological impact for patients approaching the end of the treatment pathway, where further treatment options are limited. The committee was aware that clinicians value having a range of different treatment options for patients. One patient expert noted that although some treatments are oral and people can take them at home, some people prefer to have their treatment in hospital. He also highlighted that patients value treatments that delay the disease progressing, which outweighs the negative impact of their side effects. The committee recognised the need for effective treatment options for previously treated multiple myeloma, and concluded that people would welcome a new treatment option.\n\n# Treatment pathway\n\n## The treatment pathway for multiple myeloma is rapidly evolving\n\nTreatment options for multiple myeloma depend on how many previous lines of treatment a person has had, the specific treatments, their response to these treatments, and their preferences. If a stem cell transplant is suitable:\n\nInduction treatment is bortezomib, given before the transplant.\n\nAfter 1\xa0previous line of treatment, people may have bortezomib again, along with a second stem cell transplant.If a stem cell transplant is not suitable:\n\nFor untreated disease, treatments include thalidomide or bortezomib plus an alkylating agent, for example, melphalan or cyclophosphamide, and a corticosteroid, for example, dexamethasone. Lenalidomide plus dexamethasone is also an option when thalidomide is not appropriate.\n\nAfter 1\xa0previous line of treatment, options include lenalidomide plus dexamethasone if the person has had bortezomib before, or carfilzomib plus dexamethasone if they have not had bortezomib before. Also, daratumumab plus bortezomib and dexamethasone is available in the Cancer Drugs Fund.After this, the options do not depend on whether a stem cell transplant is suitable:\n\nAfter 2\xa0previous lines of treatment, options include lenalidomide plus dexamethasone or panobinostat plus bortezomib and dexamethasone. Also, ixazomib plus lenalidomide and dexamethasone is available in the Cancer Drugs Fund.\n\nAfter 3\xa0previous lines of treatment, options include pomalidomide plus dexamethasone or panobinostat plus bortezomib and dexamethasone. Daratumumab alone or ixazomib plus lenalidomide and dexamethasone are available in the Cancer Drugs Fund.Isatuximab plus pomalidomide and dexamethasone can be used whether or not people have had a stem cell transplant. The clinical experts explained that, following recent NICE guidance, the use of lenalidomide plus dexamethasone for untreated disease and the use of daratumumab plus bortezomib and dexamethasone after 1\xa0previous line of treatment is increasing. The committee understood that the multiple myeloma pathway is rapidly evolving.\n\n## The company positions isatuximab plus pomalidomide and dexamethasone after 3\xa0previous lines of treatment\n\nThe marketing authorisation for isatuximab plus pomalidomide and dexamethasone states that it must be used after lenalidomide and a proteasome inhibitor, which means after 2\xa0previous lines of treatment or later. Proteasome inhibitors include bortezomib, carfilzomib and ixazomib. But the marketing authorisation does not specify the position in the treatment pathway. The company chose to position isatuximab plus pomalidomide and dexamethasone after 3\xa0previous lines of treatment. It did this based on unmet clinical need and advice from clinical experts. The committee noted that the company's positioning meant that the population was narrower than defined by both the marketing authorisation and NICE's final scope. The clinical expert explained that to have isatuximab plus pomalidomide and dexamethasone, a person must have had lenalidomide. But currently many clinicians use lenalidomide after 2\xa0previous lines of treatment, with ixazomib and dexamethasone in the Cancer Drugs Fund, or with dexamethasone. Therefore, the clinical experts agreed that the company's positioning was appropriate. The committee concluded at its first meeting that it would focus its discussion on people who have had 3\xa0previous lines of treatment.\n\n## There is unmet need for new effective options after 2\xa0previous lines of treatment\n\nThe committee recalled that for isatuximab plus pomalidomide and dexamethasone both the marketing authorisation and NICE's final scope included people who have had at least 2\xa0previous lines of treatment, to include lenalidomide and a proteasome inhibitor. It also recalled that lenalidomide and bortezomib are now options for untreated multiple myeloma and after 1\xa0previous line of treatment (see section\xa03.2). The patient expert explained that patients would prefer any NICE recommendation to include the population covered by the marketing authorisation rather than restrict it to those who have had 3\xa0previous lines of treatment. The Cancer Drugs Fund clinical lead explained at the first meeting that lenalidomide and a proteasome inhibitor is now being used more often at earlier points in the treatment pathway. This has meant that there is an increasing need for new and effective options after 2\xa0previous lines of treatment. In response to the committee's request at the first meeting, the company did a cost-effectiveness analysis for isatuximab plus pomalidomide and dexamethasone after 2\xa0previous lines of treatment compared with the comparator in NICE's final scope (see section\xa03.24). The committee concluded that there is unmet need for new effective treatment options for people who have had 2\xa0previous lines of treatment.\n\n# Comparators\n\n## After 3\xa0previous lines of treatment, pomalidomide plus dexamethasone is the only relevant comparator\n\nNICE guidance recommends both pomalidomide plus dexamethasone and panobinostat plus bortezomib and dexamethasone after 3\xa0previous lines of treatment for multiple myeloma. NICE's final scope for this appraisal lists these as the comparators. The committee recalled that treatments recommended in the Cancer Drugs Fund are not considered to be comparators. The company did not consider panobinostat plus bortezomib and dexamethasone to be a relevant comparator to isatuximab plus pomalidomide and dexamethasone after 3\xa0previous lines of treatment. It explained that this was because of toxic adverse effects and the lack of perceived efficacy noted by clinicians it consulted, which means it is usually used after 4\xa0previous lines of treatment. To comply with NICE's final scope, the company compared the clinical and cost effectiveness of isatuximab plus pomalidomide and dexamethasone with panobinostat plus bortezomib and dexamethasone and pomalidomide plus dexamethasone. The comparison with panobinostat plus bortezomib and dexamethasone included an indirect treatment comparison for clinical effectiveness because there was no trial directly comparing the 2\xa0treatments. The ERG noted that 1\xa0of its clinical advisers agreed with the company's position, but 2\xa0other advisers\xa0stated that panobinostat plus bortezomib and dexamethasone is used after 3\xa0previous lines of treatment and toxicity is managed by adjusting the dose. The clinical experts at the meeting explained that daratumumab, available in the Cancer Drugs Fund, or pomalidomide plus dexamethasone are the most commonly used options after 3\xa0previous lines of treatment. They stated that panobinostat plus bortezomib and dexamethasone is very rarely used after 3\xa0previous lines of treatment because of toxicity and perceived poor clinical efficacy. The Cancer Drugs Fund clinical lead explained that clinicians can now offer bortezomib again without having to use it with panobinostat and that few clinicians offer panobinostat plus bortezomib and dexamethasone after 3\xa0previous lines of treatment. The committee concluded that after 3\xa0previous lines of treatment, pomalidomide plus dexamethasone is the only relevant comparator.\n\n# Clinical evidence\n\n## The evidence for people who have had 3\xa0previous lines of treatment is acceptable for decision making\n\nICARIA-MM is an open-label randomised trial, comparing isatuximab plus pomalidomide and dexamethasone with pomalidomide plus dexamethasone. It included people with relapsed and refractory multiple myeloma who have had at least 2\xa0previous lines of treatment, including lenalidomide and a proteasome inhibitor. The primary outcome was progression-free survival. Because the company positioned isatuximab plus pomalidomide and dexamethasone as a treatment option after 3\xa0previous lines of treatment, it provided clinical-effectiveness data from a post hoc subgroup of people from ICARIA-MM who had 3\xa0previous lines of treatment. The committee was aware that this subgroup was not stratified and therefore not a randomised group. The ERG noted that there was more uncertainty associated with the subgroup results than with the randomised population results, indicated by wider confidence intervals. The committee understood the limitations of the subgroup analysis for people who have had 3\xa0previous lines of treatment, but agreed to accept it for decision making.\n\n## Isatuximab plus pomalidomide and dexamethasone likely extends both progression-free and overall survival, but the data are immature\n\nICARIA-MM is ongoing. At the interim data cut (October 2018), median follow up was 11.6\xa0months in the trial for people who had 3\xa0previous lines of treatment. For progression-free survival, the interim subgroup analysis was based on only about half of patients having events. It showed that isatuximab plus pomalidomide and dexamethasone extended median progression-free survival compared with pomalidomide plus dexamethasone from 7.8\xa0months to 13.3\xa0months (hazard ratio 0.598; 95% confidence interval 0.348 to 1.03, p=0.0611). For time to death, the interim subgroup analysis was based on 11\xa0deaths in the treatment group (which included 52\xa0people) and 23\xa0deaths in the control group (which included 58\xa0people) and heavily censored data. It showed that median overall survival had not yet been reached for the isatuximab plus pomalidomide and dexamethasone arm. The hazard ratio for overall survival compared with pomalidomide plus dexamethasone was 0.494 (95% confidence interval 0.24 to 1.02, p=0.0502). The committee acknowledged the immaturity of the data in this ongoing trial. It concluded that isatuximab plus pomalidomide and dexamethasone was likely to extend progression-free and overall survival compared with pomalidomide plus dexamethasone after 3\xa0previous lines of treatment, but noted that median follow up was short, the subgroup was small and the data were immature.\n\n## It is not appropriate to use isatuximab plus pomalidomide and dexamethasone when disease is refractory to a previous anti-CD38 monoclonal antibody\n\nIsatuximab is an anti-CD38 monoclonal antibody. Daratumumab, another anti‑CD38 monoclonal antibody, is an option after 1\xa0previous line of treatment and 3\xa0previous lines of treatments in the Cancer Drugs Fund. ICARIA-MM included people with multiple myeloma that was not refractory to anti-CD38 antibody treatment, that is, their disease had not progressed on the treatment. But, it excluded people whose disease was refractory to anti-CD38 antibody treatment, that is, their disease progressed while on the treatment. The clinical experts explained that they would consider using isatuximab plus pomalidomide and dexamethasone for people who had previous treatment with an anti‑CD38 antibody such as daratumumab, but only if that treatment was stopped for reasons other than disease progression. They stated that they would not use an anti‑CD38 antibody again if the disease had been refractory to one in a previous line of treatment. The company noted that only 1\xa0person in ICARIA-MM had previous anti-CD38 antibody treatment. The clinical experts explained that in NHS practice many people increasingly have daratumumab after 1\xa0previous line of treatment. This means that many people with relapsed and refractory multiple myeloma after 3\xa0previous lines of treatment would have already had an anti‑CD38 antibody. The Cancer Drugs Fund clinical lead noted that daratumumab is well tolerated and few people would stop it for reasons other than disease progression. The clinical experts and the Cancer Drugs Fund clinical lead also noted that there was high biological plausibility that response to isatuximab would be reduced in people whose disease was refractory to previous daratumumab treatment. The committee acknowledged that clinical-effectiveness evidence for isatuximab plus pomalidomide and dexamethasone in people who had previously had anti-CD38 antibody treatment had not been presented. It recalled that the clinical experts explained that using an anti‑CD38 antibody treatment again later in the treatment pathway would be appropriate if it had been stopped for reasons other than disease progression. The committee concluded that it had not been presented with evidence for people whose disease was refractory to anti-CD38 antibody treatment. Also, it concluded that it was not appropriate to use isatuximab plus pomalidomide and dexamethasone when disease is refractory to a previous anti-CD38 monoclonal antibody.\n\n## Subsequent treatments in ICARIA-MM do not reflect NHS clinical practice\n\nThe subgroup of people in ICARIA-MM who had had 3\xa0previous lines of treatment had a range of subsequent treatments after disease progression. The committee was aware that some of these treatments, such as daratumumab and lenalidomide, were not available at this point in the pathway in the NHS, and may prolong life. The clinical experts explained that for people who have had 4\xa0previous lines of treatment, there are no standard treatments in current NHS clinical practice, and treatments at this point in the pathway would likely be ineffective. The clinical experts therefore considered that treatments after 4\xa0or more previous lines of treatment in ICARIA-MM were unlikely to affect the survival results in the ICARIA-MM subgroup. At the second meeting, the Cancer Drugs Fund clinical lead noted that lenalidomide would likely be ineffective after 4\xa0or more previous lines of treatment but daratumumab would give some benefit. The committee recognised that these treatment options improve clinical outcomes when used at other points in the treatment pathway, and it was appropriate to consider that they might also increase survival later in the treatment pathway. The committee also noted that the proportion of people having these treatments varied between arms in ICARIA-MM; more people had daratumumab in the pomalidomide plus dexamethasone arm and more people had lenalidomide in the isatuximab plus pomalidomide and dexamethasone arm. The committee concluded that the subsequent treatments people had in ICARIA-MM did not reflect NHS clinical practice. This made generalising the overall survival results from the trial to NHS practice problematic.\n\n# The company's economic model\n\n## The company's model is appropriate for decision making\n\nThe company chose a partitioned survival model to estimate the cost effectiveness of isatuximab plus pomalidomide and dexamethasone. The model included 3\xa0health states: progression-free, progressed, and dead. The probability of being in a given health state was defined by the area under the curves for progression-free survival and overall survival or their difference. The model cycle length was 1\xa0week and the time horizon was 20\xa0years. The committee considered the company's model to be appropriate for decision making.\n\n## Clinical experts prefer using a Weibull distribution to estimate overall survival in each trial arm\n\nFollow up for the interim data from ICARIA-MM was short in relation to the modelled time horizon. So, the company extrapolated the overall survival data for the subgroup who had had 3\xa0previous lines of treatment, choosing an exponential distribution in its base case. The committee understood that the distribution chosen to estimate overall survival affects the incremental cost-effectiveness ratio (ICER). The ERG noted that the exponential distribution provided the best statistical fit to the trial data, but other distributions had similar statistical fits. The committee noted that because there were limited trial data, the statistical fit of a curve is of limited importance when selecting the most appropriate distribution. It heard that 2 of the 3 clinical advisers to the company supported using the Weibull, whereas the other preferred the exponential distribution. The clinical experts at the first meeting also stated that the Weibull distribution produced the most plausible long-term estimates of overall survival in both trial arms. The committee noted that the overall survival estimates were uncertain because of the limited trial data and the clinical experts preferred the Weibull distribution to estimate overall survival in each arm.\n\n## The company updated its base case in response to consultation\n\nAt the second meeting, the company updated its base case to use a Weibull distribution to extrapolate the overall survival data for pomalidomide and dexamethasone from ICARIA-MM. It also provided supporting evidence for its original choice of an exponential distribution for estimating overall survival for isatuximab plus pomalidomide and dexamethasone. This evidence included no new survival data from ICARIA-MM, but it did include data documenting the experience of people who had daratumumab monotherapy after 4\xa0previous lines of treatment (see section\xa03.13). The company also included an analysis using surrogate endpoints such as progression-free survival, depth of response to treatment and attaining minimal residual disease to model overall survival (see section\xa03.14).\n\n## Clinical data are immature and there is a range of plausible distributions to estimate overall survival in each trial arm\n\nTo show potential overall survival beyond the ICARIA-MM trial follow-up period, the company identified a study that pooled overall survival for 2\xa0single-arm trials of the anti-CD38 antibody daratumumab (GEN501 and SIRUS). The pooled data had a median follow up of 36.3\xa0months compared with 11.6\xa0months for the ICARIA-MM trial. The company stated that the exponential and log-normal distributions were the best fit for the longer-term daratumumab data. The ERG noted that it was reasonable to assume that treatments of the same class might follow a similar statistical model. The ERG explained that the hazard function (likelihood of dying) over time for the pooled daratumumab survival data appeared to decrease slightly. This suggested that using the Weibull distribution (which in this case is characterised by increasing hazards) was not appropriate to extrapolate the overall survival data for isatuximab plus pomalidomide and dexamethasone. The ERG preferred the exponential (constant hazards) to the Weibull distribution to estimate survival for isatuximab plus pomalidomide and dexamethasone because it did not consider that the hazard rate increased over time. The ERG also did an analysis using the log-normal distribution, which it considered plausible based on the current evidence because the log-normal function has decreasing hazards. The ERG stated it was reasonable to use a different distribution to extrapolate the overall survival data for isatuximab plus pomalidomide and dexamethasone to that used for pomalidomide and dexamethasone given that isatuximab has a different mechanism of action. But the ERG highlighted that when using separate distributions, it is not appropriate to apply a jointly fitted distribution as the company had done for the Weibull distribution to extrapolate the pomalidomide and dexamethasone data. Instead an independently fitted Weibull should be used. The committee noted that there was a range of plausible distributions to estimate overall survival in each trial arm. It concluded that the most appropriate hazard function to model overall survival for each treatment was uncertain because the clinical data are immature. But the exponential or the log-normal extrapolation for isatuximab plus pomalidomide and dexamethasone and the independently fitted Weibull for pomalidomide plus dexamethasone were plausible.\n\n## The company's alternative survival analysis using surrogates for overall survival is not robust\n\nThe company did an alternative survival analysis using other trial outcomes including minimal residual disease, depth of response to treatment, and progression-free survival data. It considered these outcomes to be surrogates for overall survival, because the ICARIA-MM data were immature. The company highlighted that more people had minimum residual disease and disease with a partial response or better with isatuximab plus pomalidomide and dexamethasone than with pomalidomide and dexamethasone. It suggested that those whose disease responded to treatment may live for a considerable length of time. The ERG acknowledged that survival may differ depending on whether there was minimal residual disease or response to treatment but these data from ICARIA-MM were uncertain. The company also did an analysis using an assumed ratio between progression-free and overall survival based on a literature search of meta-analyses of trials. The company identified 3\xa0ratios that differed markedly and considered 1\xa0of them to be the most plausible. The ratios were applied to the log-normal distribution it had used to estimate progression-free survival. This was then used to predict overall survival with the aim of validating the company's choice of the exponential distribution to model overall survival for isatuximab plus pomalidomide and dexamethasone. The company also did a separate analysis. This used overall survival data that the company had generated using progression-free survival data from ICARIA-MM and the ratio it considered most plausible to replace some of the censored overall survival data. The company noted that the overall survival outcomes based on the curves from these alternative analyses appeared to match those predicted by the company's preferred exponential distribution. The ERG highlighted that although progression-free survival correlated with overall survival, the exact relationship between these 2\xa0parameters was uncertain and the company did not account for this. The committee was aware that progression-free survival is important to patients and is accepted by regulatory bodies as evidence of effectiveness, but is not a proxy for overall survival. The committee concluded that the analyses that used progression-free survival as a surrogate for overall survival were not robust. Also, they did not provide information on the most appropriate hazard function to extrapolate overall survival in people who had isatuximab plus pomalidomide and dexamethasone.\n\n## The company's log-normal extrapolation is appropriate to model progression-free survival\n\nThe company used a jointly fitted log-normal distribution to estimate progression-free survival in its base case. That is, it fitted a curve to data for both treatment arms and included treatment group as a covariate, implying a constant treatment effect over time. The company stated that the log-normal provided the best statistical fit to the data. The committee was aware that both the ERG and the company used other distributions in sensitivity analyses to estimate progression-free survival, but this had little effect on the economic model results. The committee agreed that the log-normal distribution was appropriate to estimate progression-free survival.\n\n## Adjusting trial data and costs for subsequent treatments is appropriate but the company did not provide the requested analysis\n\nThe committee was aware that some of the treatments given after 4\xa0or more previous lines of treatment in ICARIA-MM would not be available in NHS clinical practice and might prolong life (see section\xa03.9). It was also aware that these subsequent treatments affected total costs in both treatment arms. For the committee's first meeting, the company used the inverse probability of censoring weighting method to adjust for the effect of treatment with daratumumab and lenalidomide after 4\xa0previous lines of treatment. The company considered this analysis exploratory because it included a small number of people and may not have accounted for all the factors associated with subsequent daratumumab or lenalidomide use. The committee considered it reasonable to adjust for subsequent treatments in both arms of the trial, but noted that the company adjusted only 1\xa0arm of the ICARIA-MM data. The committee was also not satisfied that the company had provided enough information about the analysis at the first meeting. At the second meeting, it noted that the company was unable to identify the covariates it had used. The committee could not evaluate the method of adjusting for subsequent treatments without knowing which covariates the company chose. The company stated that the analysis resulted in slightly increased survival estimates for both isatuximab plus pomalidomide and dexamethasone and pomalidomide and dexamethasone when daratumumab and lenalidomide were removed. It considered this implausible and so did not present cost-effectiveness estimates using this adjustment. The committee concluded that adjusting the trial data and costs for subsequent treatments not available in clinical practice was appropriate, but the company did not fully report its methods or present results from the requested analysis.\n\n## It is reasonable to remove costs of daratumumab and lenalidomide, but this approach has limitations\n\nThe company's updated base case for the second committee meeting did not adjust for the effects or the costs of treatments given after 4\xa0previous lines of treatment (see section\xa03.16). That is, the company considered that the overall survival results from a trial that used treatments unavailable in the NHS were generalisable to the NHS, and that the NHS would incur the costs of drugs it does not offer. The company explained that the clinical experts at the first committee meeting stated that these therapies were unlikely to affect survival after 4\xa0or more previous lines of treatment. The ERG highlighted that this approach, that is, to maintain the effects but not remove the costs, was not appropriate. This was because it included high-cost treatments not recommended at this position in the treatment pathway in the NHS. The ERG noted that removing treatments reduced the total costs less in the isatuximab plus pomalidomide and dexamethasone arm than in the pomalidomide plus dexamethasone arm. This was because a higher proportion of people taking pomalidomide plus dexamethasone moved to daratumumab than did people taking isatuximab plus pomalidomide and dexamethasone. The committee recognised that the ERG's analysis that removed the costs of daratumumab and lenalidomide after 4\xa0or more previous lines of treatment did not adjust for effects. The ERG noted that the reported survival hazard ratio from the adjustment analysis was not markedly different to that from the current ICARIA‑MM data. The committee concluded that it would have preferred to have seen analyses adjusting for both effects and costs of daratumumab and lenalidomide given after 4\xa0previous lines of treatment, with the methods fully reported. But without these analyses, it was reasonable to remove the costs of these treatments, particularly because the clinical experts suggested that treatments given after 4\xa0previous lines of treatment would likely have minimal effects on survival.\n\n# Utility values in the economic model\n\n## Utility estimates in the company's model are appropriate\n\nICARIA-MM included the EQ-5D-5L health questionnaire to measure health-related quality of life. The company mapped the EQ‑5D‑5L data to the EQ‑5D‑3L to estimate mean utility for the pre-progressed and progressed disease health states. This is in line with NICE's guide to the methods of technology appraisal. The utility value used for the progression-free health state in the isatuximab plus pomalidomide and dexamethasone arm was slightly higher than for the pomalidomide plus dexamethasone arm (0.719 compared with 0.717). The company applied a utility value of 0.611 to both arms for the progressed disease state. More adverse events occurred in the isatuximab plus pomalidomide and dexamethasone arm. The company did not apply utility decrements for adverse events. It explained that health utility data were collected at the beginning of every treatment cycle (every 2\xa0weeks) in the trial and it assumed that the EQ‑5D would capture any loss in utility from adverse events. The ERG considered this to be reasonable. The patient expert stated that despite the higher rate of adverse events in the isatuximab plus pomalidomide and dexamethasone arm of the trial, fewer people stopped treatment because of adverse events than in the pomalidomide plus dexamethasone arm (7.8% compared with 17.2%). On balance, the committee concluded that the utility estimates used in the company's model were appropriate.\n\n# Costs in the economic model\n\n## Time on treatment determines cost of treatment, and the company's choice of extrapolation is reasonable\n\nThe committee understood that the cost of treatment was a key driver in the cost effectiveness of isatuximab plus pomalidomide and dexamethasone. It also appreciated that time on treatment and price largely determine the cost of treatment. The company collected time on treatment data in ICARIA-MM. The committee was aware that because the trial is ongoing, some people were on treatment at the time of the interim analysis (27.6% in the pomalidomide plus dexamethasone arm and 45.1% in the isatuximab plus pomalidomide and dexamethasone arm). This added uncertainty to any extrapolation. The company chose an exponential model in its base case to estimate time on treatment. The ERG highlighted that alternative models increased the ICER. The committee considered that there was some uncertainty around the most plausible model to use to estimate time on treatment, but concluded that the company's choice was reasonable, given the available data.\n\n## Including drug wastage and treatment costs based on relative dose intensities in ICARIA-MM is appropriate\n\nIn its base case, the company assumed drug wastage for isatuximab in line with previous NICE technology appraisal guidance in multiple myeloma. But the company also stated that there was potential for vial sharing, which could reduce drug wastage. The ERG modelled a scenario without drug wastage to highlight the effect on the ICER, while noting this was unlikely in clinical practice. The Cancer Drugs Fund clinical lead confirmed that drug wastage was likely, particularly if treatments are not widely used. The ERG noted that the relative dose intensity, that is, the ratio of the given dose to the planned dose, of pomalidomide was lower in the isatuximab plus pomalidomide and dexamethasone arm than in the pomalidomide plus dexamethasone arm in ICARIA-MM. It modelled a scenario that assumed 100% relative dose intensities in both treatment arms to highlight the effect on the ICER. The company explained that the differences in the relative dose intensities of pomalidomide between trial arms resulted from the trial allowing dose reductions of pomalidomide, but only missed doses of isatuximab. The committee concluded that drug wastage occurs, and the company's base-case drug wastage and relative dose intensity assumptions were appropriate.\n\n## Removing pomalidomide and dexamethasone costs from the isatuximab plus pomalidomide and dexamethasone arm is not appropriate\n\nThe company stated that there were challenges in showing the cost effectiveness of isatuximab plus pomalidomide and dexamethasone because of the relatively high cost of pomalidomide. Pomalidomide is made by a different company, and is available with a confidential discount. The company acknowledged at the second meeting that this meant that it did not know the price of its own treatment combination, or the comparator, both of which include pomalidomide (and dexamethasone). The company noted that pomalidomide plus dexamethasone was a NICE recommended treatment option for multiple myeloma after 3\xa0treatments and is part of standard of care. Therefore it proposed 2\xa0alternative scenario analyses, which removed the cost of pomalidomide and dexamethasone from the isatuximab plus pomalidomide and dexamethasone arm when:\n\nthose on pomalidomide plus dexamethasone are on treatment\n\nthose on pomalidomide plus dexamethasone stop treatment.The committee noted that NICE's guide to the methods of technology appraisal states that all relevant costs should be included in the analysis. It concluded that removing pomalidomide and dexamethasone costs from the isatuximab plus pomalidomide and dexamethasone arm was not appropriate.\n\n# Waning of treatment effect\n\n## An increasing relative treatment effect of isatuximab plus pomalidomide and dexamethasone over time is potentially plausible but uncertain\n\nThe company's original base case assumed that the relative survival benefit of isatuximab plus pomalidomide and dexamethasone, compared with pomalidomide plus dexamethasone, was maintained at the same level after treatment stopped, for the rest of a person's life. This means that people who survive long term have a lower risk of death at any point in time if they took isatuximab plus pomalidomide and dexamethasone arm than if they took pomalidomide plus dexamethasone, even long after treatment stops. The company did not include the possibility that the effects of treatment wane over time, but instead tested for proportional hazards, which the trial data supported. However, the ERG noted that the proportional hazards assumption was supported only for the observed trial follow-up period, with no evidence for what happens after this. The clinical experts explained that it was plausible for isatuximab plus pomalidomide and dexamethasone to have some treatment benefit that continues after stopping treatment, although it may not be maintained at the same level for the rest of a person's life. The committee heard that the point at which the relative treatment benefit starts to diminish was unknown and how long the relative benefit lasts after stopping treatment was uncertain. At the second meeting, the company included in its updated base case an exponential distribution (constant hazard rate) to extrapolate overall survival data for isatuximab plus pomalidomide and dexamethasone. It also included a Weibull distribution (increasing hazard rate) to extrapolate overall survival for pomalidomide and dexamethasone (see section\xa03.12). The company stated that the exponential distribution likely included treatment effect waning because people whose disease responds to isatuximab plus pomalidomide and dexamethasone could be expected to live for a considerable length of time (see section\xa03.14). The ERG explained that by using an exponential distribution for isatuximab plus pomalidomide and dexamethasone, and a Weibull distribution for pomalidomide and dexamethasone, the relative treatment effect of isatuximab plus pomalidomide and dexamethasone increased over time. The ERG stated that this may be plausible because of the different mechanisms of action of the treatments but also based on the hazards seen in the daratumumab survival data (see section\xa03.13). The company did an analysis that included treatment effect waning by setting the hazard ratio associated with survival to 1.0 (no effect of treatment) at 3\xa0years in the model, when approximately 90% of people had died. The company stated that this did not give plausible survival estimates for isatuximab plus pomalidomide and dexamethasone. This was because the estimated overall survival was shorter than for daratumumab monotherapy (see section\xa03.13), which the company considered should be inferior to triple combination therapy. The committee understood that this conclusion, based on an informal and naive comparison, would hold only if the people in ICARIA‑MM and the pooled daratumumab monotherapy trials were similar. The committee considered that an increasing relative treatment effect of isatuximab plus pomalidomide and dexamethasone over time was potentially plausible, but is highly uncertain because of the immaturity of the ICARIA-MM data.\n\n# End of life\n\n## Isatuximab plus pomalidomide and dexamethasone after 3\xa0previous lines of treatment meets NICE's end-of-life criteria\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. Median overall survival in the pomalidomide plus dexamethasone arm of the ICARIA-MM subgroup who had 3\xa0previous lines of treatment was 14.4\xa0months. The ERG noted that the modelled mean survival was higher than the median (these values are commercial in confidence and cannot be reported here). The company referred to epidemiological evidence showing that median overall survival was less than 14\xa0months in people with relapsed or refractory multiple myeloma who had 3\xa0previous lines of treatment. The clinical experts stated that life expectancy for people in this group was less than 2\xa0years. Therefore, the committee concluded that the short life expectancy criterion was met. Median overall survival was not reached in the isatuximab plus pomalidomide and dexamethasone arm of ICARIA‑MM. But both the Weibull (committee's preferred distribution) and the exponential model (company's base case) estimated that it extended life by more than 3\xa0months compared with pomalidomide plus dexamethasone in people who had 3\xa0previous lines of treatment. The committee acknowledged the uncertainty in the life-extending benefits of the treatment. But, on balance, it concluded that isatuximab plus pomalidomide and dexamethasone extended mean overall survival by over 3\xa0months compared with pomalidomide plus dexamethasone. The committee concluded that isatuximab plus pomalidomide and dexamethasone, after 3\xa0previous lines of treatment, met the criteria to be considered a life-extending, end-of-life treatment.\n\n# Cost-effectiveness results\n\n## The cost-effectiveness analysis after 2\xa0previous lines of treatment is not robust enough for decision making\n\nAt the second meeting, the company did an analysis using data from people who had had 2\xa0previous lines of treatment. It compared isatuximab plus pomalidomide and dexamethasone with panobinostat plus bortezomib and dexamethasone, the comparator listed in NICE's final scope after 2\xa0previous lines of treatment. This was in response to the committee's request at the first meeting after hearing that there was unmet need at this part of the treatment pathway (see section\xa03.4). The company explained that it considered this analysis exploratory because the ICARIA-MM data were even less mature for people who had 2\xa0previous lines of treatments than it was for people who had 3\xa0previous lines of treatment. The company did not consider the indirect comparison to be robust and noted that panobinostat plus bortezomib and dexamethasone is not widely used in the NHS at this point in the treatment pathway. The committee agreed that there is unmet need for new effective treatment options for people who have had 2\xa0previous lines of treatment, but concluded that the analysis of isatuximab plus pomalidomide and dexamethasone compared with panobinostat plus bortezomib and dexamethasone after 2\xa0previous lines of treatment was not robust enough for decision making.\n\n## The committee states its preferred assumptions\n\nBecause of confidential commercial arrangements for isatuximab, pomalidomide and the comparators, none of the cost-effectiveness results are reported here. The committee recalled its preferred assumptions for analyses that:\n\nestimate overall survival using an exponential or log-normal extrapolation in the isatuximab plus pomalidomide and dexamethasone arm and an independently fitted Weibull extrapolation in the pomalidomide and dexamethasone arm (see section\xa03.13)\n\nuse survival estimates for both treatment arms that are adjusted for daratumumab and lenalidomide, which are not used in NHS clinical practice after 4\xa0or more previous lines of treatment; with or without (depending on the validity of the adjustment analysis) removing the costs of these treatments (see section\xa03.9 and section\xa03.17)\n\napply the drug wastage and relative dose intensity assumptions from the company's base case (see section\xa03.20).\n\n## Isatuximab plus pomalidomide and dexamethasone is not recommended for routine use in the NHS\n\nThe committee considered that the evidence base was immature, which meant that the most plausible ICER range was highly uncertain. The committee agreed that the uncertainty in the current evidence base was too high for it to be confident that the most plausible ICER range was below the range NICE normally considers to be a cost-effective use of NHS resources for a life-extending treatment at the end of life. It therefore concluded that it could not recommend isatuximab plus pomalidomide and dexamethasone for routine use in adults with relapsed and refractory multiple myeloma.\n\n# Cancer Drugs Fund\n\n## Isatuximab plus pomalidomide and dexamethasone meets the Cancer Drugs Fund criteria\n\nHaving concluded that isatuximab plus pomalidomide and dexamethasone could not be recommended for routine use, the committee then considered if it could be recommended for treating multiple myeloma within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum). It recalled:\n\nThe company expressed an interest in isatuximab plus pomalidomide and dexamethasone being considered for the Cancer Drugs Fund.\n\nData from ICARIA-MM were immature (data cut was October 2018) and median overall survival was not reached in the isatuximab plus pomalidomide and dexamethasone arm.\n\nICARIA-MM is due to finish in March 2022. Further data from this trial could help reduce uncertainties in estimating long-term progression-free and overall survival and the time on treatment. The committee was aware that overall survival and time on treatment estimates were key drivers of the cost-effectiveness results (see sections\xa03.11, 3.12, 3.13 and 3.19).\n\nData collection through the Systemic Anti-Cancer Therapy dataset could be used to collect evidence on clinical outcomes for people with multiple myeloma who have had 3\xa0previous lines of treatment. It may also provide information on the proportion of people having treatment after progression on 4\xa0previous lines of treatment and the treatments used. However, there may not be enough time for these data to be collected before ICARIA‑MM ends.\n\nThe Cancer Drugs Fund clinical lead stated that because daratumumab, an anti‑CD38 monoclonal antibody, is used after 1\xa0previous line of treatment, there are fewer people eligible for isatuximab, another anti‑CD38 monoclonal antibody treatment, after 3\xa0previous lines of treatment. This may further limit the amount of data that would be collected for isatuximab in clinical practice.\n\nThe company's price for isatuximab, including a commercial arrangement, means that it has plausible potential to be cost effective after 3\xa0previous lines of treatment.The committee concluded that isatuximab plus pomalidomide and dexamethasone met the criteria to be considered for inclusion in the Cancer Drugs Fund, when the company's commercial offer as part of the managed access agreement is used. It recommended isatuximab plus pomalidomide and dexamethasone for use through the Cancer Drugs Fund as an option for relapsed and refractory multiple myeloma. It is only recommended if people have had 3\xa0previous lines of treatment (including lenalidomide and a proteasome inhibitor), and their disease has progressed on the last treatment. Also, the conditions in the managed access agreement must be followed. When the guidance is next reviewed, the company should use the committee's preferred assumptions (unless new evidence indicates otherwise), as set out in section\xa03.25.\n\n# Innovation\n\n## The model adequately captures the benefits of isatuximab plus pomalidomide and dexamethasone\n\nThe company considered isatuximab plus pomalidomide and dexamethasone to be innovative. This is because it is the first treatment option for relapsed and refractory multiple myeloma to combine an anti‑CD38 monoclonal antibody and an immunomodulatory agent. The company also highlighted that the treatment shows benefit in a population who have had many previous lines of treatment. The Cancer Drugs Fund clinical lead stated that there are currently no anti‑CD38 antibody treatments recommended for NHS routine commissioning to treat multiple myeloma. He also noted that the company supported a recommendation in the Cancer Drugs Fund. But the Cancer Drugs Fund already offers access to anti-CD38 antibody treatment after 1\xa0previous line of treatment (daratumumab plus bortezomib and dexamethasone) and after 3\xa0previous lines of treatment (daratumumab alone). At the second meeting, the company stated that although all relevant health benefits were captured in the model, there were likely to be other benefits that the model did not account for. These additional benefits included hope for people with multiple myeloma at later lines of treatment and improved quality of life for carers. The ERG noted the possibility that hope was captured by the anxiety and depression domain of the EQ‑5D in the clinical trial and that the company did not investigate the impact on caregiver quality of life. The committee considered that the model captured all health-related quality-of-life benefits. It concluded that it had not been presented with any evidence of additional benefits from treatment with isatuximab plus pomalidomide and dexamethasone.\n\n# Other factors\n\nNo equality or social value judgement issues were identified."}
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https://www.nice.org.uk/guidance/ta658
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Evidence-based recommendations on isatuximab (Sarclisa) with pomalidomide and dexamethasone for treating relapsed and refractory multiple myeloma in adults.
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f7fa9e080643a1e7bc4eaabd7c166bf049caab8a
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nice
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Galcanezumab for preventing migraine
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Galcanezumab for preventing migraine
Evidence-based recommendations on galcanezumab (Emgality) for preventing migraine in adults.
# Recommendations
Galcanezumab is recommended as an option for preventing migraine in adults, only if:
they have 4 or more migraine days a month
at least 3 preventive drug treatments have failed and
the company provides it according to the commercial arrangement.
Stop galcanezumab after 12 weeks of treatment if:
in episodic migraine (less than 15 headache days a month) the frequency does not reduce by at least 50%
in chronic migraine (15 headache days a month or more with at least 8 of those having features of migraine) the frequency does not reduce by at least 30%.
This recommendation is not intended to affect treatment with galcanezumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Treatment options for preventing episodic or chronic migraine include beta-blockers, antidepressants and anticonvulsant drugs. If episodic migraine does not respond to at least 3 oral preventive drug treatments, best supportive care (treatment for the migraine symptoms) is offered. If chronic migraine does not respond to at least 3 oral preventive drug treatments, botulinum toxin type A or best supportive care is offered.
For migraine that has not responded to at least 3 preventive treatments, clinical trial evidence shows that galcanezumab works better than best supportive care in both episodic and chronic migraine. It is plausible that galcanezumab may work better than botulinum toxin type A.
For episodic and chronic migraine, the most likely cost-effectiveness estimates are within what NICE normally considers an acceptable use of NHS resources. So galcanezumab is recommended for episodic and chronic migraine.# Information about galcanezumab
# Marketing authorisation indication
Galcanezumab (Emgality, Eli Lilly) is 'indicated for the prophylaxis of migraine in adults who have at least 4 migraine days per month'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price of galcanezumab is £450.00 per 120‑mg injection (excluding VAT; Monthly Index of Medical Specialities online, accessed October 2020). The company has a commercial arrangement. This makes galcanezumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Eli Lilly, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:
the time horizon in the model is 45 years to represent lifetime treatment (issue 1, see technical report page 9)
the response rate differs between treatments and the change from baseline in migraine headache days differs for 'responders' based on results from the indirect treatment comparison (issue 4, see technical report page 13)
treatment-effect waning periods are equal for galcanezumab and botulinum toxin A (issue 5, see technical report page 16)
treatment-effect waning periods are equal for episodic and chronic migraine populations (issue 5, see technical report page 16)
utility values are based on relevant utility data from all trials (issue 6, see technical report page 17)
age-related disutility is applied in the model (issue 6, see technical report page 17)
an additional cost for administering galcanezumab is applied for 10% of people (issue 7, see technical report page 19)
resource costs are generated from the National Health and Wellness Survey (issue 7, see technical report page 19).It recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, table 2, page 25), and took these into account in its decision making. It discussed the following issues that were outstanding after the technical engagement stage: the high-frequency episodic migraine subgroup (issue 2), the position of galcanezumab in the treatment pathway (issue 3), the indirect treatment comparison for chronic migraine (issue 4), the utility values applied to treatments (issue 6) and additional monitoring costs (issue 7).
# The condition
## Migraine substantially affects health-related quality of life
Migraine is a headache disorder with recurring attacks usually lasting between 4 and 72 hours. The patient expert explained the debilitating effect of migraine on their daily life with symptoms including fatigue, severe head pain, sensitivity to light, difficulty concentrating, nausea, stiff neck or back, feeling down, and sensitivity to sound. These symptoms were noted to adversely affect someone's ability to do their usual activities, including work, and to negatively affect their family. Chronic migraine is defined as 15 or more headache days a month with at least 8 of those having features of migraine. Episodic migraine is defined as less than 15 headache days a month. The clinical and patient experts explained that the severity and frequency can fluctuate over time and that recovery from a migraine can take a few days. The committee concluded that migraine, particularly chronic migraine, is a debilitating condition that substantially affects both physical and psychological aspects of health-related quality of life.
# Treatment pathway and comparators
## There is an unmet need for migraine-specific treatments
The committee understood that current oral treatment options for preventing migraine include drugs that are used to treat other conditions including beta-blockers, antidepressants and anticonvulsant medications. The patient expert explained that these treatments can have significant side effects and any beneficial effects do not last or may not work at all for some people. This leads many people to try different medications to find one that works. The clinical expert stated that there is a risk of medication overuse with some of the current treatments for migraine such as triptans, which needs to be managed. The committee noted that NICE's technology appraisal guidance on botulinum toxin type A for the prevention of headaches recommends botulinum toxin type A for people with chronic migraine that has not responded to at least 3 previous oral preventive drugs. The clinical expert stated that some people who are eligible for botulinum toxin type A are unable to have it because there is no local specialist centre to administer it, or they have to wait a long time for it. The committee acknowledged that there may be an increase in the number of specialist centres, which may increase treatment access. A clinical expert also noted that face-to-face appointments are currently restricted in the NHS because of the COVID‑19 pandemic, so there is a greater demand for virtual appointments. The committee understood that this has reduced the availability of botulinum toxin type A and increased the need for a migraine-specific self-administered treatment that could be managed with virtual appointments. The committee concluded that effective and well-tolerated migraine-specific treatment options are needed.
## At least 3 oral preventive treatments are tried before specialist treatment is considered
The company's submission focused on people with migraine for whom at least 3 previous oral preventive treatments had failed (defined as lack of a clinically meaningful response, intolerance to the treatment or the treatment was contraindicated or unsuitable). The company considered this group to reflect people most in need of treatment options, who would likely be offered galcanezumab in NHS clinical practice. The clinical expert explained that the aim of treatment is to reduce the frequency, severity or duration of migraine and improve quality of life. The committee noted that, in chronic migraine, a 30% reduction in migraine frequency is considered a clinically meaningful response to treatment. In episodic migraine, a 50% reduction is considered a clinically meaningful response. If clinical response is less than this, or the person is not able to have an adequate dosage for long enough or has adverse events, treatment is stopped and another oral preventive treatment is tried. The clinical expert explained that it is important for people to try a range of oral preventive treatments before considering more specialist treatment, such as botulinum toxin type A (for chronic migraine) or galcanezumab. The committee concluded that an insufficient response to an adequate trial of at least 3 oral preventive treatments represents usual NHS practice before more specialist treatment is considered. It also concluded that a clinically meaningful response is a 30% reduction in migraine frequency for chronic migraine and a 50% reduction for episodic migraine.
## The most relevant comparators are best supportive care for episodic migraine, and botulinum toxin type A and best supportive care for chronic migraine
The company presented clinical-effectiveness evidence for galcanezumab, compared with placebo for episodic migraine and compared with placebo and botulinum toxin type A for chronic migraine. It considered that placebo was representative of best supportive care, because people were allowed to use the acute treatments they would usually take when preventive treatments failed. The clinical experts agreed that it is most likely that people would have best supportive care for episodic migraine, and botulinum toxin type A or best supportive care for chronic migraine, after 3 preventive oral treatments had failed. The committee was aware of NICE's recently published technology appraisal guidance recommending fremanezumab for chronic migraine but noted that fremanezumab treatment was not routine clinical practice in the NHS at the time of its decision making, so it is not considered a comparator for galcanezumab. The committee concluded that best supportive care is the most appropriate comparator in episodic migraine, and that botulinum toxin type A and best supportive care are both relevant comparators in chronic migraine.
# Clinical evidence
## High-frequency episodic migraine is not a clinically distinct subgroup
The company defined high-frequency episodic migraine as between 8 and 14 migraine headache days a month. The clinical expert explained that there is no internationally recognised classification of high-frequency episodic migraine and that it is not a clearly defined clinical subgroup. They also noted that the definition of high-frequency episodic migraine is arbitrary, and a person's quality of life is negatively affected irrespective of which type of migraine they have. The nature of the condition means that some people's migraine can be episodic one month and chronic the next, according to the definitions. The committee concluded that high-frequency episodic migraine is not a distinct subgroup and agreed not to consider it further.
## The trials provide the most relevant clinical evidence for this appraisal
The company's systematic literature review identified 4 randomised controlled trials evaluating galcanezumab:
CONQUER for episodic or chronic migraine that had inadequately responded to 2 to 4 previous classes of preventive treatment
REGAIN for chronic migraine
EVOLVE‑1 for episodic migraine
EVOLVE‑2 for episodic migraine.All the trials compared galcanezumab (120 mg monthly dose after a 240 mg initial loading dose) with placebo in adults. The placebo-controlled period was 3 months for CONQUER and REGAIN and 6 months for EVOLVE. The company's submission focused on a subgroup of people from all the trials who had an inadequate response to 3 or more previous preventive medications. The committee concluded that the subgroup of people for whom 3 preventive treatments had failed provided the most relevant data for the population of interest.
## Galcanezumab is clinically effective compared with placebo for episodic and chronic migraine
The company presented clinical-effectiveness results for the subgroup of people for whom 3 or 4 preventive migraine therapies failed to produce clinically meaningful improvement from CONQUER, REGAIN, EVOLVE‑1 and EVOLVE‑2. The results showed:
galcanezumab reduced the number of monthly migraine days more than placebo for episodic and chronic migraine
galcanezumab reduced the number of monthly headache days more than placebo for episodic and chronic migraine
more people having galcanezumab had a reduction of at least 50% in the average monthly number of migraine days compared with placebo for episodic migraine
more people having galcanezumab had a reduction of at least 30% in the average monthly number of migraine days compared with placebo for chronic migraine.The ERG noted that some people in CONQUER had botulinum toxin type A as 1 of the 3 prior failed treatments, which does not reflect standard NHS clinical practice. However, the company provided additional analyses that excluded people who had botulinum toxin type A as 1 of 3 or more prior preventive treatments. The results of this subgroup were similar, although the mean differences were slightly lower than the subgroup that included botulinum toxin type A. The results were considered academic in confidence by the company and cannot be reported here. The committee concluded that galcanezumab is an effective treatment compared with placebo for people with episodic or chronic migraine when 3 or 4 preventive treatments have failed.
## The long-term effectiveness of galcanezumab is unknown
The duration of the blinded placebo-controlled phase was 3 months for CONQUER and REGAIN and 6 months for EVOLVE. The ERG noted the uncertainty about the long-term benefits of galcanezumab for extrapolating beyond these phases to an assumption of lifetime treatment. The committee concluded that the long-term benefits of galcanezumab compared with best supportive care remained uncertain.
## Galcanezumab may be clinically effective for chronic migraine after failure of 3 preventive treatments and botulinum toxin type A
The committee acknowledged that there is a high unmet need in the group of people for whom 3 preventive treatments and botulinum toxin type A have failed, because they have a high disease burden and no further treatment options. The clinical expert stated that galcanezumab has a potential role as a treatment option when botulinum toxin type A has failed. However, considering that access to botulinum toxin type A varies within the NHS and it is more burdensome to administer than galcanezumab, the clinical expert agreed that the preferred position for galcanezumab would be after 3 oral preventive treatments have failed. This is the same position as other drugs in the same class as galcanezumab; that is, anti-calcitonin gene-related peptides (CGRPs). At technical engagement, the company provided the patient numbers from CONQUER for people with chronic migraine who had galcanezumab after 3 oral preventive treatments and botulinum toxin type A. The company explained that the patient numbers are too small to provide meaningful results from any analysis. The company presented a post-hoc analysis for galcanezumab as a fourth-line treatment after botulinum toxin type A has failed. The results showed a significant decrease in migraine frequency for galcanezumab compared with placebo. The company considered these results to be representative of the effect of galcanezumab after 3 oral treatments and botulinum toxin type A have failed. The ERG agreed that the company's model did not consider this potential sequence and that there is no clinical evidence to support the use of galcanezumab as a fifth-line treatment after botulinum toxin type A. The committee acknowledged the results from the trials, which showed the clinical effectiveness of galcanezumab treatment after failure of botulinum toxin type A (see section 3.7). It concluded that while there is uncertainty in the evidence, galcanezumab may be clinically effective as a fifth-line treatment after 3 oral treatments and botulinum toxin type A.
## Treatment with a second anti-CGRP drug is not recommended
The committee was not presented with any evidence to support subsequent treatment with other anti-CGRPs, if the initial clinically meaningful response to treatment with galcanezumab is subsequently lost. The committee was aware although the scope included 2 medicines in this class as potential comparators, neither was established practice in the NHS at the time of the decision-making and therefore did not formally compare galcanezumab with them. However, the committee heard from the clinical expert that there is no clinical evidence to support any difference in efficacy between the different anti-CGRP drugs. The committee noted that treatment preferences are not outlined in the British Association for the Study of Headache's guidelines, and therefore considered it reasonable that the least expensive drug would be used unless an alternative was more suitable for the patient. The committee concluded that treatment with another anti-CGRP drug, after failure of a previous anti-CGRP drug, is not supported by evidence and is not recommended.
## It is appropriate to apply a negative stopping rule
The company's model assumed that people stopped galcanezumab treatment at 3 months if their symptoms had not responded. This 'negative' stopping rule was applied to people having less than a 50% reduction in monthly migraine days for episodic migraine, and less than a 30% reduction in monthly migraine days for chronic migraine. The committee considered the 30% and 50% thresholds. It agreed these are appropriate measures of treatment response and are consistent with NICE's technology appraisal guidance on botulinum toxin type A for preventing chronic migraine and the British Association for the Study of Headache's guidelines. The committee concluded that it was appropriate to include a negative stopping rule at 3 months if there was insufficient response to treatment based on the agreed thresholds.
# Indirect treatment comparison
## It is appropriate to use clinical-effectiveness estimates from the indirect treatment comparison for chronic migraine
There was no direct evidence comparing galcanezumab with botulinum toxin type A for chronic migraine so the company did an indirect comparison, using data from:
trials of galcanezumab (CONQUER and REGAIN)
trials comparing botulinum toxin type A with placebo (PREEMPT‑1 and PREEMPT‑2).The comparison was in the subgroup of people for whom 3 or more preventive treatments had failed. It compared galcanezumab with botulinum toxin type A for the reduction in monthly migraine days, reduction in monthly headache days and 3 domains of the Migraine-Specific Quality of Life Questionnaire. The company acknowledged that there were limitations with the indirect treatment comparison including small sample sizes, differences in placebo response rates, differences in measuring and defining key outcome measures and missing data. To account for some of these limitations, the company did additional analyses that included a population with less than 3 prior failed preventative treatments, termed 'all-comers'. Most of the results of the indirect treatment comparison were not statistically significant for the all-comers population or the population with 3 or more prior treatment failures, but they did numerically favour galcanezumab. The only statistically significant result was the change in migraine headache days for the population with 3 or more prior treatment failures (results are academic in confidence and cannot be reported here). The company and the ERG noted that because of the limitations of the indirect treatment comparison, these results should be interpreted with caution. Despite this, the ERG advised that the indirect treatment comparison was sufficiently robust for use in the economic model. Given the concerns with the indirect treatment comparison and the low number of statistically significant results, the committee noted that there was a high degree of uncertainty about whether galcanezumab is more clinically effective than botulinum toxin type A for chronic migraine. It agreed it was appropriate to consider a scenario in which equivalent efficacy was assumed and another scenario that included the results of the indirect treatment comparison. It noted 2 surveys done by the Migraine Trust, which showed that most patient and clinical experts consider anti-CGRPs to be more effective than botulinum toxin type A. The ERG acknowledged that there is some statistical uncertainty in the indirect treatment comparison for galcanezumab but that this uncertainty had been addressed in the model. The committee noted that there were other sources of uncertainty such as small sample sizes, differences in placebo response rates and differences in outcome measures that were not quantified in the model. It concluded that although there is uncertainty it is plausible that galcanezumab may be more clinically effective than botulinum toxin type A, and that it was appropriate to use the clinical-effectiveness estimates from the indirect treatment comparison for decision making.
# Utilities
## There is evidence for using differential utility values for treatments
The utility values used in the model were generated from mapping the Migraine Specific Questionnaire results to the EQ-5D-3L using the Gillard et al. (2012) algorithm. The committee understood that the company used estimated utility values for the population of patients who had a history of 3 or more failed prior preventatives from the relevant clinical trials (CONQUER, EVOLVE‑1, EVOLVE‑2 and REGAIN). The company presented evidence for a treatment-related difference in utility values. This demonstrated that utility values for galcanezumab were higher across all mean migraine headache day values compared with placebo. Also a regression analysis showed a large, statistically significant benefit of galcanezumab compared with placebo. The ERG considered this evidence to be of high quality and explained that the use of differential utilities applied to galcanezumab and comparators would allow for improvements in migraine severity to be captured beyond the number of migraine headache days. The committee noted that using differential utilities is not consistent with the approach used in NICE's technology appraisal of fremanezumab for preventing migraine. However, the ERG explained that compelling evidence for differential utilities has been presented by the company, which has not been presented in previous appraisals. The company provided the results of a correlation study as further evidence to support the use of differential utilities, and it demonstrated that galcanezumab reduced the levels of impairment and burden between migraine attacks. The ERG considered that the correlation study results provided evidence that galcanezumab improves the burden of migraine beyond that captured by the Migraine Specific Questionnaire. The patient expert described how galcanezumab reduced the impact of migraine attacks and improved recovery between attacks. The ERG noted that any differences in baseline (before treatment) utility values between treatment arms are accounted for in the applied statistical model and there is a statistically significant difference in utility values after treatment. The committee acknowledged that there may be important aspects of the burden of migraine that are missed if only considering the frequency of migraine headache days. It acknowledged the uncertainties in using differential utility values, so it also considered a scenario of equal utility values. However, the committee concluded that there is evidence for the use of differential utility values between treatments.
# Costs
## Some people will not be able to self-administer galcanezumab
The company assumed that galcanezumab could be self-administered by subcutaneous injection. At the technical engagement stage, the clinical experts suggested that most people would be capable of self-administering galcanezumab. However, they noted that some disabled people, people who have a learning disability, are older or who have a phobia of needles may need help. They also noted that additional services may be needed to train people how to self-administer treatment. The committee noted that NICE's guidance on fremanezumab for preventing migraine concluded that it was unlikely that everyone will be able to self-administer treatment. It agreed that applying administration costs for 10% of people having galcanezumab was reasonable but acknowledged that this had little effect on the model results.
## It is appropriate to include additional monitoring costs for galcanezumab
The company submission did not include costs associated with monitoring galcanezumab treatment. The clinical expert explained that people having galcanezumab are likely to need monitoring at regular intervals, and the committee acknowledged that monitoring is important for new treatments. The company and the ERG did not consider it appropriate to include the costs of monitoring without also including the benefits of positive discontinuation associated with it (that is, stopping treatment because it has been successful). However, the committee did not consider it appropriate to include positive discontinuation because there are no clear criteria for when people should stop treatment. It also understood that positive discontinuation could be challenging to implement in clinical practice. The committee concluded that additional monitoring costs for galcanezumab should be included in the model to account for an appointment with a consultant every 6 months.
# Cost-effectiveness estimates
## Because of the uncertainty an acceptable ICER will be towards the lower end of what is normally considered cost effective for episodic migraine
NICE's guide to the methods of technology appraisal notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee is more cautious about recommending a technology if it is less certain about the ICERs presented. The committee considered that the impact on NHS resources of introducing galcanezumab may be higher for episodic migraine than for chronic migraine. This is because episodic migraine is more common than chronic migraine. Because of the uncertainty in the clinical and economic evidence, the committee agreed that an acceptable ICER would be towards the lower end of the range normally considered a cost-effective use of NHS resources (£20,000 to £30,000 per QALY gained) for episodic migraine.
## Galcanezumab is cost effective compared with best supportive care for episodic migraine after 3 oral preventive treatments have failed
The company's revised base-case ICER for galcanezumab compared with best supportive care for episodic migraine was within the range NICE normally considers an acceptable use of NHS resources. The company's revised base case included the committee's preferred assumptions:
including the ERG's corrections to model
applying a lifetime (45 years) model time horizon
using a consistent waning period for episodic and chronic migraine
using data from all the trials to generate utility values
using differential utilities for galcanezumab and the comparator
applying age-related disutility
including an administration cost for 10% of people having galcanezumab
using resource consumption rates from the National Health and Wellness Survey.However, the revised base case did not include the committee's preferred assumption of:
applying additional monitoring costs to galcanezumab treatment for a consultant appointment every 6 months.Taking its preferences into account, the committee agreed that the most plausible ICER for galcanezumab compared with best supportive care for episodic migraine was towards the lower end of the range NICE normally considers an acceptable use of NHS resources. Therefore, it concluded that galcanezumab is a cost-effective use of NHS resources for preventing episodic migraine after 3 oral preventive treatments have failed.
## Galcanezumab is cost effective compared with best supportive care for chronic migraine after 3 oral preventive treatments have failed
The company's revised base-case ICER for galcanezumab compared with best supportive care for chronic migraine was below the range NICE normally considers an acceptable use of NHS resources. The company's revised base case included the committee's preferred assumptions:
including the ERG's corrections in the model
applying a lifetime (45 years) model time horizon
using a consistent waning period for episodic and chronic migraine
using data from all the trials to generate utility values
using differential utilities for galcanezumab and the comparator
applying age-related disutility
including an administration cost for 10% of people having galcanezumab
using resource consumption rates from the National Health and Wellness Survey.However, the revised base case did not include the committee's preferred assumption of:
applying additional monitoring costs to galcanezumab treatment for a consultant appointment every 6 months.Taking its preferences into account, the committee agreed that the most plausible ICER for galcanezumab compared with best supportive care for chronic migraine was below the lower end of the range NICE normally considers an acceptable use of NHS resources. Therefore, it concluded that galcanezumab is a cost-effective use of NHS resources for preventing chronic migraine after 3 oral preventive treatments have failed.
## Galcanezumab is cost effective compared with botulinum toxin type A for chronic migraine after 3 oral preventive treatments have failed
The company's revised base-case ICER for galcanezumab compared with botulinum toxin type A for chronic migraine was below the range NICE normally considers an acceptable use of NHS resources. The company's revised base case included the committee's preferred assumptions:
including the ERG's corrections in the model
applying a lifetime (45 years) model time horizon
using a consistent waning period for episodic and chronic migraine
using a consistent waning period for different treatments
discontinuers wane back from responder migraine headache days (MHDs)
using equivalent discontinuation rates for different treatments
differing the response rate and the change from baseline in MHD based on results from the indirect treatment comparison
using data from all the trials to generate utility values
using differential utilities for galcanezumab and the comparator
applying age-related disutility
including an administration cost for 10% of people having galcanezumab
using resource consumption rates from the National Health and Wellness SurveyHowever, the revised base case did not include the committee's preferred assumption of:
applying additional monitoring costs to galcanezumab treatment for a consultant appointment every 6 months.The committee acknowledged that botulinum toxin type A could be administered by a nurse rather than a neurology consultant and this could reduce costs. However, it noted that the proportion of people having botulinum toxin type A administered by a nurse was unknown. Taking its preferences into account and including the confidential commercial medicine unit price for botulinum toxin type A, the committee agreed that the most plausible ICER for galcanezumab compared with botulinum toxin type A for chronic migraine was below what NICE normally considers an acceptable use of NHS resources. Therefore, it concluded that galcanezumab is a cost-effective use of NHS resources for preventing chronic migraine after 3 oral preventive treatments have failed.
## Galcanezumab is cost effective for chronic migraine after botulinum toxin type A has failed
The committee noted that clinical evidence was not available for galcanezumab as a fifth-line treatment after botulinum toxin type A has failed (see section 3.9), and that no cost-effectiveness evidence had been provided. However, it acknowledged the post-hoc analysis showing the effect of galcanezumab as a fourth-line treatment after botulinum toxin type A had failed. It noted that the company considered these results to be representative of the effect of galcanezumab as a fifth-line treatment. The committee considered the uncertainty in the evidence for galcanezumab when used as a fifth-line treatment after botulinum toxin type A. However, it acknowledged that galcanezumab was clinically effective and cost effective as a fourth-line treatment after botulinum toxin type A and accepted this as a proxy for fifth-line use. It concluded that galcanezumab is cost effective compared with best supportive care for chronic migraine after botulinum toxin type A has failed.
# Other factors
## There are no additional equalities issues
No equalities issues were identified by the company. The clinical and patient submissions highlighted that migraine can be classed as a disability under the Equality Act 2010. Because migraine is most common in people of working age and affects more women than men, women may be further disadvantaged in the workplace. It was also noted that there may be unequal access to specialist headache clinics. The committee considered these issues and concluded that there were no specific adjustments needed to the NICE methods in this instance.
## There are no health-related benefits that are not captured in the analyses
The committee acknowledged that galcanezumab administration may be considered more convenient and less unpleasant than administration of botulinum toxin type A. But it concluded that the modelling had adequately captured the benefits of galcanezumab.
# Conclusion
## Galcanezumab is recommended for episodic migraine
The committee noted that the most relevant comparator for episodic migraine was best supportive care. It considered that the evidence showed that galcanezumab is clinically effective compared with best supportive care. It also considered that high-frequency episodic migraine was not a clinically distinct subgroup and did not consider it further. At technical engagement, the company submitted a revised base case, which included a confidential simple discount patient access scheme for galcanezumab and most of the committee's preferred assumptions. Applying the additional committee assumption that monitoring costs for galcanezumab should be included, the most plausible ICER was likely to be towards the lower end of what NICE normally considers an acceptable use of NHS resources. Therefore, galcanezumab is recommended for preventing episodic migraine in adults after at least 3 oral preventive treatments have failed. Treatment with galcanezumab should be stopped if migraine frequency does not reduce by at least 50% after 12 weeks of treatment.
## Galcanezumab is recommended for chronic migraine
The committee recognised the high degree of burden that chronic migraine has on quality of life and daily functioning. It acknowledged that people with chronic migraine have the most severe form of the condition and that there is an unmet need for effective treatments. The committee noted that the most relevant comparators for chronic migraine were botulinum toxin type A and best supportive care. It considered that galcanezumab is a clinically effective treatment compared with placebo. However, the committee considered that there was uncertainty about whether galcanezumab is more clinically effective than botulinum toxin type A. At technical engagement the company submitted a revised base case, which included a confidential simple discount patient access scheme for galcanezumab and most of the committee's preferred assumptions. Applying the additional committee assumption that monitoring costs for galcanezumab should be included, the most plausible ICER is likely to be below what NICE normally considers an acceptable use of NHS resources compared with best supportive care and botulinum toxin type A. Therefore, galcanezumab is recommended for preventing chronic migraine in adults after at least 3 preventive treatments have failed. This includes the chronic migraine population for whom treatment with botulinum toxin type A has failed. Treatment with galcanezumab should be stopped if migraine frequency does not reduce by at least 30% after 12 weeks of treatment.
|
{'Recommendations': 'Galcanezumab is recommended as an option for preventing migraine in adults, only if:\n\nthey have 4\xa0or more migraine days a month\n\nat least 3\xa0preventive drug treatments have failed and\n\nthe company provides it according to the commercial arrangement.\n\nStop galcanezumab after 12\xa0weeks of treatment if:\n\nin episodic migraine (less than 15\xa0headache days a month) the frequency does not reduce by at least 50%\n\nin chronic migraine (15\xa0headache days a month or more with at least 8\xa0of those having features of migraine) the frequency does not reduce by at least 30%.\n\nThis recommendation is not intended to affect treatment with galcanezumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nTreatment options for preventing episodic or chronic migraine include beta-blockers, antidepressants and anticonvulsant drugs. If episodic migraine does not respond to at least 3\xa0oral preventive drug treatments, best supportive care (treatment for the migraine symptoms) is offered. If chronic migraine does not respond to at least 3\xa0oral preventive drug treatments, botulinum toxin type\xa0A or best supportive care is offered.\n\nFor migraine that has not responded to at least 3\xa0preventive treatments, clinical trial evidence shows that galcanezumab works better than best supportive care in both episodic and chronic migraine. It is plausible that galcanezumab may work better than botulinum toxin type\xa0A.\n\nFor episodic and chronic migraine, the most likely cost-effectiveness estimates are within what NICE normally considers an acceptable use of NHS resources. So galcanezumab is recommended for episodic and chronic migraine.', 'Information about galcanezumab': "# Marketing authorisation indication\n\nGalcanezumab (Emgality, Eli Lilly) is 'indicated for the prophylaxis of migraine in adults who have at least 4\xa0migraine days per month'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price of galcanezumab is £450.00 per 120‑mg injection (excluding VAT; Monthly Index of Medical Specialities online, accessed October 2020). The company has a commercial arrangement. This makes galcanezumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Eli Lilly, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:\n\nthe time horizon in the model is 45\xa0years to represent lifetime treatment (issue\xa01, see technical report page\xa09)\n\nthe response rate differs between treatments and the change from baseline in migraine headache days differs for 'responders' based on results from the indirect treatment comparison (issue\xa04, see technical report page\xa013)\n\ntreatment-effect waning periods are equal for galcanezumab and botulinum toxin A (issue\xa05, see technical report page\xa016)\n\ntreatment-effect waning periods are equal for episodic and chronic migraine populations (issue\xa05, see technical report page\xa016)\n\nutility values are based on relevant utility data from all trials (issue\xa06, see technical report page\xa017)\n\nage-related disutility is applied in the model (issue\xa06, see technical report page\xa017)\n\nan additional cost for administering galcanezumab is applied for 10% of people (issue\xa07, see technical report page\xa019)\n\nresource costs are generated from the National Health and Wellness Survey (issue\xa07, see technical report page\xa019).It recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, table\xa02, page\xa025), and took these into account in its decision making. It discussed the following issues that were outstanding after the technical engagement stage: the high-frequency episodic migraine subgroup (issue\xa02), the position of galcanezumab in the treatment pathway (issue\xa03), the indirect treatment comparison for chronic migraine (issue\xa04), the utility values applied to treatments (issue\xa06) and additional monitoring costs (issue\xa07).\n\n# The condition\n\n## Migraine substantially affects health-related quality of life\n\nMigraine is a headache disorder with recurring attacks usually lasting between 4\xa0and 72\xa0hours. The patient expert explained the debilitating effect of migraine on their daily life with symptoms including fatigue, severe head pain, sensitivity to light, difficulty concentrating, nausea, stiff neck or back, feeling down, and sensitivity to sound. These symptoms were noted to adversely affect someone's ability to do their usual activities, including work, and to negatively affect their family. Chronic migraine is defined as 15 or more headache days a month with at least 8\xa0of those having features of migraine. Episodic migraine is defined as less than 15\xa0headache days a month. The clinical and patient experts explained that the severity and frequency can fluctuate over time and that recovery from a migraine can take a few days. The committee concluded that migraine, particularly chronic migraine, is a debilitating condition that substantially affects both physical and psychological aspects of health-related quality of life.\n\n# Treatment pathway and comparators\n\n## There is an unmet need for migraine-specific treatments\n\nThe committee understood that current oral treatment options for preventing migraine include drugs that are used to treat other conditions including beta-blockers, antidepressants and anticonvulsant medications. The patient expert explained that these treatments can have significant side effects and any beneficial effects do not last or may not work at all for some people. This leads many people to try different medications to find one that works. The clinical expert stated that there is a risk of medication overuse with some of the current treatments for migraine such as triptans, which needs to be managed. The committee noted that NICE's technology appraisal guidance on botulinum toxin type A for the prevention of headaches recommends botulinum toxin type\xa0A for people with chronic migraine that has not responded to at least 3\xa0previous oral preventive drugs. The clinical expert stated that some people who are eligible for botulinum toxin type\xa0A are unable to have it because there is no local specialist centre to administer it, or they have to wait a long time for it. The committee acknowledged that there may be an increase in the number of specialist centres, which may increase treatment access. A clinical expert also noted that face-to-face appointments are currently restricted in the NHS because of the COVID‑19 pandemic, so there is a greater demand for virtual appointments. The committee understood that this has reduced the availability of botulinum toxin type\xa0A and increased the need for a migraine-specific self-administered treatment that could be managed with virtual appointments. The committee concluded that effective and well-tolerated migraine-specific treatment options are needed.\n\n## At least 3 oral preventive treatments are tried before specialist treatment is considered\n\nThe company's submission focused on people with migraine for whom at least 3\xa0previous oral preventive treatments had failed (defined as lack of a clinically meaningful response, intolerance to the treatment or the treatment was contraindicated or unsuitable). The company considered this group to reflect people most in need of treatment options, who would likely be offered galcanezumab in NHS clinical practice. The clinical expert explained that the aim of treatment is to reduce the frequency, severity or duration of migraine and improve quality of life. The committee noted that, in chronic migraine, a 30%\xa0reduction in migraine frequency is considered a clinically meaningful response to treatment. In episodic migraine, a 50%\xa0reduction is considered a clinically meaningful response. If clinical response is less than this, or the person is not able to have an adequate dosage for long enough or has adverse events, treatment is stopped and another oral preventive treatment is tried. The clinical expert explained that it is important for people to try a range of oral preventive treatments before considering more specialist treatment, such as botulinum toxin type\xa0A (for chronic migraine) or galcanezumab. The committee concluded that an insufficient response to an adequate trial of at least 3\xa0oral preventive treatments represents usual NHS practice before more specialist treatment is considered. It also concluded that a clinically meaningful response is a 30%\xa0reduction in migraine frequency for chronic migraine and a 50%\xa0reduction for episodic migraine.\n\n## The most relevant comparators are best supportive care for episodic migraine, and botulinum toxin type A and best supportive care for chronic migraine\n\nThe company presented clinical-effectiveness evidence for galcanezumab, compared with placebo for episodic migraine and compared with placebo and botulinum toxin type\xa0A for chronic migraine. It considered that placebo was representative of best supportive care, because people were allowed to use the acute treatments they would usually take when preventive treatments failed. The clinical experts agreed that it is most likely that people would have best supportive care for episodic migraine, and botulinum toxin type\xa0A or best supportive care for chronic migraine, after 3\xa0preventive oral treatments had failed. The committee was aware of NICE's recently published technology appraisal guidance recommending fremanezumab for chronic migraine but noted that fremanezumab treatment was not routine clinical practice in the NHS at the time of its decision making, so it is not considered a comparator for galcanezumab. The committee concluded that best supportive care is the most appropriate comparator in episodic migraine, and that botulinum toxin type\xa0A and best supportive care are both relevant comparators in chronic migraine.\n\n# Clinical evidence\n\n## High-frequency episodic migraine is not a clinically distinct subgroup\n\nThe company defined high-frequency episodic migraine as between 8\xa0and 14\xa0migraine headache days a month. The clinical expert explained that there is no internationally recognised classification of high-frequency episodic migraine and that it is not a clearly defined clinical subgroup. They also noted that the definition of high-frequency episodic migraine is arbitrary, and a person's quality of life is negatively affected irrespective of which type of migraine they have. The nature of the condition means that some people's migraine can be episodic one month and chronic the next, according to the definitions. The committee concluded that high-frequency episodic migraine is not a distinct subgroup and agreed not to consider it further.\n\n## The trials provide the most relevant clinical evidence for this appraisal\n\nThe company's systematic literature review identified 4\xa0randomised controlled trials evaluating galcanezumab:\n\nCONQUER for episodic or chronic migraine that had inadequately responded to 2\xa0to\xa04\xa0previous classes of preventive treatment\n\nREGAIN for chronic migraine\n\nEVOLVE‑1 for episodic migraine\n\nEVOLVE‑2 for episodic migraine.All the trials compared galcanezumab (120\xa0mg monthly dose after a 240\xa0mg initial loading dose) with placebo in adults. The placebo-controlled period was 3\xa0months for CONQUER and REGAIN and 6\xa0months for EVOLVE. The company's submission focused on a subgroup of people from all the trials who had an inadequate response to 3\xa0or more previous preventive medications. The committee concluded that the subgroup of people for whom 3\xa0preventive treatments had failed provided the most relevant data for the population of interest.\n\n## Galcanezumab is clinically effective compared with placebo for episodic and chronic migraine\n\nThe company presented clinical-effectiveness results for the subgroup of people for whom 3\xa0or\xa04\xa0preventive migraine therapies failed to produce clinically meaningful improvement from CONQUER, REGAIN, EVOLVE‑1 and EVOLVE‑2. The results showed:\n\ngalcanezumab reduced the number of monthly migraine days more than placebo for episodic and chronic migraine\n\ngalcanezumab reduced the number of monthly headache days more than placebo for episodic and chronic migraine\n\nmore people having galcanezumab had a reduction of at least 50% in the average monthly number of migraine days compared with placebo for episodic migraine\n\nmore people having galcanezumab had a reduction of at least 30% in the average monthly number of migraine days compared with placebo for chronic migraine.The ERG noted that some people in CONQUER had botulinum toxin type\xa0A as 1 of the 3\xa0prior failed treatments, which does not reflect standard NHS clinical practice. However, the company provided additional analyses that excluded people who had botulinum toxin type\xa0A as 1 of 3\xa0or more prior preventive treatments. The results of this subgroup were similar, although the mean differences were slightly lower than the subgroup that included botulinum toxin type\xa0A. The results were considered academic in confidence by the company and cannot be reported here. The committee concluded that galcanezumab is an effective treatment compared with placebo for people with episodic or chronic migraine when 3\xa0or\xa04 preventive treatments have failed.\n\n## The long-term effectiveness of galcanezumab is unknown\n\nThe duration of the blinded placebo-controlled phase was 3\xa0months for CONQUER and REGAIN and 6\xa0months for EVOLVE. The ERG noted the uncertainty about the long-term benefits of galcanezumab for extrapolating beyond these phases to an assumption of lifetime treatment. The committee concluded that the long-term benefits of galcanezumab compared with best supportive care remained uncertain.\n\n## Galcanezumab may be clinically effective for chronic migraine after failure of 3\xa0preventive treatments and botulinum toxin type\xa0A\n\nThe committee acknowledged that there is a high unmet need in the group of people for whom 3\xa0preventive treatments and botulinum toxin type\xa0A have failed, because they have a high disease burden and no further treatment options. The clinical expert stated that galcanezumab has a potential role as a treatment option when botulinum toxin type\xa0A has failed. However, considering that access to botulinum toxin type\xa0A varies within the NHS and it is more burdensome to administer than galcanezumab, the clinical expert agreed that the preferred position for galcanezumab would be after 3\xa0oral preventive treatments have failed. This is the same position as other drugs in the same class as galcanezumab; that is, anti-calcitonin gene-related peptides (CGRPs). At technical engagement, the company provided the patient numbers from CONQUER for people with chronic migraine who had galcanezumab after 3\xa0oral preventive treatments and botulinum toxin type\xa0A. The company explained that the patient numbers are too small to provide meaningful results from any analysis. The company presented a post-hoc analysis for galcanezumab as a fourth-line treatment after botulinum toxin type\xa0A has failed. The results showed a significant decrease in migraine frequency for galcanezumab compared with placebo. The company considered these results to be representative of the effect of galcanezumab after 3\xa0oral treatments and botulinum toxin type\xa0A have failed. The ERG agreed that the company's model did not consider this potential sequence and that there is no clinical evidence to support the use of galcanezumab as a fifth-line treatment after botulinum toxin type\xa0A. The committee acknowledged the results from the trials, which showed the clinical effectiveness of galcanezumab treatment after failure of botulinum toxin type\xa0A (see section\xa03.7). It concluded that while there is uncertainty in the evidence, galcanezumab may be clinically effective as a fifth-line treatment after 3\xa0oral treatments and botulinum toxin type\xa0A.\n\n## Treatment with a second anti-CGRP drug is not recommended\n\nThe committee was not presented with any evidence to support subsequent treatment with other anti-CGRPs, if the initial clinically meaningful response to treatment with galcanezumab is subsequently lost. The committee was aware although the scope included 2\xa0medicines in this class as potential comparators, neither was established practice in the NHS at the time of the decision-making and therefore did not formally compare galcanezumab with them. However, the committee heard from the clinical expert that there is no clinical evidence to support any difference in efficacy between the different anti-CGRP drugs. The committee noted that treatment preferences are not outlined in the British Association for the Study of Headache's guidelines, and therefore considered it reasonable that the least expensive drug would be used unless an alternative was more suitable for the patient. The committee concluded that treatment with another anti-CGRP drug, after failure of a previous anti-CGRP drug, is not supported by evidence and is not recommended.\n\n## It is appropriate to apply a negative stopping rule\n\nThe company's model assumed that people stopped galcanezumab treatment at 3\xa0months if their symptoms had not responded. This 'negative' stopping rule was applied to people having less than a 50%\xa0reduction in monthly migraine days for episodic migraine, and less than a 30%\xa0reduction in monthly migraine days for chronic migraine. The committee considered the 30% and 50%\xa0thresholds. It agreed these are appropriate measures of treatment response and are consistent with NICE's technology appraisal guidance on botulinum toxin type\xa0A for preventing chronic migraine and the British Association for the Study of Headache's guidelines. The committee concluded that it was appropriate to include a negative stopping rule at 3\xa0months if there was insufficient response to treatment based on the agreed thresholds.\n\n# Indirect treatment comparison\n\n## It is appropriate to use clinical-effectiveness estimates from the indirect treatment comparison for chronic migraine\n\nThere was no direct evidence comparing galcanezumab with botulinum toxin type\xa0A for chronic migraine so the company did an indirect comparison, using data from:\n\ntrials of galcanezumab (CONQUER and REGAIN)\n\ntrials comparing botulinum toxin type\xa0A with placebo (PREEMPT‑1 and PREEMPT‑2).The comparison was in the subgroup of people for whom 3 or more preventive treatments had failed. It compared galcanezumab with botulinum toxin type\xa0A for the reduction in monthly migraine days, reduction in monthly headache days and 3\xa0domains of the Migraine-Specific Quality of Life Questionnaire. The company acknowledged that there were limitations with the indirect treatment comparison including small sample sizes, differences in placebo response rates, differences in measuring and defining key outcome measures and missing data. To account for some of these limitations, the company did additional analyses that included a population with less than 3\xa0prior failed preventative treatments, termed 'all-comers'. Most of the results of the indirect treatment comparison were not statistically significant for the all-comers population or the population with 3\xa0or more prior treatment failures, but they did numerically favour galcanezumab. The only statistically significant result was the change in migraine headache days for the population with 3\xa0or more prior treatment failures (results are academic in confidence and cannot be reported here). The company and the ERG noted that because of the limitations of the indirect treatment comparison, these results should be interpreted with caution. Despite this, the ERG advised that the indirect treatment comparison was sufficiently robust for use in the economic model. Given the concerns with the indirect treatment comparison and the low number of statistically significant results, the committee noted that there was a high degree of uncertainty about whether galcanezumab is more clinically effective than botulinum toxin type\xa0A for chronic migraine. It agreed it was appropriate to consider a scenario in which equivalent efficacy was assumed and another scenario that included the results of the indirect treatment comparison. It noted 2\xa0surveys done by the Migraine Trust, which showed that most patient and clinical experts consider anti-CGRPs to be more effective than botulinum toxin type\xa0A. The ERG acknowledged that there is some statistical uncertainty in the indirect treatment comparison for galcanezumab but that this uncertainty had been addressed in the model. The committee noted that there were other sources of uncertainty such as small sample sizes, differences in placebo response rates and differences in outcome measures that were not quantified in the model. It concluded that although there is uncertainty it is plausible that galcanezumab may be more clinically effective than botulinum toxin type\xa0A, and that it was appropriate to use the clinical-effectiveness estimates from the indirect treatment comparison for decision making.\n\n# Utilities\n\n## There is evidence for using differential utility values for treatments\n\nThe utility values used in the model were generated from mapping the Migraine Specific Questionnaire results to the EQ-5D-3L using the Gillard et al. (2012) algorithm. The committee understood that the company used estimated utility values for the population of patients who had a history of 3 or more failed prior preventatives from the relevant clinical trials (CONQUER, EVOLVE‑1, EVOLVE‑2 and REGAIN). The company presented evidence for a treatment-related difference in utility values. This demonstrated that utility values for galcanezumab were higher across all mean migraine headache day values compared with placebo. Also a regression analysis showed a large, statistically significant benefit of galcanezumab compared with placebo. The ERG considered this evidence to be of high quality and explained that the use of differential utilities applied to galcanezumab and comparators would allow for improvements in migraine severity to be captured beyond the number of migraine headache days. The committee noted that using differential utilities is not consistent with the approach used in NICE's technology appraisal of fremanezumab for preventing migraine. However, the ERG explained that compelling evidence for differential utilities has been presented by the company, which has not been presented in previous appraisals. The company provided the results of a correlation study as further evidence to support the use of differential utilities, and it demonstrated that galcanezumab reduced the levels of impairment and burden between migraine attacks. The ERG considered that the correlation study results provided evidence that galcanezumab improves the burden of migraine beyond that captured by the Migraine Specific Questionnaire. The patient expert described how galcanezumab reduced the impact of migraine attacks and improved recovery between attacks. The ERG noted that any differences in baseline (before treatment) utility values between treatment arms are accounted for in the applied statistical model and there is a statistically significant difference in utility values after treatment. The committee acknowledged that there may be important aspects of the burden of migraine that are missed if only considering the frequency of migraine headache days. It acknowledged the uncertainties in using differential utility values, so it also considered a scenario of equal utility values. However, the committee concluded that there is evidence for the use of differential utility values between treatments.\n\n# Costs\n\n## Some people will not be able to self-administer galcanezumab\n\nThe company assumed that galcanezumab could be self-administered by subcutaneous injection. At the technical engagement stage, the clinical experts suggested that most people would be capable of self-administering galcanezumab. However, they noted that some disabled people, people who have a learning disability, are older or who have a phobia of needles may need help. They also noted that additional services may be needed to train people how to self-administer treatment. The committee noted that NICE's guidance on fremanezumab for preventing migraine concluded that it was unlikely that everyone will be able to self-administer treatment. It agreed that applying administration costs for 10% of people having galcanezumab was reasonable but acknowledged that this had little effect on the model results.\n\n## It is appropriate to include additional monitoring costs for galcanezumab\n\nThe company submission did not include costs associated with monitoring galcanezumab treatment. The clinical expert explained that people having galcanezumab are likely to need monitoring at regular intervals, and the committee acknowledged that monitoring is important for new treatments. The company and the ERG did not consider it appropriate to include the costs of monitoring without also including the benefits of positive discontinuation associated with it (that is, stopping treatment because it has been successful). However, the committee did not consider it appropriate to include positive discontinuation because there are no clear criteria for when people should stop treatment. It also understood that positive discontinuation could be challenging to implement in clinical practice. The committee concluded that additional monitoring costs for galcanezumab should be included in the model to account for an appointment with a consultant every 6\xa0months.\n\n# Cost-effectiveness estimates\n\n## Because of the uncertainty an acceptable ICER will be towards the lower end of what is normally considered cost effective for episodic migraine\n\nNICE's guide to the methods of technology appraisal notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee is more cautious about recommending a technology if it is less certain about the ICERs presented. The committee considered that the impact on NHS resources of introducing galcanezumab may be higher for episodic migraine than for chronic migraine. This is because episodic migraine is more common than chronic migraine. Because of the uncertainty in the clinical and economic evidence, the committee agreed that an acceptable ICER would be towards the lower end of the range normally considered a cost-effective use of NHS resources (£20,000 to £30,000 per QALY gained) for episodic migraine.\n\n## Galcanezumab is cost effective compared with best supportive care for episodic migraine after 3 oral preventive treatments have failed\n\nThe company's revised base-case ICER for galcanezumab compared with best supportive care for episodic migraine was within the range NICE normally considers an acceptable use of NHS resources. The company's revised base case included the committee's preferred assumptions:\n\nincluding the ERG's corrections to model\n\napplying a lifetime (45\xa0years) model time horizon\n\nusing a consistent waning period for episodic and chronic migraine\n\nusing data from all the trials to generate utility values\n\nusing differential utilities for galcanezumab and the comparator\n\napplying age-related disutility\n\nincluding an administration cost for 10% of people having galcanezumab\n\nusing resource consumption rates from the National Health and Wellness Survey.However, the revised base case did not include the committee's preferred assumption of:\n\napplying additional monitoring costs to galcanezumab treatment for a consultant appointment every 6\xa0months.Taking its preferences into account, the committee agreed that the most plausible ICER for galcanezumab compared with best supportive care for episodic migraine was towards the lower end of the range NICE normally considers an acceptable use of NHS resources. Therefore, it concluded that galcanezumab is a cost-effective use of NHS resources for preventing episodic migraine after 3\xa0oral preventive treatments have failed.\n\n## Galcanezumab is cost effective compared with best supportive care for chronic migraine after 3 oral preventive treatments have failed\n\nThe company's revised base-case ICER for galcanezumab compared with best supportive care for chronic migraine was below the range NICE normally considers an acceptable use of NHS resources. The company's revised base case included the committee's preferred assumptions:\n\nincluding the ERG's corrections in the model\n\napplying a lifetime (45\xa0years) model time horizon\n\nusing a consistent waning period for episodic and chronic migraine\n\nusing data from all the trials to generate utility values\n\nusing differential utilities for galcanezumab and the comparator\n\napplying age-related disutility\n\nincluding an administration cost for 10% of people having galcanezumab\n\nusing resource consumption rates from the National Health and Wellness Survey.However, the revised base case did not include the committee's preferred assumption of:\n\napplying additional monitoring costs to galcanezumab treatment for a consultant appointment every 6\xa0months.Taking its preferences into account, the committee agreed that the most plausible ICER for galcanezumab compared with best supportive care for chronic migraine was below the lower end of the range NICE normally considers an acceptable use of NHS resources. Therefore, it concluded that galcanezumab is a cost-effective use of NHS resources for preventing chronic migraine after 3\xa0oral preventive treatments have failed.\n\n## Galcanezumab is cost effective compared with botulinum toxin type A for chronic migraine after 3 oral preventive treatments have failed\n\nThe company's revised base-case ICER for galcanezumab compared with botulinum toxin type\xa0A for chronic migraine was below the range NICE normally considers an acceptable use of NHS resources. The company's revised base case included the committee's preferred assumptions:\n\nincluding the ERG's corrections in the model\n\napplying a lifetime (45\xa0years) model time horizon\n\nusing a consistent waning period for episodic and chronic migraine\n\nusing a consistent waning period for different treatments\n\ndiscontinuers wane back from responder migraine headache days (MHDs)\n\nusing equivalent discontinuation rates for different treatments\n\ndiffering the response rate and the change from baseline in MHD based on results from the indirect treatment comparison\n\nusing data from all the trials to generate utility values\n\nusing differential utilities for galcanezumab and the comparator\n\napplying age-related disutility\n\nincluding an administration cost for 10% of people having galcanezumab\n\nusing resource consumption rates from the National Health and Wellness SurveyHowever, the revised base case did not include the committee's preferred assumption of:\n\napplying additional monitoring costs to galcanezumab treatment for a consultant appointment every 6\xa0months.The committee acknowledged that botulinum toxin type\xa0A could be administered by a nurse rather than a neurology consultant and this could reduce costs. However, it noted that the proportion of people having botulinum toxin type\xa0A administered by a nurse was unknown. Taking its preferences into account and including the confidential commercial medicine unit price for botulinum toxin type\xa0A, the committee agreed that the most plausible ICER for galcanezumab compared with botulinum toxin type\xa0A for chronic migraine was below what NICE normally considers an acceptable use of NHS resources. Therefore, it concluded that galcanezumab is a cost-effective use of NHS resources for preventing chronic migraine after 3\xa0oral preventive treatments have failed.\n\n## Galcanezumab is cost effective for chronic migraine after botulinum toxin type A has failed\n\nThe committee noted that clinical evidence was not available for galcanezumab as a fifth-line treatment after botulinum toxin type\xa0A has failed (see section\xa03.9), and that no cost-effectiveness evidence had been provided. However, it acknowledged the post-hoc analysis showing the effect of galcanezumab as a fourth-line treatment after botulinum toxin type\xa0A had failed. It noted that the company considered these results to be representative of the effect of galcanezumab as a fifth-line treatment. The committee considered the uncertainty in the evidence for galcanezumab when used as a fifth-line treatment after botulinum toxin type\xa0A. However, it acknowledged that galcanezumab was clinically effective and cost effective as a fourth-line treatment after botulinum toxin type\xa0A and accepted this as a proxy for fifth-line use. It concluded that galcanezumab is cost effective compared with best supportive care for chronic migraine after botulinum toxin type\xa0A has failed.\n\n# Other factors\n\n## There are no additional equalities issues\n\nNo equalities issues were identified by the company. The clinical and patient submissions highlighted that migraine can be classed as a disability under the Equality Act\xa02010. Because migraine is most common in people of working age and affects more women than men, women may be further disadvantaged in the workplace. It was also noted that there may be unequal access to specialist headache clinics. The committee considered these issues and concluded that there were no specific adjustments needed to the NICE methods in this instance.\n\n## There are no health-related benefits that are not captured in the analyses\n\nThe committee acknowledged that galcanezumab administration may be considered more convenient and less unpleasant than administration of botulinum toxin type\xa0A. But it concluded that the modelling had adequately captured the benefits of galcanezumab.\n\n# Conclusion\n\n## Galcanezumab is recommended for episodic migraine\n\nThe committee noted that the most relevant comparator for episodic migraine was best supportive care. It considered that the evidence showed that galcanezumab is clinically effective compared with best supportive care. It also considered that high-frequency episodic migraine was not a clinically distinct subgroup and did not consider it further. At technical engagement, the company submitted a revised base case, which included a confidential simple discount patient access scheme for galcanezumab and most of the committee's preferred assumptions. Applying the additional committee assumption that monitoring costs for galcanezumab should be included, the most plausible ICER was likely to be towards the lower end of what NICE normally considers an acceptable use of NHS resources. Therefore, galcanezumab is recommended for preventing episodic migraine in adults after at least 3\xa0oral preventive treatments have failed. Treatment with galcanezumab should be stopped if migraine frequency does not reduce by at least 50% after 12\xa0weeks of treatment.\n\n## Galcanezumab is recommended for chronic migraine\n\nThe committee recognised the high degree of burden that chronic migraine has on quality of life and daily functioning. It acknowledged that people with chronic migraine have the most severe form of the condition and that there is an unmet need for effective treatments. The committee noted that the most relevant comparators for chronic migraine were botulinum toxin type\xa0A and best supportive care. It considered that galcanezumab is a clinically effective treatment compared with placebo. However, the committee considered that there was uncertainty about whether galcanezumab is more clinically effective than botulinum toxin type\xa0A. At technical engagement the company submitted a revised base case, which included a confidential simple discount patient access scheme for galcanezumab and most of the committee's preferred assumptions. Applying the additional committee assumption that monitoring costs for galcanezumab should be included, the most plausible ICER is likely to be below what NICE normally considers an acceptable use of NHS resources compared with best supportive care and botulinum toxin type\xa0A. Therefore, galcanezumab is recommended for preventing chronic migraine in adults after at least 3\xa0preventive treatments have failed. This includes the chronic migraine population for whom treatment with botulinum toxin type\xa0A has failed. Treatment with galcanezumab should be stopped if migraine frequency does not reduce by at least 30% after 12\xa0weeks of treatment."}
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https://www.nice.org.uk/guidance/ta659
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Evidence-based recommendations on galcanezumab (Emgality) for preventing migraine in adults.
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14787ca44a2babebac09c7b2cad0e344e48d5bc7
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nice
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Human and animal bites: antimicrobial prescribing
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Human and animal bites: antimicrobial prescribing
This guideline sets out an antimicrobial prescribing strategy for human and animal bites (excluding insect bites) in adults, young people and children aged 72 hours and over. It aims to optimise antibiotic use and reduce antibiotic resistance.
# Recommendations
# Managing human and animal bites
## Assessment
For people with a human or animal bite:
assess the type and severity of the bite, including what animal caused the bite, the site and depth of the wound, and whether it is infected (see the recommendation on taking a swab in the section on treating infected bites)
assess the risk of tetanus, rabies or a bloodborne viral infection and take appropriate action
manage the wound with irrigation and debridement as necessary
be aware of potential safeguarding issues in vulnerable adults and children, for example, as outlined in NICE's guidelines on child maltreatment, challenging behaviour and learning disabilities and domestic violence and abuse.Also see the recommendations on referral and seeking specialist advice.
Seek specialist advice from a microbiologist for bites from a wild or exotic animal (including birds and non-traditional pets) because the spectrum of bacteria involved may be different, and there may be a risk of other serious non-bacterial infections.
Consider seeking specialist advice from a microbiologist for domestic animal bites (including farm animal bites), that you are unfamiliar with.
For a short explanation of why the committee made these recommendations, see the rationale section on assessment .
For more details, see the evidence review.
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## Antibiotic prophylaxis for uninfected bites
Do not offer antibiotic prophylaxis to people with a human bite that has not broken the skin.
Offer antibiotic prophylaxis (see the recommendations on choice of antibiotic) to people with a human bite that has broken the skin and drawn blood.
Consider antibiotic prophylaxis for people with a human bite that has broken the skin but not drawn blood if it:
involves a high-risk area such as the hands, feet, face, genitals, skin overlying cartilaginous structures or an area of poor circulation or
is in a person at risk of a serious wound infection because of a comorbidity (such as diabetes, immunosuppression, asplenia or decompensated liver disease).
Do not offer antibiotic prophylaxis to people with a cat bite that has not broken the skin.
Offer antibiotic prophylaxis (see the recommendations on choice of antibiotic) to people with a cat bite that has broken the skin and drawn blood.
Consider antibiotic prophylaxis for people with a cat bite that has broken the skin but not drawn blood if the wound could be deep.
Do not offer antibiotic prophylaxis to people with a bite from a dog or other traditional pet (excluding cat bites) that:
has not broken the skin or
has broken the skin but not drawn blood.
Offer antibiotic prophylaxis (see the recommendations on choice of antibiotic) to people with a bite from a dog or other traditional pet (excluding cat bites) that has broken the skin and drawn blood if it:
has penetrated bone, joint, tendon or vascular structures or
is deep, is a puncture or crush wound, or has caused significant tissue damage or
is visibly contaminated (for example, if there is dirt or a tooth in the wound).
Consider antibiotic prophylaxis (see the recommendations on choice of antibiotic) for people with a bite from a dog or other traditional pet (excluding cat bites) that has broken the skin and drawn blood if it:
involves a high-risk area such as the hands, feet, face, genitals, skin overlying cartilaginous structures or an area of poor circulation or
is in a person at risk of a serious wound infection because of a comorbidity (such as diabetes, immunosuppression, asplenia or decompensated liver disease).
For a short explanation of why the committee made these recommendations, see the rationale section on antibiotic prophylaxis for uninfected human and animal bites .
For more details, see the evidence review.
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## Treating infected bites
Take a swab for microbiological testing to guide treatment if there is discharge (purulent or non-purulent) from the human or animal bite wound.
Offer an antibiotic (see the recommendations on choice of antibiotic) for people with a human or animal bite if there are symptoms or signs of infection, such as increased pain, inflammation, fever, discharge or an unpleasant smell.
For a short explanation of why the committee made these recommendations, see the rationale section on treating infected human and animal bites .
For more details, see the evidence review.
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## Advice
Give advice to people with a human or animal bite about:
possible adverse effects of antibiotics (if they have been offered antibiotics)
seeking medical help if symptoms or signs of infection develop or worsen rapidly or significantly at any time, or do not start to improve within 24 to 48 hours of starting treatment.
## Reassessment
Reassess the human or animal bite if:
symptoms or signs of infection develop or worsen rapidly or significantly at any time, or do not start to improve within 24 to 48 hours of starting treatment or
the person becomes systemically unwell or
the person has severe pain that is out of proportion to the infection.
Be aware that people who have difficulty communicating may have non-verbal signs of pain, such as a change in behaviour.
If a skin swab has been sent for microbiological testing, review the choice of antibiotic based on the swab results. If a change of antibiotic is needed, use a narrow-spectrum antibiotic if possible.
For a short explanation of why the committee made these recommendations, see the rationale section on reassessment .
For more details, see the evidence review.
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## Referral and seeking specialist advice
Refer people with a human or animal bite to hospital if they have:
symptoms or signs suggesting a more serious illness or condition (these include severe cellulitis, abscess, osteomyelitis, septic arthritis, necrotising fasciitis or sepsis) or
a penetrating wound involving arteries, joints, nerves, muscles, tendons, bones or the central nervous system.
Consider referral or seeking specialist advice for people with a human or animal bite if:
they are systemically unwell or
they have developed symptoms or signs of infection after taking prophylactic antibiotics or
they have lymphangitis or
they are at risk of a serious wound infection because of a pre-existing medical condition or
they cannot take oral antibiotics (in which case, explore with the specialist whether locally available options for parenteral antibiotics at home or in the community, rather than in hospital, are appropriate) or
the bite is infected and is not responding to oral antibiotics or
the bite is in an area of poor circulation.
For a short explanation of why the committee made these recommendations, see the rationale section on referral and seeing specialist advice .
For more details, see the evidence review.
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# Choice of antibiotic
When prescribing an antibiotic for a bite from a human, cat, dog or other traditional pet:
follow table 1 for adults aged 18 years and over
follow table 2 for children and young people under 18 years.
Give oral antibiotics if the person can take oral medicines, and the severity of their condition does not need intravenous antibiotics.
If intravenous antibiotics are given, review within 48 hours and consider switching to oral antibiotics if possible.
Prophylaxis and treatment
Antibiotic, dosage and course length for prophylaxis (3 days) and treatment (5 days)
First-choice oral antibiotic
Co‑amoxiclav:
/125 mg or 500/125 mg three times a day
Alternative first-choice oral antibiotics for penicillin allergy or if co‑amoxiclav is unsuitable
Doxycycline:
mg on first day, then 100 mg or 200 mg daily
with
Metronidazole:
mg three times a day
Alternative first-choice oral antibiotics in pregnancy for penicillin allergy or if co‑amoxiclav is unsuitable
Seek specialist advice
First-choice intravenous antibiotic (if unable to take oral antibiotics or severely unwell)
Co‑amoxiclav:
g three times a day
Alternative first-choice intravenous antibiotics for penicillin allergy or if co‑amoxiclav is unsuitable
Cefuroxime (caution in penicillin allergy):
mg three times a day (increased to 750 mg four times a day or 1.5 g three or four times a day if infection is severe)
with
Metronidazole:
mg three times a day
Ceftriaxone (caution in penicillin allergy)
g once a day
with
Metronidazole:
mg three times a day
If cephalosporin is not appropriate
Seek specialist advice
See the BNF and summary of product characteristics for appropriate use and dosing in specific populations, for example, for people with hepatic or renal impairment, in pregnancy and breastfeeding, and when administering intravenous (or, if appropriate, intramuscular) antibiotics.
A 5‑day course is appropriate for treating most human or animal bites, but course length can be increased to 7 days (with review) based on clinical assessment of the wound, for example, if there is significant tissue destruction or it has penetrated bone, joint, tendon or vascular structures.
Prophylaxis and treatment
Antibiotic, dosage and course length for prophylaxis (3 days) and treatment (5 days)
Choice for children under 1 month
Seek specialist advice
First-choice oral antibiotic for children aged 1 month and over
Co‑amoxiclav:
month to 11 months: 0.25 ml/kg of 125/31 suspension three times a day
year to 5 years: 0.25 ml/kg or 5 ml of 125/31 suspension three times a day
years to 11 years: 0.15 ml/kg or 5 ml of 250/62 suspension three times a day
years to 17 years: 250/125 mg or 500/125 mg three times a day
Co‑amoxiclav 400/57 suspension may also be considered to allow for twice-daily dosing
Alternative first-choice oral antibiotic for children under 12 years for penicillin allergy or if co‑amoxiclav is unsuitable
Co‑trimoxazole (off-label use):
weeks to 5 months: 120 mg or 24 mg/kg twice a day
months to 5 years: 240 mg or 24 mg/kg twice a day
years to 11 years: 480 mg or 24 mg/kg twice a day
See the BNF for Children for information on monitoring
Alternative first-choice oral antibiotics for young people aged 12 to 17 years for penicillin allergy or if co‑amoxiclav is unsuitable
Doxycycline:
mg on first day, then 100 mg or 200 mg daily
with
Metronidazole:
mg three times a day
Alternative first-choice oral antibiotics in pregnancy for penicillin allergy or if co‑amoxiclav unsuitable
Seek specialist advice
First-choice intravenous antibiotic (if unable to take oral antibiotics or severely ill)
Co‑amoxiclav:
month to 2 months: 30 mg/kg twice a day
months to 17 years: 30 mg/kg three times a day (maximum per dose 1.2g)
Alternative first-choice intravenous antibiotics for penicillin allergy or if co‑amoxiclav is unsuitable
Cefuroxime (caution in penicillin allergy):
month to 17 years: 20 mg/kg three times a day (maximum 750 mg per dose), which can be increased to 50 mg/kg to 60 mg/kg three or four times a day (maximum per dose 1.5 g)
with
Metronidazole:
month: loading dose 15 mg/kg, then (after 8 hours) 7.5 mg/kg three times a day
months to 17 years: 7.5 mg/kg three times a day (maximum per dose 500 mg)
Ceftriaxone (caution in penicillin allergy):
month to 11 years (up to 50 kg): 50 mg/kg to 80 mg/kg once a day (maximum 4 g per day)
years to 11 years (50 kg and above) and 12 years to 17 years: 1 g to 2 g once a day
with
Metronidazole:
month: loading dose 15 mg/kg, then (after 8 hours) 7.5 mg/kg three times a day
months to 17 years: 7.5 mg/kg three times a day (maximum per dose 500 mg)
If a cephalosporin is not appropriate
Seek specialist advice
See the BNF for Children and summary of product characteristics for appropriate use and dosing in specific populations, for example, for people with hepatic or renal impairment, in pregnancy and breastfeeding, and when administering intravenous (or, if appropriate, intramuscular) antibiotics.
A 5‑day course is appropriate for treating most human or animal bites, but course length can be increased to 7 days (with review) based on clinical assessment of the wound, for example, if there is significant tissue destruction or it has penetrated bone, joint, tendon or vascular structures.
For off-label use, the prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council's good practice in prescribing and managing medicines and devices for further information.
For a short explanation of why the committee made these recommendations, see the rationale section on choice of antibiotic .
For more details, see the summary of the evidence.
Loading. Please wait.# Rationales
The recommendations in this guideline are based on the evidence identified and the experience of the committee.
# Assessment
## Why the committee made the recommendations
Recommendations 1.1.1 to 1.1.3
The committee agreed that it was good practice to assess and manage the wound in line with NICE's clinical knowledge summary on human and animal bites. They also agreed that, for human and animal bites, healthcare professionals should also consider potential safeguarding issues for vulnerable adults and children in line with NICE guidelines.
There was only evidence on managing bites from humans, dogs and cats; no evidence was identified for bites from other animal species. The committee agreed that it was reasonable to extrapolate this evidence to bites from other animals traditionally kept as pets, such as rabbits and hamsters. The committee agreed that specialist advice should be sought for bites from wild and exotic animals (including birds and non-traditional pets), such as snakes, lizards, monkeys or bats. This was because there may be a different spectrum of bacteria involved and a risk of other serious non-bacterial infections. For example, monkey bites are associated with herpes B virus, which may have serious consequences if not treated early, including fatal encephalomyelitis or severe neurological impairment. Healthcare professionals may also wish to seek specialist advice for domestic animal bites (including farm animal bites) they are not familiar with.
Return to the recommendations
# Antibiotic prophylaxis for uninfected human and animal bites
## Why the committee made the recommendations
Recommendations 1.1.4 to 1.1.12
Evidence was only identified for antibiotic prophylaxis after a dog, cat or human bite, and it was limited and of low quality. The committee agreed that, if a bite has not broken the skin, antibiotic prophylaxis is not needed. Many bites are superficial abrasions, meaning that they break the skin but do not draw blood. These bites are at low risk of infection because the dermis will not have been penetrated, so do not always need antibiotic prophylaxis.
The committee went on to discuss and agree when antibiotic prophylaxis should either be offered, considered, or not offered for a human, cat or dog (or other traditional pet) bite, based on the evidence and their knowledge of the risk of infection.
The committee discussed the pooled evidence on human bites, which suggested that antibiotic prophylaxis was more effective than placebo at reducing the incidence of infection. They discussed that a human bite that has broken the skin is at high risk of infection and other serious consequences because of the associated oral bacteria. However, they also discussed that the site and depth of a bite affects the risk of infection. In a study of human bites to the hand, antibiotic prophylaxis was particularly effective. The committee discussed that wounds to the hand have a higher risk of infection because of the multiple small compartments and number of joints. The same high level of infection risk applies to the feet and skin overlying cartilaginous structures.
The committee went on to discuss the evidence for human bites that are at lower risk of infection, as outlined in Broder et al. (2004). These bites penetrated only the epidermis (that is, they broke the skin but did not draw blood) and did not involve the high-risk areas of the hands, feet, or skin overlying joints or cartilaginous structures. For this study, there was a very low rate of infection; signs of infection were seen in 1 of 62 people in the placebo group and none of the 63 people taking antibiotics.
The committee agreed that, if a human bite has not broken the skin, antibiotic prophylaxis should not be offered. If it has broken the skin and drawn blood, antibiotic prophylaxis should be offered. The committee agreed that, for people with a human bite that has broken the skin but not drawn blood, antibiotic prophylaxis is not routinely needed. However, they agreed that it can be considered for bites in high-risk areas or in people at risk of a serious wound infection because of a comorbidity.
The committee went on to discuss when antibiotic prophylaxis should be offered for a cat bite. The evidence on cat bites, which was based on a very small sample size of 11 did not show a statistically significant difference between antibiotic prophylaxis and placebo in reducing the incidence of infection in cat bites. Based on such limited data, the committee could not judge the certainty of the evidence. However, based on their expertise and experience, they agreed that antibiotic prophylaxis should be offered if a cat bite has broken the skin and drawn blood. Cat bites are at high risk of infection because of cat oral bacteria and because the needle-like nature of the wounds (small, deep punctures) is hard to irrigate. The committee went on to discuss that this type of wound is often deeper than it appears, which can cause assessment difficulties. They also noted that infection in deep skin structures is possible, which has serious consequences such as bone infections. The committee agreed that antibiotic prophylaxis is not needed if a cat bite has not broken the skin. However, it can be considered if the cat bite has broken the skin but not drawn blood if, despite appearances and the lack of blood, the wound could still be deep.
The committee went on to discuss and agree situations when antibiotic prophylaxis should be offered for a dog bite (or a bite from another traditional pet other than a cat). Evidence suggested no difference between antibiotic prophylaxis and placebo in reducing the incidence of infection based on the type and location of the dog bite wound. However, based on their experience, the committee agreed that antibiotic prophylaxis should be offered for a dog bite (or a bite from another traditional pet) if it:
has broken the skin and penetrated bone, joint, tendon or vascular structures or
is deep, a puncture or crush wound, or has caused significant tissue damage or
is visibly contaminated (for example, if there is dirt or a tooth in the wound).
They also agreed that antibiotic prophylaxis could be considered for a dog bite (or a bite from another traditional pet other than a cat) that has broken the skin and drawn blood if it involves a high-risk area or is in a person at risk of a serious wound infection because of a comorbidity. The committee agreed that the principles of the evidence from Broder et al. (2004) on human bites could be extrapolated to bites from dogs or other traditional pets). The committee discussed that antibiotic prophylaxis would only be considered for a dog bite (or a bite from another traditional pet) fulfilling these criteria because, in their experience, these bites have a lower risk of infection than human bites. This is supported by the evidence that showed no difference between antibiotic prophylaxis and placebo in reducing the incidence of infection after a dog bite. Antibiotic prophylaxis is not needed for a dog bite (or a bite from another traditional pet) that has not broken the skin, or has only caused a superficial wound that has broken the skin but not drawn blood.
For more details, see the summary of the evidence on antibiotics.
Return to the recommendations
# Treating infected human and animal bites
## Why the committee made the recommendations
Recommendations 1.1.13 to 1.1.14
There was no evidence on the treatment of human or animal bites. However, the committee agreed that antibiotics should be offered for human or animal bites with symptoms or signs of infection because of the potential consequences of not treating an infected bite.
The committee also agreed that, if there is discharge from the bite wound this should be swabbed and sent for microbiological testing before antibiotics are taken. This includes purulent and non-purulent discharge because certain bacteria associated with a human or animal bite, such as Eikenella, may not form pus.
For more details, see the summary of the evidence on antibiotics.
Return to the recommendations
# Reassessment
## Why the committee made the recommendations
Recommendations 1.1.16 to 1.1.18
The committee agreed that a human or animal bite should be reassessed if an infection develops or worsens rapidly or significantly at any time or does not start to improve within 24 to 48 hours of starting treatment because of the consequences of complications from an infection. Reassessment is also recommended if the person becomes systemically unwell or has severe pain that is out of proportion to the infection (which can be a symptom of necrotising fasciitis).
The committee agreed that it is good antimicrobial stewardship to review and potentially change the antibiotic used when microbiological testing results are available. A narrow-spectrum antibiotic should be used if appropriate.
They also discussed that reassessment is another opportunity to reconsider potential safeguarding issues for vulnerable adults or children, and to consider non-verbal signs of pain, such as a change in behaviour, in people who have difficulty communicating.
Return to the recommendations
# Referral and seeking specialist advice
## Why the committee made the recommendations
Recommendations 1.1.19 to 1.1.20
The committee agreed that people with a human or animal bite should be referred to hospital if they have symptoms or signs of a more serious illness or condition, or if they have penetrating wounds with certain features because of the serious consequences of these.
The committee agreed other circumstances when the prescriber may want to refer the person or seek specialist advice.
Return to the recommendations
# Choice of antibiotic
Recommendations 1.2.1 to 1.2.3
## Why the committee made the recommendations
No evidence was found comparing different antibiotics to inform the choice of antibiotic for human and animal bites. Therefore, the committee based these recommendations on their experience, current practice, antimicrobial resistance, and the need to provide choices that cover the relevant range of likely aerobic and anaerobic pathogens in human and animal bites.
The committee agreed that the same antibiotic choices should be available for both prophylaxis and treatment because the pathogens will be the same.
The committee agreed that the first-choice oral antibiotic for all people with a human or animal bite is co‑amoxiclav, which has good activity against the relevant range of likely pathogens.
The committee were aware of the BNF entry for co‑amoxiclav. Advice was also sought from the UK Teratology Information Service (UKTIS), which confirmed that the association between co‑amoxiclav and necrotising enterocolitis has only been identified in the context of prelabour premature rupture of the membranes (PPROM). Outside of this, there is no evidence to show that general co‑amoxiclav use in pregnancy is associated with an increased risk of necrotising enterocolitis. UKTIS advised that there should be no restriction around the use of co‑amoxiclav in pregnancy, provided it is not being given for PPROM. It was agreed that human or animal bites are a suitable clinical indication for co‑amoxiclav use in pregnancy.
If co‑amoxiclav is unsuitable, the alternative first-choice oral antibiotics for adults and young people over 12 years are doxycycline with metronidazole (an antibiotic with high activity against anaerobic bacteria). If co‑amoxiclav is unsuitable and a woman is pregnant, specialist advice should be sought for an alternative antibiotic with good activity against Pasteurella.
The committee agreed that if co‑amoxiclav is unsuitable, the alternative first-choice oral antibiotic for children under 12 years is co‑trimoxazole because this also has good activity against the range of likely pathogens.
The committee agreed that intravenous antibiotics should only be used if a person cannot take oral antibiotics or the severity of their condition warrants intravenous antibiotics. The first-choice intravenous antibiotic for all people with a human or animal bite is co‑amoxiclav because it has good activity against the relevant range of likely pathogens.
If co‑amoxiclav is unsuitable, the alternative first-choice intravenous antibiotics for all people with a human or animal bite are:
cefuroxime with metronidazole
ceftriaxone with metronidazole.
The committee agreed that both options have good activity against the relevant likely pathogens. The cephalosporins, cefuroxime and ceftriaxone have a similar spectrum of activity but providing more than 1 option allows for choice to be made locally. If a cephalosporin is not appropriate, for example, in people with a history of immediate hypersensitivity to penicillins, the committee agreed that a local microbiologist should be consulted to suggest a suitable alternative.
There was no evidence comparing antibiotic dosage, course length and route of administration. Therefore, the recommendations were based on the committee's experience and current practice. The committee agreed that the shortest course that is likely to be effective should be prescribed to reduce the risk of antimicrobial resistance and adverse effects. However, because the type and severity of bites can vary, a longer course may be needed based on clinical assessment of the wound.
The committee agreed that, for both oral and intravenous routes of administration (which would be switched to oral antibiotics when possible), a course length of 3 days should be effective for prophylaxis, and a course length of 5 days should be effective for treatment. However, the committee discussed that because the type and severity of bites can vary, a longer course of up to 7 days (with review) may be needed. This would be based on a clinical assessment of the wound, and whether it has, for example, caused significant tissue destruction or penetrated bone, joint, tendon or vascular structures.
Return to the recommendations# Context
Human and animal bites are at risk of infection. Human bites are most commonly infected by Streptococcus, Staphylococcus aureus, Haemophilus, Eikenella corrodens, Bacteroides and other anaerobes. Most infections from animal bites are polymicrobial and contain both aerobic and anaerobic organisms. Causative organisms for infections from cat and dog bites (the most common animal bites) include Pasteurella, Streptococcus, Staphylococcus, Neisseria, Corynebacterium, Fusobacterium nucleatum and Bacteroides (Abrahamian et al. 2011).# Summary of the evidence
This is a summary of the evidence, for full details see the evidence review.
The evidence included 1 systematic review (Medeiros et al. 2001) and 2 randomised controlled trials (Quinn et al. 2010, Broder et al. 2004). These studies considered various prophylactic antibiotics compared with no antibiotic or placebo for managing animal and human bites. No evidence was identified for choice of antibiotic, course length or route of administration.
# Antibiotic efficacy
If no route of administration for an antibiotic is given in the evidence review, no details were reported in the primary study.
## For human bites
Prophylactic antibiotics (oral cefaclor, intravenous cefazolin, intravenous benzylpenicillin, and oral cefalexin or penicillin) were shown to be more effective than placebo at reducing signs of infection after human bites in adults.
## For animal bites
There was no difference between prophylactic antibiotics (oral phenoxymethylpenicillin, oral dicloxacillin, oxacillin, oral cefalexin, oral erythromycin, co‑trimoxazole, cloxacillin and oral co‑amoxiclav) and no treatment or placebo in signs of infection after dog bites in adults, young people and children.
One small study suggests that there was no difference between a prophylactic antibiotic (oxacillin) and placebo in signs of infection after cat bites in adults.
## By bite type
There was no difference between prophylactic antibiotics (oxacillin, oral phenoxymethylpenicillin, oral dicloxacillin, oral cefalexin and oral erythromycin) and no treatment or placebo in the incidence of infection in adults, young people and children when treating puncture, laceration or avulsion wounds.
## By bite location
There was no difference between prophylactic antibiotics (oral dicloxacillin, oral cefalexin, oral erythromycin, oral phenoxymethylpenicillin, co‑trimoxazole, oral cefaclor, intravenous cefazolin and intravenous penicillin) and no treatment or placebo in the incidence of infection in adults, young people and children when treating trunk, head and neck, hand or arm wounds.
# Choice of antibiotic
There was no evidence identified about the choice of antibiotic.
# Course length
There was no evidence identified about the course length of antibiotics.
# Route of administration
There was no evidence identified about the route of administration of antibiotics.# Other considerations
# Medicines safety
Antibiotic-associated diarrhoea is estimated to occur in 2% to 25% of people taking antibiotics, depending on the antibiotic used (NICE clinical knowledge summary on diarrhoea – antibiotic associated).
About 10% of the general population claim to have a penicillin allergy; this is often because of a skin rash that occurred while taking a course of penicillin as a child. Fewer than 10% of people who think they are allergic to penicillin are truly allergic. See the NICE guideline on drug allergy: diagnosis and management for more information. People with a history of immediate hypersensitivity to penicillins may also react to cephalosporins and other beta lactam antibiotics (BNF information on phenoxymethylpenicillin).
Cholestatic jaundice can occur with co‑amoxiclav, and is more common in people over 65 years and in men; treatment should not usually exceed 14 days (BNF information on co-amoxiclav).
Tetracyclines (for example, doxycycline) can deposit in growing bone and teeth (by binding to calcium) causing staining and occasionally dental hypoplasia. They should not be given to pregnant or breastfeeding women, and use in children under 12 years is either contraindicated or there is a caution for use only in severe or life-threatening infections when there are no alternatives (BNF information on doxycycline).
Co‑trimoxazole is associated with rare but serious side effects, including blood disorders and Stevens–Johnson syndrome. There is caution for use in older people because there is an increased risk of serious side effects. There is also caution for use in people with a predisposition to hyperkalaemia. Monitoring of blood counts is recommended with prolonged treatment (BNF information on co-trimoxazole).
See the summaries of product characteristics for information on contraindications, cautions and adverse effects of individual medicines.
# Medicines adherence
Medicines adherence may be a problem for some people taking antibiotics that need frequent dosing or longer treatment duration (see the NICE guideline on medicines adherence).
# Resource implications
Recommended antibiotics are available as generic formulations. See the NHS Drug Tariff for costs.
See the evidence review for more information.
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{'Recommendations': "# Managing human and animal bites\n\n## Assessment\n\nFor people with a human or animal bite:\n\nassess the type and severity of the bite, including what animal caused the bite, the site and depth of the wound, and whether it is infected (see the recommendation on taking a swab in the section on treating infected bites)\n\nassess the risk of tetanus, rabies or a bloodborne viral infection and take appropriate action\n\nmanage the wound with irrigation and debridement as necessary\n\nbe aware of potential safeguarding issues in vulnerable adults and children, for example, as outlined in NICE's guidelines on child maltreatment, challenging behaviour and learning disabilities and domestic violence and abuse.Also see the recommendations on referral and seeking specialist advice.\n\nSeek specialist advice from a microbiologist for bites from a wild or exotic animal (including birds and non-traditional pets) because the spectrum of bacteria involved may be different, and there may be a risk of other serious non-bacterial infections.\n\nConsider seeking specialist advice from a microbiologist for domestic animal bites (including farm animal bites), that you are unfamiliar with.\n\nFor a short explanation of why the committee made these recommendations, see the rationale section on assessment\xa0.\n\nFor more details, see the evidence review.\n\nLoading. Please wait.\n\n## Antibiotic prophylaxis for uninfected bites\n\nDo not offer antibiotic prophylaxis to people with a human bite that has not broken the skin.\n\nOffer antibiotic prophylaxis (see the recommendations on choice of antibiotic) to people with a human bite that has broken the skin and drawn blood.\n\nConsider antibiotic prophylaxis for people with a human bite that has broken the skin but not drawn blood if it:\n\ninvolves a high-risk area such as the hands, feet, face, genitals, skin overlying cartilaginous structures or an area of poor circulation or\n\nis in a person at risk of a serious wound infection because of a comorbidity (such as diabetes, immunosuppression, asplenia or decompensated liver disease).\n\nDo not offer antibiotic prophylaxis to people with a cat bite that has not broken the skin.\n\nOffer antibiotic prophylaxis (see the recommendations on choice of antibiotic) to people with a cat bite that has broken the skin and drawn blood.\n\nConsider antibiotic prophylaxis for people with a cat bite that has broken the skin but not drawn blood if the wound could be deep.\n\nDo not offer antibiotic prophylaxis to people with a bite from a dog or other traditional pet (excluding cat bites) that:\n\nhas not broken the skin or\n\nhas broken the skin but not drawn blood.\n\nOffer antibiotic prophylaxis (see the recommendations on choice of antibiotic) to people with a bite from a dog or other traditional pet (excluding cat bites) that has broken the skin and drawn blood if it:\n\nhas penetrated bone, joint, tendon or vascular structures or\n\nis deep, is a puncture or crush wound, or has caused significant tissue damage or\n\nis visibly contaminated (for example, if there is dirt or a tooth in the wound).\n\nConsider antibiotic prophylaxis (see the recommendations on choice of antibiotic) for people with a bite from a dog or other traditional pet (excluding cat bites) that has broken the skin and drawn blood if it:\n\ninvolves a high-risk area such as the hands, feet, face, genitals, skin overlying cartilaginous structures or an area of poor circulation or\n\nis in a person at risk of a serious wound infection because of a comorbidity (such as diabetes, immunosuppression, asplenia or decompensated liver disease).\n\nFor a short explanation of why the committee made these recommendations, see the rationale section on antibiotic prophylaxis for uninfected human and animal bites\xa0.\n\nFor more details, see the evidence review.\n\nLoading. Please wait.\n\n## Treating infected bites\n\nTake a swab for microbiological testing to guide treatment if there is discharge (purulent or non-purulent) from the human or animal bite wound.\n\nOffer an antibiotic (see the recommendations on choice of antibiotic) for people with a human or animal bite if there are symptoms or signs of infection, such as increased pain, inflammation, fever, discharge or an unpleasant smell.\n\nFor a short explanation of why the committee made these recommendations, see the rationale section on treating infected human and animal bites\xa0.\n\nFor more details, see the evidence review.\n\nLoading. Please wait.\n\n## Advice\n\nGive advice to people with a human or animal bite about:\n\npossible adverse effects of antibiotics (if they have been offered antibiotics)\n\nseeking medical help if symptoms or signs of infection develop or worsen rapidly or significantly at any time, or do not start to improve within 24\xa0to 48\xa0hours of starting treatment.\n\n## Reassessment\n\nReassess the human or animal bite if:\n\nsymptoms or signs of infection develop or worsen rapidly or significantly at any time, or do not start to improve within 24\xa0to 48\xa0hours of starting treatment or\n\nthe person becomes systemically unwell or\n\nthe person has severe pain that is out of proportion to the infection.\n\nBe aware that people who have difficulty communicating may have non-verbal signs of pain, such as a change in behaviour.\n\nIf a skin swab has been sent for microbiological testing, review the choice of antibiotic based on the swab results. If a change of antibiotic is needed, use a narrow-spectrum antibiotic if possible.\n\nFor a short explanation of why the committee made these recommendations, see the rationale section on reassessment\xa0.\n\nFor more details, see the evidence review.\n\nLoading. Please wait.\n\n## Referral and seeking specialist advice\n\nRefer people with a human or animal bite to hospital if they have:\n\nsymptoms or signs suggesting a more serious illness or condition (these include severe cellulitis, abscess, osteomyelitis, septic arthritis, necrotising fasciitis or sepsis) or\n\na penetrating wound involving arteries, joints, nerves, muscles, tendons, bones or the central nervous system.\n\nConsider referral or seeking specialist advice for people with a human or animal bite if:\n\nthey are systemically unwell or\n\nthey have developed symptoms or signs of infection after taking prophylactic antibiotics or\n\nthey have lymphangitis or\n\nthey are at risk of a serious wound infection because of a pre-existing medical condition or\n\nthey cannot take oral antibiotics (in which case, explore with the specialist whether locally available options for parenteral antibiotics at home or in the community, rather than in hospital, are appropriate) or\n\nthe bite is infected and is not responding to oral antibiotics or\n\nthe bite is in an area of poor circulation.\n\nFor a short explanation of why the committee made these recommendations, see the rationale section on referral and seeing specialist advice\xa0.\n\nFor more details, see the evidence review.\n\nLoading. Please wait.\n\n# Choice of antibiotic\n\nWhen prescribing an antibiotic for a bite from a human, cat, dog or other traditional pet:\n\nfollow table\xa01 for adults aged 18\xa0years and over\n\nfollow table\xa02 for children and young people under 18\xa0years.\n\nGive oral antibiotics if the person can take oral medicines, and the severity of their condition does not need intravenous antibiotics.\n\nIf intravenous antibiotics are given, review within 48\xa0hours and consider switching to oral antibiotics if possible.\n\nProphylaxis and treatment\n\nAntibiotic, dosage and course length for prophylaxis (3\xa0days) and treatment (5\xa0days)\n\nFirst-choice oral antibiotic\n\nCo‑amoxiclav:\n\n/125\xa0mg or 500/125\xa0mg three times a day\n\nAlternative first-choice oral antibiotics for penicillin allergy or if co‑amoxiclav is unsuitable\n\nDoxycycline:\n\nmg on first day, then 100\xa0mg or 200\xa0mg daily\n\nwith\n\nMetronidazole:\n\nmg three times a day\n\nAlternative first-choice oral antibiotics in pregnancy for penicillin allergy or if co‑amoxiclav is unsuitable\n\nSeek specialist advice\n\nFirst-choice intravenous antibiotic (if unable to take oral antibiotics or severely unwell)\n\nCo‑amoxiclav:\n\ng three times a day\n\nAlternative first-choice intravenous antibiotics for penicillin allergy or if co‑amoxiclav is unsuitable\n\nCefuroxime (caution in penicillin allergy):\n\nmg three times a day (increased to 750\xa0mg four times a day or 1.5\xa0g three or four times a day if infection is severe)\n\nwith\n\nMetronidazole:\n\nmg three times a day\n\n\n\nCeftriaxone (caution in penicillin allergy)\n\ng once a day\n\nwith\n\nMetronidazole:\n\nmg three times a day\n\nIf cephalosporin is not appropriate\n\nSeek specialist advice\n\nSee the BNF and summary of product characteristics for appropriate use and dosing in specific populations, for example, for people with hepatic or renal impairment, in pregnancy and breastfeeding, and when administering intravenous (or, if appropriate, intramuscular) antibiotics.\n\nA 5‑day course is appropriate for treating most human or animal bites, but course length can be increased to 7\xa0days (with review) based on clinical assessment of the wound, for example, if there is significant tissue destruction or it has penetrated bone, joint, tendon or vascular structures.\n\nProphylaxis and treatment\n\nAntibiotic, dosage and course length for prophylaxis (3\xa0days) and treatment (5\xa0days)\n\nChoice for children under 1\xa0month\n\nSeek specialist advice\n\nFirst-choice oral antibiotic for children aged 1\xa0month and over\n\nCo‑amoxiclav:\n\nmonth to 11\xa0months: 0.25\xa0ml/kg of 125/31 suspension three times a day\n\nyear to 5\xa0years: 0.25\xa0ml/kg or 5\xa0ml of 125/31 suspension three times a day\n\nyears to 11\xa0years: 0.15\xa0ml/kg or 5\xa0ml of 250/62 suspension three times a day\n\nyears to 17\xa0years: 250/125\xa0mg or 500/125\xa0mg three times a day\n\nCo‑amoxiclav 400/57 suspension may also be considered to allow for twice-daily dosing\n\nAlternative first-choice oral antibiotic for children under 12\xa0years for penicillin allergy or if co‑amoxiclav is unsuitable\n\nCo‑trimoxazole (off-label use):\n\nweeks to 5\xa0months: 120\xa0mg or 24\xa0mg/kg twice a day\n\nmonths to 5\xa0years: 240\xa0mg or 24\xa0mg/kg twice a day\n\nyears to 11\xa0years: 480\xa0mg or 24\xa0mg/kg twice a day\n\nSee the BNF for Children for information on monitoring\n\nAlternative first-choice oral antibiotics for young people aged 12\xa0to 17\xa0years for penicillin allergy or if co‑amoxiclav is unsuitable\n\nDoxycycline:\n\nmg on first day, then 100\xa0mg or 200\xa0mg daily\n\nwith\n\nMetronidazole:\n\nmg three times a day\n\nAlternative first-choice oral antibiotics in pregnancy for penicillin allergy or if co‑amoxiclav unsuitable\n\nSeek specialist advice\n\nFirst-choice intravenous antibiotic (if unable to take oral antibiotics or severely ill)\n\nCo‑amoxiclav:\n\nmonth to 2\xa0months: 30\xa0mg/kg twice a day\n\nmonths to 17\xa0years: 30\xa0mg/kg three times a day (maximum per dose\xa01.2g)\n\nAlternative first-choice intravenous antibiotics for penicillin allergy or if co‑amoxiclav is unsuitable\n\nCefuroxime (caution in penicillin allergy):\n\nmonth to 17\xa0years: 20\xa0mg/kg three times a day (maximum 750\xa0mg per dose), which can be increased to 50\xa0mg/kg to 60\xa0mg/kg three or four times a day (maximum per dose 1.5\xa0g)\n\nwith\n\nMetronidazole:\n\nmonth: loading dose 15\xa0mg/kg, then (after 8\xa0hours) 7.5\xa0mg/kg three times a day\n\nmonths to 17\xa0years: 7.5\xa0mg/kg three times a day (maximum per dose 500\xa0mg)\n\n\n\nCeftriaxone (caution in penicillin allergy):\n\nmonth to 11\xa0years (up to 50\xa0kg): 50\xa0mg/kg to 80\xa0mg/kg once a day (maximum 4\xa0g per day)\n\nyears to 11\xa0years (50\xa0kg and above) and 12\xa0years to 17\xa0years: 1\xa0g to 2\xa0g once a day\n\nwith\n\nMetronidazole:\n\nmonth: loading dose 15\xa0mg/kg, then (after 8\xa0hours) 7.5\xa0mg/kg three times a day\n\nmonths to 17\xa0years: 7.5\xa0mg/kg three times a day (maximum per dose 500\xa0mg)\n\nIf a cephalosporin is not appropriate\n\nSeek specialist advice\n\nSee the BNF for Children and summary of product characteristics for appropriate use and dosing in specific populations, for example, for people with hepatic or renal impairment, in pregnancy and breastfeeding, and when administering intravenous (or, if appropriate, intramuscular) antibiotics.\n\nA 5‑day course is appropriate for treating most human or animal bites, but course length can be increased to 7\xa0days (with review) based on clinical assessment of the wound, for example, if there is significant tissue destruction or it has penetrated bone, joint, tendon or vascular structures.\n\nFor off-label use, the prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council's good practice in prescribing and managing medicines and devices for further information.\n\nFor a short explanation of why the committee made these recommendations, see the rationale section on choice of antibiotic\xa0.\n\nFor more details, see the summary of the evidence.\n\nLoading. Please wait.", 'Rationales': "The recommendations in this guideline are based on the evidence identified and the experience of the committee.\n\n# Assessment\n\n## Why the committee made the recommendations\n\nRecommendations 1.1.1 to 1.1.3\n\nThe committee agreed that it was good practice to assess and manage the wound in line with NICE's clinical knowledge summary on human and animal bites. They also agreed that, for human and animal bites, healthcare professionals should also consider potential safeguarding issues for vulnerable adults and children in line with NICE guidelines.\n\nThere was only evidence on managing bites from humans, dogs and cats; no evidence was identified for bites from other animal species. The committee agreed that it was reasonable to extrapolate this evidence to bites from other animals traditionally kept as pets, such as rabbits and hamsters. The committee agreed that specialist advice should be sought for bites from wild and exotic animals (including birds and non-traditional pets), such as snakes, lizards, monkeys or bats. This was because there may be a different spectrum of bacteria involved and a risk of other serious non-bacterial infections. For example, monkey bites are associated with herpes\xa0B virus, which may have serious consequences if not treated early, including fatal encephalomyelitis or severe neurological impairment. Healthcare professionals may also wish to seek specialist advice for domestic animal bites (including farm animal bites) they are not familiar with.\n\nReturn to the recommendations\n\n# Antibiotic prophylaxis for uninfected human and animal bites\n\n## Why the committee made the recommendations\n\nRecommendations 1.1.4 to 1.1.12\n\nEvidence was only identified for antibiotic prophylaxis after a dog, cat or human bite, and it was limited and of low quality. The committee agreed that, if a bite has not broken the skin, antibiotic prophylaxis is not needed. Many bites are superficial abrasions, meaning that they break the skin but do not draw blood. These bites are at low risk of infection because the dermis will not have been penetrated, so do not always need antibiotic prophylaxis.\n\nThe committee went on to discuss and agree when antibiotic prophylaxis should either be offered, considered, or not offered for a human, cat or dog (or other traditional pet) bite, based on the evidence and their knowledge of the risk of infection.\n\nThe committee discussed the pooled evidence on human bites, which suggested that antibiotic prophylaxis was more effective than placebo at reducing the incidence of infection. They discussed that a human bite that has broken the skin is at high risk of infection and other serious consequences because of the associated oral bacteria. However, they also discussed that the site and depth of a bite affects the risk of infection. In a study of human bites to the hand, antibiotic prophylaxis was particularly effective. The committee discussed that wounds to the hand have a higher risk of infection because of the multiple small compartments and number of joints. The same high level of infection risk applies to the feet and skin overlying cartilaginous structures.\n\nThe committee went on to discuss the evidence for human bites that are at lower risk of infection, as outlined in Broder et al. (2004). These bites penetrated only the epidermis (that is, they broke the skin but did not draw blood) and did not involve the high-risk areas of the hands, feet, or skin overlying joints or cartilaginous structures. For this study, there was a very low rate of infection; signs of infection were seen in 1\xa0of 62\xa0people in the placebo group and none of the 63\xa0people taking antibiotics.\n\nThe committee agreed that, if a human bite has not broken the skin, antibiotic prophylaxis should not be offered. If it has broken the skin and drawn blood, antibiotic prophylaxis should be offered. The committee agreed that, for people with a human bite that has broken the skin but not drawn blood, antibiotic prophylaxis is not routinely needed. However, they agreed that it can be considered for bites in high-risk areas or in people at risk of a serious wound infection because of a comorbidity.\n\nThe committee went on to discuss when antibiotic prophylaxis should be offered for a cat bite. The evidence on cat bites, which was based on a very small sample size of 11 did not show a statistically significant difference between antibiotic prophylaxis and placebo in reducing the incidence of infection in cat bites. Based on such limited data, the committee could not judge the certainty of the evidence. However, based on their expertise and experience, they agreed that antibiotic prophylaxis should be offered if a cat bite has broken the skin and drawn blood. Cat bites are at high risk of infection because of cat oral bacteria and because the needle-like nature of the wounds (small, deep punctures) is hard to irrigate. The committee went on to discuss that this type of wound is often deeper than it appears, which can cause assessment difficulties. They also noted that infection in deep skin structures is possible, which has serious consequences such as bone infections. The committee agreed that antibiotic prophylaxis is not needed if a cat bite has not broken the skin. However, it can be considered if the cat bite has broken the skin but not drawn blood if, despite appearances and the lack of blood, the wound could still be deep.\n\nThe committee went on to discuss and agree situations when antibiotic prophylaxis should be offered for a dog bite (or a bite from another traditional pet other than a cat). Evidence suggested no difference between antibiotic prophylaxis and placebo in reducing the incidence of infection based on the type and location of the dog bite wound. However, based on their experience, the committee agreed that antibiotic prophylaxis should be offered for a dog bite (or a bite from another traditional pet) if it:\n\nhas broken the skin and penetrated bone, joint, tendon or vascular structures or\n\nis deep, a puncture or crush wound, or has caused significant tissue damage or\n\nis visibly contaminated (for example, if there is dirt or a tooth in the wound).\n\nThey also agreed that antibiotic prophylaxis could be considered for a dog bite (or a bite from another traditional pet other than a cat) that has broken the skin and drawn blood if it involves a high-risk area or is in a person at risk of a serious wound infection because of a comorbidity. The committee agreed that the principles of the evidence from Broder et al. (2004) on human bites could be extrapolated to bites from dogs or other traditional pets). The committee discussed that antibiotic prophylaxis would only be considered for a dog bite (or a bite from another traditional pet) fulfilling these criteria because, in their experience, these bites have a lower risk of infection than human bites. This is supported by the evidence that showed no difference between antibiotic prophylaxis and placebo in reducing the incidence of infection after a dog bite. Antibiotic prophylaxis is not needed for a dog bite (or a bite from another traditional pet) that has not broken the skin, or has only caused a superficial wound that has broken the skin but not drawn blood.\n\nFor more details, see the summary of the evidence on antibiotics.\n\nReturn to the recommendations\n\n# Treating infected human and animal bites\n\n## Why the committee made the recommendations\n\nRecommendations 1.1.13 to 1.1.14\n\nThere was no evidence on the treatment of human or animal bites. However, the committee agreed that antibiotics should be offered for human or animal bites with symptoms or signs of infection because of the potential consequences of not treating an infected bite.\n\nThe committee also agreed that, if there is discharge from the bite wound this should be swabbed and sent for microbiological testing before antibiotics are taken. This includes purulent and non-purulent discharge because certain bacteria associated with a human or animal bite, such as Eikenella, may not form pus.\n\nFor more details, see the summary of the evidence on antibiotics.\n\nReturn to the recommendations\n\n# Reassessment\n\n## Why the committee made the recommendations\n\nRecommendations 1.1.16 to 1.1.18\n\nThe committee agreed that a human or animal bite should be reassessed if an infection develops or worsens rapidly or significantly at any time or does not start to improve within 24\xa0to 48\xa0hours of starting treatment because of the consequences of complications from an infection. Reassessment is also recommended if the person becomes systemically unwell or has severe pain that is out of proportion to the infection (which can be a symptom of necrotising fasciitis).\n\nThe committee agreed that it is good antimicrobial stewardship to review and potentially change the antibiotic used when microbiological testing results are available. A narrow-spectrum antibiotic should be used if appropriate.\n\nThey also discussed that reassessment is another opportunity to reconsider potential safeguarding issues for vulnerable adults or children, and to consider non-verbal signs of pain, such as a change in behaviour, in people who have difficulty communicating.\n\nReturn to the recommendations\n\n# Referral and seeking specialist advice\n\n## Why the committee made the recommendations\n\nRecommendations 1.1.19 to 1.1.20\n\nThe committee agreed that people with a human or animal bite should be referred to hospital if they have symptoms or signs of a more serious illness or condition, or if they have penetrating wounds with certain features because of the serious consequences of these.\n\nThe committee agreed other circumstances when the prescriber may want to refer the person or seek specialist advice.\n\nReturn to the recommendations\n\n# Choice of antibiotic\n\nRecommendations 1.2.1 to 1.2.3\n\n## Why the committee made the recommendations\n\nNo evidence was found comparing different antibiotics to inform the choice of antibiotic for human and animal bites. Therefore, the committee based these recommendations on their experience, current practice, antimicrobial resistance, and the need to provide choices that cover the relevant range of likely aerobic and anaerobic pathogens in human and animal bites.\n\nThe committee agreed that the same antibiotic choices should be available for both prophylaxis and treatment because the pathogens will be the same.\n\nThe committee agreed that the first-choice oral antibiotic for all people with a human or animal bite is co‑amoxiclav, which has good activity against the relevant range of likely pathogens.\n\nThe committee were aware of the BNF entry for co‑amoxiclav. Advice was also sought from the UK Teratology Information Service (UKTIS), which confirmed that the association between co‑amoxiclav and necrotising enterocolitis has only been identified in the context of prelabour premature rupture of the membranes (PPROM). Outside of this, there is no evidence to show that general co‑amoxiclav use in pregnancy is associated with an increased risk of necrotising enterocolitis. UKTIS advised that there should be no restriction around the use of co‑amoxiclav in pregnancy, provided it is not being given for PPROM. It was agreed that human or animal bites are a suitable clinical indication for co‑amoxiclav use in pregnancy.\n\nIf co‑amoxiclav is unsuitable, the alternative first-choice oral antibiotics for adults and young people over 12\xa0years are doxycycline with metronidazole (an antibiotic with high activity against anaerobic bacteria). If co‑amoxiclav is unsuitable and a woman is pregnant, specialist advice should be sought for an alternative antibiotic with good activity against Pasteurella.\n\nThe committee agreed that if co‑amoxiclav is unsuitable, the alternative first-choice oral antibiotic for children under 12\xa0years is co‑trimoxazole because this also has good activity against the range of likely pathogens.\n\nThe committee agreed that intravenous antibiotics should only be used if a person cannot take oral antibiotics or the severity of their condition warrants intravenous antibiotics. The first-choice intravenous antibiotic for all people with a human or animal bite is co‑amoxiclav because it has good activity against the relevant range of likely pathogens.\n\nIf co‑amoxiclav is unsuitable, the alternative first-choice intravenous antibiotics for all people with a human or animal bite are:\n\ncefuroxime with metronidazole\n\nceftriaxone with metronidazole.\n\nThe committee agreed that both options have good activity against the relevant likely pathogens. The cephalosporins, cefuroxime and ceftriaxone have a similar spectrum of activity but providing more than 1\xa0option allows for choice to be made locally. If a cephalosporin is not appropriate, for example, in people with a history of immediate hypersensitivity to penicillins, the committee agreed that a local microbiologist should be consulted to suggest a suitable alternative.\n\nThere was no evidence comparing antibiotic dosage, course length and route of administration. Therefore, the recommendations were based on the committee's experience and current practice. The committee agreed that the shortest course that is likely to be effective should be prescribed to reduce the risk of antimicrobial resistance and adverse effects. However, because the type and severity of bites can vary, a longer course may be needed based on clinical assessment of the wound.\n\nThe committee agreed that, for both oral and intravenous routes of administration (which would be switched to oral antibiotics when possible), a course length of 3\xa0days should be effective for prophylaxis, and a course length of 5\xa0days should be effective for treatment. However, the committee discussed that because the type and severity of bites can vary, a longer course of up to 7\xa0days (with review) may be needed. This would be based on a clinical assessment of the wound, and whether it has, for example, caused significant tissue destruction or penetrated bone, joint, tendon or vascular structures.\n\nReturn to the recommendations", 'Context': 'Human and animal bites are at risk of infection. Human bites are most commonly infected by Streptococcus, Staphylococcus aureus, Haemophilus, Eikenella corrodens, Bacteroides and other anaerobes. Most infections from animal bites are polymicrobial and contain both aerobic and anaerobic organisms. Causative organisms for infections from cat and dog bites (the most common animal bites) include Pasteurella, Streptococcus, Staphylococcus, Neisseria, Corynebacterium, Fusobacterium nucleatum and Bacteroides (Abrahamian et al. 2011).', 'Summary of the evidence': 'This is a summary of the evidence, for full details see the evidence review.\n\nThe evidence included 1\xa0systematic review (Medeiros et al. 2001) and 2\xa0randomised controlled trials (Quinn et al. 2010, Broder et al. 2004). These studies considered various prophylactic antibiotics compared with no antibiotic or placebo for managing animal and human bites. No evidence was identified for choice of antibiotic, course length or route of administration.\n\n# Antibiotic efficacy\n\nIf no route of administration for an antibiotic is given in the evidence review, no details were reported in the primary study.\n\n## For human bites\n\nProphylactic antibiotics (oral cefaclor, intravenous cefazolin, intravenous benzylpenicillin, and oral cefalexin or penicillin) were shown to be more effective than placebo at reducing signs of infection after human bites in adults.\n\n## For animal bites\n\nThere was no difference between prophylactic antibiotics (oral phenoxymethylpenicillin, oral dicloxacillin, oxacillin, oral cefalexin, oral erythromycin, co‑trimoxazole, cloxacillin and oral co‑amoxiclav) and no treatment or placebo in signs of infection after dog bites in adults, young people and children.\n\nOne small study suggests that there was no difference between a prophylactic antibiotic (oxacillin) and placebo in signs of infection after cat bites in adults.\n\n## By bite type\n\nThere was no difference between prophylactic antibiotics (oxacillin, oral phenoxymethylpenicillin, oral dicloxacillin, oral cefalexin and oral erythromycin) and no treatment or placebo in the incidence of infection in adults, young people and children when treating puncture, laceration or avulsion wounds.\n\n## By bite location\n\nThere was no difference between prophylactic antibiotics (oral dicloxacillin, oral cefalexin, oral erythromycin, oral phenoxymethylpenicillin, co‑trimoxazole, oral cefaclor, intravenous cefazolin and intravenous penicillin) and no treatment or placebo in the incidence of infection in adults, young people and children when treating trunk, head and neck, hand or arm wounds.\n\n# Choice of antibiotic\n\nThere was no evidence identified about the choice of antibiotic.\n\n# Course length\n\nThere was no evidence identified about the course length of antibiotics.\n\n# Route of administration\n\nThere was no evidence identified about the route of administration of antibiotics.', 'Other considerations': '# Medicines safety\n\nAntibiotic-associated diarrhoea is estimated to occur in 2% to 25% of people taking antibiotics, depending on the antibiotic used (NICE clinical knowledge summary on diarrhoea – antibiotic associated).\n\nAbout 10% of the general population claim to have a penicillin allergy; this is often because of a skin rash that occurred while taking a course of penicillin as a child. Fewer than 10% of people who think they are allergic to penicillin are truly allergic. See the NICE guideline on drug allergy: diagnosis and management for more information. People with a history of immediate hypersensitivity to penicillins may also react to cephalosporins and other beta lactam antibiotics (BNF information on phenoxymethylpenicillin).\n\nCholestatic jaundice can occur with co‑amoxiclav, and is more common in people over 65\xa0years and in men; treatment should not usually exceed 14\xa0days (BNF information on co-amoxiclav).\n\nTetracyclines (for example, doxycycline) can deposit in growing bone and teeth (by binding to calcium) causing staining and occasionally dental hypoplasia. They should not be given to pregnant or breastfeeding women, and use in children under 12\xa0years is either contraindicated or there is a caution for use only in severe or life-threatening infections when there are no alternatives (BNF information on doxycycline).\n\nCo‑trimoxazole is associated with rare but serious side effects, including blood disorders and Stevens–Johnson syndrome. There is caution for use in older people because there is an increased risk of serious side effects. There is also caution for use in people with a predisposition to hyperkalaemia. Monitoring of blood counts is recommended with prolonged treatment (BNF information on co-trimoxazole).\n\nSee the summaries of product characteristics for information on contraindications, cautions and adverse effects of individual medicines.\n\n# Medicines adherence\n\nMedicines adherence may be a problem for some people taking antibiotics that need frequent dosing or longer treatment duration (see the NICE guideline on medicines adherence).\n\n# Resource implications\n\nRecommended antibiotics are available as generic formulations. See the NHS Drug Tariff for costs.\n\nSee the evidence review for more information.'}
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https://www.nice.org.uk/guidance/ng184
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This guideline sets out an antimicrobial prescribing strategy for human and animal bites (excluding insect bites) in adults, young people and children aged 72 hours and over. It aims to optimise antibiotic use and reduce antibiotic resistance.
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6b92fc7b94eb2aa50d306746e718dba8f3863dba
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nice
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Testing strategies for Lynch syndrome in people with endometrial cancer
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Testing strategies for Lynch syndrome in people with endometrial cancer
Evidence-based recommendations on testing strategies for Lynch syndrome for people with endometrial cancer.
# Recommendations
Offer testing for Lynch syndrome to people who are diagnosed with endometrial cancer. Use immunohistochemistry (IHC) to identify tumours with mismatch repair (MMR) deficiency:
If IHC is abnormal with loss of MLH1, or loss of both MLH1 and PMS2 protein expression, do MLH1 promoter hypermethylation testing of tumour DNA. If MLH1 promoter hypermethylation is not detected, offer germline genetic testing to confirm Lynch syndrome.
If IHC is abnormal with loss of MSH2, MSH6 or isolated PMS2 protein expression, offer germline genetic testing to confirm Lynch syndrome.
Healthcare professionals should inform people about the possible implications of test results for both themselves and their relatives, and give support and information. Discussion of genetic testing and obtaining consent should be done by a healthcare professional with appropriate training.
Laboratories doing IHC for MMR proteins, MLH1 promoter hypermethylation testing or germline genetic testing should take part in a recognised external quality assurance programme.
Why the committee made these recommendations
Lynch syndrome is an inherited condition that increases the risk of certain types of cancer, including endometrial and colorectal cancer. NICE recommends testing for Lynch syndrome after a colorectal cancer diagnosis. But endometrial cancer is often the first cancer that people with Lynch syndrome will have. So, Lynch syndrome could be identified earlier if tests are done after a diagnosis of endometrial cancer.
If Lynch syndrome is diagnosed, treatment and surveillance can be offered to reduce the risk of having another Lynch syndrome-associated cancer (in particular colorectal cancer) or identify it earlier. Genetic testing for Lynch syndrome can also be offered to relatives with the aim of preventing Lynch syndrome-associated cancer developing or detecting it at an early stage.
Several types of tests can be done in different orders and combinations to see if endometrial cancer is likely to have been caused by Lynch syndrome. Economic modelling has shown that IHC testing then MLH1 promoter testing is likely to be the most cost-effective approach. If both these tests show that a person may have Lynch syndrome, genetic testing of a person's non-tumour DNA should be done to confirm this.
It is important that support and information are available for people deciding to be tested for Lynch syndrome.# The diagnostic tests
# Clinical need and practice
Lynch syndrome is an inherited genetic condition associated with an increased risk of several cancers, particularly endometrial and colorectal cancer. It is caused by mutations in, or near, the DNA sequence of mismatch repair (MMR) genes. If a person has Lynch syndrome, these mutations are in every cell of their body and can be identified by genetic testing of non-tumour tissue. This testing shows mutations inherited by a person in their 'germline' instead of those that are only in cancerous tissue.
Identifying Lynch syndrome at the point of endometrial cancer diagnosis could:
prevent other cancers in people with Lynch syndrome (such as colorectal cancer) through increased surveillance and strategies to reduce risk
help to identify relatives with Lynch syndrome, to reduce their risk of Lynch syndrome-associated cancers or increase early detection of cancer
help relatives diagnosed at an early age to consider family planning and, if they wish, have risk-reducing interventions, for example, a hysterectomy.
Currently, testing for Lynch syndrome in people diagnosed with endometrial cancer is often not done, or may only be done for people with an identified risk factor for the condition. This could be age at diagnosis or a family history of Lynch syndrome-related cancers. Clinical experts commented that even if tumour testing for potential Lynch syndrome is routinely done, a referral to clinical genetics services may still be needed if the tumour tests do not indicate Lynch syndrome but a person has an identified risk factor that suggests the condition is likely.
# The interventions
Most endometrial cancers do not develop because of Lynch syndrome (sporadic cancer). Tests done on endometrial tumour tissue can help identify how likely it is that the cancer happened because a person has Lynch syndrome and if genetic testing of non-tumour tissue should be done to check for the condition.
Testing for microsatellite instability (MSI) in endometrial tumour tissue or testing for loss of MMR proteins using immunohistochemistry (IHC), or doing both, can show potential Lynch syndrome. But both tests can give false positive results for potential Lynch syndrome. So, another test (MLH1 promoter hypermethylation testing) can be done on tumour tissue if MSI is present or if IHC shows loss of MLH1 protein. If MLH1 promoter hypermethylation is present in the tumour the cancer is likely to be sporadic, instead of being caused by Lynch syndrome.
This assessment includes different combinations of IHC, MSI and MLH1 promoter hypermethylation testing done on endometrial tumour tissue to see if the cancer is likely to have been caused by Lynch syndrome.
All strategies include final genetic testing of non-tumour tissue to make a diagnosis of Lynch syndrome (germline testing). Sometimes this testing can show changes in the sequences of the MMR genes, but it is not known if these changes cause Lynch syndrome or not. These are called variants of uncertain significance.
# The comparator
The comparator was no testing to identify Lynch syndrome for people with endometrial cancer.# Evidence
The diagnostics advisory committee considered evidence on testing strategies using immunohistochemistry (IHC) and microsatellite instability (MSI) testing for Lynch syndrome from several sources. Full details of all the evidence are in the committee papers.
The external assessment group (EAG) did a systematic review to identify evidence on the clinical effectiveness and diagnostic accuracy of IHC- and MSI-based testing strategies for detecting Lynch syndrome in people with endometrial cancer.
# Test performance
The EAG identified 41 studies (reported in 44 papers) with data on the test accuracy of IHC- and MSI-based strategies for detecting Lynch syndrome in people with endometrial cancer, prevalence of Lynch syndrome in this population, and concordance of IHC and MSI testing done on endometrial tumour samples. One unpublished study (PETALS) was also available as academic in confidence (this study has now published as Ryan et al. 2020).
Two studies were done in the UK (Anagnostopoulos et al. 2017 and PETALS). Nine studies (Backes et al. 2009, Bruegl et al. 2017, Buchanan et al. 2014, Dillon et al. 2017, Dudley et al. 2015, Egoavil et al. 2013, Hampel et al. 2006, PETALS, Svampane et al. 2014) were in unselected populations. That is, all patients diagnosed with endometrial cancer during the study's recruitment period were included.
Seven complete test accuracy studies were identified. These were studies in which people who had IHC or MSI testing, with or without MLH1 promoter hypermethylation testing, went on to have reference standard testing whatever the results of the index tests were. The reference standard used was germline testing (testing of non-tumour tissue) for Lynch syndrome-associated mutations in mismatch repair (MMR) genes. The EAG only included studies in which at least 95% of people who had index tests also had the reference standard test.
Data on the prevalence of Lynch syndrome from 33 studies and concordance between IHC and MSI-based testing in 23 studies were also extracted.
## Prevalence of Lynch syndrome in people with endometrial cancer
Prevalence of Lynch syndrome was lower in studies that recruited unselected samples of people (which matches the population for this assessment). The median value was 3.2%. In the studies with unselected samples, variants in the MSH6 MMR gene were the most common, then MSH2.
## Accuracy of index tests
The EAG did not do a meta-analysis of test accuracy because the few studies identified were heterogeneous. Individual patient data from Lu et al. (2007) were used to inform strategy accuracy estimates in the economic model base case.
Accuracy of the index tests, that is, IHC- and MSI-based testing strategies used alone, in combination, and with or without subsequent MLH1 promoter hypermethylation testing, was compared against the reference standard to determine if a person did have Lynch syndrome.
Data on the accuracy of IHC alone (that is, without MLH1 promoter hypermethylation testing) were available from 5 studies (Berends et al. 2003, Chao et al. 2019, Lu et al. 2007, Rubio et al. 2016, Tian et al. 2019). Sensitivity values ranged from 66.7% to 100%. Specificity values ranged from 6.5% to 83.3%.
Data on the accuracy of MSI testing alone (that is, without MLH1 promoter hypermethylation testing) were available from 4 studies (Berends et al. 2003, Chao et al. 2019, Lu et al. 2007, Rubio et al. 2016). Sensitivity values ranged from 41.7% to 100%. Specificity values ranged from 69.2% to 88.9%.
There were data from 4 studies on the accuracy of IHC- or MSI-based testing strategies when these tests were done before MLH1 promoter hypermethylation testing. The studies varied in when promoter hypermethylation testing was done:
In 2 studies (Lu et al. 2007, Salvador et al. 2019) MLH1 promoter hypermethylation testing was done for tumours that were categorised as MSI-H or had IHC loss (MLH1 or MLH1 plus PMS2). In Lu et al. (2007), 92.3% of tumours tested were hypermethylated.
In Chao et al. (2019) MLH1 promoter hypermethylation testing was done only if MLH1 loss was seen on IHC; 80% of tumours tested were hypermethylated.
In Ring et al. (2016) the circumstances for MLH1 promoter hypermethylation testing were not reported.Sensitivity values ranged from 90.5% to 100%. Specificity values ranged from 6.6% to 92.3%.
Four of the complete test accuracy studies assessed both IHC and MSI testing on the same population (Lu et al. 2007, Berends et al. 2003, Chao et al. 2019, Rubio et al. 2016). Point estimates for sensitivity ranged from 66.7% to 100% for IHC and from 41.7% to 100% for MSI. For specificity, point estimates for IHC ranged from 60.9% to 83.3%. For MSI the range was 69.2% to 89.9%. The EAG commented that there was no statistically significant difference between the tests.
## Concordance between IHC and MSI testing
Complete concordance between IHC and MSI testing was reported in 20 studies. That is, in these studies IHC and MSI testing were both done on samples whatever the results of 1 of the tests. There was a median agreement of 91.8% with a range of 68.2% to 100%.
# Clinical effectiveness
The EAG did a systematic review to identify evidence on the benefits and harms of testing for Lynch syndrome for people with endometrial cancer and their relatives, with a focus on the benefits and harms of colorectal and endometrial cancer surveillance. No studies met the inclusion criteria.
# Cost effectiveness
## Systematic review of cost-effectiveness evidence
The EAG did a systematic review to find studies assessing the cost effectiveness of testing for Lynch syndrome in people with endometrial cancer using IHC- and MSI-based strategies, compared with no testing for Lynch syndrome. Five studies were identified (Resnick et al. 2009, Kwon et al. 2011, Bruegl et al. 2014, Goverde et al. 2016, Snowsill et al. 2019). Snowsill et al. (2019) was the only study that took a UK perspective. The EAG thought that Snowsill et al. (2019) provided a comprehensive reference model. It used this study and previous reviews of testing for Lynch syndrome for people with colorectal cancer (Snowsill et al. 2014; Snowsill et al. 2017) to inform its modelling approach.
## Economic model
The EAG developed a de novo economic model to estimate the costs and benefits of offering testing to identify Lynch syndrome (using different testing strategies) for people with a new diagnosis of endometrial cancer. The EAG's model had 2 parts. A decision tree (in Excel) modelled the accuracy and costs of the different testing strategies to identify people with Lynch syndrome after being diagnosed with endometrial cancer (known as probands; the first family member to have medical testing for a genetic condition). This also included testing for the relatives of people diagnosed with Lynch syndrome (cascade testing). A second model (in R) then modelled the longer-term effects of this diagnosis (and adopting surveillance and risk-reducing interventions) on colorectal and endometrial cancer incidence across the rest of people's lives. This was for both the first family member to have Lynch syndrome identified after endometrial cancer and their relatives.
## Population
The age of the people in the cohort entering the model with recently diagnosed endometrial cancer was 48 years old. Relatives diagnosed with Lynch syndrome could be any age between 25 and 74 years old. The prevalence of Lynch syndrome in this population (3.2%) was taken from the PETALS study. The proportion of each MMR gene mutation in people with Lynch syndrome diagnosed after endometrial cancer was pooled from 4 studies (Hampel et al. 2006, Bruegl et al. 2017, Egoavil et al. 2013, Ryan et al. 2020 ).
## Model inputs
The EAG used data from 1 study (Lu et al. 2007) to inform estimates of sensitivity and specificity for the different test strategies for the model. One study was used for consistency (that is, accuracy estimates produced from the same population) and to avoid illogical results, which may have happened if different studies were used for different strategies. The EAG did not consider that pooling results across studies was appropriate because the few studies identified were heterogeneous. Data from a recent meta-analysis (Snowsill et al. 2019), Chao et al. (2019) and the PETALS study (Ryan et al. 2020) were used in scenario analyses.
Age-related incidence of colorectal cancer for people with Lynch syndrome was taken from Snowsill et al. (2019). This was assumed to differ by which MMR gene was mutated and was estimated using gene specific data from the Prospective Lynch Syndrome Database. A log-normal distribution was fitted to the data to estimate the incidence of colorectal cancer over time. A hazard ratio of 0.387 (Järvinen et al. 2000) was applied to estimate the effect of colonoscopic surveillance on reducing the incidence of colorectal cancer. If a person was having colonoscopic surveillance because Lynch syndrome had been diagnosed, this was assumed to identify colorectal cancer at an earlier stage (as well as reducing incidence).
Incidence data for endometrial cancer were taken from the Prospective Lynch Syndrome Database (Dominguez-Valentin et al. 2020). The incidence differed by which MMR gene was mutated. A fitted piecewise linear model was used to estimate annual incidence at different ages. Data from Cancer Research UK on uterine cancer survival statistics were used for the incidence of death from endometrial cancer, assuming no difference for people with and without Lynch syndrome.
Female relatives with Lynch syndrome could choose to have hysterectomy with removal of both ovaries and fallopian tubes (bilateral salpingo-oophorectomy), which eliminated all future risk of endometrial cancer. The uptake of this surgery increased with age, from 20% at 35 years old to 80% at 75 years old. The EAG highlighted considerable uncertainty about the benefit of gynaecological surveillance, and variation in practice across the UK. In its base case, the EAG assumed all female relatives with Lynch syndrome who were 25 years or older (who had not had a hysterectomy) would have annual non-invasive gynaecological surveillance done by a GP. Of these, 10% would be referred for invasive surveillance (gynaecological examination, pelvic ultrasound, cancer antigen‑125 analysis and aspiration biopsy). Gynaecological surveillance was assumed to reduce mortality by 10.2% (Snowsill et al. 2017).
Most costs were taken from work done for previous NICE guidance on testing for Lynch syndrome after colorectal cancer (Snowsill et al. 2017). Hospital-related costs were from the most current NHS reference tables. The EAG used test costs from the UK Genetic Testing Network (confirmed by clinical experts) in the base case.
Baseline health-related quality of life for people in the model was calculated based on age and sex. Testing, a diagnosis of Lynch syndrome, surveillance and risk-reducing interventions were assumed to have no effect on health-related quality of life.
In the base case, a decrease in health-related quality of life for people with colorectal cancer was only assumed to occur at stage 4 (a multiplier of 0.789; Snowsill et al. 2017). Because this may underestimate the effect of colorectal cancer on a person's quality of life, the EAG did a scenario analysis in which people with stage 3 colorectal cancer also had a decrease in health-related quality of life. The health-related quality of life of people with endometrial cancer decreased by 0.036 (Snowsill et al. 2017) for 1 year.
## Base-case results
When compared independently with no testing, all strategies had an incremental cost-effectiveness ratio (ICER) of less than £17,500 per quality-adjusted life year (QALY) gained. The fully incremental analysis (that is, all testing strategies compared against each other as well as no testing) is shown in table 1.
Strategy
Incremental costs
Incremental QALYs
ICER
Net monetary benefit (compared with no testing; using a maximum ICER of £20,000 per QALY gained)
No testing
Strategy 2: MSI then MLH1 promoter hypermethylation testing
Extendedly dominated
Strategy 4: IHC then MLH1 promoter hypermethylation testing
Strategy 6: MSI then IHC then MLH1 promoter hypermethylation testing
Dominated
Strategy 3: IHC alone
Strategy 1: MSI alone
Strategy 8: IHC then MSI then MLH1 promoter hypermethylation testing
Dominated
Strategy 10: MSI and IHC then MLH1 promoter hypermethylation testing
Dominated
Strategy 7: IHC then MSI
Strategy 5: MSI then IHC
Dominated
Strategy 9: MSI and IHC
Dominated
Strategy 11: No index testing (straight to germline testing)
Dominated
Abbreviations in table: ICER, incremental cost-effectiveness ratio; IHC, immunohistochemistry; MSI, microsatellite instability; QALY, quality-adjusted life year.
Extendedly dominated means the ICER for a given strategy is higher than that of the next, more effective, alternative that is not extendedly dominated or dominated (that is, it is dominated by a combination of 2 alternatives and should not be used to calculate appropriate ICERs). Dominated means if a strategy has higher costs and worse outcomes than an alternative strategy.
The probabilistic ICER for strategy 4 was £11,600 per QALY gained compared with no testing (compared with a deterministic ICER of £9,420 per QALY gained). At a maximum ICER of £20,000 per QALY gained, which is what NICE normally considers a cost-effective use of NHS resources, this strategy had a 93% probability of being cost effective compared with no testing.
The EAG did several scenario analyses in its main report:
Scenario 1: Using alternative test accuracy estimates (for strategies 1, 2, 3 and 4) from the PETALS study.
Scenario 2: Using alternative test costs from a micro-costing study (Ryan et al. 2019).
Scenario 3: Combining scenarios 1 and 2.
Scenario 4: Including further disutility for colorectal cancer (for stage 3) and including the same utility for people with endometrial cancer as people with stage 4 colorectal cancer in their last year of life.
Scenario 5: Excluding gynaecological surveillance (cost and benefits).
Scenario 6: Colonoscopy assumed to be every 3 years (instead of 2).
Scenario 7: Aspirin removed from model.
Scenario 8: Surveillance for colorectal cancer assumed to have no benefit.
In the fully incremental analysis in the base case, IHC then MLH1 promoter hypermethylation testing (strategy number 4) was the most cost-effective strategy. In all scenarios except scenario 8, this strategy had an ICER of less than £12,000 per QALY gained in fully incremental analyses. In scenario 8, the ICER was £20,740 per QALY gained. In all scenarios except scenario 4, all other strategies were either extendedly dominated (the ICER was higher than that of the next more effective alternative), fully dominated (had higher costs and worse outcomes than an alternative strategy) or had ICERs of over £90,000 per QALY gained (fully incremental analysis). In scenario 4, the ICER for IHC testing alone was £41,180 per QALY gained in the fully incremental analysis.
The EAG also did more scenario analyses in an addendum to its main report. In additional scenario 1, diagnostic accuracy estimates from a meta-analysis done for recent modelling work (Snowsill et al. 2019) were used instead of estimates from Lu et al. (2007). Accuracy data were only available for strategies using MSI and IHC alone (with or without subsequent MLH1 promoter hypermethylation; strategies 1 to 4 in this assessment). In fully incremental analysis, IHC with MLH1 promoter hypermethylation testing had an ICER of £10,464 per QALY gained and IHC alone had an ICER of about £100,000 per QALY gained. MSI and MSI done before MLH1 promoter hypermethylation were either dominated or extendedly dominated.
In additional scenario 2, accuracy data from Chao et al. (2019) were used. Only accuracy estimates for IHC and MSI alone were available. Here, MSI and no testing extendedly dominated IHC testing and MSI testing had an ICER of £10,455 per QALY gained compared with no testing. In Chao et al. higher estimates of both sensitivity and specificity were seen for MSI testing than IHC testing.
In additional scenario analysis 3, people with variants of uncertain significance and people who were assumed to have Lynch syndrome did not gain any benefit from surveillance and risk-reducing interventions (in the base case, they were assumed to get the same benefit as people with Lynch syndrome). IHC with MLH1 promoter hypermethylation had an ICER of £9,514 per QALY gained and dominated or extendedly dominated all other strategies.# Committee discussion
# Clinical need
## It is likely that people and their families will benefit substantially if Lynch syndrome is identified after endometrial cancer is diagnosed
A patient expert highlighted that identifying Lynch syndrome after a diagnosis of endometrial cancer means interventions and surveillance can be adopted to reduce the risk of other Lynch syndrome-associated cancers or detect them earlier. Another benefit is that it allows testing for the condition to be offered to relatives, who can be identified as having Lynch syndrome before they have cancer. The patient expert commented that if a person knows they have Lynch syndrome they can make lifestyle changes to help reduce their cancer risk. As well as offering clinical surveillance to people with Lynch syndrome, such as colonoscopies, the symptoms of Lynch syndrome-associated cancers can be highlighted to make sure people seek medical advice if they have symptoms. Knowing that they are at higher risk of gynaecological cancer may also help people make decisions about family planning. The committee noted that endometrial cancer is often the first Lynch syndrome-associated cancer that people are diagnosed with. So at this point there is an opportunity to identify Lynch syndrome before other associated cancers, such as colorectal cancer, develop. The committee concluded that people and their families would likely benefit substantially if Lynch syndrome was identified after endometrial cancer is diagnosed.
## People should be informed of the possible implications of test results for both themselves and their families
There can be considerable anxiety and uncertainty associated with genetic testing for hereditary cancer syndromes such as Lynch syndrome. A patient expert explained that waiting for test results can be a very anxious time. Test results can have a substantial effect on a person, so it is very important that people understand the full implications of a diagnosis of Lynch syndrome, for themselves and their families. This is especially important for people with a learning disability, who may need support from a carer to fully engage in discussions about testing and to give informed consent. For people who have not had children yet, or who want more children, there may be anxiety and uncertainty about risk-reducing surgery, because after this it is not possible to give birth. Making this decision needs a good understanding of their risk of cancer (for example, based on their specific pathogenic variant of a mismatch repair gene). People may also have concerns about the invasive nature of surveillance for cancer. The committee concluded that genetic counselling is very important for people with Lynch syndrome, or who are at risk of having Lynch syndrome, because it can help people understand if genetic testing is appropriate or not. It can also help people understand the importance of telling extended family about their risk of having Lynch syndrome and the benefits of being tested. The committee also noted the importance of developing information resources to help people decide about testing, and the need for these to be available at the appropriate time.
# Testing strategies
## IHC testing may give quicker results than MSI testing, which can give people more chances to join clinical trials
A patient expert explained that waiting for test results can be a very anxious time. The strategies assessed included immunohistochemistry (IHC) and microsatellite instability (MSI) as the first tests used to identify tumours with MMR deficiency. The external assessment group (EAG) commented that it did not find data on the time taken to get test results when using IHC or MSI. However, clinical experts commented that based on their experience in the NHS the time taken to get IHC results (about 1 day) is much shorter than for MSI results (about 6 weeks). They highlighted that when MSI testing is used, information may not be available for the first multidisciplinary team discussions on a person's cancer where decisions about treatment and further testing are made. They also noted that there is a risk that results arriving weeks later, separate to the histopathology report, may be missed and not acted on. Also, if a person's tumour is quickly identified as having MMR deficiency, they are able to be considered for clinical trials for new treatments such as immunotherapies. Clinical experts highlighted that it is important for everyone with cancer to have the opportunity to enter relevant clinical trials, and that this is a way to access new treatments which could benefit them. The committee noted a consultation comment that increased genomic analysis of tumours and streamlining of the testing pipeline could mean that MSI test results based on next generation sequencing technology will be available in a shorter time. However, the committee noted that this is a future development and still may not mean that MSI test results are available as quickly as IHC test results. Clinical experts also commented that an advantage of IHC testing is that it shows which MMR gene is likely to contain a pathogenic mutation. The committee concluded that there may be benefits for people and their clinicians from using IHC compared with MSI as a first test for potential Lynch syndrome.
# Clinical effectiveness
## The relative accuracy of IHC and MSI testing is uncertain, but IHC may detect more people with Lynch syndrome
The EAG commented that in studies assessing both MSI and IHC testing on the same sample of people (4 studies, see section 3.12) there was no statistically significant difference between the accuracy of the tests. But the committee noted that the studies were unlikely to be powered to show any difference. The committee preferred to use comparative estimates of sensitivity and specificity for IHC and MSI from the individual studies, rather than ranges of midpoint estimates from all 4 studies. It noted that sensitivity estimates were generally higher for IHC than for MSI (that is, using IHC as the first test may detect more people with Lynch syndrome). Clinical experts commented that a concern about MSI testing is that it may miss tumours with mutations in MSH6 and they highlighted the relatively high prevalence of mutations in this gene in Lynch syndrome-associated endometrial cancer (see section 3.6). The committee further noted that the level of concordance between IHC and MSI studies was in a range of 68% to 100% (see section 3.13). The committee concluded that there was uncertainty about the relative accuracy of IHC and MSI testing for potential Lynch syndrome done on endometrial tumour samples, but there was some evidence that IHC may detect more people with Lynch syndrome.
## The PETALS study is highly relevant for this assessment
An unpublished manuscript of the PETALS study was given to the committee as academic in confidence. This study has now published as Ryan et al. (2020). The study authors commented that their results showed that IHC was more sensitive than MSI. The sensitivity of MSI testing was 56.3% compared with 100% for IHC testing. The MSI test used in PETALS was the Promega MSI analysis system v1.2, which assesses 5 mononucleotide repeat markers. The committee noted that this was in general agreement with the results of the 4 studies directly comparing IHC and MSI in the EAG's systematic review (see section 4.4). The study authors also commented that people with both MSI and IHC test results that did not indicate potential Lynch syndrome did not have the reference standard (germline testing) because of the cost. The committee noted that this may be a limitation of the study. It concluded that PETALS was likely to be highly relevant for this assessment. This was because it was a recent UK study that assessed IHC, MSI and MLH1 promoter hypermethylation testing in a population in the NHS who were newly diagnosed with endometrial cancer.
# Cost effectiveness
## There is uncertainty about the effect of colonoscopic surveillance on colorectal cancer incidence
For the effect of colonoscopic surveillance on colorectal cancer incidence in the model, the EAG used a hazard ratio of 0.387 from Järvinen et al. (2000). The committee noted that this was an observational study and the true effect size was uncertain. The EAG did a scenario analysis in which no benefit of colonoscopy on colorectal cancer incidence was assumed. This was the only scenario in which the incremental cost-effectiveness ratios (ICERs) for all of the testing strategies compared with no testing were above £20,000 per quality-adjusted life year (QALY) gained, although the ICER for strategy 4 (IHC then MLH1 promoter methylation testing) was only just higher. Clinical experts commented that it would not be ethical to do a trial in which people with Lynch syndrome were randomised to have colonoscopic surveillance or not. They highlighted that the recent Guidelines for the management of hereditary colorectal cancer from the British Society of Gastroenterology (BSG)/Association of Coloproctology of Great Britain and Ireland (ACPGBI)/United Kingdom Cancer Genetics Group (UKCGG) recommend colonoscopic surveillance for people with Lynch syndrome. The committee concluded that although there is uncertainty about the effect of colonoscopic surveillance on colorectal cancer incidence, the EAG's scenario assuming no benefit was extreme and unlikely to be realistic.
## There is uncertainty about the benefit of gynaecological surveillance, but raising awareness of symptoms is likely to improve earlier detection
Clinical experts commented that the extent of surveillance for gynaecological cancers offered to people with Lynch syndrome varies across the NHS. There was also considerable uncertainty about how effective this surveillance is in reducing the occurrence or severity of gynaecological cancer. The EAG included the cost and impact of gynaecological surveillance in its base-case model but highlighted that removing it in a scenario analysis did not have a large effect on results. Clinical and patient experts (see section 4.1) commented that, even if gynaecological surveillance is not done, raising awareness of the early symptoms of gynaecological cancers for people with Lynch syndrome is likely to improve early diagnosis.
## The costs of straight to germline testing may have been underestimated
Strategy 11 assessed the costs and benefits of going straight to germline testing for people diagnosed with endometrial cancer. That is, no first testing of tumour samples to identify people likely to have Lynch syndrome. Clinical experts commented that this would result in more variants of uncertain significance being detected (that is, mutations in MMR genes which may or may not cause Lynch syndrome). This is because initial tumour tests rule out non-pathogenic mutations (with no MMR deficiency in the tumour). This would mean staff time would be needed to analyse and assess if the person should be considered as having Lynch syndrome. Tests on endometrial tumour tissue may be needed to determine if the tumour was MMR-deficient. Costs related to this were not included in the economic model. In addition, clinical experts commented that if everyone with endometrial cancer had germline testing this would drastically increase the workload of genetic services, who would need to offer genetic counselling to ensure informed consent for the tests. Clinical experts also highlighted that there have been fewer studies done on Lynch syndrome-causing mutations for some ethnic groups, so there were likely to be more variants of uncertain significance identified by a straight to germline testing strategy (without the benefit of information from the tumour tests). The committee concluded that the costs of strategy 11 were likely to have been underestimated in the model.
## The effect of cancer on health-related quality of life is likely to have been underestimated, which undervalues the benefit of diagnosing Lynch syndrome
In the economic model, a reduction in health-related quality of life for people with colorectal cancer was only assumed to happen at stage 4 of the disease. A relatively small reduction in health-related quality of life for people with endometrial cancer was also assumed, which lasted for only 1 year in the model. A scenario analysis in which people with stage 3 colorectal cancer also had reduced health-related quality of life increased the incremental QALY gain for all strategies compared with no testing (and cost effectiveness compared with no testing). The committee concluded that the effect of cancer on health-related quality of life was likely to have been underestimated in the model, so the cost effectiveness of testing for Lynch syndrome may also have been underestimated.
## There is uncertainty about the costs of testing for Lynch syndrome
The EAG explained that the post-test clinic-related costs and follow-up costs it had used in its model (about £141) were for the time taken to give people their test results. Clinical experts commented that this cost was likely to be an underestimate. The committee also discussed the costs for the tests used in the base-case model. The EAG commented that costs of testing were reducing over time. It had used cost estimates from a micro-costing study (Ryan et al. 2019) in a scenario analysis to investigate this, which were much lower than the base-case values. Using these lower costs improved the cost effectiveness of testing for Lynch syndrome. The committee concluded that there was some uncertainty about the true costs associated with testing for Lynch syndrome.
## It is appropriate to use a linked-evidence approach to estimate the cost effectiveness of testing for Lynch syndrome after endometrial cancer
The EAG did not find any evidence on the effect on clinical outcomes of testing for Lynch syndrome when people were diagnosed with endometrial cancer. So, it used a linked-evidence approach to assess:
how many people with Lynch syndrome each of the strategies would identify and
the effect of changes to care for people with a diagnosis on their future incidence of endometrial and colorectal cancer (and for their families).A clinical expert commented that their hospital has been routinely testing for Lynch syndrome in everyone with endometrial cancer for about 5 years. This has led to Lynch syndrome being identified in many families who otherwise would not have known. It has also meant that relatives can start cancer surveillance and risk-reducing measures. Clinical experts also highlighted the strong link between Lynch syndrome and increased risk of cancer. The committee also noted that the strategies all included the gold standard assessment (germline testing) to diagnose Lynch syndrome. The committee concluded that it was appropriate to use a linked-evidence approach to estimate the cost effectiveness of testing for Lynch syndrome after a diagnosis of endometrial cancer.
## Testing for Lynch syndrome for people with endometrial cancer is likely to be a cost-effective use of NHS resources
In the base case, all testing strategies had ICERs of under £20,000 per QALY gained compared with no testing. Excluding the scenario in which no benefit was assumed for colonoscopic surveillance on colorectal cancer incidence (which the committee considered was unrealistic, see section 4.6), almost all of the testing strategies had ICERs under £20,000 per QALY gained compared with no testing in scenario analyses. In the scenario in which no benefit for aspirin was assumed, some strategies had ICERs of just over £20,000 per QALY gained. The committee also recalled that the effect of cancer on health-related quality of life was likely to have been underestimated in the model (see section 4.9). If a greater effect of cancer was used this would have improved the cost effectiveness of the testing strategies. The committee concluded that the most likely ICER for testing for Lynch syndrome for people with endometrial cancer was likely to be less than £20,000 per QALY gained. So testing was likely to be a cost-effective use of NHS resources.
## IHC then MLH1 promoter hypermethylation testing is likely to be the most cost-effective strategy
In its base case, the EAG used data from Lu et al. (2007) for the testing strategies' accuracy. This was because this study had individual patient data that could be used to estimate sensitivity and specificity for most of the strategies. But, because of a lack of data, the EAG had to make assumptions to estimate values for MSI testing then MLH1 promoter hypermethylation testing. The EAG explained that its assumption that 66% of MLH1 promoter hypermethylation tests done after MSI testing were correct was based on an estimate used in Snowsill et al. (2019) of the probability of MLH1 promoter hypermethylation in sporadic tumours with MSI. The committee noted that when test accuracy estimates from Lu et al. (2007), the PETALS study and a recent meta-analysis (Snowsill et al. 2019) were used in the model, IHC then MLH1 promoter hypermethylation testing was consistently the most cost-effective strategy. Accuracy estimates from Chao et al. (2019) had also been used in a scenario analysis (only for IHC alone and MSI alone). Unlike the other studies, sensitivity was higher for MSI than IHC in this study, and MSI testing and no testing extendedly dominated IHC testing. Clinical experts highlighted that the sensitivity estimate from this study was based on 6 people with Lynch syndrome (4 people whose Lynch syndrome was identified by IHC testing and 2 people whose Lynch syndrome was not identified). A clinical expert highlighted that the 2 people whose Lynch syndrome was not identified by IHC had mutations in either the MSH2 or MSH6 gene. They explained that pathogenic mutations in these genes in particular often show some expression on IHC, which can make identifying MMR deficiency more difficult. They highlighted that the sensitivity of IHC to detect such mutations depends on the expertise of the pathologist and will be improved by following guidance such as the British Association of Gynaecological Pathologist's guidance on interpretation of MMR IHC. The committee concluded that, based on the base case and scenario analyses, IHC then MLH1 promoter hypermethylation testing (then germline testing to confirm a Lynch syndrome diagnosis) was likely to be the most cost-effective strategy.
## MLH1 promoter hypermethylation testing should be done if IHC is abnormal with loss of MLH1 protein expression
The committee considered under what circumstances MLH1 promoter hypermethylation testing should be done after IHC for MMR proteins. Clinical experts commented that MLH1 promoter hypermethylation testing may be done if there is loss of PMS2 expression alone. This could mean that people with Lynch syndrome caused by PMS2 mutations would be missed if detection of MLH1 promoter hypermethylation in the tumour prevents germline genetic testing that would identify PMS2 mutations. Clinical experts further commented that isolated loss of PMS2 protein expression is likely to be rare, and could be because of artefacts of MLH1 protein expression that are mistaken for normal expression. The committee concluded that there was too much uncertainty to recommend MLH1 promoter hypermethylation testing if IHC showed loss of PMS2 expression alone, and this should be done only if IHC also shows loss of MLH1 protein expression in the tumour.
## There is a lack of data for constitutional MLH1 promoter methylation testing
Clinical experts noted that the recommended testing strategy would not detect people with Lynch syndrome caused by constitutional epimutation of MLH1 (that is, methylation of the MLH1 promoter that is present in all cells in the body and is not acquired in the tumour). The committee noted that the EAG had not included testing non-tumour tissue for MLH1 promoter hypermethylation, as well as tumour tissue, in its economic model because of a lack of data to inform the clinical effectiveness of this. Clinical experts commented that constitutional MLH1 promoter methylation is likely to be rare, although prevalence may be underestimated because of lack of testing to identify it. The committee concluded that based on the EAG's model it was not able to make a recommendation on testing for constitutional MLH1 promoter methylation.
## Laboratories doing testing recommended in this guidance should take part in recognised external quality assurance programmes
Clinical experts emphasised the importance of quality assurance to ensure that IHC testing for MMR proteins is done correctly. They also highlighted the British Association of Gynaecological Pathologists' recommended terminology for reporting mismatch repair protein immunohistochemistry with or without MLH1 promoter methylation results. The committee concluded that laboratories doing IHC testing for MMR proteins, MLH1 promoter hypermethylation testing or germline genetic testing should take part in a recognised external quality assurance programme.
# Research considerations
## Future developments in testing, interventions and increased testing for Lynch syndrome may affect cost effectiveness
The committee noted that costs and other parameter estimates used in the economic model can change over time, which may affect the cost effectiveness of testing. For example, if more testing for Lynch syndrome increases the number of people with known Lynch syndrome in the general population, fewer people with the condition will need testing after endometrial cancer, and the prevalence of the condition for those tested will decrease. This could reduce the cost effectiveness of testing. However, the committee noted that in sensitivity analysis decreasing the prevalence of Lynch syndrome to 1.6% only increased the ICER for strategy 4 to about £13,500 per QALY gained. Clinical experts also highlighted ongoing research on further interventions that could be used for people with Lynch syndrome. The committee also noted that the costs of sequencing DNA are decreasing. It recognised that emerging developments, such as next generation sequencing to test for MSI as part of tumour characterisation, could improve sensitivity to detect MSI in endometrial tumours. The committee concluded that future developments may affect the clinical and cost effectiveness of testing strategies, or their relative cost effectiveness compared with each other. It also concluded that it is important to monitor future developments to identify if any changes to the recommendations are needed.
## It is important to monitor the effect of more widespread testing for Lynch syndrome to make sure that the expected benefits are seen in the NHS
The committee considered it important to monitor the effect of adopting testing for Lynch syndrome for people with endometrial cancer. For example:
the number of people tested (including relatives of people with Lynch syndrome identified after endometrial cancer who have cascade testing)
the number diagnosed with Lynch syndrome (after endometrial cancer and their relatives) and
the uptake of surveillance and risk-reducing interventions.Clinical experts commented that there are plans to set up a national registry for Lynch syndrome, but no funding for this work has yet been identified. The committee concluded that it is important to monitor the outcomes related to implementing more widespread testing for Lynch syndrome after endometrial cancer, to make sure that the expected benefits, as estimated by the model, are seen in the NHS.
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{'Recommendations': "Offer testing for Lynch syndrome to people who are diagnosed with endometrial cancer. Use immunohistochemistry (IHC) to identify tumours with mismatch repair (MMR) deficiency:\n\nIf IHC is abnormal with loss of MLH1, or loss of both MLH1 and PMS2 protein expression, do MLH1 promoter hypermethylation testing of tumour DNA. If MLH1 promoter hypermethylation is not detected, offer germline genetic testing to confirm Lynch syndrome.\n\nIf IHC is abnormal with loss of MSH2, MSH6 or isolated PMS2 protein expression, offer germline genetic testing to confirm Lynch syndrome.\n\nHealthcare professionals should inform people about the possible implications of test results for both themselves and their relatives, and give support and information. Discussion of genetic testing and obtaining consent should be done by a healthcare professional with appropriate training.\n\nLaboratories doing IHC for MMR proteins, MLH1 promoter hypermethylation testing or germline genetic testing should take part in a recognised external quality assurance programme.\n\nWhy the committee made these recommendations\n\nLynch syndrome is an inherited condition that increases the risk of certain types of cancer, including endometrial and colorectal cancer. NICE recommends testing for Lynch syndrome after a colorectal cancer diagnosis. But endometrial cancer is often the first cancer that people with Lynch syndrome will have. So, Lynch syndrome could be identified earlier if tests are done after a diagnosis of endometrial cancer.\n\nIf Lynch syndrome is diagnosed, treatment and surveillance can be offered to reduce the risk of having another Lynch syndrome-associated cancer (in particular colorectal cancer) or identify it earlier. Genetic testing for Lynch syndrome can also be offered to relatives with the aim of preventing Lynch syndrome-associated cancer developing or detecting it at an early stage.\n\nSeveral types of tests can be done in different orders and combinations to see if endometrial cancer is likely to have been caused by Lynch syndrome. Economic modelling has shown that IHC testing then MLH1 promoter testing is likely to be the most cost-effective approach. If both these tests show that a person may have Lynch syndrome, genetic testing of a person's non-tumour DNA should be done to confirm this.\n\nIt is important that support and information are available for people deciding to be tested for Lynch syndrome.", 'The diagnostic tests': "# Clinical need and practice\n\nLynch syndrome is an inherited genetic condition associated with an increased risk of several cancers, particularly endometrial and colorectal cancer. It is caused by mutations in, or near, the DNA sequence of mismatch repair (MMR) genes. If a person has Lynch syndrome, these mutations are in every cell of their body and can be identified by genetic testing of non-tumour tissue. This testing shows mutations inherited by a person in their 'germline' instead of those that are only in cancerous tissue.\n\nIdentifying Lynch syndrome at the point of endometrial cancer diagnosis could:\n\nprevent other cancers in people with Lynch syndrome (such as colorectal cancer) through increased surveillance and strategies to reduce risk\n\nhelp to identify relatives with Lynch syndrome, to reduce their risk of Lynch syndrome-associated cancers or increase early detection of cancer\n\nhelp relatives diagnosed at an early age to consider family planning and, if they wish, have risk-reducing interventions, for example, a hysterectomy.\n\nCurrently, testing for Lynch syndrome in people diagnosed with endometrial cancer is often not done, or may only be done for people with an identified risk factor for the condition. This could be age at diagnosis or a family history of Lynch syndrome-related cancers. Clinical experts commented that even if tumour testing for potential Lynch syndrome is routinely done, a referral to clinical genetics services may still be needed if the tumour tests do not indicate Lynch syndrome but a person has an identified risk factor that suggests the condition is likely.\n\n# The interventions\n\nMost endometrial cancers do not develop because of Lynch syndrome (sporadic cancer). Tests done on endometrial tumour tissue can help identify how likely it is that the cancer happened because a person has Lynch syndrome and if genetic testing of non-tumour tissue should be done to check for the condition.\n\nTesting for microsatellite instability (MSI) in endometrial tumour tissue or testing for loss of MMR proteins using immunohistochemistry (IHC), or doing both, can show potential Lynch syndrome. But both tests can give false positive results for potential Lynch syndrome. So, another test (MLH1 promoter hypermethylation testing) can be done on tumour tissue if MSI is present or if IHC shows loss of MLH1 protein. If MLH1 promoter hypermethylation is present in the tumour the cancer is likely to be sporadic, instead of being caused by Lynch syndrome.\n\nThis assessment includes different combinations of IHC, MSI and MLH1 promoter hypermethylation testing done on endometrial tumour tissue to see if the cancer is likely to have been caused by Lynch syndrome.\n\nAll strategies include final genetic testing of non-tumour tissue to make a diagnosis of Lynch syndrome (germline testing). Sometimes this testing can show changes in the sequences of the MMR genes, but it is not known if these changes cause Lynch syndrome or not. These are called variants of uncertain significance.\n\n# The comparator\n\nThe comparator was no testing to identify Lynch syndrome for people with endometrial cancer.", 'Evidence': "The diagnostics advisory committee considered evidence on testing strategies using immunohistochemistry (IHC) and microsatellite instability (MSI) testing for Lynch syndrome from several sources. Full details of all the evidence are in the committee papers.\n\nThe external assessment group (EAG) did a systematic review to identify evidence on the clinical effectiveness and diagnostic accuracy of IHC- and MSI-based testing strategies for detecting Lynch syndrome in people with endometrial cancer.\n\n# Test performance\n\nThe EAG identified 41\xa0studies (reported in 44\xa0papers) with data on the test accuracy of IHC- and MSI-based strategies for detecting Lynch syndrome in people with endometrial cancer, prevalence of Lynch syndrome in this population, and concordance of IHC and MSI testing done on endometrial tumour samples. One unpublished study (PETALS) was also available as academic in confidence (this study has now published as Ryan et al. 2020).\n\nTwo studies were done in the UK (Anagnostopoulos et al. 2017 and PETALS). Nine studies (Backes et al. 2009, Bruegl et al. 2017, Buchanan et al. 2014, Dillon et al. 2017, Dudley et al. 2015, Egoavil et al. 2013, Hampel et al. 2006, PETALS, Svampane et al. 2014) were in unselected populations. That is, all patients diagnosed with endometrial cancer during the study's recruitment period were included.\n\nSeven complete test accuracy studies were identified. These were studies in which people who had IHC or MSI testing, with or without MLH1 promoter hypermethylation testing, went on to have reference standard testing whatever the results of the index tests were. The reference standard used was germline testing (testing of non-tumour tissue) for Lynch syndrome-associated mutations in mismatch repair (MMR) genes. The EAG only included studies in which at least 95% of people who had index tests also had the reference standard test.\n\nData on the prevalence of Lynch syndrome from 33\xa0studies and concordance between IHC and MSI-based testing in 23\xa0studies were also extracted.\n\n## Prevalence of Lynch syndrome in people with endometrial cancer\n\nPrevalence of Lynch syndrome was lower in studies that recruited unselected samples of people (which matches the population for this assessment). The median value was 3.2%. In the studies with unselected samples, variants in the MSH6 MMR gene were the most common, then MSH2.\n\n## Accuracy of index tests\n\nThe EAG did not do a meta-analysis of test accuracy because the few studies identified were heterogeneous. Individual patient data from Lu et al. (2007) were used to inform strategy accuracy estimates in the economic model base case.\n\nAccuracy of the index tests, that is, IHC- and MSI-based testing strategies used alone, in combination, and with or without subsequent MLH1 promoter hypermethylation testing, was compared against the reference standard to determine if a person did have Lynch syndrome.\n\nData on the accuracy of IHC alone (that is, without MLH1 promoter hypermethylation testing) were available from 5\xa0studies (Berends et al. 2003, Chao et al. 2019, Lu et al. 2007, Rubio et al. 2016, Tian et al. 2019). Sensitivity values ranged from 66.7% to 100%. Specificity values ranged from 6.5% to 83.3%.\n\nData on the accuracy of MSI testing alone (that is, without MLH1 promoter hypermethylation testing) were available from 4\xa0studies (Berends et al. 2003, Chao et al. 2019, Lu et al. 2007, Rubio et al. 2016). Sensitivity values ranged from 41.7% to 100%. Specificity values ranged from 69.2% to 88.9%.\n\nThere were data from 4\xa0studies on the accuracy of IHC- or MSI-based testing strategies when these tests were done before MLH1 promoter hypermethylation testing. The studies varied in when promoter hypermethylation testing was done:\n\nIn 2\xa0studies (Lu et al. 2007, Salvador et al. 2019) MLH1 promoter hypermethylation testing was done for tumours that were categorised as MSI-H or had IHC loss (MLH1 or MLH1 plus PMS2). In Lu et al. (2007), 92.3% of tumours tested were hypermethylated.\n\nIn Chao et al. (2019) MLH1 promoter hypermethylation testing was done only if MLH1 loss was seen on IHC; 80% of tumours tested were hypermethylated.\n\nIn Ring et al. (2016) the circumstances for MLH1 promoter hypermethylation testing were not reported.Sensitivity values ranged from 90.5% to 100%. Specificity values ranged from 6.6% to 92.3%.\n\nFour of the complete test accuracy studies assessed both IHC and MSI testing on the same population (Lu et al. 2007, Berends et al. 2003, Chao et al. 2019, Rubio et al. 2016). Point estimates for sensitivity ranged from 66.7% to 100% for IHC and from 41.7% to 100% for MSI. For specificity, point estimates for IHC ranged from 60.9% to 83.3%. For MSI the range was 69.2% to 89.9%. The EAG commented that there was no statistically significant difference between the tests.\n\n## Concordance between IHC and MSI testing\n\nComplete concordance between IHC and MSI testing was reported in 20\xa0studies. That is, in these studies IHC and MSI testing were both done on samples whatever the results of 1\xa0of the tests. There was a median agreement of 91.8% with a range of 68.2% to 100%.\n\n# Clinical effectiveness\n\nThe EAG did a systematic review to identify evidence on the benefits and harms of testing for Lynch syndrome for people with endometrial cancer and their relatives, with a focus on the benefits and harms of colorectal and endometrial cancer surveillance. No studies met the inclusion criteria.\n\n# Cost effectiveness\n\n## Systematic review of cost-effectiveness evidence\n\nThe EAG did a systematic review to find studies assessing the cost effectiveness of testing for Lynch syndrome in people with endometrial cancer using IHC- and MSI-based strategies, compared with no testing for Lynch syndrome. Five studies were identified (Resnick et al. 2009, Kwon et al. 2011, Bruegl et al. 2014, Goverde et al. 2016, Snowsill et al. 2019). Snowsill et al. (2019) was the only study that took a UK perspective. The EAG thought that Snowsill et al. (2019) provided a comprehensive reference model. It used this study and previous reviews of testing for Lynch syndrome for people with colorectal cancer (Snowsill et al. 2014; Snowsill et al. 2017) to inform its modelling approach.\n\n## Economic model\n\nThe EAG developed a de novo economic model to estimate the costs and benefits of offering testing to identify Lynch syndrome (using different testing strategies) for people with a new diagnosis of endometrial cancer. The EAG's model had 2\xa0parts. A decision tree (in Excel) modelled the accuracy and costs of the different testing strategies to identify people with Lynch syndrome after being diagnosed with endometrial cancer (known as probands; the first family member to have medical testing for a genetic condition). This also included testing for the relatives of people diagnosed with Lynch syndrome (cascade testing). A second model (in R) then modelled the longer-term effects of this diagnosis (and adopting surveillance and risk-reducing interventions) on colorectal and endometrial cancer incidence across the rest of people's lives. This was for both the first family member to have Lynch syndrome identified after endometrial cancer and their relatives.\n\n## Population\n\nThe age of the people in the cohort entering the model with recently diagnosed endometrial cancer was 48\xa0years old. Relatives diagnosed with Lynch syndrome could be any age between 25\xa0and 74\xa0years old. The prevalence of Lynch syndrome in this population (3.2%) was taken from the PETALS study. The proportion of each MMR gene mutation in people with Lynch syndrome diagnosed after endometrial cancer was pooled from 4\xa0studies (Hampel et al. 2006, Bruegl et al. 2017, Egoavil et al. 2013, Ryan et al. 2020 [PETALS study]).\n\n## Model inputs\n\nThe EAG used data from 1\xa0study (Lu et al. 2007) to inform estimates of sensitivity and specificity for the different test strategies for the model. One study was used for consistency (that is, accuracy estimates produced from the same population) and to avoid illogical results, which may have happened if different studies were used for different strategies. The EAG did not consider that pooling results across studies was appropriate because the few studies identified were heterogeneous. Data from a recent meta-analysis (Snowsill et al. 2019), Chao et al. (2019) and the PETALS study (Ryan et al. 2020) were used in scenario analyses.\n\nAge-related incidence of colorectal cancer for people with Lynch syndrome was taken from Snowsill et al. (2019). This was assumed to differ by which MMR gene was mutated and was estimated using gene specific data from the Prospective Lynch Syndrome Database. A log-normal distribution was fitted to the data to estimate the incidence of colorectal cancer over time. A hazard ratio of 0.387 (Järvinen et al. 2000) was applied to estimate the effect of colonoscopic surveillance on reducing the incidence of colorectal cancer. If a person was having colonoscopic surveillance because Lynch syndrome had been diagnosed, this was assumed to identify colorectal cancer at an earlier stage (as well as reducing incidence).\n\nIncidence data for endometrial cancer were taken from the Prospective Lynch Syndrome Database (Dominguez-Valentin et al. 2020). The incidence differed by which MMR gene was mutated. A fitted piecewise linear model was used to estimate annual incidence at different ages. Data from Cancer Research UK on uterine cancer survival statistics were used for the incidence of death from endometrial cancer, assuming no difference for people with and without Lynch syndrome.\n\nFemale relatives with Lynch syndrome could choose to have hysterectomy with removal of both ovaries and fallopian tubes (bilateral salpingo-oophorectomy), which eliminated all future risk of endometrial cancer. The uptake of this surgery increased with age, from 20% at 35\xa0years old to 80% at 75\xa0years old. The EAG highlighted considerable uncertainty about the benefit of gynaecological surveillance, and variation in practice across the UK. In its base case, the EAG assumed all female relatives with Lynch syndrome who were 25\xa0years or older (who had not had a hysterectomy) would have annual non-invasive gynaecological surveillance done by a GP. Of these, 10% would be referred for invasive surveillance (gynaecological examination, pelvic ultrasound, cancer antigen‑125 analysis and aspiration biopsy). Gynaecological surveillance was assumed to reduce mortality by 10.2% (Snowsill et al. 2017).\n\nMost costs were taken from work done for previous NICE guidance on testing for Lynch syndrome after colorectal cancer (Snowsill et al. 2017). Hospital-related costs were from the most current NHS reference tables. The EAG used test costs from the UK Genetic Testing Network (confirmed by clinical experts) in the base case.\n\nBaseline health-related quality of life for people in the model was calculated based on age and sex. Testing, a diagnosis of Lynch syndrome, surveillance and risk-reducing interventions were assumed to have no effect on health-related quality of life.\n\nIn the base case, a decrease in health-related quality of life for people with colorectal cancer was only assumed to occur at stage\xa04 (a multiplier of 0.789; Snowsill et al. 2017). Because this may underestimate the effect of colorectal cancer on a person's quality of life, the EAG did a scenario analysis in which people with stage\xa03 colorectal cancer also had a decrease in health-related quality of life. The health-related quality of life of people with endometrial cancer decreased by 0.036 (Snowsill et al. 2017) for 1\xa0year.\n\n## Base-case results\n\nWhen compared independently with no testing, all strategies had an incremental cost-effectiveness ratio (ICER) of less than £17,500 per quality-adjusted life year (QALY) gained. The fully incremental analysis (that is, all testing strategies compared against each other as well as no testing) is shown in table\xa01.\n\n\n\nStrategy\n\nIncremental costs\n\nIncremental QALYs\n\nICER\n\nNet monetary benefit (compared with no testing; using a maximum ICER of £20,000 per QALY gained)\n\nNo testing\n\n–\n\n–\n\n–\n\n£0\n\nStrategy\xa02: MSI then MLH1 promoter hypermethylation testing\n\n£520\n\n\n\nExtendedly dominated\n\n£323\n\nStrategy\xa04: IHC then MLH1 promoter hypermethylation testing\n\n£630\n\n\n\n£9,460\n\n£705\n\nStrategy\xa06: MSI then IHC then MLH1 promoter hypermethylation testing\n\n£90\n\n-0.0249\n\nDominated\n\n£124\n\nStrategy\xa03: IHC alone\n\n£160\n\n\n\n£133,330\n\n£570\n\nStrategy\xa01: MSI alone\n\n£50\n\n\n\n£250,000\n\n£529\n\nStrategy\xa08: IHC then MSI then MLH1 promoter hypermethylation testing\n\n£30\n\n-0.0012\n\nDominated\n\n£475\n\nStrategy\xa010: MSI and IHC then MLH1 promoter hypermethylation testing\n\n£20\n\n\n\nDominated\n\n£451\n\nStrategy\xa07: IHC then MSI\n\n£185\n\n\n\n£925,000\n\n£344\n\nStrategy\xa05: MSI then IHC\n\n£5\n\n\n\nDominated\n\n£341\n\nStrategy\xa09: MSI and IHC\n\n£45\n\n\n\nDominated\n\n£302\n\nStrategy\xa011: No index testing (straight to germline testing)\n\n£135\n\n-0.0019\n\nDominated\n\n£168\n\nAbbreviations in table: ICER, incremental cost-effectiveness ratio; IHC, immunohistochemistry; MSI, microsatellite instability; QALY, quality-adjusted life year.\n\nExtendedly dominated means the ICER for a given strategy is higher than that of the next, more effective, alternative that is not extendedly dominated or dominated (that is, it is dominated by a combination of 2\xa0alternatives and should not be used to calculate appropriate ICERs). Dominated means if a strategy has higher costs and worse outcomes than an alternative strategy.\n\nThe probabilistic ICER for strategy\xa04 was £11,600 per QALY gained compared with no testing (compared with a deterministic ICER of £9,420 per QALY gained). At a maximum ICER of £20,000 per QALY gained, which is what NICE normally considers a cost-effective use of NHS resources, this strategy had a 93% probability of being cost effective compared with no testing.\n\nThe EAG did several scenario analyses in its main report:\n\nScenario\xa01: Using alternative test accuracy estimates (for strategies\xa01, 2, 3\xa0and\xa04) from the PETALS study.\n\nScenario\xa02: Using alternative test costs from a micro-costing study (Ryan et al. 2019).\n\nScenario\xa03: Combining scenarios 1\xa0and\xa02.\n\nScenario\xa04: Including further disutility for colorectal cancer (for stage\xa03) and including the same utility for people with endometrial cancer as people with stage\xa04 colorectal cancer in their last year of life.\n\nScenario\xa05: Excluding gynaecological surveillance (cost and benefits).\n\nScenario\xa06: Colonoscopy assumed to be every 3\xa0years (instead of\xa02).\n\nScenario\xa07: Aspirin removed from model.\n\nScenario\xa08: Surveillance for colorectal cancer assumed to have no benefit.\n\nIn the fully incremental analysis in the base case, IHC then MLH1 promoter hypermethylation testing (strategy number\xa04) was the most cost-effective strategy. In all scenarios except scenario\xa08, this strategy had an ICER of less than £12,000 per QALY gained in fully incremental analyses. In scenario\xa08, the ICER was £20,740 per QALY gained. In all scenarios except scenario\xa04, all other strategies were either extendedly dominated (the ICER was higher than that of the next more effective alternative), fully dominated (had higher costs and worse outcomes than an alternative strategy) or had ICERs of over £90,000 per QALY gained (fully incremental analysis). In scenario\xa04, the ICER for IHC testing alone was £41,180 per QALY gained in the fully incremental analysis.\n\nThe EAG also did more scenario analyses in an addendum to its main report. In additional scenario\xa01, diagnostic accuracy estimates from a meta-analysis done for recent modelling work (Snowsill et al. 2019) were used instead of estimates from Lu et al. (2007). Accuracy data were only available for strategies using MSI and IHC alone (with or without subsequent MLH1 promoter hypermethylation; strategies 1\xa0to\xa04 in this assessment). In fully incremental analysis, IHC with MLH1 promoter hypermethylation testing had an ICER of £10,464 per QALY gained and IHC alone had an ICER of about £100,000 per QALY gained. MSI and MSI done before MLH1 promoter hypermethylation were either dominated or extendedly dominated.\n\nIn additional scenario\xa02, accuracy data from Chao et al. (2019) were used. Only accuracy estimates for IHC and MSI alone were available. Here, MSI and no testing extendedly dominated IHC testing and MSI testing had an ICER of £10,455 per QALY gained compared with no testing. In Chao et al. higher estimates of both sensitivity and specificity were seen for MSI testing than IHC testing.\n\nIn additional scenario analysis\xa03, people with variants of uncertain significance and people who were assumed to have Lynch syndrome did not gain any benefit from surveillance and risk-reducing interventions (in the base case, they were assumed to get the same benefit as people with Lynch syndrome). IHC with MLH1 promoter hypermethylation had an ICER of £9,514 per QALY gained and dominated or extendedly dominated all other strategies.", 'Committee discussion': "# Clinical need\n\n## It is likely that people and their families will benefit substantially if Lynch syndrome is identified after endometrial cancer is diagnosed\n\nA patient expert highlighted that identifying Lynch syndrome after a diagnosis of endometrial cancer means interventions and surveillance can be adopted to reduce the risk of other Lynch syndrome-associated cancers or detect them earlier. Another benefit is that it allows testing for the condition to be offered to relatives, who can be identified as having Lynch syndrome before they have cancer. The patient expert commented that if a person knows they have Lynch syndrome they can make lifestyle changes to help reduce their cancer risk. As well as offering clinical surveillance to people with Lynch syndrome, such as colonoscopies, the symptoms of Lynch syndrome-associated cancers can be highlighted to make sure people seek medical advice if they have symptoms. Knowing that they are at higher risk of gynaecological cancer may also help people make decisions about family planning. The committee noted that endometrial cancer is often the first Lynch syndrome-associated cancer that people are diagnosed with. So at this point there is an opportunity to identify Lynch syndrome before other associated cancers, such as colorectal cancer, develop. The committee concluded that people and their families would likely benefit substantially if Lynch syndrome was identified after endometrial cancer is diagnosed.\n\n## People should be informed of the possible implications of test results for both themselves and their families\n\nThere can be considerable anxiety and uncertainty associated with genetic testing for hereditary cancer syndromes such as Lynch syndrome. A patient expert explained that waiting for test results can be a very anxious time. Test results can have a substantial effect on a person, so it is very important that people understand the full implications of a diagnosis of Lynch syndrome, for themselves and their families. This is especially important for people with a learning disability, who may need support from a carer to fully engage in discussions about testing and to give informed consent. For people who have not had children yet, or who want more children, there may be anxiety and uncertainty about risk-reducing surgery, because after this it is not possible to give birth. Making this decision needs a good understanding of their risk of cancer (for example, based on their specific pathogenic variant of a mismatch repair [MMR] gene). People may also have concerns about the invasive nature of surveillance for cancer. The committee concluded that genetic counselling is very important for people with Lynch syndrome, or who are at risk of having Lynch syndrome, because it can help people understand if genetic testing is appropriate or not. It can also help people understand the importance of telling extended family about their risk of having Lynch syndrome and the benefits of being tested. The committee also noted the importance of developing information resources to help people decide about testing, and the need for these to be available at the appropriate time.\n\n# Testing strategies\n\n## IHC testing may give quicker results than MSI testing, which can give people more chances to join clinical trials\n\nA patient expert explained that waiting for test results can be a very anxious time. The strategies assessed included immunohistochemistry (IHC) and microsatellite instability (MSI) as the first tests used to identify tumours with MMR deficiency. The external assessment group (EAG) commented that it did not find data on the time taken to get test results when using IHC or MSI. However, clinical experts commented that based on their experience in the NHS the time taken to get IHC results (about 1\xa0day) is much shorter than for MSI results (about 6\xa0weeks). They highlighted that when MSI testing is used, information may not be available for the first multidisciplinary team discussions on a person's cancer where decisions about treatment and further testing are made. They also noted that there is a risk that results arriving weeks later, separate to the histopathology report, may be missed and not acted on. Also, if a person's tumour is quickly identified as having MMR deficiency, they are able to be considered for clinical trials for new treatments such as immunotherapies. Clinical experts highlighted that it is important for everyone with cancer to have the opportunity to enter relevant clinical trials, and that this is a way to access new treatments which could benefit them. The committee noted a consultation comment that increased genomic analysis of tumours and streamlining of the testing pipeline could mean that MSI test results based on next generation sequencing technology will be available in a shorter time. However, the committee noted that this is a future development and still may not mean that MSI test results are available as quickly as IHC test results. Clinical experts also commented that an advantage of IHC testing is that it shows which MMR gene is likely to contain a pathogenic mutation. The committee concluded that there may be benefits for people and their clinicians from using IHC compared with MSI as a first test for potential Lynch syndrome.\n\n# Clinical effectiveness\n\n## The relative accuracy of IHC and MSI testing is uncertain, but IHC may detect more people with Lynch syndrome\n\nThe EAG commented that in studies assessing both MSI and IHC testing on the same sample of people (4\xa0studies, see section\xa03.12) there was no statistically significant difference between the accuracy of the tests. But the committee noted that the studies were unlikely to be powered to show any difference. The committee preferred to use comparative estimates of sensitivity and specificity for IHC and MSI from the individual studies, rather than ranges of midpoint estimates from all 4\xa0studies. It noted that sensitivity estimates were generally higher for IHC than for MSI (that is, using IHC as the first test may detect more people with Lynch syndrome). Clinical experts commented that a concern about MSI testing is that it may miss tumours with mutations in MSH6 and they highlighted the relatively high prevalence of mutations in this gene in Lynch syndrome-associated endometrial cancer (see section\xa03.6). The committee further noted that the level of concordance between IHC and MSI studies was in a range of 68% to 100% (see section\xa03.13). The committee concluded that there was uncertainty about the relative accuracy of IHC and MSI testing for potential Lynch syndrome done on endometrial tumour samples, but there was some evidence that IHC may detect more people with Lynch syndrome.\n\n## The PETALS study is highly relevant for this assessment\n\nAn unpublished manuscript of the PETALS study was given to the committee as academic in confidence. This study has now published as Ryan et al. (2020). The study authors commented that their results showed that IHC was more sensitive than MSI. The sensitivity of MSI testing was 56.3% compared with 100% for IHC testing. The MSI test used in PETALS was the Promega MSI analysis system v1.2, which assesses 5\xa0mononucleotide repeat markers. The committee noted that this was in general agreement with the results of the 4\xa0studies directly comparing IHC and MSI in the EAG's systematic review (see section\xa04.4). The study authors also commented that people with both MSI and IHC test results that did not indicate potential Lynch syndrome did not have the reference standard (germline testing) because of the cost. The committee noted that this may be a limitation of the study. It concluded that PETALS was likely to be highly relevant for this assessment. This was because it was a recent UK study that assessed IHC, MSI and MLH1 promoter hypermethylation testing in a population in the NHS who were newly diagnosed with endometrial cancer.\n\n# Cost effectiveness\n\n## There is uncertainty about the effect of colonoscopic surveillance on colorectal cancer incidence\n\nFor the effect of colonoscopic surveillance on colorectal cancer incidence in the model, the EAG used a hazard ratio of 0.387 from Järvinen et al. (2000). The committee noted that this was an observational study and the true effect size was uncertain. The EAG did a scenario analysis in which no benefit of colonoscopy on colorectal cancer incidence was assumed. This was the only scenario in which the incremental cost-effectiveness ratios (ICERs) for all of the testing strategies compared with no testing were above £20,000 per quality-adjusted life year (QALY) gained, although the ICER for strategy\xa04 (IHC then MLH1 promoter methylation testing) was only just higher. Clinical experts commented that it would not be ethical to do a trial in which people with Lynch syndrome were randomised to have colonoscopic surveillance or not. They highlighted that the recent Guidelines for the management of hereditary colorectal cancer from the British Society of Gastroenterology (BSG)/Association of Coloproctology of Great Britain and Ireland (ACPGBI)/United Kingdom Cancer Genetics Group (UKCGG) recommend colonoscopic surveillance for people with Lynch syndrome. The committee concluded that although there is uncertainty about the effect of colonoscopic surveillance on colorectal cancer incidence, the EAG's scenario assuming no benefit was extreme and unlikely to be realistic.\n\n## There is uncertainty about the benefit of gynaecological surveillance, but raising awareness of symptoms is likely to improve earlier detection\n\nClinical experts commented that the extent of surveillance for gynaecological cancers offered to people with Lynch syndrome varies across the NHS. There was also considerable uncertainty about how effective this surveillance is in reducing the occurrence or severity of gynaecological cancer. The EAG included the cost and impact of gynaecological surveillance in its base-case model but highlighted that removing it in a scenario analysis did not have a large effect on results. Clinical and patient experts (see section\xa04.1) commented that, even if gynaecological surveillance is not done, raising awareness of the early symptoms of gynaecological cancers for people with Lynch syndrome is likely to improve early diagnosis.\n\n## The costs of straight to germline testing may have been underestimated\n\nStrategy\xa011 assessed the costs and benefits of going straight to germline testing for people diagnosed with endometrial cancer. That is, no first testing of tumour samples to identify people likely to have Lynch syndrome. Clinical experts commented that this would result in more variants of uncertain significance being detected (that is, mutations in MMR genes which may or may not cause Lynch syndrome). This is because initial tumour tests rule out non-pathogenic mutations (with no MMR deficiency in the tumour). This would mean staff time would be needed to analyse and assess if the person should be considered as having Lynch syndrome. Tests on endometrial tumour tissue may be needed to determine if the tumour was MMR-deficient. Costs related to this were not included in the economic model. In addition, clinical experts commented that if everyone with endometrial cancer had germline testing this would drastically increase the workload of genetic services, who would need to offer genetic counselling to ensure informed consent for the tests. Clinical experts also highlighted that there have been fewer studies done on Lynch syndrome-causing mutations for some ethnic groups, so there were likely to be more variants of uncertain significance identified by a straight to germline testing strategy (without the benefit of information from the tumour tests). The committee concluded that the costs of strategy\xa011 were likely to have been underestimated in the model.\n\n## The effect of cancer on health-related quality of life is likely to have been underestimated, which undervalues the benefit of diagnosing Lynch syndrome\n\nIn the economic model, a reduction in health-related quality of life for people with colorectal cancer was only assumed to happen at stage\xa04 of the disease. A relatively small reduction in health-related quality of life for people with endometrial cancer was also assumed, which lasted for only 1\xa0year in the model. A scenario analysis in which people with stage\xa03 colorectal cancer also had reduced health-related quality of life increased the incremental QALY gain for all strategies compared with no testing (and cost effectiveness compared with no testing). The committee concluded that the effect of cancer on health-related quality of life was likely to have been underestimated in the model, so the cost effectiveness of testing for Lynch syndrome may also have been underestimated.\n\n## There is uncertainty about the costs of testing for Lynch syndrome\n\nThe EAG explained that the post-test clinic-related costs and follow-up costs it had used in its model (about £141) were for the time taken to give people their test results. Clinical experts commented that this cost was likely to be an underestimate. The committee also discussed the costs for the tests used in the base-case model. The EAG commented that costs of testing were reducing over time. It had used cost estimates from a micro-costing study (Ryan et al. 2019) in a scenario analysis to investigate this, which were much lower than the base-case values. Using these lower costs improved the cost effectiveness of testing for Lynch syndrome. The committee concluded that there was some uncertainty about the true costs associated with testing for Lynch syndrome.\n\n## It is appropriate to use a linked-evidence approach to estimate the cost effectiveness of testing for Lynch syndrome after endometrial cancer\n\nThe EAG did not find any evidence on the effect on clinical outcomes of testing for Lynch syndrome when people were diagnosed with endometrial cancer. So, it used a linked-evidence approach to assess:\n\nhow many people with Lynch syndrome each of the strategies would identify and\n\nthe effect of changes to care for people with a diagnosis on their future incidence of endometrial and colorectal cancer (and for their families).A clinical expert commented that their hospital has been routinely testing for Lynch syndrome in everyone with endometrial cancer for about 5\xa0years. This has led to Lynch syndrome being identified in many families who otherwise would not have known. It has also meant that relatives can start cancer surveillance and risk-reducing measures. Clinical experts also highlighted the strong link between Lynch syndrome and increased risk of cancer. The committee also noted that the strategies all included the gold standard assessment (germline testing) to diagnose Lynch syndrome. The committee concluded that it was appropriate to use a linked-evidence approach to estimate the cost effectiveness of testing for Lynch syndrome after a diagnosis of endometrial cancer.\n\n## Testing for Lynch syndrome for people with endometrial cancer is likely to be a cost-effective use of NHS resources\n\nIn the base case, all testing strategies had ICERs of under £20,000 per QALY gained compared with no testing. Excluding the scenario in which no benefit was assumed for colonoscopic surveillance on colorectal cancer incidence (which the committee considered was unrealistic, see section\xa04.6), almost all of the testing strategies had ICERs under £20,000 per QALY gained compared with no testing in scenario analyses. In the scenario in which no benefit for aspirin was assumed, some strategies had ICERs of just over £20,000 per QALY gained. The committee also recalled that the effect of cancer on health-related quality of life was likely to have been underestimated in the model (see section\xa04.9). If a greater effect of cancer was used this would have improved the cost effectiveness of the testing strategies. The committee concluded that the most likely ICER for testing for Lynch syndrome for people with endometrial cancer was likely to be less than £20,000 per QALY gained. So testing was likely to be a cost-effective use of NHS resources.\n\n## IHC then MLH1 promoter hypermethylation testing is likely to be the most cost-effective strategy\n\nIn its base case, the EAG used data from Lu et al. (2007) for the testing strategies' accuracy. This was because this study had individual patient data that could be used to estimate sensitivity and specificity for most of the strategies. But, because of a lack of data, the EAG had to make assumptions to estimate values for MSI testing then MLH1 promoter hypermethylation testing. The EAG explained that its assumption that 66% of MLH1 promoter hypermethylation tests done after MSI testing were correct was based on an estimate used in Snowsill et al. (2019) of the probability of MLH1 promoter hypermethylation in sporadic tumours with MSI. The committee noted that when test accuracy estimates from Lu et al. (2007), the PETALS study and a recent meta-analysis (Snowsill et al. 2019) were used in the model, IHC then MLH1 promoter hypermethylation testing was consistently the most cost-effective strategy. Accuracy estimates from Chao et al. (2019) had also been used in a scenario analysis (only for IHC alone and MSI alone). Unlike the other studies, sensitivity was higher for MSI than IHC in this study, and MSI testing and no testing extendedly dominated IHC testing. Clinical experts highlighted that the sensitivity estimate from this study was based on 6\xa0people with Lynch syndrome (4\xa0people whose Lynch syndrome was identified by IHC testing and 2\xa0people whose Lynch syndrome was not identified). A clinical expert highlighted that the 2\xa0people whose Lynch syndrome was not identified by IHC had mutations in either the MSH2 or MSH6 gene. They explained that pathogenic mutations in these genes in particular often show some expression on IHC, which can make identifying MMR deficiency more difficult. They highlighted that the sensitivity of IHC to detect such mutations depends on the expertise of the pathologist and will be improved by following guidance such as the British Association of Gynaecological Pathologist's guidance on interpretation of MMR IHC. The committee concluded that, based on the base case and scenario analyses, IHC then MLH1 promoter hypermethylation testing (then germline testing to confirm a Lynch syndrome diagnosis) was likely to be the most cost-effective strategy.\n\n## MLH1 promoter hypermethylation testing should be done if IHC is abnormal with loss of MLH1 protein expression\n\nThe committee considered under what circumstances MLH1 promoter hypermethylation testing should be done after IHC for MMR proteins. Clinical experts commented that MLH1 promoter hypermethylation testing may be done if there is loss of PMS2 expression alone. This could mean that people with Lynch syndrome caused by PMS2 mutations would be missed if detection of MLH1 promoter hypermethylation in the tumour prevents germline genetic testing that would identify PMS2 mutations. Clinical experts further commented that isolated loss of PMS2 protein expression is likely to be rare, and could be because of artefacts of MLH1 protein expression that are mistaken for normal expression. The committee concluded that there was too much uncertainty to recommend MLH1 promoter hypermethylation testing if IHC showed loss of PMS2 expression alone, and this should be done only if IHC also shows loss of MLH1 protein expression in the tumour.\n\n## There is a lack of data for constitutional MLH1 promoter methylation testing\n\nClinical experts noted that the recommended testing strategy would not detect people with Lynch syndrome caused by constitutional epimutation of MLH1 (that is, methylation of the MLH1 promoter that is present in all cells in the body and is not acquired in the tumour). The committee noted that the EAG had not included testing non-tumour tissue for MLH1 promoter hypermethylation, as well as tumour tissue, in its economic model because of a lack of data to inform the clinical effectiveness of this. Clinical experts commented that constitutional MLH1 promoter methylation is likely to be rare, although prevalence may be underestimated because of lack of testing to identify it. The committee concluded that based on the EAG's model it was not able to make a recommendation on testing for constitutional MLH1 promoter methylation.\n\n## Laboratories doing testing recommended in this guidance should take part in recognised external quality assurance programmes\n\nClinical experts emphasised the importance of quality assurance to ensure that IHC testing for MMR proteins is done correctly. They also highlighted the British Association of Gynaecological Pathologists' recommended terminology for reporting mismatch repair protein immunohistochemistry with or without MLH1 promoter methylation results. The committee concluded that laboratories doing IHC testing for MMR proteins, MLH1 promoter hypermethylation testing or germline genetic testing should take part in a recognised external quality assurance programme.\n\n# Research considerations\n\n## Future developments in testing, interventions and increased testing for Lynch syndrome may affect cost effectiveness\n\nThe committee noted that costs and other parameter estimates used in the economic model can change over time, which may affect the cost effectiveness of testing. For example, if more testing for Lynch syndrome increases the number of people with known Lynch syndrome in the general population, fewer people with the condition will need testing after endometrial cancer, and the prevalence of the condition for those tested will decrease. This could reduce the cost effectiveness of testing. However, the committee noted that in sensitivity analysis decreasing the prevalence of Lynch syndrome to 1.6% only increased the ICER for strategy\xa04 to about £13,500 per QALY gained. Clinical experts also highlighted ongoing research on further interventions that could be used for people with Lynch syndrome. The committee also noted that the costs of sequencing DNA are decreasing. It recognised that emerging developments, such as next generation sequencing to test for MSI as part of tumour characterisation, could improve sensitivity to detect MSI in endometrial tumours. The committee concluded that future developments may affect the clinical and cost effectiveness of testing strategies, or their relative cost effectiveness compared with each other. It also concluded that it is important to monitor future developments to identify if any changes to the recommendations are needed.\n\n## It is important to monitor the effect of more widespread testing for Lynch syndrome to make sure that the expected benefits are seen in the NHS\n\nThe committee considered it important to monitor the effect of adopting testing for Lynch syndrome for people with endometrial cancer. For example:\n\nthe number of people tested (including relatives of people with Lynch syndrome identified after endometrial cancer who have cascade testing)\n\nthe number diagnosed with Lynch syndrome (after endometrial cancer and their relatives) and\n\nthe uptake of surveillance and risk-reducing interventions.Clinical experts commented that there are plans to set up a national registry for Lynch syndrome, but no funding for this work has yet been identified. The committee concluded that it is important to monitor the outcomes related to implementing more widespread testing for Lynch syndrome after endometrial cancer, to make sure that the expected benefits, as estimated by the model, are seen in the NHS."}
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https://www.nice.org.uk/guidance/dg42
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Evidence-based recommendations on testing strategies for Lynch syndrome for people with endometrial cancer.
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ac25dda3db42e99eabf1fd744bd3f3c66867d1c5
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nice
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Pressurised intraperitoneal aerosol chemotherapy for peritoneal carcinomatosis
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Pressurised intraperitoneal aerosol chemotherapy for peritoneal carcinomatosis
Evidence-based recommendations on pressurised intraperitoneal aerosol chemotherapy for peritoneal carcinomatosis in adults. This involves spraying the inside of the peritoneal cavity with chemotherapy.
# Recommendations
Evidence on the safety of pressurised intraperitoneal aerosol chemotherapy for peritoneal carcinomatosis shows that this procedure can cause serious but well-recognised side effects. Evidence on its efficacy is inadequate in quality. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE website.
Further research should be in the form of randomised controlled trials comparing pressurised intraperitoneal aerosol chemotherapy with standard care. Studies should report details of patient selection including type of tumour, the chemotherapy drugs used, survival and quality-of-life outcomes.# The condition, current treatments and procedure
# The condition
Peritoneal metastases commonly result from the regional spread of gastrointestinal, gynaecological and other malignancies. Peritoneal carcinomatosis is an advanced form of cancer associated with short survival and poor quality of life. It may lead to bowel obstruction, fluid build-up in the peritoneal cavity and pain.
# Current treatments
There is no curative treatment. Current standard treatment uses systemic chemotherapy or surgery for short-term palliation of complications such as bowel obstruction.
# The procedure
Pressurised intraperitoneal aerosol chemotherapy for peritoneal carcinomatosis is a laparoscopic procedure that is usually done using general anaesthesia. The aim is to distribute the drug uniformly to all surfaces of the abdomen and pelvis.
Trocars are inserted and the abdomen insufflated with carbon dioxide. Peritoneal biopsies or local partial peritonectomy may be done at this time. The chemotherapy is delivered using an aerosol device containing normothermic chemotherapy solution. This device is connected to a high-pressure injector, which is inserted into the abdomen through an access port. For operator safety, the procedure takes place in an operating room with laminar air flow. Once in position, the device is operated remotely. A laparoscopic camera can be used to visualise the treatment. The chemotherapy is kept in the insufflated peritoneum for about 30 minutes. The chemotherapy aerosol is then exsufflated using a closed extraction system. The trocars are removed, and the laparoscopy completed. The procedure is usually repeated several weeks later. One standard course of treatment comprises 3 procedures, usually given 6 weeks apart, although the timing can vary.
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{'Recommendations': 'Evidence on the safety of pressurised intraperitoneal aerosol chemotherapy for peritoneal carcinomatosis shows that this procedure can cause serious but well-recognised side effects. Evidence on its efficacy is inadequate in quality. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE website.\n\nFurther research should be in the form of randomised controlled trials comparing pressurised intraperitoneal aerosol chemotherapy with standard care. Studies should report details of patient selection including type of tumour, the chemotherapy drugs used, survival and quality-of-life outcomes.', 'The condition, current treatments and procedure': '# The condition\n\nPeritoneal metastases commonly result from the regional spread of gastrointestinal, gynaecological and other malignancies. Peritoneal carcinomatosis is an advanced form of cancer associated with short survival and poor quality of life. It may lead to bowel obstruction, fluid build-up in the peritoneal cavity and pain.\n\n# Current treatments\n\nThere is no curative treatment. Current standard treatment uses systemic chemotherapy or surgery for short-term palliation of complications such as bowel obstruction.\n\n# The procedure\n\nPressurised intraperitoneal aerosol chemotherapy for peritoneal carcinomatosis is a laparoscopic procedure that is usually done using general anaesthesia. The aim is to distribute the drug uniformly to all surfaces of the abdomen and pelvis.\n\nTrocars are inserted and the abdomen insufflated with carbon dioxide. Peritoneal biopsies or local partial peritonectomy may be done at this time. The chemotherapy is delivered using an aerosol device containing normothermic chemotherapy solution. This device is connected to a high-pressure injector, which is inserted into the abdomen through an access port. For operator safety, the procedure takes place in an operating room with laminar air flow. Once in position, the device is operated remotely. A laparoscopic camera can be used to visualise the treatment. The chemotherapy is kept in the insufflated peritoneum for about 30\xa0minutes. The chemotherapy aerosol is then exsufflated using a closed extraction system. The trocars are removed, and the laparoscopy completed. The procedure is usually repeated several weeks later. One standard course of treatment comprises 3\xa0procedures, usually given 6\xa0weeks apart, although the timing can vary.'}
|
https://www.nice.org.uk/guidance/ipg681
|
Evidence-based recommendations on pressurised intraperitoneal aerosol chemotherapy for peritoneal carcinomatosis in adults. This involves spraying the inside of the peritoneal cavity with chemotherapy.
|
ff25086238dda231c9235f2a0dabd0033c3ce73f
|
nice
|
Balloon cryoablation for Barrett's oesophagus
|
Balloon cryoablation for Barrett's oesophagus
Evidence-based recommendations on balloon cryoablation for Barrett’s oesophagus. This involves using a balloon filled with cold gas to destroy abnormal cells.
# Recommendations
Evidence on the safety and efficacy of balloon cryoablation for Barrett's oesophagus is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research. This could be in the form of randomised controlled trials or published registry data. Find out what only in research means on the NICE interventional procedures guidance page.
Patient selection should be done by clinicians experienced in managing Barrett's oesophagus.
Further research should report patient selection, longer-term follow up and complications, including oesophageal stricture.# The condition, current treatments and procedure
# The condition
Barrett's oesophagus happens when the normal stratified squamous epithelium in the oesophagus transforms into simple columnar epithelium. In some people, this condition may become malignant.
# Current treatments
Current management includes lifestyle change, acid-suppressing medicines, endoscopic mucosal resection, endoscopic submucosal dissection, ablative therapies and surgery. Ablative therapies include radiofrequency ablation, photodynamic therapy, argon plasma coagulation, laser ablation, multipolar electrocoagulation and cryotherapy. See the section on endoscopy treatments in NICE's guideline on Barrett's oesophagus: ablative therapy.
# The procedure
This procedure is usually done using sedation. A balloon catheter is inserted through an endoscope, aligned with the dysplastic tissue in the oesophagus, and inflated. Nitrous oxide is then sprayed through a radial diffuser head within the balloon aimed at the target tissue. The tissue is destroyed by the extreme cold. The nitrous oxide gas remains fully contained within the balloon and exits through the proximal end of the catheter.
The ablation sequence is repeated until all the abnormal cells have been destroyed. Multiple ablations can be done without removing the balloon. The procedure typically takes 15 to 20 minutes to complete.
|
{'Recommendations': "Evidence on the safety and efficacy of balloon cryoablation for Barrett's oesophagus is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research. This could be in the form of randomised controlled trials or published registry data. Find out what only in research means on the NICE interventional procedures guidance page.\n\nPatient selection should be done by clinicians experienced in managing Barrett's oesophagus.\n\nFurther research should report patient selection, longer-term follow up and complications, including oesophageal stricture.", 'The condition, current treatments and procedure': "# The condition\n\nBarrett's oesophagus happens when the normal stratified squamous epithelium in the oesophagus transforms into simple columnar epithelium. In some people, this condition may become malignant.\n\n# Current treatments\n\nCurrent management includes lifestyle change, acid-suppressing medicines, endoscopic mucosal resection, endoscopic submucosal dissection, ablative therapies and surgery. Ablative therapies include radiofrequency ablation, photodynamic therapy, argon plasma coagulation, laser ablation, multipolar electrocoagulation and cryotherapy. See the section on endoscopy treatments in NICE's guideline on Barrett's oesophagus: ablative therapy.\n\n# The procedure\n\nThis procedure is usually done using sedation. A balloon catheter is inserted through an endoscope, aligned with the dysplastic tissue in the oesophagus, and inflated. Nitrous oxide is then sprayed through a radial diffuser head within the balloon aimed at the target tissue. The tissue is destroyed by the extreme cold. The nitrous oxide gas remains fully contained within the balloon and exits through the proximal end of the catheter.\n\nThe ablation sequence is repeated until all the abnormal cells have been destroyed. Multiple ablations can be done without removing the balloon. The procedure typically takes 15\xa0to 20\xa0minutes to complete."}
|
https://www.nice.org.uk/guidance/ipg682
|
Evidence-based recommendations on balloon cryoablation for Barrett’s oesophagus. This involves using a balloon filled with cold gas to destroy abnormal cells.
|
4f63a1d625a39381cceda72a8456960095c6c1c0
|
nice
|
Balloon cryoablation for squamous dysplasia of the oesophagus
|
Balloon cryoablation for squamous dysplasia of the oesophagus
Evidence-based recommendations on balloon cryoablation for squamous dysplasia of the oesophagus. This involves using a balloon filled with cold gas to destroy abnormal cells.
# Recommendations
Evidence on the safety and efficacy of balloon cryoablation for squamous dysplasia of the oesophagus is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research. This could be in the form of randomised controlled trials or published registry data. Find out what only in research means on the NICE interventional procedures guidance page.
Patient selection should be done by clinicians experienced in managing squamous dysplasia of the oesophagus.
Further research should report patient selection, longer-term follow up and complications, including oesophageal stricture.# The condition, current treatments and procedure
# The condition
Squamous cells in the oesophagus may become dysplastic (squamous dysplasia). In some people, this condition may become malignant.
# Current treatments
Current management includes lifestyle change, acid-suppressing medicines, endoscopic mucosal resection, endoscopic submucosal dissection, ablative therapies and surgery. Ablative therapies include radiofrequency ablation, photodynamic therapy, argon plasma coagulation, laser ablation, multipolar electrocoagulation and cryotherapy.
# The procedure
This procedure is usually done using sedation. A balloon catheter is inserted through an endoscope, aligned with the dysplastic tissue in the oesophagus, and inflated. Nitrous oxide is then sprayed through a radial diffuser head within the balloon aimed at the target tissue. The tissue is destroyed by the extreme cold. The nitrous oxide gas remains fully contained within the balloon and exits through the proximal end of the catheter.
The ablation sequence is repeated until all the abnormal cells have been destroyed. Multiple ablations can be done without removing the balloon. The procedure typically takes 15 to 20 minutes to complete.
|
{'Recommendations': 'Evidence on the safety and efficacy of balloon cryoablation for squamous dysplasia of the oesophagus is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research. This could be in the form of randomised controlled trials or published registry data. Find out what only in research means on the NICE interventional procedures guidance page.\n\nPatient selection should be done by clinicians experienced in managing squamous dysplasia of the oesophagus.\n\nFurther research should report patient selection, longer-term follow up and complications, including oesophageal stricture.', 'The condition, current treatments and procedure': '# The condition\n\nSquamous cells in the oesophagus may become dysplastic (squamous dysplasia). In some people, this condition may become malignant.\n\n# Current treatments\n\nCurrent management includes lifestyle change, acid-suppressing medicines, endoscopic mucosal resection, endoscopic submucosal dissection, ablative therapies and surgery. Ablative therapies include radiofrequency ablation, photodynamic therapy, argon plasma coagulation, laser ablation, multipolar electrocoagulation and cryotherapy.\n\n# The procedure\n\nThis procedure is usually done using sedation. A balloon catheter is inserted through an endoscope, aligned with the dysplastic tissue in the oesophagus, and inflated. Nitrous oxide is then sprayed through a radial diffuser head within the balloon aimed at the target tissue. The tissue is destroyed by the extreme cold. The nitrous oxide gas remains fully contained within the balloon and exits through the proximal end of the catheter.\n\nThe ablation sequence is repeated until all the abnormal cells have been destroyed. Multiple ablations can be done without removing the balloon. The procedure typically takes 15 to 20\xa0minutes to complete.'}
|
https://www.nice.org.uk/guidance/ipg683
|
Evidence-based recommendations on balloon cryoablation for squamous dysplasia of the oesophagus. This involves using a balloon filled with cold gas to destroy abnormal cells.
|
167a2b42bbcdfc212f970f71cb12950a8d3113ba
|
nice
|
Nivolumab for advanced squamous non-small-cell lung cancer after chemotherapy
|
Nivolumab for advanced squamous non-small-cell lung cancer after chemotherapy
Evidence-based recommendations on nivolumab (Opdivo) for advanced squamous non-small-cell lung cancer in adults after chemotherapy.
# Recommendations
Nivolumab is recommended as an option for treating locally advanced or metastatic squamous non-small-cell lung cancer (NSCLC) in adults after chemotherapy, only if:
it is stopped at 2 years of uninterrupted treatment, or earlier if their disease progresses and
they have not had a PD‑1 or PD‑L1 inhibitor before. It is recommended only if the company provides nivolumab according to the commercial arrangement.
Why the committee made these recommendations
The treatment pathway for locally advanced or metastatic squamous NSCLC starts with a PD‑1 or PD‑L1 inhibitor or chemotherapy. Nivolumab would be used after chemotherapy. In line with clinical practice, nivolumab is a treatment option for people who have not had a PD‑1 or PD‑L1 inhibitor.
Evidence was collected in the Cancer Drugs Fund for people with advanced or metastatic squamous NSCLC having up to 2 years of nivolumab treatment in the NHS. The key clinical trial shows that people who have nivolumab live longer than those who have docetaxel, which is the most appropriate comparator. There is uncertainty about how long people should have nivolumab for, but evidence suggests that there is continued benefit when treatment is stopped at 2 years.
Nivolumab meets NICE's criteria to be considered a life‑extending treatment at the end of life. The cost‑effectiveness estimates for nivolumab compared with docetaxel are likely to be within what NICE considers to be an acceptable use of NHS resources. Therefore, it is now recommended in the NHS after chemotherapy for people who have not had a PD‑1 or PD‑L1 inhibitor before, if it is stopped at 2 years.# Information about nivolumab
# Marketing authorisation indication
Nivolumab (Opdivo, Bristol-Myers Squibb) has a marketing authorisation in the UK for 'the treatment of locally advanced or metastatic non‑small‑cell lung cancer after prior chemotherapy in adults'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price of nivolumab is £2,633 per 240 mg per 24‑ml vial (excluding VAT; BNF online, accessed March 2020). The company has a commercial arrangement. This makes nivolumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Bristol‑Myers Squibb, a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.
This review looks at data collected after time in the Cancer Drugs Fund (CDF) to address uncertainties identified during the original appraisal. Further information about the original appraisal can be found in the committee papers. As a condition of the CDF funding and the managed access arrangement, the company was required to collect updated efficacy data from the CheckMate 017 study for people with advanced squamous non‑small‑cell lung cancer (NSCLC). In addition, data were collected on nivolumab for people with squamous NSCLC after chemotherapy in the NHS through the CDF using the Systemic Anti-Cancer Therapy (SACT) dataset.
The committee was aware that several issues were resolved during the technical engagement stage, and agreed that:
the progression‑free survival curve using the hybrid exponential extrapolation underestimated observed progression-free survival, so the spline 1‑knot‑hazard gave a better fit and was appropriate to model progression‑free survival
it was appropriate to consider the full population regardless of PD‑L1 expression.
The committee recognised that there were remaining areas of uncertainty in the analyses presented (see technical report, table 2, page 17) and took these into account in its decision making. The committee discussed the following issues, which were outstanding after the technical engagement stage:
choice of parametric models to predict overall survival
the 2‑year stopping rule for nivolumab and the continued duration of treatment benefit if nivolumab is stopped at 2 years.
# Clinical need
## People with treated advanced squamous NSCLC value having nivolumab as a treatment option
People who have treatment with nivolumab see it as an effective treatment option that is generally well tolerated. The committee considered patient accounts of living with squamous NSCLC. Patient concerns were not only about their own health and wellbeing, but included the effect that living with cancer may have on their family members. The committee noted that some patients had experienced anxiety and distress because of the 2‑year stopping rule used in the original guidance. This was because they did not want to stop benefiting from treatment. Patients wanted treatment options to be personalised to their needs and be reassured that effective care would be available after a treatment had stopped if needed. The clinical expert submission suggested that in clinical practice, nivolumab would be used in people who had not had a PD‑1 or PD‑L1 inhibitor before. The committee concluded that people with previously treated squamous NSCLC value having nivolumab as a treatment option.
## Docetaxel alone is the most appropriate comparator
In the original appraisal, docetaxel monotherapy was considered the most relevant comparator. The committee was aware that since its publication, pembrolizumab and atezolizumab have been recommended for previously treated locally advanced or metastatic NSCLC (see NICE's technology appraisal guidance on atezolizumab for treating locally advanced or metastatic NSCLC after chemotherapy and pembrolizumab for treating PD-L1-positive NSCLC after chemotherapy). There have also been changes to treatment options for untreated disease (see NICE's technology appraisal guidance on pembrolizumab for untreated PD-L1-positive metastatic NSCLC). The CDF clinical lead confirmed that the treatment pathway had changed and because immunotherapies were now available for untreated disease, nivolumab was not used as often for previously treated disease. In line with NICE's methods guide for technology appraisals, the original scope was not changed for this CDF review. This meant that pembrolizumab and atezolizumab could not be considered comparators because they were recommended after the original guidance was published. Therefore, the committee concluded that docetaxel alone was the most appropriate comparator for this CDF review.
# Clinical effectiveness
## Nivolumab is clinically effective compared with docetaxel alone for people with squamous NSCLC after chemotherapy
There were new data from CheckMate 017, which is an open-label randomised trial. It included adults with squamous NSCLC, whose disease had progressed during or after treatment with 1 platinum combination chemotherapy. The committee noted that there were 135 patients in the nivolumab arm and 137 patients in the docetaxel arm. Patients were randomised to have either nivolumab (3 mg per kg, the recommended dose in the summary of product characteristics at the time) or docetaxel. The hazard ratio using 5‑year data from CheckMate 017 showed nivolumab was associated with a statistically significant improvement in overall survival compared with docetaxel (the exact data are confidential and cannot be reported here). The committee concluded that nivolumab was clinically effective compared with docetaxel alone for people with squamous NSCLC after chemotherapy.
## Results from CheckMate 017 are generalisable to the NHS in England
The committee was aware that as well as new data from CheckMate 017, there were new SACT data. These were collected from 348 people who had nivolumab in the CDF, with a median follow up of 487 days (with a range of 5 months to 20 months). The median treatment duration was 3.5 months. The overall survival estimates using the SACT data were similar to CheckMate 017 data. The committee concluded that results from CheckMate 017 were generalisable to the NHS in England.
# Dosing
## The new dosage of nivolumab was not used in CheckMate 017 but is unlikely to have a large effect on clinical- and cost-effectiveness results
At the time of the original appraisal, the recommended dose of nivolumab in its summary of product characteristics was 3 mg per kg every 2 weeks, but this has since changed to 240 mg every 2 weeks. The company assumed that the new dose had the same clinical effectiveness as the previously recommended dose of 3 mg per kg. The committee understood that there were no clinical‑effectiveness data using the new dosage. The CDF clinical lead advised that the dose change for nivolumab had been accepted by the regulatory body and was already being used in clinical practice in the NHS in England. The committee concluded that although it had not seen clinical‑effectiveness evidence for the new dosage, it was unlikely to have had a large effect on the clinical- and cost‑effectiveness results.
# Economic model
## The company's economic model is suitable for decision making
The updated model used the same approach as the original appraisal. The model had 3 health states: progression‑free disease, progressed disease and death. Health‑state occupancy over time was informed by overall survival and progression‑free survival curves fitted to data from CheckMate 017. The company modelled nivolumab using clinical‑effectiveness data for the 3 mg per kg dose, but applied the costs of the currently recommended flat dose of 240 mg every 2 weeks. The committee considered that this approach was appropriate and concluded that the company's model was suitable for decision making.
# Modelling overall survival and progression-free survival
## The company's spline hazard 1-knot model is appropriate for progression-free survival
In the previous appraisal, the committee considered that the most appropriate method of extrapolation was applying an exponential curve after the trial data split at 2.2 months (hybrid exponential). This method reduced the influence of data collected before the first radiological assessment on the long‑term extrapolation. But, the hybrid exponential extrapolation did not fit well with the long‑term data in CheckMate 017 and consistently underestimated observed progression‑free survival. The company fitted several models to the updated 5‑year progression‑free survival data from CheckMate 017 for both treatment arms and preferred the spline 1‑knot normal curve for its base-case analysis. At technical engagement, it was agreed that extrapolation of progression‑free survival using the spline hazard 1‑knot model was appropriate in both the nivolumab and docetaxel treatment arms. The committee concluded that the company's spline hazard 1‑knot model was clinically plausible.
## The company's spline hazard 2‑knot model is appropriate for overall survival
The committee and the company agreed that the 5‑year data suggested that the generalised gamma distribution (preferred by the committee in the original appraisal) was likely to underestimate overall survival. The company fitted several models to the updated 5‑year overall survival data from CheckMate 017 for both treatment arms and preferred the spline 2‑knot hazard model for its base-case analysis. The ERG stated that overall survival may be plausibly modelled using the spline 2‑knot hazard, the spline 1‑knot hazard or the Gompertz models. The committee recognised that the 5‑year data gave greater certainty in survival extrapolation, noting that overall survival estimates did not change to a large extent with the 3 plausible choices of extrapolation models. However, the additional follow‑up data were for a population of people who had nivolumab without a stopping rule in place. So, the committee also took into account the percentage of people from CheckMate 017 who continued having treatment over the time horizon of the 5‑year follow‑up data. The committee concluded that it was clinically plausible to model overall survival using the spline 2‑knot hazard model to extrapolate the 5‑year data.
# Stopping rule and continued treatment effect
## It is likely that nivolumab's survival benefit continues after it is stopped
The company preferred to include a 2‑year stopping rule for nivolumab and assumed that the overall survival benefit would accumulate over the patients' lifetimes. At technical engagement, a professional organisation commented that it is clinically plausible that the immune system could be 'reset'. This means benefit from treatment could be maintained for years after nivolumab is stopped. The committee understood that the summary of product characteristics approved nivolumab while clinical benefit is seen or until treatment is no longer tolerated. The committee considered CheckMate 003, a single‑arm study that included 129 patients with squamous or non-squamous NSCLC, of whom 54 had squamous disease. It included people who had between 1 and 5 previous treatments, whose disease had progressed after at least 1 platinum- or taxane‑based chemotherapy, and who had stopped nivolumab treatment after 1.8 years. The company explained that data from CheckMate 003 showed that of 16 people who survived for 5 years and had no therapy after stopping nivolumab, 12 (75%) were still progression free. The committee agreed the study had evidence that supported the continued treatment effect but noted there was uncertainty because of the mixed population and small sample size (only 18 of the 129 patients with NSCLC had squamous NSCLC and a 3 mg per kg dose). The committee considered if data from CheckMate 153 would be informative. CheckMate 153 is an ongoing study investigating the effect of a maximum of 1‑year treatment with nivolumab, but it was not reported within the company submission. The company explained that findings of CheckMate 153 were similar to CheckMate 003 and showed survival benefit after the 1‑year stopping rule. The committee concluded that although there was uncertainty about how long people should have nivolumab, survival benefit was likely to continue for at least 3 years after treatment had stopped.
## The 2-year stopping rule for nivolumab is appropriate
The company preferred to include a 2‑year stopping rule for nivolumab. The committee recalled that CheckMate 017 did not specify a stopping rule and questioned if it was appropriate for the 2‑year stopping rule to remain. The ERG explained that there was no robust evidence to show the optimal duration of treatment with nivolumab. The committee recalled its earlier conclusion that it is plausible that a survival benefit from nivolumab would continue after it is stopped at 2 years. The committee also recalled that some patients experienced anxiety and distress because their treatment was stopped at 2 years (see section 3.1). The company suggested that this was not the experience of all patients and some may welcome a break from treatment. The CDF clinical lead explained that a 2‑year stopping rule for immunotherapies such as nivolumab was commonly being used in clinical practice for squamous NSCLC in the NHS in England. The committee concluded that a 2‑year stopping rule for nivolumab was appropriate because it was likely the benefit would continue after it is stopped. Also, there was no new evidence to show that continuing for longer gave additional benefit.
## When nivolumab is stopped at 2 years, it is acceptable to assume an additional survival benefit for at least 3 more years
In its base‑case analysis, the company preferred to assume that if nivolumab is stopped at 2 years, patients will continue to accumulate a lifetime survival benefit after that point. But, the committee was not convinced that the company's preferred lifetime survival benefit was plausible. In the original guidance, a 3‑year continued benefit after stopping nivolumab was accepted. The committee recognised that 5‑year data were now available from CheckMate 017. But, it noted that there was no new robust evidence on the duration of the continued benefit after stopping nivolumab that would change the assumption accepted in the original guidance. It was aware that removing the stopping rule and changing the duration of treatment benefit had a large effect on the cost-effectiveness results. It considered plausible durations of treatment benefit and believed that the cost‑effectiveness estimate preferred by the company was likely to be optimistic. This was because a lifetime treatment effect was not supported by the evidence. The committee considered that a cost‑effectiveness estimate based on 2 years of treatment and 3 years of continued benefit after treatment had stopped was likely to be conservative. This was because treatment effect was unlikely to stop immediately after 5 years. It also considered alternative treatment waning scenarios presented by the company during technical engagement, for which the modelling approach was adapted so that treatment benefit did not suddenly stop at a given time point. The exact treatment benefit duration was not known. The committee's preferred assumption was that if nivolumab was offered for 2 years of uninterrupted treatment, it was likely that its survival benefit would continue for 3 or more years after being stopped.
# End of life
## Nivolumab meets the end-of-life criteria
The committee considered the advice about life‑extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. In the original appraisal, the data showed that life expectancy for people with NSCLC was less than 24 months and that nivolumab extended life by at least 3 months. The committee noted that no evidence had been identified to change this conclusion. So, the committee concluded that nivolumab meets the end‑of‑life criteria and can be considered a life‑extending treatment at the end of life.
# Cost effectiveness
## The most plausible ICER is within what NICE considers an acceptable use of NHS resources
The company's preferred incremental cost‑effectiveness ratio (ICER) for nivolumab compared with docetaxel alone for people with squamous NSCLC was £35,710 per quality‑adjusted life year gained. This included a 2‑year stopping rule for nivolumab and continuing to accumulate a lifetime survival benefit after stopping treatment, which the committee did not feel was plausible. Using the committee's preferred assumptions of 2 years of treatment and 3 years of continued benefit once treatment had stopped, the most plausible ICER was likely to be below £40,168. This scenario was modelled using the company's preferred assumptions, including a spline 2‑knot hazard extrapolation for overall survival. Given that end‑of‑life criteria was met, the committee concluded that this was within what NICE considers a cost‑effective use of NHS resources.
# Other factors
No equality or social value judgement issues were identified.
# Conclusion
## Nivolumab is recommended for routine commissioning for people with advanced squamous NSCLC after chemotherapy
Considering new evidence from CheckMate 017, SACT data and the committee's preferred assumptions, all plausible cost‑effectiveness estimates were within what is considered a cost‑effective use of NHS resources when the end‑of‑life criteria were applied. Nivolumab was therefore recommended for use in the NHS as an option for treating locally advanced or metastatic squamous NSCLC in adults after chemotherapy, only if:
it is stopped at 2 years of uninterrupted treatment, or earlier if disease progresses and
they have not had a PD‑1 or PD‑L1 inhibitor before.
|
{'Recommendations': "Nivolumab is recommended as an option for treating locally advanced or metastatic squamous non-small-cell lung cancer (NSCLC) in adults after chemotherapy, only if:\n\nit is stopped at 2\xa0years of uninterrupted treatment, or earlier if their disease progresses and\n\nthey have not had a PD‑1 or PD‑L1 inhibitor before. It is recommended only if the company provides nivolumab according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nThe treatment pathway for locally advanced or metastatic squamous NSCLC starts with a PD‑1 or PD‑L1 inhibitor or chemotherapy. Nivolumab would be used after chemotherapy. In line with clinical practice, nivolumab is a treatment option for people who have not had a PD‑1 or PD‑L1 inhibitor.\n\nEvidence was collected in the Cancer Drugs Fund for people with advanced or metastatic squamous NSCLC having up to 2\xa0years of nivolumab treatment in the NHS. The key clinical trial shows that people who have nivolumab live longer than those who have docetaxel, which is the most appropriate comparator. There is uncertainty about how long people should have nivolumab for, but evidence suggests that there is continued benefit when treatment is stopped at 2\xa0years.\n\nNivolumab meets NICE's criteria to be considered a life‑extending treatment at the end of life. The cost‑effectiveness estimates for nivolumab compared with docetaxel are likely to be within what NICE considers to be an acceptable use of NHS resources. Therefore, it is now recommended in the NHS after chemotherapy for people who have not had a PD‑1 or PD‑L1 inhibitor before, if it is stopped at 2\xa0years.", 'Information about nivolumab': "# Marketing authorisation indication\n\nNivolumab (Opdivo, Bristol-Myers Squibb) has a marketing authorisation in the UK for 'the treatment of locally advanced or metastatic non‑small‑cell lung cancer after prior chemotherapy in adults'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price of nivolumab is £2,633 per 240\xa0mg per 24‑ml vial (excluding VAT; BNF online, accessed March 2020). The company has a commercial arrangement. This makes nivolumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Bristol‑Myers Squibb, a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.\n\nThis review looks at data collected after time in the Cancer Drugs Fund (CDF) to address uncertainties identified during the original appraisal. Further information about the original appraisal can be found in the committee papers. As a condition of the CDF funding and the managed access arrangement, the company was required to collect updated efficacy data from the CheckMate\xa0017 study for people with advanced squamous non‑small‑cell lung cancer (NSCLC). In addition, data were collected on nivolumab for people with squamous NSCLC after chemotherapy in the NHS through the CDF using the Systemic Anti-Cancer Therapy (SACT) dataset.\n\nThe committee was aware that several issues were resolved during the technical engagement stage, and agreed that:\n\nthe progression‑free survival curve using the hybrid exponential extrapolation underestimated observed progression-free survival, so the spline 1‑knot‑hazard gave a better fit and was appropriate to model progression‑free survival\n\nit was appropriate to consider the full population regardless of PD‑L1 expression.\n\nThe committee recognised that there were remaining areas of uncertainty in the analyses presented (see technical report, table\xa02, page\xa017) and took these into account in its decision making. The committee discussed the following issues, which were outstanding after the technical engagement stage:\n\nchoice of parametric models to predict overall survival\n\nthe 2‑year stopping rule for nivolumab and the continued duration of treatment benefit if nivolumab is stopped at 2\xa0years.\n\n# Clinical need\n\n## People with treated advanced squamous NSCLC value having nivolumab as a treatment option\n\nPeople who have treatment with nivolumab see it as an effective treatment option that is generally well tolerated. The committee considered patient accounts of living with squamous NSCLC. Patient concerns were not only about their own health and wellbeing, but included the effect that living with cancer may have on their family members. The committee noted that some patients had experienced anxiety and distress because of the 2‑year stopping rule used in the original guidance. This was because they did not want to stop benefiting from treatment. Patients wanted treatment options to be personalised to their needs and be reassured that effective care would be available after a treatment had stopped if needed. The clinical expert submission suggested that in clinical practice, nivolumab would be used in people who had not had a PD‑1 or PD‑L1 inhibitor before. The committee concluded that people with previously treated squamous NSCLC value having nivolumab as a treatment option.\n\n## Docetaxel alone is the most appropriate comparator\n\nIn the original appraisal, docetaxel monotherapy was considered the most relevant comparator. The committee was aware that since its publication, pembrolizumab and atezolizumab have been recommended for previously treated locally advanced or metastatic NSCLC (see NICE's technology appraisal guidance on atezolizumab for treating locally advanced or metastatic NSCLC after chemotherapy and pembrolizumab for treating PD-L1-positive NSCLC after chemotherapy). There have also been changes to treatment options for untreated disease (see NICE's technology appraisal guidance on pembrolizumab for untreated PD-L1-positive metastatic NSCLC). The CDF clinical lead confirmed that the treatment pathway had changed and because immunotherapies were now available for untreated disease, nivolumab was not used as often for previously treated disease. In line with NICE's methods guide for technology appraisals, the original scope was not changed for this CDF review. This meant that pembrolizumab and atezolizumab could not be considered comparators because they were recommended after the original guidance was published. Therefore, the committee concluded that docetaxel alone was the most appropriate comparator for this CDF review.\n\n# Clinical effectiveness\n\n## Nivolumab is clinically effective compared with docetaxel alone for people with squamous NSCLC after chemotherapy\n\nThere were new data from CheckMate\xa0017, which is an open-label randomised trial. It included adults with squamous NSCLC, whose disease had progressed during or after treatment with 1\xa0platinum combination chemotherapy. The committee noted that there were 135\xa0patients in the nivolumab arm and 137\xa0patients in the docetaxel arm. Patients were randomised to have either nivolumab (3\xa0mg per kg, the recommended dose in the summary of product characteristics at the time) or docetaxel. The hazard ratio using 5‑year data from CheckMate\xa0017 showed nivolumab was associated with a statistically significant improvement in overall survival compared with docetaxel (the exact data are confidential and cannot be reported here). The committee concluded that nivolumab was clinically effective compared with docetaxel alone for people with squamous NSCLC after chemotherapy.\n\n## Results from CheckMate\xa0017 are generalisable to the NHS in England\n\nThe committee was aware that as well as new data from CheckMate\xa0017, there were new SACT data. These were collected from 348\xa0people who had nivolumab in the CDF, with a median follow up of 487\xa0days (with a range of 5\xa0months to 20\xa0months). The median treatment duration was 3.5\xa0months. The overall survival estimates using the SACT data were similar to CheckMate\xa0017 data. The committee concluded that results from CheckMate\xa0017 were generalisable to the NHS in England.\n\n# Dosing\n\n## The new dosage of nivolumab was not used in CheckMate\xa0017 but is unlikely to have a large effect on clinical- and cost-effectiveness results\n\nAt the time of the original appraisal, the recommended dose of nivolumab in its summary of product characteristics was 3\xa0mg per kg every 2\xa0weeks, but this has since changed to 240\xa0mg every 2\xa0weeks. The company assumed that the new dose had the same clinical effectiveness as the previously recommended dose of 3\xa0mg per kg. The committee understood that there were no clinical‑effectiveness data using the new dosage. The CDF clinical lead advised that the dose change for nivolumab had been accepted by the regulatory body and was already being used in clinical practice in the NHS in England. The committee concluded that although it had not seen clinical‑effectiveness evidence for the new dosage, it was unlikely to have had a large effect on the clinical- and cost‑effectiveness results.\n\n# Economic model\n\n## The company's economic model is suitable for decision making\n\nThe updated model used the same approach as the original appraisal. The model had 3\xa0health states: progression‑free disease, progressed disease and death. Health‑state occupancy over time was informed by overall survival and progression‑free survival curves fitted to data from CheckMate\xa0017. The company modelled nivolumab using clinical‑effectiveness data for the 3\xa0mg per kg dose, but applied the costs of the currently recommended flat dose of 240\xa0mg every 2\xa0weeks. The committee considered that this approach was appropriate and concluded that the company's model was suitable for decision making.\n\n# Modelling overall survival and progression-free survival\n\n## The company's spline hazard 1-knot model is appropriate for progression-free survival\n\nIn the previous appraisal, the committee considered that the most appropriate method of extrapolation was applying an exponential curve after the trial data split at 2.2\xa0months (hybrid exponential). This method reduced the influence of data collected before the first radiological assessment on the long‑term extrapolation. But, the hybrid exponential extrapolation did not fit well with the long‑term data in CheckMate\xa0017 and consistently underestimated observed progression‑free survival. The company fitted several models to the updated 5‑year progression‑free survival data from CheckMate\xa0017 for both treatment arms and preferred the spline 1‑knot normal curve for its base-case analysis. At technical engagement, it was agreed that extrapolation of progression‑free survival using the spline hazard 1‑knot model was appropriate in both the nivolumab and docetaxel treatment arms. The committee concluded that the company's spline hazard 1‑knot model was clinically plausible.\n\n## The company's spline hazard 2‑knot model is appropriate for overall survival\n\nThe committee and the company agreed that the 5‑year data suggested that the generalised gamma distribution (preferred by the committee in the original appraisal) was likely to underestimate overall survival. The company fitted several models to the updated 5‑year overall survival data from CheckMate\xa0017 for both treatment arms and preferred the spline 2‑knot hazard model for its base-case analysis. The ERG stated that overall survival may be plausibly modelled using the spline 2‑knot hazard, the spline 1‑knot hazard or the Gompertz models. The committee recognised that the 5‑year data gave greater certainty in survival extrapolation, noting that overall survival estimates did not change to a large extent with the 3\xa0plausible choices of extrapolation models. However, the additional follow‑up data were for a population of people who had nivolumab without a stopping rule in place. So, the committee also took into account the percentage of people from CheckMate\xa0017 who continued having treatment over the time horizon of the 5‑year follow‑up data. The committee concluded that it was clinically plausible to model overall survival using the spline 2‑knot hazard model to extrapolate the 5‑year data.\n\n# Stopping rule and continued treatment effect\n\n## It is likely that nivolumab's survival benefit continues after it is stopped\n\nThe company preferred to include a 2‑year stopping rule for nivolumab and assumed that the overall survival benefit would accumulate over the patients' lifetimes. At technical engagement, a professional organisation commented that it is clinically plausible that the immune system could be 'reset'. This means benefit from treatment could be maintained for years after nivolumab is stopped. The committee understood that the summary of product characteristics approved nivolumab while clinical benefit is seen or until treatment is no longer tolerated. The committee considered CheckMate\xa0003, a single‑arm study that included 129\xa0patients with squamous or non-squamous NSCLC, of whom 54\xa0had squamous disease. It included people who had between 1 and 5\xa0previous treatments, whose disease had progressed after at least 1\xa0platinum- or taxane‑based chemotherapy, and who had stopped nivolumab treatment after 1.8\xa0years. The company explained that data from CheckMate\xa0003 showed that of 16\xa0people who survived for 5\xa0years and had no therapy after stopping nivolumab, 12\xa0(75%) were still progression free. The committee agreed the study had evidence that supported the continued treatment effect but noted there was uncertainty because of the mixed population and small sample size (only 18 of the 129\xa0patients with NSCLC had squamous NSCLC and a 3\xa0mg per kg dose). The committee considered if data from CheckMate\xa0153 would be informative. CheckMate\xa0153 is an ongoing study investigating the effect of a maximum of 1‑year treatment with nivolumab, but it was not reported within the company submission. The company explained that findings of CheckMate\xa0153 were similar to CheckMate\xa0003 and showed survival benefit after the 1‑year stopping rule. The committee concluded that although there was uncertainty about how long people should have nivolumab, survival benefit was likely to continue for at least 3\xa0years after treatment had stopped.\n\n## The 2-year stopping rule for nivolumab is appropriate\n\nThe company preferred to include a 2‑year stopping rule for nivolumab. The committee recalled that CheckMate\xa0017 did not specify a stopping rule and questioned if it was appropriate for the 2‑year stopping rule to remain. The ERG explained that there was no robust evidence to show the optimal duration of treatment with nivolumab. The committee recalled its earlier conclusion that it is plausible that a survival benefit from nivolumab would continue after it is stopped at 2\xa0years. The committee also recalled that some patients experienced anxiety and distress because their treatment was stopped at 2\xa0years (see section\xa03.1). The company suggested that this was not the experience of all patients and some may welcome a break from treatment. The CDF clinical lead explained that a 2‑year stopping rule for immunotherapies such as nivolumab was commonly being used in clinical practice for squamous NSCLC in the NHS in England. The committee concluded that a 2‑year stopping rule for nivolumab was appropriate because it was likely the benefit would continue after it is stopped. Also, there was no new evidence to show that continuing for longer gave additional benefit.\n\n## When nivolumab is stopped at 2\xa0years, it is acceptable to assume an additional survival benefit for at least 3\xa0more years\n\nIn its base‑case analysis, the company preferred to assume that if nivolumab is stopped at 2\xa0years, patients will continue to accumulate a lifetime survival benefit after that point. But, the committee was not convinced that the company's preferred lifetime survival benefit was plausible. In the original guidance, a 3‑year continued benefit after stopping nivolumab was accepted. The committee recognised that 5‑year data were now available from CheckMate\xa0017. But, it noted that there was no new robust evidence on the duration of the continued benefit after stopping nivolumab that would change the assumption accepted in the original guidance. It was aware that removing the stopping rule and changing the duration of treatment benefit had a large effect on the cost-effectiveness results. It considered plausible durations of treatment benefit and believed that the cost‑effectiveness estimate preferred by the company was likely to be optimistic. This was because a lifetime treatment effect was not supported by the evidence. The committee considered that a cost‑effectiveness estimate based on 2\xa0years of treatment and 3\xa0years of continued benefit after treatment had stopped was likely to be conservative. This was because treatment effect was unlikely to stop immediately after 5\xa0years. It also considered alternative treatment waning scenarios presented by the company during technical engagement, for which the modelling approach was adapted so that treatment benefit did not suddenly stop at a given time point. The exact treatment benefit duration was not known. The committee's preferred assumption was that if nivolumab was offered for 2\xa0years of uninterrupted treatment, it was likely that its survival benefit would continue for 3\xa0or more years after being stopped.\n\n# End of life\n\n## Nivolumab meets the end-of-life criteria\n\nThe committee considered the advice about life‑extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. In the original appraisal, the data showed that life expectancy for people with NSCLC was less than 24\xa0months and that nivolumab extended life by at least 3\xa0months. The committee noted that no evidence had been identified to change this conclusion. So, the committee concluded that nivolumab meets the end‑of‑life criteria and can be considered a life‑extending treatment at the end of life.\n\n# Cost effectiveness\n\n## The most plausible ICER is within what NICE considers an acceptable use of NHS resources\n\nThe company's preferred incremental cost‑effectiveness ratio (ICER) for nivolumab compared with docetaxel alone for people with squamous NSCLC was £35,710 per quality‑adjusted life year gained. This included a 2‑year stopping rule for nivolumab and continuing to accumulate a lifetime survival benefit after stopping treatment, which the committee did not feel was plausible. Using the committee's preferred assumptions of 2\xa0years of treatment and 3\xa0years of continued benefit once treatment had stopped, the most plausible ICER was likely to be below £40,168. This scenario was modelled using the company's preferred assumptions, including a spline 2‑knot hazard extrapolation for overall survival. Given that end‑of‑life criteria was met, the committee concluded that this was within what NICE considers a cost‑effective use of NHS resources.\n\n# Other factors\n\nNo equality or social value judgement issues were identified.\n\n# Conclusion\n\n## Nivolumab is recommended for routine commissioning for people with advanced squamous NSCLC after chemotherapy\n\nConsidering new evidence from CheckMate\xa0017, SACT data and the committee's preferred assumptions, all plausible cost‑effectiveness estimates were within what is considered a cost‑effective use of NHS resources when the end‑of‑life criteria were applied. Nivolumab was therefore recommended for use in the NHS as an option for treating locally advanced or metastatic squamous NSCLC in adults after chemotherapy, only if:\n\nit is stopped at 2\xa0years of uninterrupted treatment, or earlier if disease progresses and\n\nthey have not had a PD‑1 or PD‑L1 inhibitor before."}
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https://www.nice.org.uk/guidance/ta655
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Evidence-based recommendations on nivolumab (Opdivo) for advanced squamous non-small-cell lung cancer in adults after chemotherapy.
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c173189828f64a073606e0d32ebd6ae3386d8aa9
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nice
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SEM Scanner 200 for preventing pressure ulcers
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SEM Scanner 200 for preventing pressure ulcers
Evidence-based recommendations on SEM Scanner 200 for preventing pressure ulcers.
# Recommendations
SEM Scanner 200, with visual skin assessment, shows promise for preventing pressure ulcers. However, there is not enough good-quality evidence to support the case for routine adoption in the NHS.
A randomised controlled trial is recommended to address uncertainties about the clinical benefits of using the scanner compared with standard risk assessment. This should assess:
using the scanner plus visual skin assessment compared with visual skin assessment alone for identifying pressure ulcer risk
whether changes in clinical decision making from using the scanner reduce pressure ulcer incidence
the clinical benefits and resource impact of using the scanner in different care settings
the clinical benefits for different skin tones
how well the scanner works across populations with a range of comorbidities
patient-related outcome measures.
Why the committee made these recommendations
Inflammation occurs when tissue is damaged. Increased moisture under the skin is thought to reflect inflammation and may mean an increased risk of pressure ulcer formation. SEM Scanner 200 is a device that measures differences in moisture under the skin of the heels and the area around the base of the spine (sacrum). Using SEM Scanner 200 could mean that measures to prevent pressure ulcers can be taken before visible or tactile signs of tissue damage develop.
SEM Scanner 200 is used with standard care in studies looking at its effect on pressure ulcer incidence. This makes it difficult to distinguish between the effect of SEM Scanner 200 alone and that of increased awareness of preventing pressure ulcers. Also, standard care is poorly described in the studies. More evidence is needed on how using SEM Scanner 200 affects clinical decision making and whether this benefits patients.# The technology
# Technology
SEM Scanner 200 is a portable, hand-held skin assessment device. It detects an increased risk of pressure ulcers developing by identifying early pressure-induced tissue damage at the heel and sacrum. Published evidence suggests that damage to underlying soft tissues can happen 3 days to 10 days before tissue damage shows at the epidermis (Moore et al. 2017). Tissue inflammation is the first response to damage and causes increased dilation and permeability of surrounding blood vessels. This leads to leakage of plasma and fluid, creating a layer of subepidermal moisture. As damage increases, so does the level of subepidermal moisture. SEM Scanner 200 measures variation in subepidermal moisture across a small area. Healthy tissue has little variation, whereas inflamed or dead tissue has more variation. The variation is reported as a 'delta' value, with healthy tissue giving a low numerical reading and inflamed or dead tissue giving a higher numerical reading. A subepidermal moisture delta value of 0.6 or more is thought to represent clinically significant levels of tissue damage.
# Innovative aspects
SEM Scanner 200 uses a novel method of identifying subepidermal moisture in the tissue of the heels and sacrum. SEM Scanner is the only CE marked device that assesses the anatomical risk of pressure ulcer formation before pressure-induced damage happens.
# Intended use
SEM Scanner 200 is intended to be used on the heels and sacrum of people who are at risk or at high risk of developing a pressure ulcer. Risk categories are defined in NICE's guideline on pressure ulcers: prevention and management.
SEM Scanner 200 is used by healthcare professionals on hospital admission, during the patient's stay and on discharge. Users need training to use the device and interpret the results. For information on how to use the technology see the SEM Scanner 200 information for use document.
# Costs
SEM Scanner 200 costs £5,835 per device.
For more details, see the website for SEM Scanner 200.# Evidence
# Clinical evidence
## The main clinical evidence comprises 7 studies
The evidence assessed by the external assessment centre (EAC) included 7 studies; 3 were full text peer reviewed publications (Gefan et al. 2018; O'Brian et al. 2018; Raizman et al. 2018) and 4 were abstracts (Hancock and Lawrance 2018; Okonkwo et al. 2017; Okonkwo et al. 2018; O'Keefe et al. 2019). The studies included 2,213 patients at risk of developing pressure ulcers in secondary care. Two of the studies were before-and-after comparative studies, the remaining 5 studies were single-arm observational studies. For full details of the clinical evidence, see section 3 of the assessment report.
## The 2 before-and-after studies are relevant to the decision problem and report pressure ulcer incidence
Both studies compared pressure ulcer incidence before and after using SEM Scanner 200 as a risk assessment tool to be used alongside standard care. Both studies reported reduced pressure ulcer incidence after using SEM Scanner 200. One study reported that pressure ulcer incidence reduced from 2.17% to 0.95% (Hancock and Lawrance 2019) and the other reported a reduction from 13% to 1% (Raizman et al. 2018). Neither study included a detailed description of the protocol used for assessment and management in the standard care arm. Also, there was heterogeneity in the reporting of pressure ulcer incidence, with only 1 study including stage 1 pressure ulcers. These limitations made it difficult to be certain about how well SEM Scanner 200 works when used as the only test.
## Diagnostic accuracy is reported in 3 of the observational studies but they use an inappropriate reference standard
All 3 studies reporting the diagnostic accuracy of SEM Scanner 200 used visual skin assessment (a standard clinical measure for detecting pressure ulcers based on visual signs of skin deterioration) as a reference standard. SEM Scanner 200 is intended to detect subepidermal moisture changes before visible signs of pressure ulcers are present and is not a diagnostic test for pressure ulcers. The EAC noted that using visual skin assessment for measuring the diagnostic accuracy of SEM Scanner 200 may underestimate its specificity. This is because non-visible damage correctly identified by SEM Scanner 200 would be recorded as a false positive.
## In 3 of the observational studies SEM Scanner 200 detects subepidermal moisture changes earlier than visual skin assessment
All 3 studies reported that subepidermal moisture changes indicating pressure-induced damage were detected earlier than visible signs of skin deterioration reported by visual skin assessment. The studies provided no additional information about the effect of these findings on clinical management or on the clinical benefits of earlier detection.
# Cost evidence
## The company's model compares the costs of using SEM Scanner 200 plus standard care with using standard care alone
The company submitted 10 studies relevant to the economic assessment of SEM Scanner 200. The EAC reviewed the literature and found 1 study (Burns et al. unpublished) that it considered to be relevant to the decision problem. The company used a decision tree, based on standard care as defined by NICE's guideline on pressure ulcers: prevention and management, to assess the effect of SEM Scanner 200 on the cost of preventing pressure ulcers, over a 1-year time horizon. In this model, the heels and sacrum of each patient were assessed and categorised as low risk, at risk or at high risk. Patients assessed to be at risk or at high risk had repositioning every 6 hours or 4 hours, respectively. The key clinical parameters were:
an assumed pressure ulcer incidence of 4.09% in the at-risk group
a pressure ulcer incidence of 1.637% in the standard care arm and 0.509% in the SEM Scanner 200 arm (a 68% reduction).These parameters were from the unpublished Hancock and Lawrance (2018) before-and-after study.
The company used a cost of £18 per hour for band 5 nursing time as stated in NICE's costing statement for pressure ulcers published in 2014. The EAC considered this source to be outdated and updated the cost to £37 per hour (Curtis and Burns 2018). The EAC also added a 3.5% depreciation rate for the device, which had not been included in the company submission.
## The updated company model results in cost savings of £59 per person from reduced pressure ulcer incidence
The updated company model resulted in cost savings of £59 per patient. Sensitivity analyses applied to the assumed percentage pressure ulcer reduction found SEM Scanner 200 to be cost-neutral at a 28% reduction in pressure ulcer incidence. The model included the costs of 1 scanner per 9 beds for 210 beds. The model showed that the increased costs for preventive measures were offset by cost savings related to the reduced need for pressure ulcer treatment. Results were reported to be robust to sensitivity analyses, however, the results were not presented. The EAC noted there was uncertainty around estimates from an unpublished study used to populate the company model.
## The EAC's model shows that SEM Scanner 200 is cost incurring by £45 per person
The EAC used its preferred assumptions to calculate a pressure ulcer incidence of 8.05%. These assumptions were the predicted number of positive stage 1 pressure ulcers, the prevalence of pressure ulcers and the diagnostic accuracy of SEM Scanner 200 plus visual skin assessment. The model assumed that 50% of stage 1 pressure ulcers would progress to stage 2 without diagnosis and treatment and that 36.5% would do so with diagnosis and treatment. The EAC acknowledged that this model did not adequately capture any potential benefit of earlier identification of pressure-induced damage. The EAC's base case resulted in SEM Scanner 200 plus visual skin assessment being cost incurring by £45 per person when compared with visual skin assessment alone.
## The cost of SEM Scanner 200 increases if healthcare assistants do the repositioning
The EAC's base case assumed that 2 band 5 nurses were needed for repositioning. Experts advised the committee that repositioning can be done by other healthcare professionals. The EAC's sensitivity analyses reported that reducing the cost of repositioning had a considerable effect on the cost of SEM Scanner 200 and standard care. If repositioning was done by 1 nurse and 1 healthcare assistant or 2 healthcare assistants, SEM Scanner 200 would cost an additional £38 or £30 per person respectively, compared with standard care. The costs used in these analyses reflect a hospital setting.# Committee discussion
# Clinical-effectiveness overview
## SEM Scanner 200 can reduce pressure ulcer incidence but there are considerable uncertainties
The committee noted that the published evidence suggested that using SEM Scanner 200 could result in statistically significant reductions in pressure ulcer incidence. But the clinical experts explained that the size of this benefit was greater than they would expect from their own clinical experience. One clinical expert commented that using SEM Scanner 200 had substantially reduced pressure ulcer incidence in their hospice, but not to the same degree as reported in the studies. The committee also considered that it was unclear from the studies whether reduced pressure ulcer incidence was because of:
the scanner results guiding care management decisions or
increased attention to pressure ulcer prevention from greater patient engagement by healthcare professionals.It concluded that the evidence was unclear about whether changes in clinical decision making from using SEM Scanner 200 reduce pressure ulcer incidence.
## Research is needed on whether using preventive measures earlier affects pressure ulcer incidence
The clinical experts considered that SEM Scanner 200 provides information that could affect decisions about when to intensify preventive measures. These measures include improving the specification of the foam mattress, doing more regular repositioning of the patient, or other pressure-relieving measures. One clinical expert said that using SEM Scanner 200 allows nurses to intensify preventive measures earlier than when using clinical judgement alone. The committee acknowledged that using SEM Scanner 200 may result in preventive measures being introduced or intensified earlier. It noted that there was no evidence to show the effect of earlier interventions on pressure ulcer incidence. The committee concluded that research is needed to assess the effect of introducing preventive measures earlier on pressure ulcer incidence.
## SEM Scanner 200 assesses the risk of pressure ulcers developing
The company explained that SEM Scanner is not intended to diagnose pressure ulcers but to diagnose the risk of pressure ulcers developing. Correspondence with the Medicines and Healthcare products Regulatory Agency confirmed that SEM Scanner 200 is used to identify patients at an increased clinical risk of pressure ulcers and should be seen as a diagnostic risk assessment tool.
## Further research on using SEM Scanner 200 for pressure ulcer risk assessment is needed
The company acknowledged there is no appropriate reference standard for measuring subepidermal moisture and that this limited the assessment of diagnostic accuracy. The clinical experts also said that using visual skin assessment as a reference standard would confound the results. This was because SEM Scanner 200 is designed to assess the risk of pressure ulcers developing before any visible signs, such as redness, appear whereas visual skin assessment records visible pressure injuries. The committee concluded that further research is needed on the use of SEM Scanner 200 plus visual skin assessment compared with visual skin assessment alone for pressure ulcer risk assessment.
## The evidence does not address how SEM Scanner 200 performs across different populations
The clinical experts explained that part of the visual skin assessment is to identify redness, which may not be visible in people with dark skin. Using a non-visual method such as SEM Scanner 200 for people with dark skin may offer advantages and could address an unmet need. The committee also considered that comorbidities and conditions associated with skin damage or swelling may influence subepidermal moisture levels and affect the clinical accuracy of SEM Scanner 200 to identify pressure ulcer risk. The committee concluded that further research should be done to assess the efficacy of SEM Scanner 200 in preventing pressure ulcers for patients with dark skin and for those with comorbidities.
# Relevance to the NHS
## There is NHS interest in SEM Scanner 200 because community and hospital-acquired pressure ulcers remain a significant problem
The NHS safety thermometer report states that from April 2014 to March 2015 approximately 25,000 patients developed new pressure ulcers. The proportion of people with a stage 2 to 4 pressure ulcer in the UK is estimated to be 5%. The clinical experts explained that, in view of the continued clinical challenges of preventing pressure ulcers in the community and in hospitals, there is increasing interest in using SEM Scanner 200 across the NHS.
## Using devices for measuring subepidermal moisture is referenced in global clinical practice guidelines
The committee noted the recently updated US National Pressure Ulcer Advisory Panel (NPUAP), European Pressure Ulcer Advisory Panel (EPUAP) and Pan Pacific Pressure Injury Alliance (PPPIA) global clinical practice guideline in the treatment and prevention of pressure ulcers. This states that healthcare professionals should consider using a subepidermal or oedema measurement device in addition to routine visual skin assessment to assess the clinical risk of pressure ulcers. The committee also noted that, based on evidence, the guideline only proposed a weak positive recommendation for these devices when assessing risk in people with dark skin.
# NHS considerations overview
## SEM Scanner 200 provides an objective measure of pressure ulcer risk, which would be an advantage
SEM Scanner 200 provides an objective measure of variations in subepidermal moisture. Current risk assessment involves the combined use of validated scales and clinical judgement. The clinical experts explained that the availability of an accurate and objective measure of risk would be an advantage, particularly for training staff in pressure ulcer risk assessment.
## The rationale for using SEM Scanner 200 needs further clinical testing
The company explained that the SEM Scanner 200 delta value reflects a measure of relative difference between the subepidermal moisture recorded over the bony prominences and surrounding tissues of the heels or sacrum. The greater the variation in subepidermal moisture (and therefore the delta value), the greater the likelihood of underlying localised inflammation. Although the committee accepted the rationale for this hypothesis, it considered that patients may have oedema from other causes and the hypothesis needs to be further tested in well-constructed clinical studies. It further noted that the interrater reliability of the device was reported by the company to be 83%. The committee concluded that further research would help to understand the reproducibility of the result.
## SEM Scanner 200 needs cleaning between patients
The SEM Scanner 200 is classified as having a medium risk of cross-contamination. The company explained that cleaning has been shown to be effective in addressing the risk of cross-contamination. The clinical experts advised that cleansing wipes are used to clean SEM Scanner 200 and this is in keeping with NHS infection and control procedures. The company stated that there have been no reported cross-contamination adverse events with SEM Scanner 200.
## SEM Scanner 200 has a battery life of 3 hours and a lifespan of over 3 years
The company explained that SEM Scanner 200 has a 3-year warranty but the battery life of the device may be longer than 3 years. The clinical experts advised that 3-hour battery capacity is adequate because SEM Scanner 200 is left on a charging station when not being used.
# Training
## The company provides free training
The clinical experts explained that the company provides free training in the use of SEM Scanner 200. The device is easy to use, and the clinical experts described that staff became comfortable and familiar with its use within 2 weeks or so.
# Cost modelling overview
## Uncertainties about the clinical benefit of SEM Scanner 200 result in uncertain cost effectiveness
The committee noted that the key cost drivers, the reduction in pressure ulcer incidence and specificity of the device, were subject to considerable uncertainty. It concluded that more research was needed to establish the clinical and cost benefits of SEM Scanner 200.
# Further research
## Further research is needed to address the uncertainty about the efficacy of SEM Scanner 200 in reducing pressure ulcer incidence
The committee concluded that further research was needed to address uncertainties about the efficacy of SEM Scanner 200 in reducing pressure ulcer incidence. This research should investigate using SEM Scanner with visual skin assessment compared with standard risk assessment alone in judging the risk of pressure ulcers. It should control for the effect of increased engagement with healthcare professionals on pressure ulcer incidence. Pressure ulcers occur in acute and community care so research should address the effect of adopting the scanner in each of these settings independently. Additional research should specifically address the possible benefit of using the scanner in people with dark skin and those with a range of comorbidities known to influence fluid levels in the subepidermis and underlying tissues. Clinical studies using the scanner should be clear about how it affects clinical decision making; what effect it has on clinical outcomes and patient-related outcome measures; and the cost implications of its use.
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{'Recommendations': 'SEM Scanner\xa0200, with visual skin assessment, shows promise for preventing pressure ulcers. However, there is not enough good-quality evidence to support the case for routine adoption in the NHS.\n\nA randomised controlled trial is recommended to address uncertainties about the clinical benefits of using the scanner compared with standard risk assessment. This should assess:\n\nusing the scanner plus visual skin assessment compared with visual skin assessment alone for identifying pressure ulcer risk\n\nwhether changes in clinical decision making from using the scanner reduce pressure ulcer incidence\n\nthe clinical benefits and resource impact of using the scanner in different care settings\n\nthe clinical benefits for different skin tones\n\nhow well the scanner works across populations with a range of comorbidities\n\npatient-related outcome measures.\n\nWhy the committee made these recommendations\n\nInflammation occurs when tissue is damaged. Increased moisture under the skin is thought to reflect inflammation and may mean an increased risk of pressure ulcer formation. SEM Scanner\xa0200 is a device that measures differences in moisture under the skin of the heels and the area around the base of the spine (sacrum). Using SEM Scanner\xa0200 could mean that measures to prevent pressure ulcers can be taken before visible or tactile signs of tissue damage develop.\n\nSEM Scanner\xa0200 is used with standard care in studies looking at its effect on pressure ulcer incidence. This makes it difficult to distinguish between the effect of SEM Scanner\xa0200 alone and that of increased awareness of preventing pressure ulcers. Also, standard care is poorly described in the studies. More evidence is needed on how using SEM Scanner\xa0200 affects clinical decision making and whether this benefits patients.', 'The technology': "# Technology\n\nSEM Scanner\xa0200 is a portable, hand-held skin assessment device. It detects an increased risk of pressure ulcers developing by identifying early pressure-induced tissue damage at the heel and sacrum. Published evidence suggests that damage to underlying soft tissues can happen 3\xa0days to 10\xa0days before tissue damage shows at the epidermis (Moore et al. 2017). Tissue inflammation is the first response to damage and causes increased dilation and permeability of surrounding blood vessels. This leads to leakage of plasma and fluid, creating a layer of subepidermal moisture. As damage increases, so does the level of subepidermal moisture. SEM Scanner\xa0200 measures variation in subepidermal moisture across a small area. Healthy tissue has little variation, whereas inflamed or dead tissue has more variation. The variation is reported as a 'delta' value, with healthy tissue giving a low numerical reading and inflamed or dead tissue giving a higher numerical reading. A subepidermal moisture delta value of 0.6 or more is thought to represent clinically significant levels of tissue damage.\n\n# Innovative aspects\n\nSEM Scanner\xa0200 uses a novel method of identifying subepidermal moisture in the tissue of the heels and sacrum. SEM Scanner is the only CE marked device that assesses the anatomical risk of pressure ulcer formation before pressure-induced damage happens.\n\n# Intended use\n\nSEM Scanner\xa0200 is intended to be used on the heels and sacrum of people who are at risk or at high risk of developing a pressure ulcer. Risk categories are defined in NICE's guideline on pressure ulcers: prevention and management.\n\nSEM Scanner\xa0200 is used by healthcare professionals on hospital admission, during the patient's stay and on discharge. Users need training to use the device and interpret the results. For information on how to use the technology see the SEM Scanner\xa0200 information for use document.\n\n# Costs\n\nSEM Scanner\xa0200 costs £5,835 per device.\n\nFor more details, see the website for SEM Scanner\xa0200.", 'Evidence': "# Clinical evidence\n\n## The main clinical evidence comprises 7\xa0studies\n\nThe evidence assessed by the external assessment centre (EAC) included 7\xa0studies; 3 were full text peer reviewed publications (Gefan et al. 2018; O'Brian et al. 2018; Raizman et al. 2018) and 4 were abstracts (Hancock and Lawrance 2018; Okonkwo et al. 2017; Okonkwo et al. 2018; O'Keefe et al. 2019). The studies included 2,213\xa0patients at risk of developing pressure ulcers in secondary care. Two of the studies were before-and-after comparative studies, the remaining 5\xa0studies were single-arm observational studies. For full details of the clinical evidence, see section\xa03 of the assessment report.\n\n## The 2 before-and-after studies are relevant to the decision problem and report pressure ulcer incidence\n\nBoth studies compared pressure ulcer incidence before and after using SEM Scanner\xa0200 as a risk assessment tool to be used alongside standard care. Both studies reported reduced pressure ulcer incidence after using SEM Scanner\xa0200. One study reported that pressure ulcer incidence reduced from 2.17% to 0.95% (Hancock and Lawrance 2019) and the other reported a reduction from 13% to 1% (Raizman et al. 2018). Neither study included a detailed description of the protocol used for assessment and management in the standard care arm. Also, there was heterogeneity in the reporting of pressure ulcer incidence, with only 1\xa0study including stage\xa01 pressure ulcers. These limitations made it difficult to be certain about how well SEM Scanner\xa0200 works when used as the only test.\n\n## Diagnostic accuracy is reported in 3 of the observational studies but they use an inappropriate reference standard\n\nAll 3\xa0studies reporting the diagnostic accuracy of SEM Scanner\xa0200 used visual skin assessment (a standard clinical measure for detecting pressure ulcers based on visual signs of skin deterioration) as a reference standard. SEM Scanner\xa0200 is intended to detect subepidermal moisture changes before visible signs of pressure ulcers are present and is not a diagnostic test for pressure ulcers. The EAC noted that using visual skin assessment for measuring the diagnostic accuracy of SEM Scanner\xa0200 may underestimate its specificity. This is because non-visible damage correctly identified by SEM Scanner\xa0200 would be recorded as a false positive.\n\n## In 3 of the observational studies SEM Scanner\xa0200 detects subepidermal moisture changes earlier than visual skin assessment\n\nAll 3\xa0studies reported that subepidermal moisture changes indicating pressure-induced damage were detected earlier than visible signs of skin deterioration reported by visual skin assessment. The studies provided no additional information about the effect of these findings on clinical management or on the clinical benefits of earlier detection.\n\n# Cost evidence\n\n## The company's model compares the costs of using SEM Scanner\xa0200 plus standard care with using standard care alone\n\nThe company submitted 10\xa0studies relevant to the economic assessment of SEM Scanner\xa0200. The EAC reviewed the literature and found 1\xa0study (Burns et al. unpublished) that it considered to be relevant to the decision problem. The company used a decision tree, based on standard care as defined by NICE's guideline on pressure ulcers: prevention and management, to assess the effect of SEM Scanner\xa0200 on the cost of preventing pressure ulcers, over a 1-year time horizon. In this model, the heels and sacrum of each patient were assessed and categorised as low risk, at risk or at high risk. Patients assessed to be at risk or at high risk had repositioning every 6\xa0hours or 4\xa0hours, respectively. The key clinical parameters were:\n\nan assumed pressure ulcer incidence of 4.09% in the at-risk group\n\na pressure ulcer incidence of 1.637% in the standard care arm and 0.509% in the SEM Scanner\xa0200 arm (a 68% reduction).These parameters were from the unpublished Hancock and Lawrance (2018) before-and-after study.\n\nThe company used a cost of £18 per hour for band\xa05 nursing time as stated in NICE's costing statement for pressure ulcers published in 2014. The EAC considered this source to be outdated and updated the cost to £37 per hour (Curtis and Burns 2018). The EAC also added a 3.5% depreciation rate for the device, which had not been included in the company submission.\n\n## The updated company model results in cost savings of £59 per person from reduced pressure ulcer incidence\n\nThe updated company model resulted in cost savings of £59 per patient. Sensitivity analyses applied to the assumed percentage pressure ulcer reduction found SEM Scanner\xa0200 to be cost-neutral at a 28% reduction in pressure ulcer incidence. The model included the costs of 1\xa0scanner per 9\xa0beds for 210\xa0beds. The model showed that the increased costs for preventive measures were offset by cost savings related to the reduced need for pressure ulcer treatment. Results were reported to be robust to sensitivity analyses, however, the results were not presented. The EAC noted there was uncertainty around estimates from an unpublished study used to populate the company model.\n\n## The EAC's model shows that SEM Scanner\xa0200 is cost incurring by £45 per person\n\nThe EAC used its preferred assumptions to calculate a pressure ulcer incidence of 8.05%. These assumptions were the predicted number of positive stage\xa01 pressure ulcers, the prevalence of pressure ulcers and the diagnostic accuracy of SEM Scanner\xa0200 plus visual skin assessment. The model assumed that 50% of stage\xa01 pressure ulcers would progress to stage\xa02 without diagnosis and treatment and that 36.5% would do so with diagnosis and treatment. The EAC acknowledged that this model did not adequately capture any potential benefit of earlier identification of pressure-induced damage. The EAC's base case resulted in SEM Scanner\xa0200 plus visual skin assessment being cost incurring by £45 per person when compared with visual skin assessment alone.\n\n## The cost of SEM Scanner\xa0200 increases if healthcare assistants do the repositioning\n\nThe EAC's base case assumed that 2 band\xa05 nurses were needed for repositioning. Experts advised the committee that repositioning can be done by other healthcare professionals. The EAC's sensitivity analyses reported that reducing the cost of repositioning had a considerable effect on the cost of SEM Scanner\xa0200 and standard care. If repositioning was done by 1\xa0nurse and 1\xa0healthcare assistant or 2\xa0healthcare assistants, SEM Scanner\xa0200 would cost an additional £38 or £30 per person respectively, compared with standard care. The costs used in these analyses reflect a hospital setting.", 'Committee discussion': '# Clinical-effectiveness overview\n\n## SEM Scanner\xa0200 can reduce pressure ulcer incidence but there are considerable uncertainties\n\nThe committee noted that the published evidence suggested that using SEM Scanner\xa0200 could result in statistically significant reductions in pressure ulcer incidence. But the clinical experts explained that the size of this benefit was greater than they would expect from their own clinical experience. One clinical expert commented that using SEM Scanner\xa0200 had substantially reduced pressure ulcer incidence in their hospice, but not to the same degree as reported in the studies. The committee also considered that it was unclear from the studies whether reduced pressure ulcer incidence was because of:\n\nthe scanner results guiding care management decisions or\n\nincreased attention to pressure ulcer prevention from greater patient engagement by healthcare professionals.It concluded that the evidence was unclear about whether changes in clinical decision making from using SEM Scanner\xa0200 reduce pressure ulcer incidence.\n\n## Research is needed on whether using preventive measures earlier affects pressure ulcer incidence\n\nThe clinical experts considered that SEM Scanner\xa0200 provides information that could affect decisions about when to intensify preventive measures. These measures include improving the specification of the foam mattress, doing more regular repositioning of the patient, or other pressure-relieving measures. One clinical expert said that using SEM Scanner\xa0200 allows nurses to intensify preventive measures earlier than when using clinical judgement alone. The committee acknowledged that using SEM Scanner\xa0200 may result in preventive measures being introduced or intensified earlier. It noted that there was no evidence to show the effect of earlier interventions on pressure ulcer incidence. The committee concluded that research is needed to assess the effect of introducing preventive measures earlier on pressure ulcer incidence.\n\n## SEM Scanner\xa0200 assesses the risk of pressure ulcers developing\n\nThe company explained that SEM Scanner is not intended to diagnose pressure ulcers but to diagnose the risk of pressure ulcers developing. Correspondence with the Medicines and Healthcare products Regulatory Agency confirmed that SEM Scanner\xa0200 is used to identify patients at an increased clinical risk of pressure ulcers and should be seen as a diagnostic risk assessment tool.\n\n## Further research on using SEM Scanner\xa0200 for pressure ulcer risk assessment is needed\n\nThe company acknowledged there is no appropriate reference standard for measuring subepidermal moisture and that this limited the assessment of diagnostic accuracy. The clinical experts also said that using visual skin assessment as a reference standard would confound the results. This was because SEM Scanner\xa0200 is designed to assess the risk of pressure ulcers developing before any visible signs, such as redness, appear whereas visual skin assessment records visible pressure injuries. The committee concluded that further research is needed on the use of SEM Scanner\xa0200 plus visual skin assessment compared with visual skin assessment alone for pressure ulcer risk assessment.\n\n## The evidence does not address how SEM Scanner\xa0200 performs across different populations\n\nThe clinical experts explained that part of the visual skin assessment is to identify redness, which may not be visible in people with dark skin. Using a non-visual method such as SEM Scanner\xa0200 for people with dark skin may offer advantages and could address an unmet need. The committee also considered that comorbidities and conditions associated with skin damage or swelling may influence subepidermal moisture levels and affect the clinical accuracy of SEM Scanner\xa0200 to identify pressure ulcer risk. The committee concluded that further research should be done to assess the efficacy of SEM Scanner\xa0200 in preventing pressure ulcers for patients with dark skin and for those with comorbidities.\n\n# Relevance to the NHS\n\n## There is NHS interest in SEM Scanner\xa0200 because community and hospital-acquired pressure ulcers remain a significant problem\n\nThe NHS safety thermometer report states that from April 2014 to March 2015 approximately 25,000\xa0patients developed new pressure ulcers. The proportion of people with a stage 2\xa0to\xa04 pressure ulcer in the UK is estimated to be 5%. The clinical experts explained that, in view of the continued clinical challenges of preventing pressure ulcers in the community and in hospitals, there is increasing interest in using SEM Scanner\xa0200 across the NHS.\n\n## Using devices for measuring subepidermal moisture is referenced in global clinical practice guidelines\n\nThe committee noted the recently updated US National Pressure Ulcer Advisory Panel (NPUAP), European Pressure Ulcer Advisory Panel (EPUAP) and Pan Pacific Pressure Injury Alliance (PPPIA) global clinical practice guideline in the treatment and prevention of pressure ulcers. This states that healthcare professionals should consider using a subepidermal or oedema measurement device in addition to routine visual skin assessment to assess the clinical risk of pressure ulcers. The committee also noted that, based on evidence, the guideline only proposed a weak positive recommendation for these devices when assessing risk in people with dark skin.\n\n# NHS considerations overview\n\n## SEM Scanner\xa0200 provides an objective measure of pressure ulcer risk, which would be an advantage\n\nSEM Scanner\xa0200 provides an objective measure of variations in subepidermal moisture. Current risk assessment involves the combined use of validated scales and clinical judgement. The clinical experts explained that the availability of an accurate and objective measure of risk would be an advantage, particularly for training staff in pressure ulcer risk assessment.\n\n## The rationale for using SEM Scanner\xa0200 needs further clinical testing\n\nThe company explained that the SEM Scanner\xa0200 delta value reflects a measure of relative difference between the subepidermal moisture recorded over the bony prominences and surrounding tissues of the heels or sacrum. The greater the variation in subepidermal moisture (and therefore the delta value), the greater the likelihood of underlying localised inflammation. Although the committee accepted the rationale for this hypothesis, it considered that patients may have oedema from other causes and the hypothesis needs to be further tested in well-constructed clinical studies. It further noted that the interrater reliability of the device was reported by the company to be 83%. The committee concluded that further research would help to understand the reproducibility of the result.\n\n## SEM Scanner\xa0200 needs cleaning between patients\n\nThe SEM Scanner\xa0200 is classified as having a medium risk of cross-contamination. The company explained that cleaning has been shown to be effective in addressing the risk of cross-contamination. The clinical experts advised that cleansing wipes are used to clean SEM Scanner\xa0200 and this is in keeping with NHS infection and control procedures. The company stated that there have been no reported cross-contamination adverse events with SEM Scanner\xa0200.\n\n## SEM Scanner\xa0200 has a battery life of 3\xa0hours and a lifespan of over 3\xa0years\n\nThe company explained that SEM Scanner\xa0200 has a 3-year warranty but the battery life of the device may be longer than 3\xa0years. The clinical experts advised that 3-hour battery capacity is adequate because SEM Scanner\xa0200 is left on a charging station when not being used.\n\n# Training\n\n## The company provides free training\n\nThe clinical experts explained that the company provides free training in the use of SEM Scanner\xa0200. The device is easy to use, and the clinical experts described that staff became comfortable and familiar with its use within 2\xa0weeks or so.\n\n# Cost modelling overview\n\n## Uncertainties about the clinical benefit of SEM Scanner\xa0200 result in uncertain cost effectiveness\n\nThe committee noted that the key cost drivers, the reduction in pressure ulcer incidence and specificity of the device, were subject to considerable uncertainty. It concluded that more research was needed to establish the clinical and cost benefits of SEM Scanner\xa0200.\n\n# Further research\n\n## Further research is needed to address the uncertainty about the efficacy of SEM Scanner 200 in reducing pressure ulcer incidence\n\nThe committee concluded that further research was needed to address uncertainties about the efficacy of SEM Scanner\xa0200 in reducing pressure ulcer incidence. This research should investigate using SEM Scanner with visual skin assessment compared with standard risk assessment alone in judging the risk of pressure ulcers. It should control for the effect of increased engagement with healthcare professionals on pressure ulcer incidence. Pressure ulcers occur in acute and community care so research should address the effect of adopting the scanner in each of these settings independently. Additional research should specifically address the possible benefit of using the scanner in people with dark skin and those with a range of comorbidities known to influence fluid levels in the subepidermis and underlying tissues. Clinical studies using the scanner should be clear about how it affects clinical decision making; what effect it has on clinical outcomes and patient-related outcome measures; and the cost implications of its use.'}
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https://www.nice.org.uk/guidance/mtg51
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Evidence-based recommendations on SEM Scanner 200 for preventing pressure ulcers.
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9b6123d9535d63f5abbae15781afa5ff21dbc324
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nice
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Osimertinib for treating EGFR T790M mutation-positive advanced non-small-cell lung cancer
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Osimertinib for treating EGFR T790M mutation-positive advanced non-small-cell lung cancer
Evidence-based recommendations on osimertinib (Tagrisso) for treating epidermal growth factor receptor (EGFR) T790M mutation-positive locally advanced or metastatic non-small-cell lung cancer (NSCLC) in adults.
# Recommendations
Osimertinib is recommended as an option for treating epidermal growth factor receptor (EGFR) T790M mutation-positive locally advanced or metastatic non-small-cell lung cancer (NSCLC) in adults, only if:
their disease has progressed after first-line treatment with an EGFR tyrosine kinase inhibitor and
the company provides osimertinib according to the commercial arrangement.
This recommendation is not intended to affect treatment with osimertinib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
This appraisal reviews the additional evidence collected as part of the Cancer Drugs Fund managed access agreement for osimertinib for treating EGFR T790M mutation-positive locally advanced or metastatic NSCLC for adults whose disease has progressed after treatment with an EGFR tyrosine kinase inhibitor (NICE technology appraisal guidance 416).
EGFR T790M mutation-positive locally advanced or metastatic NSCLC that has progressed after treatment with an EGFR tyrosine kinase inhibitor is usually treated with platinum doublet chemotherapy (PDC).
Evidence from clinical trials suggests that people who take osimertinib live longer than those who have PDC, although there is some uncertainty about the results.
Osimertinib meets NICE's criteria to be considered a life-extending treatment at the end of life. Although the cost-effectiveness estimates for osimertinib are uncertain, they are likely to be within what NICE considers to be an acceptable use of NHS resources. So, osimertinib is recommended.# Information about osimertinib
# Marketing authorisation indication
Osimertinib (Tagrisso, AstraZeneca) has a marketing authorisation for 'the treatment of adult patients with locally advanced or metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small-cell lung cancer (NSCLC)'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The price for 30 tablets (either 40 mg or 80 mg) is £5,770 (BNF online, accessed February 2020). The company has a commercial arrangement that makes osimertinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by AstraZeneca, a review of this submission by the evidence review group (ERG), the technical report, and responses from stakeholders. See the committee papers for full details of the evidence, including details about the original appraisal (TA416).
As a condition of the positive recommendation and the managed access arrangement in the previous appraisal, the company was required to collect updated efficacy data from the AURA2 and AURA3 studies. Also, data were collected on the use of osimertinib in the NHS through the Cancer Drugs Fund using the Systemic Anti-Cancer Therapy (SACT) dataset.
The committee recognised that there were remaining areas of uncertainty in the analyses presented (see technical report, table 2, page 27) and took these into account in its decision making. The committee discussed the following issues (issues 1 to 6), which were outstanding after the technical engagement stage:
differences in overall survival estimates between trials and real-world evidence
treatment switching in AURA3
choice of model
choice of extrapolation to predict overall survival
choice of utility values
end-of-life criteria.
# Clinical need
## People with EGFR T790M mutation-positive locally advanced or metastatic NSCLC value having osimertinib as a treatment option
The patient and clinical experts explained that overall survival for lung cancer in the UK is poor. The patient expert noted that people with epidermal growth factor receptor (EGFR) T790M mutation-positive non-small-cell lung cancer (NSCLC) are younger and have usually never smoked. They often get a diagnosis at an advanced disease stage (that is, stage 3b or 4). The committee recalled from the original appraisal that only about 1% of the EGFR mutation-positive population would have the T790M mutation present at diagnosis and that osimertinib would very rarely be used in this setting. The patient expert explained that the adverse events, increased hospital visits, potential admissions, and additional medication associated with platinum doublet chemotherapy (PDC) can affect quality of life. Longer and more frequent hospital trips can mean less time with family and time off work, and can affect a person's social life. The patient expert explained that osimertinib and other tyrosine kinase inhibitors (TKIs) were better tolerated than PDC. But the committee noted that diarrhoea and rashes are more common with TKIs. The clinical expert explained that patients on PDC had worse clinical outcomes and more rapid disease progression than those taking osimertinib. The committee concluded that managing EGFR T790M mutation-positive NSCLC places a burden on people and their families, and that patients value having osimertinib as a treatment option.
# Clinical effectiveness
## There is uncertainty about whether overall survival estimates from trial data are generalisable to the NHS
As well as new data from the AURA3 trial, there were new SACT data. These data were collected from 357 people who had osimertinib in the Cancer Drugs Fund between October 2016 and September 2018. AURA3 is an open-label trial that included 419 patients with EGFR T790M mutation-positive NSCLC, whose disease had progressed during first-line EGFR TKI treatment. Patients were randomised to have either osimertinib or PDC. The committee noted that overall survival estimates from the SACT dataset were considerably lower for patients on osimertinib compared with AURA3 trial data. The SACT median overall survival was 13.9 months (95% confidence interval 12.1 to 17.6) compared with 26.8 months for AURA3 (95% CI 23.49 to 31.54). The committee noted that the hazard ratio in AURA3 was not statistically significant (hazard ratio 0.87; 95% CI 0.67 to 1.13) but it was aware that this estimate did not account for treatment switching (see section 3.6). The committee concluded that the difference in estimates meant there was uncertainty about the generalisability of the trial data to NHS practice.
## There are differences between the populations in the NHS and in AURA3
The Cancer Drugs Fund clinical lead highlighted that there were more patients in the SACT dataset than in the clinical trials and that SACT data were considered to be representative of UK clinical practice. The clinical expert and the Cancer Drugs Fund clinical lead explained that there were several possible reasons for the differences between the estimates from the trial data and the SACT dataset:
Patients in the SACT dataset were slightly older and possibly less well than patients in the trials. The clinical expert explained that it was possible that patients with comorbidities would have been screened out of the trials, and patients in the SACT dataset may have had significant comorbidities, but this information was not available.
The frequency of cerebral metastases in the SACT population was unknown.
Patients were included in AURA3 only if they had a performance status of 0 to 1. In the SACT dataset, 6% of patients had a performance status of 2, and in 9% of patients performance status was not known.
There was a high proportion (about 65%) of people of East Asian family origin in AURA3. The Cancer Drugs Fund clinical lead explained that the subgroup analyses in AURA3 suggested that osimertinib may have a greater relative benefit in people of East Asian family origin. The company noted that the committee had previously said that the effect of ethnicity alone in influencing outcomes is uncertain.
Most patients in the clinical trials had a first-generation TKI (erlotinib or gefitinib) but in the SACT dataset, most patients had a second-generation TKI (afatinib). However, the clinical expert, Cancer Drugs Fund clinical lead and the company explained that there was no evidence to suggest that the difference in survival could be explained by the difference in first-line treatments.
The patient expert and clinical expert noted that there may also be variation in time to receiving biopsy results, monitoring of disease progression and access to prospective scanning for brain metastases.The committee considered that the above factors could have contributed to the differences in survival results between the trials and the SACT dataset, but concluded that this could not be determined.
# Modelling of overall survival
## The hybrid economic model is appropriate for decision making
After technical engagement, the company submitted a hybrid model based on the one used in the original appraisal, with data imported from AURA3. The committee agreed that AURA3 data should be used and accepted the hybrid model.
## Overall survival data from AURA3 should be extrapolated using exponential functions
After technical engagement, the company submitted a new base case that included the ERG's preferred extrapolation, which used exponential functions for both treatment arms from the point that the available Kaplan–Meier data became heavily censored and unreliable. The committee agreed that overall survival data from AURA3 should be used and extrapolated using exponential functions.
## Overall survival estimates from AURA3 should be adjusted to account for treatment switching
The company submission outlined that in AURA3 the rate of treatment switching from PDC to osimertinib after disease progression was 71%. The committee thought that this was likely to bias overall survival results because using osimertinib in a third-line setting did not reflect NHS practice. The company used a rank-preserving structural failure time model to adjust for treatment switching (see the technical report, page 14). The company also provided scenario analyses for duration of treatment effect and methods of censoring. The committee understood that, depending on which scenario was chosen, there was a risk of over or underestimating overall survival for osimertinib compared with PDC. The company base case assumed that a treatment effect only happened while on treatment and re-censoring was only applied in the estimation of the acceleration factor (the estimation of the treatment effect of osimertinib). The ERG highlighted that the company's PDC base-case median crossover-adjusted overall survival result was more optimistic than results from the company's adjusted indirect comparison or from the SACT data. The ERG explained that, although several methods of adjusting for treatment switching were considered by the company, no method was better than any other. The committee agreed that all methods of adjustment, including the rank-preserving structural failure time model, had their weaknesses but that some method of adjustment was needed because of the high level of crossover. The committee concluded that, although it was not possible to determine which scenarios gave the most accurate estimate, the company's preferred adjustment was a reasonable estimate of survival.
# Health-related quality of life
## Modelling utility values as treatment specific could be reasonable
In its initial submission, the company modelled utility values based on health state. After technical engagement, the company submitted a new base case in which it used treatment-specific utility values rather than health-state utility values. In the company's updated analysis submitted before the committee meeting, the treatment-specific utility values for osimertinib were from AURA2, and for PDC were from LUME‑Lung 1. LUME-Lung 1 evaluated docetaxel with or without nintedanib as second-line therapy for patients with stage 3b or 4 recurrent NSCLC which had progressed after first-line chemotherapy. For the osimertinib arm, the company modelled utility values of 0.831, 0.751 and 0.715 for the response, stable disease and progressed disease health states. For the PDC arm, the company used utility values of 0.670, 0.670 and 0.640 for these states. The committee discussed the appropriateness of modelling utility values to vary between treatment arms. The patient and clinical experts stated that the differences in toxicity profiles between osimertinib and PDC may mean that people in the osimertinib arm report better health-related quality of life. The committee considered that the difference in side effect profiles between osimertinib and PDC meant that it could be reasonable to model treatment-specific utility values.
## It is preferable for treatment-specific utility values to use the same source of evidence for both treatment arms
The company used different sources of evidence (the AURA2 and LUME-Lung 1 studies) to inform the utility values used in each treatment arm (see section 3.7). The committee questioned the likelihood that the utility values for treatment response with PDC (0.67) would be so much lower than for disease progression with osimertinib (0.715). The committee discussed whether the difference in utility values between treatment arms could partly be because of differences between how the AURA2 and LUME-Lung 1 studies were designed and done. The committee concluded that it was preferable for any treatment-specific utility values to be taken from the same source of evidence for each treatment arm.
## There is uncertainty about which source of utility values is the best to use
The committee noted that health-related quality-of-life data were collected for both osimertinib and PDC in AURA3. The company explained that it had not used treatment-specific utility values from AURA3 because of the differences between trial arms at baseline. However, the committee questioned whether baseline differences could be accounted for during statistical analysis. The new evidence from AURA3 (response 0.836, stable disease 0.797 and progressed disease 0.717) produced slightly higher utility values than AURA2 (response 0.831, stable disease 0.751 and progressed disease 0.715). The company considered that this similarity showed that the most plausible values were those seen in these trials. The ERG noted that the AURA2 and AURA3 utility values seemed implausibly high when compared with age-related population values. In its base case, the ERG used utility values from AURA2, but presented another scenario using utility values from LUME‑Lung 1 (response and stable disease 0.67, progressed disease 0.64). The company did not believe that it was appropriate to use the LUME‑Lung 1 utility values because they were from a different patient population whose disease was treated with cytotoxic chemotherapy, not with an EGFR TKI, and with unknown T790M mutation status. The committee was concerned about the absolute values and relative differences between utility values when comparing the different sources. It also considered how the trial utility values would relate to NHS practice, given the significant difference between the survival outcomes in the AURA trials and those from the SACT dataset. The committee concluded that there was uncertainty about the best source of utility values to use.
## The modelled scenarios of health-state utility values from AURA2 and LUME-Lung 1 are the most plausible analyses
The committee considered that there may be a reason for using treatment-specific utility values (see section 3.7), but it had not seen a plausible analysis using them. The committee noted that the AURA2 and AURA3 utility values were consistent but was concerned that they were implausibly high. The committee was uncertain how the utility values would relate to NHS practice because of the large difference between the survival outcomes with osimertinib in the AURA trials and the SACT dataset. It recalled that the LUME‑Lung 1 utility values were much lower than those of the AURA trials, but acknowledged there were differences in patient populations between the trials (see section 3.9). The committee concluded that, based on the evidence and using a health-state utility approach, the most likely values would fall somewhere between the AURA2 utility values and the LUME‑Lung 1 utility values. So, the ERG's 2 modelled scenarios of health-state utility values were considered the most plausible of the available analyses.
# Cost-effectiveness results
## The company's base-case ICER is higher than what NICE usually considers a cost-effective use of NHS resources
In analyses incorporating the commercial arrangement submitted after the committee meeting, the company base case included the following assumptions:
Rank-preserving structural failure time model to adjust AURA3 survival results (with 'on treatment' effect and re-censoring to inform the acceleration factor).
Hybrid model A/B (see section 3.4).
Overall survival, progression-free survival and time to treatment discontinuation taken from AURA3.
Exponential extrapolation of overall survival, progression-free survival and time to treatment discontinuation from the point at which Kaplan–Meier data become heavily censored.
Treatment-specific utility values from AURA3 (osimertinib) and LUME‑Lung 1 (PDC).The company base-case incremental cost-effectiveness ratio (ICER) was £36,034 per quality-adjusted life year (QALY) gained. This estimate included the company's confidential commercial arrangement. The committee concluded that the company's preferred assumptions led to an ICER that is higher than NICE usually considers to be a cost-effective use of NHS resources.
## The most plausible ICER is below £50,000 per QALY gained
The ERG's preferred assumptions were similar to the company's preferred assumptions but were based on utility values modelled according to health state. The key difference between the company and ERG's base case was the source of utility values. In analyses incorporating the updated commercial arrangement, the company preferred treatment-specific utility values using data from AURA3 for osimertinib and LUME‑Lung 1 for PDC, giving a base case of £36,034 per QALY gained. The ERG preferred health-state utility values, and used health-state utility values derived from AURA2 data that resulted in a base-case ICER of £41,799 per QALY gained. The ERG also presented a scenario based on the LUME‑Lung 1 utility values which increased the ICER to £49,649 per QALY gained. The committee was aware that NHS England considered that the commercial arrangement delivered additional value, but the analyses relating to this are commercial in confidence. The committee concluded that the most plausible ICER was between £41,799 and £49,649 per QALY gained based on analyses using the company's commercial arrangement. It was lower when the additional commercial information from NHS England was incorporated. Considering the uncertainty about the best source of utility values, the committee agreed that the ICER would likely be closer to the top end of the range.
# End of life
## Life expectancy for people with EGFR T790M mutation-positive NSCLC is less than 24 months
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. In the original appraisal, the committee concluded that people who take osimertinib have a short life expectancy. The clinical experts explained that they would expect people with EGFR T790M mutation-positive NSCLC to live for less than 24 months. The committee concluded that the short life expectancy criterion was met.
## Osimertinib extends life by at least 3 months
The point estimates of AURA3 showed a survival difference of more than 3 months for patients having osimertinib compared with PDC. The patient and clinical experts explained that the survival benefit and improved quality of life offered by osimertinib could not be underestimated. The patient expert said that overall survival improved with osimertinib and that because most patients are diagnosed with stage 4 disease, access to osimertinib can be life changing. The committee concluded that osimertinib met the extension-to-life criterion.
# Other factors
At the meeting, the patient and clinical experts outlined that there was some regional variation in access to osimertinib during the Cancer Drugs Fund data collection period. Equality of access to treatment is not an equality issue that can be addressed by the committee.
The company did not highlight any additional benefits that had not been captured in the QALY calculations.
# Conclusion
## Osimertinib is recommended
Overall, considering new evidence from the AURA3 trial, the Cancer Drugs Fund SACT dataset, the commercial arrangement, and the committee's preferred assumptions, the estimates of cost effectiveness were within the range that is considered to be a cost-effective use of NHS resources when the end-of-life criteria were applied. So osimertinib is recommended for use in the NHS for treating EGFR T790M mutation-positive locally advanced or metastatic NSCLC that has progressed after first-line treatment with an EGFR TKI.
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{'Recommendations': "Osimertinib is recommended as an option for treating epidermal growth factor receptor (EGFR) T790M mutation-positive locally advanced or metastatic non-small-cell lung cancer (NSCLC) in adults, only if:\n\ntheir disease has progressed after first-line treatment with an EGFR tyrosine kinase inhibitor and\n\nthe company provides osimertinib according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with osimertinib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nThis appraisal reviews the additional evidence collected as part of the Cancer Drugs Fund managed access agreement for osimertinib for treating EGFR T790M mutation-positive locally advanced or metastatic NSCLC for adults whose disease has progressed after treatment with an EGFR tyrosine kinase inhibitor (NICE technology appraisal guidance\xa0416).\n\nEGFR T790M mutation-positive locally advanced or metastatic NSCLC that has progressed after treatment with an EGFR tyrosine kinase inhibitor is usually treated with platinum doublet chemotherapy (PDC).\n\nEvidence from clinical trials suggests that people who take osimertinib live longer than those who have PDC, although there is some uncertainty about the results.\n\nOsimertinib meets NICE's criteria to be considered a life-extending treatment at the end of life. Although the cost-effectiveness estimates for osimertinib are uncertain, they are likely to be within what NICE considers to be an acceptable use of NHS resources. So, osimertinib is recommended.", 'Information about osimertinib': "# Marketing authorisation indication\n\nOsimertinib (Tagrisso, AstraZeneca) has a marketing authorisation for 'the treatment of adult patients with locally advanced or metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small-cell lung cancer (NSCLC)'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe price for 30\xa0tablets (either 40\xa0mg or 80\xa0mg) is £5,770 (BNF online, accessed February 2020). The company has a commercial arrangement that makes osimertinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by AstraZeneca, a review of this submission by the evidence review group (ERG), the technical report, and responses from stakeholders. See the committee papers for full details of the evidence, including details about the original appraisal (TA416).\n\nAs a condition of the positive recommendation and the managed access arrangement in the previous appraisal, the company was required to collect updated efficacy data from the AURA2 and AURA3 studies. Also, data were collected on the use of osimertinib in the NHS through the Cancer Drugs Fund using the Systemic Anti-Cancer Therapy (SACT) dataset.\n\nThe committee recognised that there were remaining areas of uncertainty in the analyses presented (see technical report, table\xa02, page\xa027) and took these into account in its decision making. The committee discussed the following issues (issues\xa01 to\xa06), which were outstanding after the technical engagement stage:\n\ndifferences in overall survival estimates between trials and real-world evidence\n\ntreatment switching in AURA3\n\nchoice of model\n\nchoice of extrapolation to predict overall survival\n\nchoice of utility values\n\nend-of-life criteria.\n\n# Clinical need\n\n## People with EGFR T790M mutation-positive locally advanced or metastatic NSCLC value having osimertinib as a treatment option\n\nThe patient and clinical experts explained that overall survival for lung cancer in the UK is poor. The patient expert noted that people with epidermal growth factor receptor (EGFR) T790M mutation-positive non-small-cell lung cancer (NSCLC) are younger and have usually never smoked. They often get a diagnosis at an advanced disease stage (that is, stage\xa03b or\xa04). The committee recalled from the original appraisal that only about 1% of the EGFR mutation-positive population would have the T790M mutation present at diagnosis and that osimertinib would very rarely be used in this setting. The patient expert explained that the adverse events, increased hospital visits, potential admissions, and additional medication associated with platinum doublet chemotherapy (PDC) can affect quality of life. Longer and more frequent hospital trips can mean less time with family and time off work, and can affect a person's social life. The patient expert explained that osimertinib and other tyrosine kinase inhibitors (TKIs) were better tolerated than PDC. But the committee noted that diarrhoea and rashes are more common with TKIs. The clinical expert explained that patients on PDC had worse clinical outcomes and more rapid disease progression than those taking osimertinib. The committee concluded that managing EGFR T790M mutation-positive NSCLC places a burden on people and their families, and that patients value having osimertinib as a treatment option.\n\n# Clinical effectiveness\n\n## There is uncertainty about whether overall survival estimates from trial data are generalisable to the NHS\n\nAs well as new data from the AURA3 trial, there were new SACT data. These data were collected from 357\xa0people who had osimertinib in the Cancer Drugs Fund between October 2016 and September 2018. AURA3 is an open-label trial that included 419\xa0patients with EGFR T790M mutation-positive NSCLC, whose disease had progressed during first-line EGFR TKI treatment. Patients were randomised to have either osimertinib or PDC. The committee noted that overall survival estimates from the SACT dataset were considerably lower for patients on osimertinib compared with AURA3 trial data. The SACT median overall survival was 13.9\xa0months (95% confidence interval [CI] 12.1 to 17.6) compared with 26.8\xa0months for AURA3 (95% CI 23.49 to 31.54). The committee noted that the hazard ratio in AURA3 was not statistically significant (hazard ratio 0.87; 95% CI 0.67 to 1.13) but it was aware that this estimate did not account for treatment switching (see section\xa03.6). The committee concluded that the difference in estimates meant there was uncertainty about the generalisability of the trial data to NHS practice.\n\n## There are differences between the populations in the NHS and in AURA3\n\nThe Cancer Drugs Fund clinical lead highlighted that there were more patients in the SACT dataset than in the clinical trials and that SACT data were considered to be representative of UK clinical practice. The clinical expert and the Cancer Drugs Fund clinical lead explained that there were several possible reasons for the differences between the estimates from the trial data and the SACT dataset:\n\nPatients in the SACT dataset were slightly older and possibly less well than patients in the trials. The clinical expert explained that it was possible that patients with comorbidities would have been screened out of the trials, and patients in the SACT dataset may have had significant comorbidities, but this information was not available.\n\nThe frequency of cerebral metastases in the SACT population was unknown.\n\nPatients were included in AURA3 only if they had a performance status of 0 to 1. In the SACT dataset, 6% of patients had a performance status of 2, and in 9% of patients performance status was not known.\n\nThere was a high proportion (about 65%) of people of East Asian family origin in AURA3. The Cancer Drugs Fund clinical lead explained that the subgroup analyses in AURA3 suggested that osimertinib may have a greater relative benefit in people of East Asian family origin. The company noted that the committee had previously said that the effect of ethnicity alone in influencing outcomes is uncertain.\n\nMost patients in the clinical trials had a first-generation TKI (erlotinib or gefitinib) but in the SACT dataset, most patients had a second-generation TKI (afatinib). However, the clinical expert, Cancer Drugs Fund clinical lead and the company explained that there was no evidence to suggest that the difference in survival could be explained by the difference in first-line treatments.\n\nThe patient expert and clinical expert noted that there may also be variation in time to receiving biopsy results, monitoring of disease progression and access to prospective scanning for brain metastases.The committee considered that the above factors could have contributed to the differences in survival results between the trials and the SACT dataset, but concluded that this could not be determined.\n\n# Modelling of overall survival\n\n## The hybrid economic model is appropriate for decision making\n\nAfter technical engagement, the company submitted a hybrid model based on the one used in the original appraisal, with data imported from AURA3. The committee agreed that AURA3 data should be used and accepted the hybrid model.\n\n## Overall survival data from AURA3 should be extrapolated using exponential functions\n\nAfter technical engagement, the company submitted a new base case that included the ERG's preferred extrapolation, which used exponential functions for both treatment arms from the point that the available Kaplan–Meier data became heavily censored and unreliable. The committee agreed that overall survival data from AURA3 should be used and extrapolated using exponential functions.\n\n## Overall survival estimates from AURA3 should be adjusted to account for treatment switching\n\nThe company submission outlined that in AURA3 the rate of treatment switching from PDC to osimertinib after disease progression was 71%. The committee thought that this was likely to bias overall survival results because using osimertinib in a third-line setting did not reflect NHS practice. The company used a rank-preserving structural failure time model to adjust for treatment switching (see the technical report, page\xa014). The company also provided scenario analyses for duration of treatment effect and methods of censoring. The committee understood that, depending on which scenario was chosen, there was a risk of over or underestimating overall survival for osimertinib compared with PDC. The company base case assumed that a treatment effect only happened while on treatment and re-censoring was only applied in the estimation of the acceleration factor (the estimation of the treatment effect of osimertinib). The ERG highlighted that the company's PDC base-case median crossover-adjusted overall survival result was more optimistic than results from the company's adjusted indirect comparison or from the SACT data. The ERG explained that, although several methods of adjusting for treatment switching were considered by the company, no method was better than any other. The committee agreed that all methods of adjustment, including the rank-preserving structural failure time model, had their weaknesses but that some method of adjustment was needed because of the high level of crossover. The committee concluded that, although it was not possible to determine which scenarios gave the most accurate estimate, the company's preferred adjustment was a reasonable estimate of survival.\n\n# Health-related quality of life\n\n## Modelling utility values as treatment specific could be reasonable\n\nIn its initial submission, the company modelled utility values based on health state. After technical engagement, the company submitted a new base case in which it used treatment-specific utility values rather than health-state utility values. In the company's updated analysis submitted before the committee meeting, the treatment-specific utility values for osimertinib were from AURA2, and for PDC were from LUME‑Lung\xa01. LUME-Lung\xa01 evaluated docetaxel with or without nintedanib as second-line therapy for patients with stage\xa03b or\xa04 recurrent NSCLC which had progressed after first-line chemotherapy. For the osimertinib arm, the company modelled utility values of 0.831, 0.751 and 0.715 for the response, stable disease and progressed disease health states. For the PDC arm, the company used utility values of 0.670, 0.670 and 0.640 for these states. The committee discussed the appropriateness of modelling utility values to vary between treatment arms. The patient and clinical experts stated that the differences in toxicity profiles between osimertinib and PDC may mean that people in the osimertinib arm report better health-related quality of life. The committee considered that the difference in side effect profiles between osimertinib and PDC meant that it could be reasonable to model treatment-specific utility values.\n\n## It is preferable for treatment-specific utility values to use the same source of evidence for both treatment arms\n\nThe company used different sources of evidence (the AURA2 and LUME-Lung 1 studies) to inform the utility values used in each treatment arm (see section 3.7). The committee questioned the likelihood that the utility values for treatment response with PDC (0.67) would be so much lower than for disease progression with osimertinib (0.715). The committee discussed whether the difference in utility values between treatment arms could partly be because of differences between how the AURA2 and LUME-Lung\xa01 studies were designed and done. The committee concluded that it was preferable for any treatment-specific utility values to be taken from the same source of evidence for each treatment arm.\n\n## There is uncertainty about which source of utility values is the best to use\n\nThe committee noted that health-related quality-of-life data were collected for both osimertinib and PDC in AURA3. The company explained that it had not used treatment-specific utility values from AURA3 because of the differences between trial arms at baseline. However, the committee questioned whether baseline differences could be accounted for during statistical analysis. The new evidence from AURA3 (response 0.836, stable disease 0.797 and progressed disease 0.717) produced slightly higher utility values than AURA2 (response 0.831, stable disease 0.751 and progressed disease 0.715). The company considered that this similarity showed that the most plausible values were those seen in these trials. The ERG noted that the AURA2 and AURA3 utility values seemed implausibly high when compared with age-related population values. In its base case, the ERG used utility values from AURA2, but presented another scenario using utility values from LUME‑Lung\xa01 (response and stable disease 0.67, progressed disease 0.64). The company did not believe that it was appropriate to use the LUME‑Lung\xa01 utility values because they were from a different patient population whose disease was treated with cytotoxic chemotherapy, not with an EGFR TKI, and with unknown T790M mutation status. The committee was concerned about the absolute values and relative differences between utility values when comparing the different sources. It also considered how the trial utility values would relate to NHS practice, given the significant difference between the survival outcomes in the AURA trials and those from the SACT dataset. The committee concluded that there was uncertainty about the best source of utility values to use.\n\n## The modelled scenarios of health-state utility values from AURA2 and LUME-Lung\xa01 are the most plausible analyses\n\nThe committee considered that there may be a reason for using treatment-specific utility values (see section 3.7), but it had not seen a plausible analysis using them. The committee noted that the AURA2 and AURA3 utility values were consistent but was concerned that they were implausibly high. The committee was uncertain how the utility values would relate to NHS practice because of the large difference between the survival outcomes with osimertinib in the AURA trials and the SACT dataset. It recalled that the LUME‑Lung\xa01 utility values were much lower than those of the AURA trials, but acknowledged there were differences in patient populations between the trials (see section 3.9). The committee concluded that, based on the evidence and using a health-state utility approach, the most likely values would fall somewhere between the AURA2 utility values and the LUME‑Lung\xa01 utility values. So, the ERG's 2 modelled scenarios of health-state utility values were considered the most plausible of the available analyses.\n\n# Cost-effectiveness results\n\n## The company's base-case ICER is higher than what NICE usually considers a cost-effective use of NHS resources\n\nIn analyses incorporating the commercial arrangement submitted after the committee meeting, the company base case included the following assumptions:\n\nRank-preserving structural failure time model to adjust AURA3 survival results (with 'on treatment' effect and re-censoring to inform the acceleration factor).\n\nHybrid model A/B (see section\xa03.4).\n\nOverall survival, progression-free survival and time to treatment discontinuation taken from AURA3.\n\nExponential extrapolation of overall survival, progression-free survival and time to treatment discontinuation from the point at which Kaplan–Meier data become heavily censored.\n\nTreatment-specific utility values from AURA3 (osimertinib) and LUME‑Lung\xa01 (PDC).The company base-case incremental cost-effectiveness ratio (ICER) was £36,034 per quality-adjusted life year (QALY) gained. This estimate included the company's confidential commercial arrangement. The committee concluded that the company's preferred assumptions led to an ICER that is higher than NICE usually considers to be a cost-effective use of NHS resources.\n\n## The most plausible ICER is below £50,000 per QALY gained\n\nThe ERG's preferred assumptions were similar to the company's preferred assumptions but were based on utility values modelled according to health state. The key difference between the company and ERG's base case was the source of utility values. In analyses incorporating the updated commercial arrangement, the company preferred treatment-specific utility values using data from AURA3 for osimertinib and LUME‑Lung\xa01 for PDC, giving a base case of £36,034 per QALY gained. The ERG preferred health-state utility values, and used health-state utility values derived from AURA2 data that resulted in a base-case ICER of £41,799 per QALY gained. The ERG also presented a scenario based on the LUME‑Lung\xa01 utility values which increased the ICER to £49,649 per QALY gained. The committee was aware that NHS England considered that the commercial arrangement delivered additional value, but the analyses relating to this are commercial in confidence. The committee concluded that the most plausible ICER was between £41,799 and £49,649 per QALY gained based on analyses using the company's commercial arrangement. It was lower when the additional commercial information from NHS England was incorporated. Considering the uncertainty about the best source of utility values, the committee agreed that the ICER would likely be closer to the top end of the range.\n\n# End of life\n\n## Life expectancy for people with EGFR T790M mutation-positive NSCLC is less than 24\xa0months\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. In the original appraisal, the committee concluded that people who take osimertinib have a short life expectancy. The clinical experts explained that they would expect people with EGFR T790M mutation-positive NSCLC to live for less than 24\xa0months. The committee concluded that the short life expectancy criterion was met.\n\n## Osimertinib extends life by at least 3\xa0months\n\nThe point estimates of AURA3 showed a survival difference of more than 3\xa0months for patients having osimertinib compared with PDC. The patient and clinical experts explained that the survival benefit and improved quality of life offered by osimertinib could not be underestimated. The patient expert said that overall survival improved with osimertinib and that because most patients are diagnosed with stage\xa04 disease, access to osimertinib can be life changing. The committee concluded that osimertinib met the extension-to-life criterion.\n\n# Other factors\n\nAt the meeting, the patient and clinical experts outlined that there was some regional variation in access to osimertinib during the Cancer Drugs Fund data collection period. Equality of access to treatment is not an equality issue that can be addressed by the committee.\n\nThe company did not highlight any additional benefits that had not been captured in the QALY calculations.\n\n# Conclusion\n\n## Osimertinib is recommended\n\nOverall, considering new evidence from the AURA3 trial, the Cancer Drugs Fund SACT dataset, the commercial arrangement, and the committee's preferred assumptions, the estimates of cost effectiveness were within the range that is considered to be a cost-effective use of NHS resources when the end-of-life criteria were applied. So osimertinib is recommended for use in the NHS for treating EGFR T790M mutation-positive locally advanced or metastatic NSCLC that has progressed after first-line treatment with an EGFR TKI."}
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https://www.nice.org.uk/guidance/ta653
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Evidence-based recommendations on osimertinib (Tagrisso) for treating epidermal growth factor receptor (EGFR) T790M mutation-positive locally advanced or metastatic non-small-cell lung cancer (NSCLC) in adults.
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a238268cb8588da2c9a08d4c5d8582ba68c804de
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nice
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Osimertinib for untreated EGFR mutation-positive non-small-cell lung cancer
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Osimertinib for untreated EGFR mutation-positive non-small-cell lung cancer
Evidence-based recommendations on osimertinib (Tagrisso) for untreated locally advanced or metastatic epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer in adults.
# Recommendation
Osimertinib is recommended, within its marketing authorisation, as an option for untreated locally advanced or metastatic epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) in adults. It is recommended only if the company provides osimertinib according to the commercial arrangement.
Why the committee made this recommendation
Locally advanced or metastatic EGFR mutation-positive NSCLC is usually first treated with afatinib, erlotinib or gefitinib.
Evidence from a randomised controlled trial suggests that people who take osimertinib live longer than people who take erlotinib or gefitinib. They also live longer before their disease gets worse. There is some uncertainty about the comparison of osimertinib with afatinib, which may be more effective than erlotinib and gefitinib, because there is no direct evidence comparing them.
But, because of a new commercial arrangement, the cost-effectiveness estimates for osimertinib are within what NICE considers an acceptable use of NHS resources. So, osimertinib is recommended.# Information about osimertinib
# Marketing authorisation indication
Osimertinib (Tagrisso, AstraZeneca) is indicated 'for the first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutations'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The price is £5,770 for 80 mg and 40 mg osimertinib (pack of 30 tablets, excluding VAT; BNF online, accessed August 2020). The company has a commercial arrangement that makes osimertinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by AstraZeneca as part of the previous guidance (NICE technology appraisal guidance 621), another submission by AstraZeneca for the rapid review, reviews of these submissions by the evidence review group (ERG), and the technical report developed as part of the previous guidance through engagement with stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that several issues had been resolved during the technical engagement stage, and agreed that:
The utility value of 0.678 (from the AURA 2 trial, second-line treatment with osimertinib) was more representative of people in the progressed disease state (table 3, page 24 to 25 of the technical report).
A combined approach to determine the appropriate resource costs for people in the progressed disease state was acceptable (table 3, pages 24 to 25 of the technical report).
It recognised that there were remaining areas of uncertainty associated with the analyses presented (table 2, pages 22 to 23 of the technical report), and took these into account in its decision making. As part of the previous guidance, it discussed the following issues, which were outstanding after the technical engagement stage.
# Clinical need
## People would welcome a new treatment option
The patient experts explained that people with untreated locally advanced or metastatic epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) are often very unwell, with many distressing symptoms. There are no curative treatments. The prognosis is generally poor despite treatments such as targeted therapies and immunotherapy. People would therefore welcome new treatments that improve their symptoms and quality of life, and increase how long they live (even if this increase is only small). Locally advanced or metastatic EGFR mutation-positive NSCLC is first treated with an EGFR tyrosine kinase inhibitor, such as afatinib, gefitinib or erlotinib, in line with NICE guidance on afatinib, gefitinib and erlotinib. The clinical experts explained that people would usually be offered afatinib, based on the clinical evidence (see section 3.4). After afatinib, gefitinib or erlotinib, people may be offered either osimertinib if they have developed the T790M resistance mutation in the EGFR gene (in line with NICE's technology appraisal guidance on osimertinib for treating EGFR T790M mutation-positive advanced NSCLC), or chemotherapy if not. People who are not well enough to have further treatment would be offered best supportive care. After chemotherapy, people may be offered immunotherapy, docetaxel with or without nintedanib, or best supportive care. The clinical experts stated that osimertinib would be beneficial as an additional treatment option because it is better tolerated than existing treatments, with fewer side effects. Also, if osimertinib was a first-line treatment option, it would remove the need for T790M mutation testing before second-line treatment. This involves a biopsy, which is invasive and can be psychologically distressing. The committee agreed that additional options would be beneficial and concluded that osimertinib would be a useful addition to first-line treatment.
# Clinical evidence
## The FLAURA trial is broadly generalisable to people with untreated locally advanced or metastatic EGFR mutation-positive NSCLC in England
The clinical evidence for osimertinib came from the FLAURA randomised controlled trial. FLAURA compared the efficacy and safety of osimertinib with standard care (erlotinib or gefitinib) for people with locally advanced or metastatic EGFR mutation-positive NSCLC. Patients in the trial had either the exon 19 deletion (del19) or exon 21 (L858R) EGFR mutation. The clinical experts explained that these 2 mutations account for around 90% of all EGFR mutations. Also, most trials only include people with these mutations, including the trials that were carried out with other tyrosine kinase inhibitors. The committee acknowledged that, although other mutations may not respond as well to osimertinib, the marketing authorisation indication is not restricted to these 2 mutations (see section 2). It therefore agreed that the EGFR mutation status of patients in FLAURA generally reflected that seen in NHS clinical practice in England. The inclusion criteria allowed people with stable brain metastases to enter the trial but limited the trial population to people with an Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1. For this reason, the committee was aware that the clinical trial population may be in better health than people with stage 3b or stage 4 NSCLC in the NHS and that people with many comorbidities may not have been included in the trial. Also, it noted that afatinib was not a comparator in the standard care arm in FLAURA (see section 3.4) and that many subsequent treatments used in the trial are not routinely used in the NHS. Despite these concerns, the clinical experts explained that the evidence from FLAURA was broadly generalisable to NHS clinical practice. The committee agreed with the clinical experts.
## Osimertinib extends progression-free and overall survival compared with gefitinib and erlotinib but the size of the benefit is unclear
An interim analysis of FLAURA showed that progression-free survival was statistically significantly longer with osimertinib than with erlotinib or gefitinib. At the interim data cut (12 June 2017; presented in the previous guidance), median progression-free survival was 18.9 months for osimertinib (95% confidence interval 15.2 to 21.4) and 10.2 months for standard care (95% CI 9.6 to 11.1). The hazard ratio was 0.46 (95% CI 0.37 to 0.57; p<0.001). Overall survival data were very immature (25% of events) but the interim results showed that osimertinib extended overall survival compared with standard care. This produced a hazard ratio of 0.63 (95% CI 0.45 to 0.88; p=0.007), which was not statistically significant (a p value of less than 0.0015 was needed for the result to be significant). The committee acknowledged that the FLAURA data were very immature and that there was uncertainty in overall survival because of the number of events still to be reported. The trial reported more data on overall survival after the previous guidance was published, but submitting this evidence was beyond the scope of the rapid review process, so it could not be fully considered by the committee. Therefore the committee concluded, based on the evidence for the previous guidance, that osimertinib lengthened progression-free survival, and possibly overall survival, compared with erlotinib or gefitinib. But it also concluded that the overall survival benefit was difficult to establish because the data were very immature.
## EGFR tyrosine kinase inhibitors do not all have equal efficacy
The relevant comparators for this technology appraisal are erlotinib, gefitinib and afatinib. FLAURA compared osimertinib with either gefitinib or erlotinib, but not with afatinib. The Cancer Drugs Fund clinical lead noted that afatinib is currently the most prescribed EGFR tyrosine kinase inhibitor in England for this population. He also stated that previous trials, such as LUX-Lung 7, showed that afatinib statistically significantly improved progression-free survival compared with gefitinib. The clinical experts agreed that gefitinib and erlotinib are likely to have equal efficacy. They stated that people taking afatinib had a better response rate to treatment, a longer duration of response and longer progression-free survival than with erlotinib and gefitinib. Also, they usually stayed on afatinib for longer. The company stated that LUX-Lung 7 did not show a statistically significant increase in overall survival for afatinib compared with gefitinib. It therefore assumed that afatinib was equivalent in efficacy to erlotinib and gefitinib in its economic model. However, the clinical experts explained that LUX-Lung 7 was not powered (that is, it did not have enough people in the trial) to show a difference in overall survival compared with gefitinib. The ERG did its own exploratory indirect treatment comparison that suggested osimertinib statistically significantly improved progression-free survival compared with afatinib but showed no statistically significant difference in overall survival. The committee concluded that there was evidence of improved progression-free survival with afatinib compared with gefitinib, and erlotinib and gefitinib cannot be assumed to have equal efficacy with afatinib.
# Modelling of overall survival
## Assuming a 6-year treatment benefit for osimertinib is optimistic
The company used a partitioned survival structure with 3 health states (progression-free, progressed disease and death) to model overall survival in FLAURA. It used a time horizon of 20 years to capture all relevant costs and benefits for people having treatment. The company initially assumed a treatment benefit for osimertinib for the full 20-year period. The committee agreed with the ERG and clinical experts that this assumption was optimistic considering the data available and would have to be adjusted to reflect a more realistic benefit from osimertinib treatment. The company therefore revised its base case, assuming a 6‑year duration of treatment effect after the start of treatment (that is, applying a hazard ratio of 1 to both the osimertinib and standard care arms 6 years after starting treatment). The committee recalled that, in previous appraisals for locally advanced or metastatic NSCLC, the preferred treatment effect duration for immunotherapies was 3 years to 5 years. However, it acknowledged that these appraisals involved drugs with a different mechanism of action to osimertinib and a maximum treatment duration. Therefore, it was not appropriate to compare them. The clinical experts agreed that, because osimertinib is associated with improved progression-free survival and duration of response, treatment effect would continue after symptomatic and radiological progression for some people. They stated that this could plausibly give about 3 months of additional benefit after stopping treatment with osimertinib compared with erlotinib and gefitinib. The clinical experts believed that because osimertinib penetrates the blood–brain barrier better than erlotinib and gefitinib, it may help improve control of brain metastases. The committee recalled that afatinib yields longer progression-free survival than erlotinib and gefitinib, but because there was no direct evidence comparing osimertinib with afatinib (see section 3.4), it could not establish how osimertinib compared with afatinib in terms of progression-free and overall survival. The ERG's preferred analyses used durations of 3 years and 5 years. The ERG explained that the company's 6‑year duration of treatment effect would mean that people who stopped taking osimertinib within 1 year or 2 years of starting it would still benefit for the full 6 years. The ERG emphasised the limitations of modelling the duration of treatment effect with a partitioned survival model. This is because a crude approach is needed to make adjustments around the assumptions (for example, assuming equivalence at a single time point). The ERG noted that this does not fully reflect what happens in a clinical setting. The committee concluded that a 6‑year duration of treatment effect for osimertinib was optimistic and that, without more evidence, the ERG's analysis using a 3‑year or 5‑year duration of treatment effect was more appropriate.
## The economic model does not capture the benefits of subsequent treatments appropriately
The committee was aware of NICE's position statement on handling comparators and treatment sequences in the Cancer Drugs Fund. This states that 'products recommended for use in the Cancer Drugs Fund after 1 April 2016 should not be considered as comparators, or appropriately included in a treatment sequence, in subsequent relevant appraisals'. But the committee accepted that it could consider the company's approach of including osimertinib as a subsequent treatment (in line with NICE's guidance on osimertinib for treating locally advanced or metastatic EGFR T790M mutation-positive NSCLC) in the model in this appraisal, because this reflected that some patients in FLAURA did receive osimertinib as a subsequent treatment. People in the standard care arm in the model could have osimertinib as a second-line treatment, assumed to be 33% of people (based on clinical opinion). The committee noted that, although the costs of osimertinib as a second-line treatment were applied in the standard care arm of the model, efficacy was not fully captured given that only around 20% of people had osimertinib as a second-line treatment in the trial at the time of the interim analysis. The committee was aware that the subsequent treatments used in the trial may not reflect NHS practice. It noted that different subsequent therapies would mean different survival prospects and health states that cannot be captured in the modelling. The ERG explained that, to overcome the limitations of the model in capturing the efficacy of subsequent treatments, and to create more flexibility to explore varying the duration of treatment benefits, additional health states would be needed. The ERG described how an individual patient simulation model would better account for these issues but it would need lots of additional data, and trial data are usually immature. The committee agreed that the company's model was broadly appropriate for decision making. It acknowledged the limitations of the model and, given the immaturity of the data, concluded that the model did not fully capture the benefits of subsequent treatments appropriately.
## The company's modelling of overall survival is appropriate, but the immaturity of the data introduces uncertainty in estimating overall survival
At the interim data cut considered in the previous guidance, median overall survival was not achieved in either the osimertinib or standard care arm. To estimate the overall survival of people in FLAURA, the company used a piecewise Weibull extrapolation of the Kaplan–Meier curve, which was based on observed data up to 7.90 months in the trial. This estimated that mean overall survival was 66.96 months with osimertinib and 44.39 months with standard care, assuming a 20‑year time horizon in the model. The committee was aware that this extrapolation resulted in the most conservative piecewise survival estimates of those presented and fitted the data well. It understood that the FLAURA data were immature (only 25% of events occurring), which introduced uncertainty into the survival estimates, and that further data collection is planned. It concluded that, although the company's and ERG's preferred choice of distribution for modelling overall survival was appropriate, the immaturity of the data introduces uncertainty in estimating the results.
# Cost-effectiveness estimate
## The most plausible ICER for osimertinib is within the range NICE normally considers a cost-effective use of NHS resources
The committee considered the additional analyses presented for the rapid review, which incorporated the updated confidential commercial arrangement for osimertinib, and its preferred modelling assumptions:
A treatment effect duration (that is, from the start of treatment) of 3 years to 5 years (see section 3.5).
Weibull extrapolation of overall survival in both the osimertinib and standard care arms (see section 3.7).
A utility value of 0.678 (see table 3, pages 24 to 25 of the technical report).These assumptions were used in a fully incremental analysis (calculating incremental quality-adjusted life year gains and costs along a list of treatment options ranked by ascending cost), which incorporated all of the commercial arrangements for osimertinib and the comparators (gefitinib, erlotinib and afatinib). The committee was aware that NHS England considered that the commercial arrangement delivered additional value and included additional commercial information from NHS England in its decision making. Taking into account all the commercial considerations, the incremental cost-effectiveness ratio (ICER) was within the range NICE normally considers a cost-effective use of NHS resources. The exact ICERs cannot be reported here because they are commercial in confidence. The committee acknowledged that, given the available evidence from LUX-Lung 7 and clinical expert opinion, it is possible that afatinib has better efficacy than gefitinib and erlotinib (see section 3.4) and factored this into its decision making. It agreed that its most plausible ICER based on the evidence presented was within the range that NICE considers an effective use of NHS resources.
# End of life
## Osimertinib is likely to extend life by over 3 months
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. It recalled that, at the interim data cut presented and considered in the previous guidance, median overall survival had not been reached in FLAURA, and that the increased survival in the osimertinib arm was not statistically significantly different from the standard care arm (see section 3.3). However, it also noted that the company's economic model predicted mean overall survival would be 22 months longer with osimertinib than with standard care. Based on evidence from FLAURA and predictions from the economic model (using the committee's preferred assumptions), the committee concluded that osimertinib was likely to extend life by over 3 months and therefore met the extension-to-life criterion.
## FLAURA should be the primary data source for deciding if osimertinib meets the short life expectancy criterion
For the previous guidance, the company presented registry evidence from a real-world data source (National Cancer Registration and Analysis Service Public Health England data between 2014 and 2016), showing that median overall survival for the population in England was less than 24 months. The committee recognised that there was potential value in real-world evidence from the NHS in England to help inform its decision making. However, it considered there were several reasons why it was not appropriate to use these as the primary data source in isolation for its decision making on the short life expectancy criterion:
The committee recalled its conclusion that FLAURA was generalisable to clinical practice in England (see section 3.2). In addition, it noted the Cancer Drugs Fund clinical lead and ERG statements that it was inconsistent to use the FLAURA data to determine the overall survival benefit of osimertinib, but real-world evidence to determine life expectancy for people having standard care, without making some adjustments in the economic model (such as amending the efficacy estimates).
The committee noted that afatinib (the currently preferred and most prescribed EGFR tyrosine kinase inhibitor in England for this population) was not available for most of the time the NCRAS data were collected.
The committee recalled that after consultation on the technical report, the clinical experts stated that about 60% of people in clinical practice were alive 2 years after starting treatment with an EGFR tyrosine kinase inhibitor.
In the standard care arm, which used FLAURA data to inform the extrapolation of overall survival, the economic model (using the committee's preferred assumptions) predicted a median overall survival of 31.54 months and a mean overall survival of 44.39 months.
The committee was also aware that evidence from studies in similar populations, such as LUX-Lung 7 and ARCHER 1050, showed that median overall survival was more than 24 months.
The committee noted that the registry data were difficult to compare directly with the FLAURA data because possible confounders in the real-world population (such as comorbidities) were not taken into account.For these reasons, the committee considered it more appropriate to base its decision about estimating life expectancy on the FLAURA data, which the company had used in the economic model. The committee concluded that osimertinib did not meet the short life expectancy criterion of the end of life criteria.
## Subgroup analyses from FLAURA do not show that osimertinib meets the criteria for life-extending treatment at the end of life
At consultation on the previous guidance, the company provided new analyses to support its case for meeting the end of life criteria when using the committee-preferred dataset (FLAURA). The company stated that the subgroup analyses most closely reflected the cohort of NHS patients in England. However, the Cancer Drugs Fund clinical lead's nominated deputy advised caution in interpreting these registry data because the systemic anticancer therapy (SACT) data set is currently incomplete and that gaps in the evidence exist between the secondary uses service data and the corresponding SACT data. The 3 subgroups were:
No subsequent treatment with an EGFR tyrosine kinase inhibitor (because the company stated that people in England would not have a second EGFR tyrosine kinase inhibitor).
An ECOG performance score of 1 (because people in England with this condition are usually less well than those in FLAURA).
Non-Asian family origin (because most people with this condition in England are of non-Asian family origin and the company stated that they have poorer survival outcomes than people of Asian family origin).The committee noted that the subgroups in the new analyses had not been combined to calculate a value for mean or median overall survival. It agreed that this added substantial uncertainty to interpreting the results because each subgroup was linked to a single characteristic and it was not possible to determine the degree of overlap between these groups. The committee noted that the company's overall survival estimates for all 3 subgroups in the standard care arm were longer than 24 months (the modelled outputs are academic in confidence and cannot be reported). The ERG stated that because it did not have access to the FLAURA data, it could not confirm any of the company's results for the new analyses. The committee heard concerns regarding the relevance of the analyses:
The Cancer Drugs Fund clinical lead's nominated deputy commented that many people do have more than 2 subsequent therapies after progression on an EGFR tyrosine kinase inhibitor.The ERG noted that the overall survival for patients of non-Asian family origin may be shorter, but the results of the subgroup analysis were very similar to those of the intention-to-treat population in FLAURA and that no statistical testing of the difference was done. The committee agreed there was no conclusive evidence that ethnicity has an influence on overall survival and that other factors may be more influential. It noted that for NICE's technology appraisal guidance on afatinib, the clinical experts stated that differences in the effectiveness of afatinib in NSCLC are more likely to be determined by EGFR mutation status than ethnicity.The committee concluded the subgroup analyses presented in response to consultation on the previous guidance did not show that osimertinib meets the short life expectancy criterion. It noted that the short life expectancy criterion in the methods guide states 'normally less than 24 months' and discussed whether any flexibilities should be applied. The committee concluded that there were no exceptional circumstances that demanded additional flexibility in applying the end of life criteria (such as to ensure continued access to a highly effective treatment option that was perceived by patients and clinicians to be standard of care, in circumstances where access had been enabled years ahead of NICE publishing any guidance on the technology). The committee also concluded that, although the company's economic model suggests that the overall survival gain may potentially be high (see section 3.7), the immaturity of the trial data means there is considerable uncertainty about the magnitude of the benefit.
# Innovation
## Osimertinib may be innovative
The Cancer Drugs Fund clinical lead highlighted that follow up in FLAURA is short, so the economic model was unlikely to fully capture osimertinib's beneficial effect in the brain. They also stated that osimertinib is better tolerated than other EGFR tyrosine kinase inhibitors with respect to chronic grade 1 and grade 2 skin-related toxicities, and this benefit was not captured in the economic model. The committee also understood that having osimertinib for untreated EGFR mutation-positive NSCLC will reduce the need for repeat bronchoscopic biopsies in people to identify those eligible for osimertinib after an EGFR tyrosine kinase inhibitor (this is currently available via the Cancer Drugs Fund). The committee concluded that osimertinib may be innovative and agreed that there may be benefits that are not captured by the cost-effectiveness analyses.
# Other factors
No equality or social value judgement issues were identified.
# Conclusion
## Osimertinib is recommended for routine use in the NHS
The committee concluded that the estimates of cost effectiveness for osimertinib were within the range that is considered to be a cost-effective use of NHS resources. This conclusion took into account the clinical evidence from FLAURA, all the relevant commercial arrangements, including an updated commercial arrangement for osimertinib and commercial information from NHS England, and the potential benefits of osimertinib not captured by the economic model. So, osimertinib is recommended for use in the NHS for untreated locally advanced or metastatic EGFR mutation-positive NSCLC in adults.
|
{'Recommendation': 'Osimertinib is recommended, within its marketing authorisation, as an option for untreated locally advanced or metastatic epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) in adults. It is recommended only if the company provides osimertinib according to the commercial arrangement.\n\nWhy the committee made this recommendation\n\nLocally advanced or metastatic EGFR mutation-positive NSCLC is usually first treated with afatinib, erlotinib or gefitinib.\n\nEvidence from a randomised controlled trial suggests that people who take osimertinib live longer than people who take erlotinib or gefitinib. They also live longer before their disease gets worse. There is some uncertainty about the comparison of osimertinib with afatinib, which may be more effective than erlotinib and gefitinib, because there is no direct evidence comparing them.\n\nBut, because of a new commercial arrangement, the cost-effectiveness estimates for osimertinib are within what NICE considers an acceptable use of NHS resources. So, osimertinib is recommended.', 'Information about osimertinib': "# Marketing authorisation indication\n\nOsimertinib (Tagrisso, AstraZeneca) is indicated 'for the first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutations'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe price is £5,770 for 80\xa0mg and 40\xa0mg osimertinib (pack of 30\xa0tablets, excluding VAT; BNF online, accessed August 2020). The company has a commercial arrangement that makes osimertinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by AstraZeneca as part of the previous guidance (NICE technology appraisal guidance 621), another submission by AstraZeneca for the rapid review, reviews of these submissions by the evidence review group (ERG), and the technical report developed as part of the previous guidance through engagement with stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that several issues had been resolved during the technical engagement stage, and agreed that:\n\nThe utility value of 0.678 (from the AURA\xa02 trial, second-line treatment with osimertinib) was more representative of people in the progressed disease state (table\xa03, page\xa024 to\xa025 of the technical report).\n\nA combined approach to determine the appropriate resource costs for people in the progressed disease state was acceptable (table\xa03, pages\xa024 to\xa025 of the technical report).\n\nIt recognised that there were remaining areas of uncertainty associated with the analyses presented (table\xa02, pages\xa022 to\xa023 of the technical report), and took these into account in its decision making. As part of the previous guidance, it discussed the following issues, which were outstanding after the technical engagement stage.\n\n# Clinical need\n\n## People would welcome a new treatment option\n\nThe patient experts explained that people with untreated locally advanced or metastatic epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) are often very unwell, with many distressing symptoms. There are no curative treatments. The prognosis is generally poor despite treatments such as targeted therapies and immunotherapy. People would therefore welcome new treatments that improve their symptoms and quality of life, and increase how long they live (even if this increase is only small). Locally advanced or metastatic EGFR mutation-positive NSCLC is first treated with an EGFR tyrosine kinase inhibitor, such as afatinib, gefitinib or erlotinib, in line with NICE guidance on afatinib, gefitinib and erlotinib. The clinical experts explained that people would usually be offered afatinib, based on the clinical evidence (see section\xa03.4). After afatinib, gefitinib or erlotinib, people may be offered either osimertinib if they have developed the T790M resistance mutation in the EGFR gene (in line with NICE's technology appraisal guidance on osimertinib for treating EGFR T790M mutation-positive advanced NSCLC), or chemotherapy if not. People who are not well enough to have further treatment would be offered best supportive care. After chemotherapy, people may be offered immunotherapy, docetaxel with or without nintedanib, or best supportive care. The clinical experts stated that osimertinib would be beneficial as an additional treatment option because it is better tolerated than existing treatments, with fewer side effects. Also, if osimertinib was a first-line treatment option, it would remove the need for T790M mutation testing before second-line treatment. This involves a biopsy, which is invasive and can be psychologically distressing. The committee agreed that additional options would be beneficial and concluded that osimertinib would be a useful addition to first-line treatment.\n\n# Clinical evidence\n\n## The FLAURA trial is broadly generalisable to people with untreated locally advanced or metastatic EGFR mutation-positive NSCLC in England\n\nThe clinical evidence for osimertinib came from the FLAURA randomised controlled trial. FLAURA compared the efficacy and safety of osimertinib with standard care (erlotinib or gefitinib) for people with locally advanced or metastatic EGFR mutation-positive NSCLC. Patients in the trial had either the exon\xa019 deletion (del19) or exon\xa021 (L858R) EGFR mutation. The clinical experts explained that these 2\xa0mutations account for around 90% of all EGFR mutations. Also, most trials only include people with these mutations, including the trials that were carried out with other tyrosine kinase inhibitors. The committee acknowledged that, although other mutations may not respond as well to osimertinib, the marketing authorisation indication is not restricted to these 2\xa0mutations (see section\xa02). It therefore agreed that the EGFR mutation status of patients in FLAURA generally reflected that seen in NHS clinical practice in England. The inclusion criteria allowed people with stable brain metastases to enter the trial but limited the trial population to people with an Eastern Cooperative Oncology Group (ECOG) performance score of 0\xa0or\xa01. For this reason, the committee was aware that the clinical trial population may be in better health than people with stage\xa03b or stage 4 NSCLC in the NHS and that people with many comorbidities may not have been included in the trial. Also, it noted that afatinib was not a comparator in the standard care arm in FLAURA (see section\xa03.4) and that many subsequent treatments used in the trial are not routinely used in the NHS. Despite these concerns, the clinical experts explained that the evidence from FLAURA was broadly generalisable to NHS clinical practice. The committee agreed with the clinical experts.\n\n## Osimertinib extends progression-free and overall survival compared with gefitinib and erlotinib but the size of the benefit is unclear\n\nAn interim analysis of FLAURA showed that progression-free survival was statistically significantly longer with osimertinib than with erlotinib or gefitinib. At the interim data cut (12\xa0June\xa02017; presented in the previous guidance), median progression-free survival was 18.9\xa0months for osimertinib (95% confidence interval [CI] 15.2 to 21.4) and 10.2\xa0months for standard care (95% CI 9.6 to 11.1). The hazard ratio was 0.46 (95% CI 0.37 to 0.57; p<0.001). Overall survival data were very immature (25% of events) but the interim results showed that osimertinib extended overall survival compared with standard care. This produced a hazard ratio of 0.63 (95% CI 0.45 to 0.88; p=0.007), which was not statistically significant (a p value of less than 0.0015 was needed for the result to be significant). The committee acknowledged that the FLAURA data were very immature and that there was uncertainty in overall survival because of the number of events still to be reported. The trial reported more data on overall survival after the previous guidance was published, but submitting this evidence was beyond the scope of the rapid review process, so it could not be fully considered by the committee. Therefore the committee concluded, based on the evidence for the previous guidance, that osimertinib lengthened progression-free survival, and possibly overall survival, compared with erlotinib or gefitinib. But it also concluded that the overall survival benefit was difficult to establish because the data were very immature.\n\n## EGFR tyrosine kinase inhibitors do not all have equal efficacy\n\nThe relevant comparators for this technology appraisal are erlotinib, gefitinib and afatinib. FLAURA compared osimertinib with either gefitinib or erlotinib, but not with afatinib. The Cancer Drugs Fund clinical lead noted that afatinib is currently the most prescribed EGFR tyrosine kinase inhibitor in England for this population. He also stated that previous trials, such as LUX-Lung\xa07, showed that afatinib statistically significantly improved progression-free survival compared with gefitinib. The clinical experts agreed that gefitinib and erlotinib are likely to have equal efficacy. They stated that people taking afatinib had a better response rate to treatment, a longer duration of response and longer progression-free survival than with erlotinib and gefitinib. Also, they usually stayed on afatinib for longer. The company stated that LUX-Lung\xa07 did not show a statistically significant increase in overall survival for afatinib compared with gefitinib. It therefore assumed that afatinib was equivalent in efficacy to erlotinib and gefitinib in its economic model. However, the clinical experts explained that LUX-Lung\xa07 was not powered (that is, it did not have enough people in the trial) to show a difference in overall survival compared with gefitinib. The ERG did its own exploratory indirect treatment comparison that suggested osimertinib statistically significantly improved progression-free survival compared with afatinib but showed no statistically significant difference in overall survival. The committee concluded that there was evidence of improved progression-free survival with afatinib compared with gefitinib, and erlotinib and gefitinib cannot be assumed to have equal efficacy with afatinib.\n\n# Modelling of overall survival\n\n## Assuming a 6-year treatment benefit for osimertinib is optimistic\n\nThe company used a partitioned survival structure with 3\xa0health states (progression-free, progressed disease and death) to model overall survival in FLAURA. It used a time horizon of 20\xa0years to capture all relevant costs and benefits for people having treatment. The company initially assumed a treatment benefit for osimertinib for the full 20-year period. The committee agreed with the ERG and clinical experts that this assumption was optimistic considering the data available and would have to be adjusted to reflect a more realistic benefit from osimertinib treatment. The company therefore revised its base case, assuming a 6‑year duration of treatment effect after the start of treatment (that is, applying a hazard ratio of 1 to both the osimertinib and standard care arms 6\xa0years after starting treatment). The committee recalled that, in previous appraisals for locally advanced or metastatic NSCLC, the preferred treatment effect duration for immunotherapies was 3\xa0years to 5\xa0years. However, it acknowledged that these appraisals involved drugs with a different mechanism of action to osimertinib and a maximum treatment duration. Therefore, it was not appropriate to compare them. The clinical experts agreed that, because osimertinib is associated with improved progression-free survival and duration of response, treatment effect would continue after symptomatic and radiological progression for some people. They stated that this could plausibly give about 3\xa0months of additional benefit after stopping treatment with osimertinib compared with erlotinib and gefitinib. The clinical experts believed that because osimertinib penetrates the blood–brain barrier better than erlotinib and gefitinib, it may help improve control of brain metastases. The committee recalled that afatinib yields longer progression-free survival than erlotinib and gefitinib, but because there was no direct evidence comparing osimertinib with afatinib (see section\xa03.4), it could not establish how osimertinib compared with afatinib in terms of progression-free and overall survival. The ERG's preferred analyses used durations of 3\xa0years and 5\xa0years. The ERG explained that the company's 6‑year duration of treatment effect would mean that people who stopped taking osimertinib within 1\xa0year or 2\xa0years of starting it would still benefit for the full 6\xa0years. The ERG emphasised the limitations of modelling the duration of treatment effect with a partitioned survival model. This is because a crude approach is needed to make adjustments around the assumptions (for example, assuming equivalence at a single time point). The ERG noted that this does not fully reflect what happens in a clinical setting. The committee concluded that a 6‑year duration of treatment effect for osimertinib was optimistic and that, without more evidence, the ERG's analysis using a 3‑year or 5‑year duration of treatment effect was more appropriate.\n\n## The economic model does not capture the benefits of subsequent treatments appropriately\n\nThe committee was aware of NICE's position statement on handling comparators and treatment sequences in the Cancer Drugs Fund. This states that 'products recommended for use in the Cancer Drugs Fund after 1\xa0April 2016 should not be considered as comparators, or appropriately included in a treatment sequence, in subsequent relevant appraisals'. But the committee accepted that it could consider the company's approach of including osimertinib as a subsequent treatment (in line with NICE's guidance on osimertinib for treating locally advanced or metastatic EGFR T790M mutation-positive NSCLC) in the model in this appraisal, because this reflected that some patients in FLAURA did receive osimertinib as a subsequent treatment. People in the standard care arm in the model could have osimertinib as a second-line treatment, assumed to be 33% of people (based on clinical opinion). The committee noted that, although the costs of osimertinib as a second-line treatment were applied in the standard care arm of the model, efficacy was not fully captured given that only around 20% of people had osimertinib as a second-line treatment in the trial at the time of the interim analysis. The committee was aware that the subsequent treatments used in the trial may not reflect NHS practice. It noted that different subsequent therapies would mean different survival prospects and health states that cannot be captured in the modelling. The ERG explained that, to overcome the limitations of the model in capturing the efficacy of subsequent treatments, and to create more flexibility to explore varying the duration of treatment benefits, additional health states would be needed. The ERG described how an individual patient simulation model would better account for these issues but it would need lots of additional data, and trial data are usually immature. The committee agreed that the company's model was broadly appropriate for decision making. It acknowledged the limitations of the model and, given the immaturity of the data, concluded that the model did not fully capture the benefits of subsequent treatments appropriately.\n\n## The company's modelling of overall survival is appropriate, but the immaturity of the data introduces uncertainty in estimating overall survival\n\nAt the interim data cut considered in the previous guidance, median overall survival was not achieved in either the osimertinib or standard care arm. To estimate the overall survival of people in FLAURA, the company used a piecewise Weibull extrapolation of the Kaplan–Meier curve, which was based on observed data up to 7.90\xa0months in the trial. This estimated that mean overall survival was 66.96\xa0months with osimertinib and 44.39\xa0months with standard care, assuming a 20‑year time horizon in the model. The committee was aware that this extrapolation resulted in the most conservative piecewise survival estimates of those presented and fitted the data well. It understood that the FLAURA data were immature (only 25% of events occurring), which introduced uncertainty into the survival estimates, and that further data collection is planned. It concluded that, although the company's and ERG's preferred choice of distribution for modelling overall survival was appropriate, the immaturity of the data introduces uncertainty in estimating the results.\n\n# Cost-effectiveness estimate\n\n## The most plausible ICER for osimertinib is within the range NICE normally considers a cost-effective use of NHS resources\n\nThe committee considered the additional analyses presented for the rapid review, which incorporated the updated confidential commercial arrangement for osimertinib, and its preferred modelling assumptions:\n\nA treatment effect duration (that is, from the start of treatment) of 3\xa0years to 5\xa0years (see section\xa03.5).\n\nWeibull extrapolation of overall survival in both the osimertinib and standard care arms (see section\xa03.7).\n\nA utility value of 0.678 (see table\xa03, pages\xa024 to\xa025 of the technical report).These assumptions were used in a fully incremental analysis (calculating incremental quality-adjusted life year [QALY] gains and costs along a list of treatment options ranked by ascending cost), which incorporated all of the commercial arrangements for osimertinib and the comparators (gefitinib, erlotinib and afatinib). The committee was aware that NHS England considered that the commercial arrangement delivered additional value and included additional commercial information from NHS England in its decision making. Taking into account all the commercial considerations, the incremental cost-effectiveness ratio (ICER) was within the range NICE normally considers a cost-effective use of NHS resources. The exact ICERs cannot be reported here because they are commercial in confidence. The committee acknowledged that, given the available evidence from LUX-Lung\xa07 and clinical expert opinion, it is possible that afatinib has better efficacy than gefitinib and erlotinib (see section 3.4) and factored this into its decision making. It agreed that its most plausible ICER based on the evidence presented was within the range that NICE considers an effective use of NHS resources.\n\n# End of life\n\n## Osimertinib is likely to extend life by over 3\xa0months\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. It recalled that, at the interim data cut presented and considered in the previous guidance, median overall survival had not been reached in FLAURA, and that the increased survival in the osimertinib arm was not statistically significantly different from the standard care arm (see section 3.3). However, it also noted that the company's economic model predicted mean overall survival would be 22\xa0months longer with osimertinib than with standard care. Based on evidence from FLAURA and predictions from the economic model (using the committee's preferred assumptions), the committee concluded that osimertinib was likely to extend life by over 3\xa0months and therefore met the extension-to-life criterion.\n\n## FLAURA should be the primary data source for deciding if osimertinib meets the short life expectancy criterion\n\nFor the previous guidance, the company presented registry evidence from a real-world data source (National Cancer Registration and Analysis Service [NCRAS] Public Health England data between 2014 and 2016), showing that median overall survival for the population in England was less than 24\xa0months. The committee recognised that there was potential value in real-world evidence from the NHS in England to help inform its decision making. However, it considered there were several reasons why it was not appropriate to use these as the primary data source in isolation for its decision making on the short life expectancy criterion:\n\nThe committee recalled its conclusion that FLAURA was generalisable to clinical practice in England (see section\xa03.2). In addition, it noted the Cancer Drugs Fund clinical lead and ERG statements that it was inconsistent to use the FLAURA data to determine the overall survival benefit of osimertinib, but real-world evidence to determine life expectancy for people having standard care, without making some adjustments in the economic model (such as amending the efficacy estimates).\n\nThe committee noted that afatinib (the currently preferred and most prescribed EGFR tyrosine kinase inhibitor in England for this population) was not available for most of the time the NCRAS data were collected.\n\nThe committee recalled that after consultation on the technical report, the clinical experts stated that about 60% of people in clinical practice were alive 2\xa0years after starting treatment with an EGFR tyrosine kinase inhibitor.\n\nIn the standard care arm, which used FLAURA data to inform the extrapolation of overall survival, the economic model (using the committee's preferred assumptions) predicted a median overall survival of 31.54\xa0months and a mean overall survival of 44.39\xa0months.\n\nThe committee was also aware that evidence from studies in similar populations, such as LUX-Lung\xa07 and ARCHER\xa01050, showed that median overall survival was more than 24\xa0months.\n\nThe committee noted that the registry data were difficult to compare directly with the FLAURA data because possible confounders in the real-world population (such as comorbidities) were not taken into account.For these reasons, the committee considered it more appropriate to base its decision about estimating life expectancy on the FLAURA data, which the company had used in the economic model. The committee concluded that osimertinib did not meet the short life expectancy criterion of the end of life criteria.\n\n## Subgroup analyses from FLAURA do not show that osimertinib meets the criteria for life-extending treatment at the end of life\n\nAt consultation on the previous guidance, the company provided new analyses to support its case for meeting the end of life criteria when using the committee-preferred dataset (FLAURA). The company stated that the subgroup analyses most closely reflected the cohort of NHS patients in England. However, the Cancer Drugs Fund clinical lead's nominated deputy advised caution in interpreting these registry data because the systemic anticancer therapy (SACT) data set is currently incomplete and that gaps in the evidence exist between the secondary uses service data and the corresponding SACT data. The 3\xa0subgroups were:\n\nNo subsequent treatment with an EGFR tyrosine kinase inhibitor (because the company stated that people in England would not have a second EGFR tyrosine kinase inhibitor).\n\nAn ECOG performance score of 1 (because people in England with this condition are usually less well than those in FLAURA).\n\nNon-Asian family origin (because most people with this condition in England are of non-Asian family origin and the company stated that they have poorer survival outcomes than people of Asian family origin).The committee noted that the subgroups in the new analyses had not been combined to calculate a value for mean or median overall survival. It agreed that this added substantial uncertainty to interpreting the results because each subgroup was linked to a single characteristic and it was not possible to determine the degree of overlap between these groups. The committee noted that the company's overall survival estimates for all 3\xa0subgroups in the standard care arm were longer than 24\xa0months (the modelled outputs are academic in confidence and cannot be reported). The ERG stated that because it did not have access to the FLAURA data, it could not confirm any of the company's results for the new analyses. The committee heard concerns regarding the relevance of the analyses:\n\nThe Cancer Drugs Fund clinical lead's nominated deputy commented that many people do have more than 2\xa0subsequent therapies after progression on an EGFR tyrosine kinase inhibitor.The ERG noted that the overall survival for patients of non-Asian family origin may be shorter, but the results of the subgroup analysis were very similar to those of the intention-to-treat population in FLAURA and that no statistical testing of the difference was done. The committee agreed there was no conclusive evidence that ethnicity has an influence on overall survival and that other factors may be more influential. It noted that for NICE's technology appraisal guidance on afatinib, the clinical experts stated that differences in the effectiveness of afatinib in NSCLC are more likely to be determined by EGFR mutation status than ethnicity.The committee concluded the subgroup analyses presented in response to consultation on the previous guidance did not show that osimertinib meets the short life expectancy criterion. It noted that the short life expectancy criterion in the methods guide states 'normally less than 24\xa0months' and discussed whether any flexibilities should be applied. The committee concluded that there were no exceptional circumstances that demanded additional flexibility in applying the end of life criteria (such as to ensure continued access to a highly effective treatment option that was perceived by patients and clinicians to be standard of care, in circumstances where access had been enabled years ahead of NICE publishing any guidance on the technology). The committee also concluded that, although the company's economic model suggests that the overall survival gain may potentially be high (see section\xa03.7), the immaturity of the trial data means there is considerable uncertainty about the magnitude of the benefit.\n\n# Innovation\n\n## Osimertinib may be innovative\n\nThe Cancer Drugs Fund clinical lead highlighted that follow up in FLAURA is short, so the economic model was unlikely to fully capture osimertinib's beneficial effect in the brain. They also stated that osimertinib is better tolerated than other EGFR tyrosine kinase inhibitors with respect to chronic grade\xa01 and grade\xa02 skin-related toxicities, and this benefit was not captured in the economic model. The committee also understood that having osimertinib for untreated EGFR mutation-positive NSCLC will reduce the need for repeat bronchoscopic biopsies in people to identify those eligible for osimertinib after an EGFR tyrosine kinase inhibitor (this is currently available via the Cancer Drugs Fund). The committee concluded that osimertinib may be innovative and agreed that there may be benefits that are not captured by the cost-effectiveness analyses.\n\n# Other factors\n\nNo equality or social value judgement issues were identified.\n\n# Conclusion\n\n## Osimertinib is recommended for routine use in the NHS\n\nThe committee concluded that the estimates of cost effectiveness for osimertinib were within the range that is considered to be a cost-effective use of NHS resources. This conclusion took into account the clinical evidence from FLAURA, all the relevant commercial arrangements, including an updated commercial arrangement for osimertinib and commercial information from NHS England, and the potential benefits of osimertinib not captured by the economic model. So, osimertinib is recommended for use in the NHS for untreated locally advanced or metastatic EGFR mutation-positive NSCLC in adults."}
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https://www.nice.org.uk/guidance/ta654
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Evidence-based recommendations on osimertinib (Tagrisso) for untreated locally advanced or metastatic epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer in adults.
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b4677806a6f7fca26249bf6e52e32dd6473b8b1c
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nice
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Rheumatoid arthritis in adults: management
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Rheumatoid arthritis in adults: management
This guideline covers diagnosing and managing rheumatoid arthritis. It aims to improve quality of life by ensuring that people with rheumatoid arthritis have the right treatment to slow the progression of their condition and control their symptoms. People should also have rapid access to specialist care if their condition suddenly worsens.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Referral, diagnosis and investigations
## Referral from primary care
Refer for specialist opinion any adult with suspected persistent synovitis of undetermined cause. Refer urgently (even with a normal acute-phase response, negative anti-cyclic citrullinated peptide antibodies or rheumatoid factor) if any of the following apply:
the small joints of the hands or feet are affected
more than one joint is affected
there has been a delay of 3 months or longer between onset of symptoms and seeking medical advice.
## Investigations
If the following investigations are ordered in primary care, they should not delay referral for specialist opinion (see recommendation 1.1.1).
Offer to carry out a blood test for rheumatoid factor in adults with suspected rheumatoid arthritis (RA) who are found to have synovitis on clinical examination.
Consider measuring anti-CCP antibodies in adults with suspected RA if they are negative for rheumatoid factor.
X-ray the hands and feet in adults with suspected RA and persistent synovitis.
As soon as possible after establishing a diagnosis of RA:
measure anti-CCP antibodies, unless already measured to inform diagnosis
X-ray the hands and feet to establish whether erosions are present, unless X-rays were performed to inform diagnosis
measure functional ability using, for example, the Health Assessment Questionnaire (HAQ), to provide a baseline for assessing the functional response to treatment.
If anti-CCP antibodies are present or there are erosions on X-ray:
advise the person that they have an increased risk of radiological progression but not necessarily an increased risk of poor function, and
emphasise the importance of monitoring their condition, and seeking rapid access to specialist care if disease worsens or they have a flare.
For a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on investigations following diagnosis .
Full details of the evidence and the committee's discussion are in evidence review B: Risk factors.
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# Treat-to-target strategy
Treat active RA in adults with the aim of achieving a target of remission or low disease activity if remission cannot be achieved (treat-to-target). Achieving the target may involve trying multiple conventional disease-modifying anti-rheumatic drugs (cDMARDs) and biological DMARDs with different mechanisms of action, one after the other.
Consider making the target remission rather than low disease activity for people with an increased risk of radiological progression (presence of anti-CCP antibodies or erosions on X-ray at baseline assessment).
In adults with active RA, measure C-reactive protein (CRP) and disease activity (using a composite score such as DAS28) monthly in specialist care until the target of remission or low disease activity is achieved.
For a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on treat-to-target strategy .
Full details of the evidence and the committee's discussion are in evidence review C: Treat-to-target.
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# Communication and education
Explain the risks and benefits of treatment options to adults with RA in ways that can be easily understood. Throughout the course of their disease, offer them the opportunity to talk about and agree all aspects of their care, and respect the decisions they make.
Offer verbal and written information to adults with RA to:
improve their understanding of the condition and its management, and
counter any misconceptions they may have.
Adults with RA who wish to know more about their disease and its management should be offered the opportunity to take part in existing educational activities, including self-management programmes.
# Initial pharmacological management
## Conventional disease-modifying anti-rheumatic drugs
For adults with newly diagnosed active RA:
Offer first-line treatment with cDMARD monotherapy using oral methotrexate, leflunomide or sulfasalazine as soon as possible and ideally within 3 months of onset of persistent symptoms.
Consider hydroxychloroquine for first-line treatment as an alternative to oral methotrexate, leflunomide or sulfasalazine for mild or palindromic disease.
Escalate dose as tolerated.
Consider short-term bridging treatment with glucocorticoids (oral, intramuscular or intra-articular) when starting a new cDMARD.
For a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on short-term bridging treatment with glucocorticoids .
Full details of the evidence and the committee's discussion are in evidence review H: Glucocorticoids.
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Offer additional cDMARDs (oral methotrexate, leflunomide, sulfasalazine or hydroxychloroquine) in combination in a step-up strategy when the treatment target (remission or low disease activity) has not been achieved despite dose escalation.
For a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on DMARDs .
Full details of the evidence and the committee's discussion are in evidence review F: DMARDs.
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# Further pharmacological management
## Biological and targeted synthetic DMARDs
NICE has published technology appraisal guidance on biological and targeted synthetic DMARDs for RA. For full details, see RA technology appraisals on our topic page on arthritis. For guidance on using DMARDs to achieve treatment targets, see recommendation 1.2.1.
The recommendations below are from NICE technology appraisal guidance 72. The 2009 guideline committee reviewed the evidence on anakinra and incorporated the recommendations into the guideline. The technology appraisal was then withdrawn.
On the balance of its clinical benefits and cost effectiveness, anakinra is not recommended for the treatment of RA, except in the context of a controlled, long-term clinical study.
Patients currently receiving anakinra for RA may suffer loss of wellbeing if their treatment were discontinued at a time they did not anticipate. Therefore, patients should continue therapy with anakinra until they and their consultant consider it is appropriate to stop.
Do not offer the combination of tumour necrosis factor-α (TNF-α) inhibitor therapy and anakinra for RA.
## Glucocorticoids
Offer short-term treatment with glucocorticoids for managing flares in adults with recent-onset or established disease to rapidly decrease inflammation.
In adults with established RA, only continue long-term treatment with glucocorticoids when:
the long-term complications of glucocorticoid therapy have been fully discussed, and
all other treatment options (including biological and targeted synthetic DMARDs) have been offered.
# Symptom control
Consider oral non-steroidal anti-inflammatory drugs (NSAIDs, including traditional NSAIDs and cox II selective inhibitors), when control of pain or stiffness is inadequate. Take account of potential gastrointestinal, liver and cardio-renal toxicity, and the person's risk factors, including age and pregnancy.
When treating symptoms of RA with oral NSAIDs:
-ffer the lowest effective dose for the shortest possible time
-ffer a proton pump inhibitor (PPI), and
review risk factors for adverse events regularly.
If a person with RA needs to take low-dose aspirin, healthcare professionals should consider other treatments before adding an NSAID (with a PPI) if pain relief is ineffective or insufficient.
For a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on symptom control .
Full details of the evidence and the committee's discussion are in evidence review G: Analgesics.
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# The multidisciplinary team
Adults with RA should have ongoing access to a multidisciplinary team. This should provide the opportunity for periodic assessments (see 1.9.2 and 1.9.3) of the effect of the disease on their lives (such as pain, fatigue, everyday activities, mobility, ability to work or take part in social or leisure activities, quality of life, mood, impact on sexual relationships) and help to manage the condition.
Adults with RA should have access to a named member of the multidisciplinary team (for example, the specialist nurse) who is responsible for coordinating their care.
# Non-pharmacological management
## Physiotherapy
Adults with RA should have access to specialist physiotherapy, with periodic review (see 1.9.2 and 1.9.3), to:
improve general fitness and encourage regular exercise
learn exercises for enhancing joint flexibility, muscle strength and managing other functional impairments
learn about the short-term pain relief provided by methods such as transcutaneous electrical nerve stimulators (TENS) and wax baths.
## Occupational therapy
Adults with RA should have access to specialist occupational therapy, with periodic review (see 1.9.2 and 1.9.3), if they have:
difficulties with any of their everyday activities, or
problems with hand function.
## Hand exercise programmes
Consider a tailored strengthening and stretching hand exercise programme for adults with RA with pain and dysfunction of the hands or wrists if:
they are not on a drug regimen for RA, or
they have been on a stable drug regimen for RA for at least 3 months.
The tailored hand exercise programme for adults with RA should be delivered by a practitioner with training and skills in this area.
## Podiatry
All adults with RA and foot problems should have access to a podiatrist for assessment and periodic review of their foot health needs (see 1.9.2 and 1.9.3).
Functional insoles and therapeutic footwear should be available for all adults with RA if indicated.
## Psychological interventions
Offer psychological interventions (for example, relaxation, stress management and cognitive coping skills ) to help adults with RA adjust to living with their condition.
NICE has published a guideline on depression in adults with a chronic physical health problem.
## Diet and complementary therapies
Inform adults with RA who wish to experiment with their diet that there is no strong evidence that their arthritis will benefit. However, they could be encouraged to follow the principles of a Mediterranean diet (more bread, fruit, vegetables and fish; less meat; and replace butter and cheese with products based on vegetable and plant oils).
Inform adults with RA who wish to try complementary therapies that although some may provide short-term symptomatic benefit, there is little or no evidence for their long-term efficacy.
If an adult with RA decides to try complementary therapies, advise them:
these approaches should not replace conventional treatment
this should not prejudice the attitudes of members of the multidisciplinary team, or affect the care offered.
# Monitoring
Ensure that all adults with RA have:
rapid access to specialist care for flares
information about when and how to access specialist care, and
-ngoing drug monitoring.
Consider a review appointment to take place 6 months after achieving treatment target (remission or low disease activity) to ensure that the target has been maintained.
Offer all adults with RA, including those who have achieved the treatment target, an annual review to:
assess disease activity and damage, and measure functional ability (using, for example, the Health Assessment Questionnaire )
check for the development of comorbidities, such as hypertension, ischaemic heart disease, osteoporosis and depression
assess symptoms that suggest complications, such as vasculitis and disease of the cervical spine, lung or eyes
-rganise appropriate cross referral within the multidisciplinary team
assess the need for referral for surgery (see section 1.10)
assess the effect the disease is having on a person's life.Follow recommendation 1.2.1 if the target is not maintained.
For adults who have maintained the treatment target (remission or low disease activity) for at least 1 year without glucocorticoids, consider cautiously reducing drug doses or stopping drugs in a step-down strategy. Return promptly to the previous DMARD regimen if the treatment target is no longer met.
Do not use ultrasound for routine monitoring of disease activity in adults with RA.
For a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see rationale and impact section on monitoring .
Full details of the evidence and the committee's discussion are in evidence review E: Frequency of monitoring.
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# Timing and referral for surgery
Offer to refer adults with RA for an early specialist surgical opinion if any of the following do not respond to optimal non-surgical management:
persistent pain due to joint damage or other identifiable soft tissue cause
worsening joint function
progressive deformity
persistent localised synovitis.
Offer to refer adults with any of the following complications for a specialist surgical opinion before damage or deformity becomes irreversible:
imminent or actual tendon rupture
nerve compression (for example, carpal tunnel syndrome)
stress fracture.
When surgery is offered to adults with RA, explain that the main expected benefits are:
pain relief
improvement, or prevention of further deterioration, of joint function, and
prevention of deformity.Cosmetic improvements should not be the dominant concern.
Offer urgent combined medical and surgical management to adults with RA who have suspected or proven septic arthritis (especially in a prosthetic joint).
If an adult with RA develops any symptoms or signs that suggest cervical myelopathy (for example, paraesthesia, weakness, unsteadiness, reduced power, extensor plantars):
request an urgent MRI scan, and
refer for a specialist surgical opinion.
Do not let concerns about the long-term durability of prosthetic joints influence decisions to offer joint replacements to younger adults with RA.
# Terms used in this guideline
## Bridging treatment
Glucocorticoids used for a short period of time when a person is starting a new DMARD, intended to improve symptoms while waiting for the new DMARD to take effect (which can take 2 to 3 months).
## Conventional disease-modifying anti-rheumatic drugs (cDMARDs)
Conventional disease-modifying anti-rheumatic drugs are synthetic drugs that modify disease rather than just alleviating symptoms. They include methotrexate, sulfasalazine, leflunomide and hydroxychloroquine, but do not include biological DMARDs and targeted synthetic DMARDs.
## Palindromic
Palindromic rheumatism is an inflammatory arthritis that causes attacks of joint pain and swelling similar to RA. Between attacks the joints return to normal.
## Step-up strategy
Additional DMARDs are added to DMARD monotherapy when disease is not adequately controlled.
## Step-down strategy
During treatment with 2 or more DMARDs, tapering and stopping at least 1 drug once disease is adequately controlled.
## Synovitis
Soft tissue joint swelling.
## Treat-to-target
A treat-to-target strategy is a strategy that defines a treatment target (such as remission or low disease activity) and applies tight control (for example, monthly visits and respective treatment adjustment) to reach this target. The treatment strategy often follows a protocol for treatment adaptations depending on the disease activity level and degree of response to treatment.# Recommendations for research
The guideline committee has made the following high-priority recommendations for research.
# Analgesics
What is the clinical and cost effectiveness of analgesic drugs other than non-steroidal anti-inflammatory drugs (NSAIDs) in adults with rheumatoid arthritis (RA) whose pain or stiffness control is not adequate?
## Why this is important
Analgesics (including NSAIDs, paracetamol, opioids and compound analgesics) are sometimes used with disease-modifying treatments to relieve pain and stiffness when symptom control is inadequate. Current practice regarding the choice of analgesic in RA is variable. The evidence is limited for many of the analgesic drugs other than NSAIDs, and their relative effectiveness is unknown. Further research in this area may inform future guidance on the use of analgesic drugs other than NSAIDs for controlling symptoms.
# Short-term bridging treatment with glucocorticoids
What is the clinical and cost effectiveness of short-term bridging treatment with glucocorticoids for adults with RA starting a new disease-modifying anti-rheumatic drug (DMARD), including the most effective dosing strategy and mode of administration?
## Why this is important
All DMARDs have a slow onset of action. In some cases, response may not be seen for 2 to 3 months. In contrast, glucocorticoids have an immediate effect on joint pain and swelling. In clinical practice, several different regimens are prescribed to 'bridge' the time between the initial prescription of DMARDs and the clinical response. However, good quality evidence from randomised controlled trials (RCTs) demonstrating the effectiveness of glucocorticoids as bridging treatment is limited and inconclusive. Further research is needed to inform recommendations for practice regarding whether bridging treatment with steroids should be used until the new DMARD begins to take effect.
The optimal dosing strategy and mode of administration for bridging glucocorticoids also needs to be established. Although the anti-inflammatory response is dose dependent, side effects of glucocorticoids vary according to both the dose and the duration of treatment.
For a short explanation of why the committee made the recommendation for research, see the rationale section on short-term bridging treatment with glucocorticoids .
Full details of the evidence and the committee's discussion are in evidence review H: Glucocorticoids.
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# Ultrasound in monitoring
What is the clinical and cost effectiveness of using ultrasound to monitor disease in adults with RA when clinical examination is inconclusive or inconsistent with other signs of disease activity?
## Why this is important
RA is a chronic inflammatory condition that needs regular review to enable adjustments in management to achieve a target of remission or low disease activity.
Although ultrasound is able to show subclinical inflammation or erosions in some people in clinical remission, evidence from RCTs does not support using ultrasound for routine monitoring. However, ultrasound may be useful for assessing disease activity in some people with RA; specifically, when clinical examination is inconclusive or is inconsistent with other signs of disease activity (for example, pain or markers of inflammation). There is no reliable evidence on the added value of ultrasound as part of a monitoring strategy in these subgroups.
In addition, when there is inconsistency between clinical examination and disease activity, it may be unclear if the person has subclinical inflammatory synovitis or more of a widespread pain syndrome, which is not inflammatory. These need very different treatments, so it is important to define them accurately.
For a short explanation of why the committee made the recommendation for research, see the rationale section on monitoring .
Full details of the evidence and the committee's discussion are in evidence review E: Frequency of monitoring.
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# Ultrasound in diagnosis
What is the clinical and cost effectiveness of using ultrasound in addition to clinical assessment when there is uncertainty about the diagnosis in adults with suspected RA?
## Why this is important
Early diagnosis of RA is essential to reduce the impact of the disease on multiple systems in the body. The course of RA and the initial presentation can be highly variable; most people with RA have definite synovitis on clinical assessment, but sometimes this is not obvious, leading to uncertainty about the diagnosis. Ultrasound is a non-invasive and relatively inexpensive imaging modality that can detect subclinical synovitis and early erosive disease. It might help determine an early diagnosis of RA when the diagnosis would otherwise be uncertain. Early diagnosis enables earlier treatment, providing an opportunity to improve the longer term outcomes for people with RA. The use of ultrasound may also allow healthcare professionals to be more confident about ruling out a diagnosis of RA.
# Management of poor prognosis
What is the clinical and cost effectiveness of managing RA with a poor prognosis (identified as presence of anti-cyclic citrullinated peptide antibodies or evidence of erosions on X-ray at diagnosis) with a different strategy from that used for standard management of RA?
## Why this is important
Current recommendations suggest all people with RA should be offered the same management; however clinical experience suggests that the condition responds less well in some people and some suffer progressive radiographic damage and impaired function despite standard management. Several factors have been identified in the literature that, if present and identified early in the course of the disease, may predict a poor prognosis (greater radiographic progression). These include anti-CCP antibody positivity and the presence of radiographic erosions at baseline. At present it is unclear whether people with poor prognostic markers should have different management early in the disease, and whether this would improve radiographic and functional (HAQ) outcomes in this group.
# Subcutaneous methotrexate
What is the clinical and cost effectiveness of subcutaneous methotrexate compared with oral methotrexate for adults with early onset RA starting a new DMARD?
## Why this is important
Methotrexate is an important drug in the treatment of RA. Subcutaneous administration is an alternative option for people who have side effects with oral treatment. Evidence on the effectiveness of subcutaneous methotrexate is lacking, but its effects may be superior, due to increased bioavailability, and fewer side effects than with oral drugs. Research on subcutaneous methotrexate will inform future guideline recommendations.# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.
# Investigations following diagnosis
Recommendations 1.1.5 and 1.1.6
## Why the committee made the recommendations
Evidence showed that anti-cyclic citrullinated peptide (CCP) antibodies and radiographic damage at baseline were both important prognostic factors for subsequent radiographic progression. Anti-CCP antibodies are usually measured and X-rays often taken as part of diagnosis. When this has not been done, the committee agreed that the tests should be performed as soon as possible. The results will inform discussions with the patient about how their rheumatoid arthritis (RA) might progress and reinforce the importance of active monitoring and rapidly seeking specialist care if the disease worsens.
There was limited evidence on poor function, as measured by the Health Assessment Questionnaire (HAQ), as a prognostic factor. However, the committee agreed that functional ability (measured, for example, by HAQ) should be determined at diagnosis to provide a baseline for assessing response to treatment at the annual review.
Evidence suggests that all people with RA should be offered the same management strategy; however, in the committee's experience some people may respond less well and have more progressive radiographic damage and impaired function. Because the evidence was limited as to whether people with poor prognostic markers should follow a different management strategy to improve radiographic and functional (HAQ) outcomes, the committee agreed to make a research recommendation.
## How the recommendations might affect practice
Anti-CCP antibodies are usually measured so there should be no change in current practice. X-raying the hands and feet and measuring functional ability at baseline reflects current best practice, but not everyone with RA currently has these investigations. There may be an increase in the number of X-rays, especially in units without early inflammatory arthritis clinics, but this is unlikely to have a substantial resource impact.
Measuring functional ability at baseline will involve a change of practice for some providers, but the cost is low and so this is not expected to have a substantial resource impact.
Full details of the evidence and the committee's discussion are in evidence review B: Risk factors.
Return to recommendations
# Investigations (ultrasound in diagnosis)
## Why the committee made the research recommendation on ultrasound in diagnosis
Ultrasound is not used widely in diagnosing RA, but use is increasing and depends on the clinic and the rheumatologist. Evidence was inconsistent and too limited for the committee to make any recommendation for or against its use in diagnosis. The committee noted that the studies generally included only people with clinically definite synovitis and agreed that ultrasound may be more useful when there is uncertainty about the diagnosis after clinical assessment. They decided to make a research recommendation to inform future guidance on who (if anyone) should have ultrasound to aid diagnosis.
Full details of the evidence and the committee's discussion are in evidence review A: Ultrasound for diagnosis.
Return to the recommendation for research
# Treat-to-target strategy
Recommendations 1.2.1 to 1.2.3
## Why the committee made the recommendations
Evidence showed that a treat-to-target strategy was more effective than usual care for managing RA and improved outcomes at no additional cost. The committee agreed that this approach was more likely to achieve rapid and sustained disease control.
No evidence was identified to indicate whether a target of remission or low disease activity was more effective. However, the committee agreed that remission (for example, a DAS28 score of less than 2.6) is the most appropriate target for most people, but for some who are unable to achieve remission despite a treat-to-target approach with appropriate escalation, low disease activity (for example, a DAS28 score of less than 3.2) is acceptable. It was agreed that for those identified as being at risk of poor prognosis, a target of remission may be more appropriate.
No studies were identified that compared different frequencies of monitoring specifically in people with active disease. The committee noted that the 2009 guideline recommended monthly monitoring and that this was used in some of the studies of a treat-to-target strategy. The committee agreed that monthly monitoring of C-reactive protein (CRP) and disease activity was most appropriate for active disease. This allows dose escalation of disease-modifying anti-rheumatic drugs (DMARDs), checking the need for short-term bridging treatment with glucocorticoids and whether people are tolerating the drug regimen, assessing side effects, providing support and encouraging adherence.
There was no evidence that people with a poor prognosis should have different management in terms of the treatment target or the frequency of monitoring. However, in the committee's experience RA often responds less well to standard management in this group. The committee agreed that the recommendations on treat-to-target with monthly monitoring should ensure that people with a poor prognosis receive effective treatment, but they decided to make a research recommendation to inform future guidance for managing RA in this group.
## How the recommendations might affect practice
A treat-to-target strategy is current best practice in most NHS settings. The 2016 National Clinical Audit for Rheumatoid Arthritis and Early Inflammatory Arthritis indicated that healthcare professionals set a treatment target for about 90% of their patients. Although the 2018 recommendation specifies a target of remission or low disease activity, rather than a disease level previously agreed with the person, the committee agreed that these are the targets commonly used and so this is unlikely to involve a significant change in practice.
Monthly monitoring was recommended in the 2009 guideline, but the committee acknowledged that many clinics do not monitor active disease this often. A regional survey (Tugnet 2013) reported that about two-thirds of people with RA received monthly CRP monitoring but only a quarter had monthly monitoring of disease activity (with about 40% in dedicated early arthritis clinics) until disease control was achieved. The committee were unsure whether these rates reflected practice across England and noted that practice had improved since the survey was conducted in 2011. However, the committee agreed that monthly monitoring would likely involve a change in practice in some clinics.
Full details of the evidence and the committee's discussion are in evidence review C: Treat-to-target.
Return to the recommendations
# DMARDs
Recommendations 1.4.1 and 1.4.3
## Why the committee made the recommendations
Evidence showed that starting treatment with more than 1 conventional DMARD (cDMARD) was no more effective than starting with a single cDMARD. The committee agreed that cDMARD monotherapy might have fewer side effects and recommended cDMARD monotherapy as first-line treatment. This differed from the 2009 guideline which recommended combination therapy. The difference is largely a result of inclusion of different evidence and a different approach to analysing that evidence.
Many of the studies included in the 2009 guideline used cDMARDs that are no longer commonly used in UK practice (for example, ciclosporin), and these studies were excluded from the evidence for the 2018 update. In addition, the 2018 update included new evidence published after the 2009 guideline. Further, a different approach to analysing the evidence was taken, with the 2018 update aiming to identify the most effective cDMARD strategy (monotherapy, sequential monotherapy, step-up therapy, step-down therapy or parallel combination therapy) as well as which cDMARD should be used. The 2009 guideline compared treatment strategies only, regardless of the particular cDMARDs, and combined evidence according to treatment strategy.
The evidence included in the 2018 update was therefore different to that included in 2009 and supported cDMARD monotherapy as first-line treatment.
Evidence from randomised controlled trials (RCTs) in people who had never had a DMARD showed no consistent differences in the effectiveness of methotrexate, leflunomide and sulfasalazine as monotherapies. The drugs also had similar costs. The committee agreed that any of these drugs can be used as first-line treatment.
Hydroxychloroquine was less effective, but fewer people stopped treatment because of side effects. The committee agreed that hydroxychloroquine could be considered for people with mild or palindromic disease.
Evidence for different first-line treatment in people with a poor prognosis was limited so the committee decided not to make a separate recommendation for this group. They agreed that the recommendation for dose increases and treating to target (with the aim of keeping disease activity low) should ensure adequate treatment for these people. Given the limited evidence in this area, the committee also decided that the possible benefit of managing RA with a poor prognosis with a different strategy was a priority for future research.
Evidence supported adding another cDMARD when needed (step-up strategy) rather than replacing the cDMARD with another (sequential monotherapy). The committee acknowledged that more side effects were possible with a step-up strategy, but in their experience these could be managed by drug monitoring and were outweighed by the clinical benefit of combination treatment when monotherapy was inadequate. A published economic analysis supported a step-up approach rather than sequential monotherapy.
No evidence was found for subcutaneous methotrexate, but the committee agreed that the effects may be superior and side effects fewer than with oral cDMARDs. However, because subcutaneous methotrexate is significantly more expensive than other cDMARD options, the committee was not able to recommend this without evidence of clinical benefit and cost effectiveness relative to oral cDMARDs. The committee decided to make a research recommendation to inform future guidance.
## How the recommendations might affect practice
The 2009 guideline recommended a combination of cDMARDs (including methotrexate and at least 1 other cDMARD) for newly diagnosed RA and emphasised the importance of starting effective cDMARD therapy as soon as possible.
The 2009 recommendation to start with combination therapy was not widely adopted. The 2016 National Clinical Audit for Rheumatoid Arthritis and Early Inflammatory Arthritis reported that only 46% of people with RA received combination cDMARDs at any time. Currently there is variation in practice regarding the choice of cDMARD(s) and treatment strategy, with many healthcare professionals preferring to start with monotherapy and only use combination therapy when response is inadequate.
The 2018 recommendations to start with monotherapy and add drugs when the response is inadequate are unlikely to have a substantial impact on practice or resources, as they align with the current approach taken by many healthcare professionals. However, the recommendations should result in a more consistent treatment strategy and reduce the number of people prescribed combination therapy on diagnosis.
The 2009 guideline recommended methotrexate as one of the first drugs used in combination therapy. The 2018 recommendations do not specify which cDMARD should be used at any stage of treatment. Again, this will be unlikely to have a significant impact on practice, and methotrexate is likely to remain one of the most commonly prescribed drugs.
The recommendations on dose escalation and reduction have not changed substantially from the 2009 guideline and reflect current clinical practice. The committee clarified that dose reduction and the use of a step-down strategy should only be considered after a person has maintained the treatment target for at least 1 year without the use of glucocorticoids.
Full details of the evidence and the committee's discussion are in evidence review F: DMARDs.
Return to the recommendations
# Short-term bridging treatment with glucocorticoids
Recommendation 1.4.2
## Why the committee made the recommendation
Evidence from RCTs on the use of short-term bridging treatment with glucocorticoids to relieve symptoms while people are waiting for a new DMARD to take effect was limited. There was some evidence that fewer people withdrew from the studies due to inefficacy or adverse events when they were taking glucocorticoids, although there was no evidence that glucocorticoids were effective in terms of disease activity score, quality of life or function, as studies did not report these outcomes. In the committee's experience people with active arthritis may benefit from the anti-inflammatory effects of glucocorticoids. However, for others with less active disease this additional treatment may not be needed. The committee agreed that short-term glucocorticoids could be considered on a case-by-case basis.
Because of the lack of good quality evidence, the committee decided to make a research recommendation to determine the effectiveness of short-term glucocorticoids for adults taking a new DMARD, including the most effective regimen.
## How the recommendation might affect practice
Most healthcare professionals offer short-term bridging treatment with glucocorticoids to adults starting a new DMARD. They can continue to offer this but the recommendation encourages them to consider whether this additional treatment is always needed. Therefore this is unlikely to result in additional spending for the NHS.
Full details of the evidence and the committee's discussion are in evidence review H: Glucocorticoids.
Return to the recommendation
# Symptom control
Recommendations 1.6.1 and 1.6.2
## Why the committee made the recommendations
Evidence suggested that non-steroidal anti-inflammatory drugs (NSAIDs) may offer a small benefit in relieving symptoms for adults with RA (including pain and stiffness). The committee agreed that this was likely to outweigh the increase in gastrointestinal adverse events associated with NSAIDs. To minimise adverse events, the committee agreed that NSAIDs should be used at the lowest doses and for the shortest possible time, with a proton pump inhibitor, and that risk factors for adverse events should be reviewed regularly. The recommendations for analgesic treatment in this guideline replace those in the 2009 guideline.
There was limited evidence on paracetamol, opioids and tricyclic antidepressants and no evidence for nefopam, gabapentinoids or selective serotonin reuptake inhibitor (SSRI) and SSNRI antidepressants. The committee acknowledged that the 2009 guideline had recommended analgesics other than NSAIDs for pain control. However, the 2009 guideline indicated that the evidence on analgesia other than NSAIDs was 'sparse'. No further evidence on these drugs was identified since the publication of the 2009 guideline. The committee for the 2018 guideline decided to make a research recommendation rather than a practice recommendation on analgesia other than NSAIDs.
## How the recommendations might affect practice
Current practice regarding the choice of analgesic is variable, with paracetamol, compound analgesics and NSAIDs all commonly used to control symptoms. Choice of analgesic tends to be based on individual effectiveness as well as the person's risk profile, tolerance, and side effects. In particular, there are some groups of people for whom NSAIDs are unsuitable because of contraindications, comorbidities or tolerability, and other people who are currently benefiting from analgesic drugs other than NSAIDs. The current approach is likely to continue but there may be an increase in prescribing of NSAIDs instead of other analgesic drugs for people with newly diagnosed RA.
Full details of the evidence and the committee's discussion are in evidence review G: Analgesics.
Return to the recommendations
# Monitoring
Recommendations 1.9.1, 1.9.2, 1.9.4 and 1.9.5
## Why the committee made the recommendations
No evidence was identified on monitoring frequency once the treatment target has been achieved. However, the committee agreed that once people with RA had achieved the treatment target, and this was sustained at a 6-month follow-up appointment, there was no need for additional routine appointments to be scheduled other than the annual review. All people with RA should have an annual review.
In people with established RA (RA for at least 2 years), the evidence suggested that patient-initiated rapid access and scheduled medical review every 3 to 6 months were similarly effective. The committee agreed that all adults with RA should have rapid access to specialist care for disease flares, and ongoing drug monitoring.
Randomised controlled evidence did not support using ultrasound for routine monitoring of RA. However, in the committee's experience ultrasound can be useful for monitoring when clinical examination is inconclusive or is inconsistent with other signs of disease activity (for example, pain or markers of inflammation). The committee decided to make a research recommendation to inform future guidance about using ultrasound in these situations.
## How the recommendations might affect practice
The frequency of monitoring and review appointments for people who have reached the treatment target vary around the country, with some people being seen more often than needed and others not receiving adequate follow-up. The 2018 recommendations are likely to reduce unwarranted variation.
Most people with RA currently have rapid access to specialist care when they have a flare. The 2016 National Clinical Audit for Rheumatoid Arthritis and Early Inflammatory Arthritis reported that 92% of people had access to urgent advice, with 97% of providers running a telephone advice line. Therefore the recommendation will not affect current practice.
Use and availability of ultrasound varies widely across the country and even between healthcare professionals in the same department. Some healthcare professionals use it routinely whereas others use it on a case-by-case basis. The recommendation should reduce the overall use of ultrasound while still allowing its use for selected subgroups.
Full details of the evidence and the committee's discussion are in evidence review E: Frequency of monitoring.
Return to the recommendations# Context
Rheumatoid arthritis (RA) is an inflammatory disease largely affecting synovial joints. It typically affects the small joints of the hands and the feet, and usually both sides equally and symmetrically, although any synovial joint can be affected. It is a systemic disease and so can affect the whole body, including the heart, lungs and eyes.
The incidence of the condition is low, with around 1.5 men and 3.6 women developing RA per 10,000 people per year. The overall occurrence of RA is 2 to 4 times greater in women than men. The peak age of incidence in the UK for both men and women is the 70s, but people of all ages can develop the disease.
Drug management aims to relieve symptoms, as pain relief is the priority for people with RA, and to modify the disease process. Disease modification slows or stops radiological progression, which is closely correlated with progressive functional impairment.
RA can result in a wide range of complications for people with the disease, their carers, the NHS and society in general. The economic impact of this disease includes:
direct costs to the NHS and associated healthcare support services
indirect costs to the economy, including the effects of early mortality and lost productivity
the personal impact of RA and subsequent complications for people with RA and their families.
Approximately one-third of people stop work because of the disease within 2 years of onset, and this increases thereafter. Clearly this disease is costly to the UK economy and to individuals.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Referral, diagnosis and investigations\n\n## Referral from primary care\n\nRefer for specialist opinion any adult with suspected persistent synovitis of undetermined cause. Refer urgently (even with a normal acute-phase response, negative anti-cyclic citrullinated peptide [CCP] antibodies or rheumatoid factor) if any of the following apply:\n\nthe small joints of the hands or feet are affected\n\nmore than one joint is affected\n\nthere has been a delay of 3\xa0months or longer between onset of symptoms and seeking medical advice. [2009, amended 2018]\n\n## Investigations\n\nIf the following investigations are ordered in primary care, they should not delay referral for specialist opinion (see recommendation 1.1.1).\n\nOffer to carry out a blood test for rheumatoid factor in adults with suspected rheumatoid arthritis (RA) who are found to have synovitis on clinical examination. \n\nConsider measuring anti-CCP antibodies in adults with suspected RA if they are negative for rheumatoid factor. [2009, amended 2018]\n\nX-ray the hands and feet in adults with suspected RA and persistent synovitis. [2009, amended 2018]\n\nAs soon as possible after establishing a diagnosis of RA:\n\nmeasure anti-CCP antibodies, unless already measured to inform diagnosis\n\nX-ray the hands and feet to establish whether erosions are present, unless X-rays were performed to inform diagnosis\n\nmeasure functional ability using, for example, the Health Assessment Questionnaire (HAQ), to provide a baseline for assessing the functional response to treatment. \n\nIf anti-CCP antibodies are present or there are erosions on X-ray:\n\nadvise the person that they have an increased risk of radiological progression but not necessarily an increased risk of poor function, and\n\nemphasise the importance of monitoring their condition, and seeking rapid access to specialist care if disease worsens or they have a flare. \n\nFor a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on investigations following diagnosis\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B: Risk factors.\n\nLoading. Please wait.\n\n# Treat-to-target strategy\n\nTreat active RA in adults with the aim of achieving a target of remission or low disease activity if remission cannot be achieved (treat-to-target). Achieving the target may involve trying multiple conventional disease-modifying anti-rheumatic drugs (cDMARDs) and biological DMARDs with different mechanisms of action, one after the other. [2018, amended 2020]\n\nConsider making the target remission rather than low disease activity for people with an increased risk of radiological progression (presence of anti-CCP antibodies or erosions on X-ray at baseline assessment). \n\nIn adults with active RA, measure C-reactive protein (CRP) and disease activity (using a composite score such as DAS28) monthly in specialist care until the target of remission or low disease activity is achieved. \n\nFor a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on treat-to-target strategy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: Treat-to-target.\n\nLoading. Please wait.\n\n# Communication and education\n\nExplain the risks and benefits of treatment options to adults with RA in ways that can be easily understood. Throughout the course of their disease, offer them the opportunity to talk about and agree all aspects of their care, and respect the decisions they make. \n\nOffer verbal and written information to adults with RA to:\n\nimprove their understanding of the condition and its management, and\n\ncounter any misconceptions they may have. \n\nAdults with RA who wish to know more about their disease and its management should be offered the opportunity to take part in existing educational activities, including self-management programmes. \n\n# Initial pharmacological management\n\n## Conventional disease-modifying anti-rheumatic drugs\n\nFor adults with newly diagnosed active RA:\n\nOffer first-line treatment with cDMARD monotherapy using oral methotrexate, leflunomide or sulfasalazine as soon as possible and ideally within 3\xa0months of onset of persistent symptoms.\n\nConsider hydroxychloroquine for first-line treatment as an alternative to oral methotrexate, leflunomide or sulfasalazine for mild or palindromic disease.\n\nEscalate dose as tolerated. \n\nConsider short-term bridging treatment with glucocorticoids (oral, intramuscular or intra-articular) when starting a new cDMARD. \n\nFor a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on short-term bridging treatment with glucocorticoids\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review H: Glucocorticoids.\n\nLoading. Please wait.\n\nOffer additional cDMARDs (oral methotrexate, leflunomide, sulfasalazine or hydroxychloroquine) in combination in a step-up strategy when the treatment target (remission or low disease activity) has not been achieved despite dose escalation. \n\nFor a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on DMARDs\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review F: DMARDs.\n\nLoading. Please wait.\n\n# Further pharmacological management\n\n## Biological and targeted synthetic DMARDs\n\nNICE has published technology appraisal guidance on biological and targeted synthetic DMARDs for RA. For full details, see RA technology appraisals on our topic page on arthritis. For guidance on using DMARDs to achieve treatment targets, see recommendation 1.2.1.\n\nThe recommendations below are from NICE technology appraisal guidance 72. The 2009 guideline committee reviewed the evidence on anakinra and incorporated the recommendations into the guideline. The technology appraisal was then withdrawn.\n\nOn the balance of its clinical benefits and cost effectiveness, anakinra is not recommended for the treatment of RA, except in the context of a controlled, long-term clinical study. \n\nPatients currently receiving anakinra for RA may suffer loss of wellbeing if their treatment were discontinued at a time they did not anticipate. Therefore, patients should continue therapy with anakinra until they and their consultant consider it is appropriate to stop. \n\nDo not offer the combination of tumour necrosis factor-α (TNF-α) inhibitor therapy and anakinra for RA. \n\n## Glucocorticoids\n\nOffer short-term treatment with glucocorticoids for managing flares in adults with recent-onset or established disease to rapidly decrease inflammation. \n\nIn adults with established RA, only continue long-term treatment with glucocorticoids when:\n\nthe long-term complications of glucocorticoid therapy have been fully discussed, and\n\nall other treatment options (including biological and targeted synthetic DMARDs) have been offered. [2009, amended 2018]\n\n# Symptom control\n\nConsider oral non-steroidal anti-inflammatory drugs (NSAIDs, including traditional NSAIDs and cox II selective inhibitors), when control of pain or stiffness is inadequate. Take account of potential gastrointestinal, liver and cardio-renal toxicity, and the person's risk factors, including age and pregnancy. \n\nWhen treating symptoms of RA with oral NSAIDs:\n\noffer the lowest effective dose for the shortest possible time\n\noffer a proton pump inhibitor (PPI), and\n\nreview risk factors for adverse events regularly. \n\nIf a person with RA needs to take low-dose aspirin, healthcare professionals should consider other treatments before adding an NSAID (with a PPI) if pain relief is ineffective or insufficient. [2009, amended 2018]\n\nFor a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on symptom control\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review G: Analgesics.\n\nLoading. Please wait.\n\n# The multidisciplinary team\n\nAdults with RA should have ongoing access to a multidisciplinary team. This should provide the opportunity for periodic assessments (see 1.9.2 and 1.9.3) of the effect of the disease on their lives (such as pain, fatigue, everyday activities, mobility, ability to work or take part in social or leisure activities, quality of life, mood, impact on sexual relationships) and help to manage the condition. \n\nAdults with RA should have access to a named member of the multidisciplinary team (for example, the specialist nurse) who is responsible for coordinating their care. \n\n# Non-pharmacological management\n\n## Physiotherapy\n\nAdults with RA should have access to specialist physiotherapy, with periodic review (see 1.9.2 and 1.9.3), to:\n\nimprove general fitness and encourage regular exercise\n\nlearn exercises for enhancing joint flexibility, muscle strength and managing other functional impairments\n\nlearn about the short-term pain relief provided by methods such as transcutaneous electrical nerve stimulators (TENS) and wax baths. \n\n## Occupational therapy\n\nAdults with RA should have access to specialist occupational therapy, with periodic review (see 1.9.2 and 1.9.3), if they have:\n\ndifficulties with any of their everyday activities, or\n\nproblems with hand function. \n\n## Hand exercise programmes\n\nConsider a tailored strengthening and stretching hand exercise programme for adults with RA with pain and dysfunction of the hands or wrists if:\n\nthey are not on a drug regimen for RA, or\n\nthey have been on a stable drug regimen for RA for at least 3\xa0months. \n\nThe tailored hand exercise programme for adults with RA should be delivered by a practitioner with training and skills in this area. \n\n## Podiatry\n\nAll adults with RA and foot problems should have access to a podiatrist for assessment and periodic review of their foot health needs (see 1.9.2 and 1.9.3). \n\nFunctional insoles and therapeutic footwear should be available for all adults with RA if indicated. \n\n## Psychological interventions\n\nOffer psychological interventions (for example, relaxation, stress management and cognitive coping skills [such as managing negative thinking]) to help adults with RA adjust to living with their condition. \n\nNICE has published a guideline on depression in adults with a chronic physical health problem.\n\n## Diet and complementary therapies\n\nInform adults with RA who wish to experiment with their diet that there is no strong evidence that their arthritis will benefit. However, they could be encouraged to follow the principles of a Mediterranean diet (more bread, fruit, vegetables and fish; less meat; and replace butter and cheese with products based on vegetable and plant oils). \n\nInform adults with RA who wish to try complementary therapies that although some may provide short-term symptomatic benefit, there is little or no evidence for their long-term efficacy. \n\nIf an adult with RA decides to try complementary therapies, advise them:\n\nthese approaches should not replace conventional treatment\n\nthis should not prejudice the attitudes of members of the multidisciplinary team, or affect the care offered. \n\n# Monitoring\n\nEnsure that all adults with RA have:\n\nrapid access to specialist care for flares\n\ninformation about when and how to access specialist care, and\n\nongoing drug monitoring. \n\nConsider a review appointment to take place 6\xa0months after achieving treatment target (remission or low disease activity) to ensure that the target has been maintained. \n\nOffer all adults with RA, including those who have achieved the treatment target, an annual review to:\n\nassess disease activity and damage, and measure functional ability (using, for example, the Health Assessment Questionnaire [HAQ])\n\ncheck for the development of comorbidities, such as hypertension, ischaemic heart disease, osteoporosis and depression\n\nassess symptoms that suggest complications, such as vasculitis and disease of the cervical spine, lung or eyes\n\norganise appropriate cross referral within the multidisciplinary team\n\nassess the need for referral for surgery (see section 1.10)\n\nassess the effect the disease is having on a person's life.Follow recommendation 1.2.1 if the target is not maintained. [2009, amended 2020]\n\nFor adults who have maintained the treatment target (remission or low disease activity) for at least 1\xa0year without glucocorticoids, consider cautiously reducing drug doses or stopping drugs in a step-down strategy. Return promptly to the previous DMARD regimen if the treatment target is no longer met. \n\nDo not use ultrasound for routine monitoring of disease activity in adults with RA. \n\nFor a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see rationale and impact section on monitoring\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review E: Frequency of monitoring.\n\nLoading. Please wait.\n\n# Timing and referral for surgery\n\nOffer to refer adults with RA for an early specialist surgical opinion if any of the following do not respond to optimal non-surgical management:\n\npersistent pain due to joint damage or other identifiable soft tissue cause\n\nworsening joint function\n\nprogressive deformity\n\npersistent localised synovitis. \n\nOffer to refer adults with any of the following complications for a specialist surgical opinion before damage or deformity becomes irreversible:\n\nimminent or actual tendon rupture\n\nnerve compression (for example, carpal tunnel syndrome)\n\nstress fracture. \n\nWhen surgery is offered to adults with RA, explain that the main expected benefits are:\n\npain relief\n\nimprovement, or prevention of further deterioration, of joint function, and\n\nprevention of deformity.Cosmetic improvements should not be the dominant concern. \n\nOffer urgent combined medical and surgical management to adults with RA who have suspected or proven septic arthritis (especially in a prosthetic joint). \n\nIf an adult with RA develops any symptoms or signs that suggest cervical myelopathy (for example, paraesthesia, weakness, unsteadiness, reduced power, extensor plantars):\n\nrequest an urgent MRI scan, and\n\nrefer for a specialist surgical opinion. \n\nDo not let concerns about the long-term durability of prosthetic joints influence decisions to offer joint replacements to younger adults with RA. \n\n# Terms used in this guideline\n\n## Bridging treatment\n\nGlucocorticoids used for a short period of time when a person is starting a new DMARD, intended to improve symptoms while waiting for the new DMARD to take effect (which can take 2 to 3\xa0months).\n\n## Conventional disease-modifying anti-rheumatic drugs (cDMARDs)\n\nConventional disease-modifying anti-rheumatic drugs are synthetic drugs that modify disease rather than just alleviating symptoms. They include methotrexate, sulfasalazine, leflunomide and hydroxychloroquine, but do not include biological DMARDs and targeted synthetic DMARDs.\n\n## Palindromic\n\nPalindromic rheumatism is an inflammatory arthritis that causes attacks of joint pain and swelling similar to RA. Between attacks the joints return to normal.\n\n## Step-up strategy\n\nAdditional DMARDs are added to DMARD monotherapy when disease is not adequately controlled.\n\n## Step-down strategy\n\nDuring treatment with 2 or more DMARDs, tapering and stopping at least 1 drug once disease is adequately controlled.\n\n## Synovitis\n\nSoft tissue joint swelling.\n\n## Treat-to-target\n\nA treat-to-target strategy is a strategy that defines a treatment target (such as remission or low disease activity) and applies tight control (for example, monthly visits and respective treatment adjustment) to reach this target. The treatment strategy often follows a protocol for treatment adaptations depending on the disease activity level and degree of response to treatment.", 'Recommendations for research': "The guideline committee has made the following high-priority recommendations for research.\n\n# Analgesics\n\nWhat is the clinical and cost effectiveness of analgesic drugs other than non-steroidal anti-inflammatory drugs (NSAIDs) in adults with rheumatoid arthritis (RA) whose pain or stiffness control is not adequate?\n\n## Why this is important\n\nAnalgesics (including NSAIDs, paracetamol, opioids and compound analgesics) are sometimes used with disease-modifying treatments to relieve pain and stiffness when symptom control is inadequate. Current practice regarding the choice of analgesic in RA is variable. The evidence is limited for many of the analgesic drugs other than NSAIDs, and their relative effectiveness is unknown. Further research in this area may inform future guidance on the use of analgesic drugs other than NSAIDs for controlling symptoms.\n\n# Short-term bridging treatment with glucocorticoids\n\nWhat is the clinical and cost effectiveness of short-term bridging treatment with glucocorticoids for adults with RA starting a new disease-modifying anti-rheumatic drug (DMARD), including the most effective dosing strategy and mode of administration?\n\n## Why this is important\n\nAll DMARDs have a slow onset of action. In some cases, response may not be seen for 2 to 3\xa0months. In contrast, glucocorticoids have an immediate effect on joint pain and swelling. In clinical practice, several different regimens are prescribed to 'bridge' the time between the initial prescription of DMARDs and the clinical response. However, good quality evidence from randomised controlled trials (RCTs) demonstrating the effectiveness of glucocorticoids as bridging treatment is limited and inconclusive. Further research is needed to inform recommendations for practice regarding whether bridging treatment with steroids should be used until the new DMARD begins to take effect.\n\nThe optimal dosing strategy and mode of administration for bridging glucocorticoids also needs to be established. Although the anti-inflammatory response is dose dependent, side effects of glucocorticoids vary according to both the dose and the duration of treatment.\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on short-term bridging treatment with glucocorticoids\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review H: Glucocorticoids.\n\nLoading. Please wait.\n\n# Ultrasound in monitoring\n\nWhat is the clinical and cost effectiveness of using ultrasound to monitor disease in adults with RA when clinical examination is inconclusive or inconsistent with other signs of disease activity?\n\n## Why this is important\n\nRA is a chronic inflammatory condition that needs regular review to enable adjustments in management to achieve a target of remission or low disease activity.\n\nAlthough ultrasound is able to show subclinical inflammation or erosions in some people in clinical remission, evidence from RCTs does not support using ultrasound for routine monitoring. However, ultrasound may be useful for assessing disease activity in some people with RA; specifically, when clinical examination is inconclusive or is inconsistent with other signs of disease activity (for example, pain or markers of inflammation). There is no reliable evidence on the added value of ultrasound as part of a monitoring strategy in these subgroups.\n\nIn addition, when there is inconsistency between clinical examination and disease activity, it may be unclear if the person has subclinical inflammatory synovitis or more of a widespread pain syndrome, which is not inflammatory. These need very different treatments, so it is important to define them accurately.\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on monitoring\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review E: Frequency of monitoring.\n\nLoading. Please wait.\n\n# Ultrasound in diagnosis\n\nWhat is the clinical and cost effectiveness of using ultrasound in addition to clinical assessment when there is uncertainty about the diagnosis in adults with suspected RA?\n\n## Why this is important\n\nEarly diagnosis of RA is essential to reduce the impact of the disease on multiple systems in the body. The course of RA and the initial presentation can be highly variable; most people with RA have definite synovitis on clinical assessment, but sometimes this is not obvious, leading to uncertainty about the diagnosis. Ultrasound is a non-invasive and relatively inexpensive imaging modality that can detect subclinical synovitis and early erosive disease. It might help determine an early diagnosis of RA when the diagnosis would otherwise be uncertain. Early diagnosis enables earlier treatment, providing an opportunity to improve the longer term outcomes for people with RA. The use of ultrasound may also allow healthcare professionals to be more confident about ruling out a diagnosis of RA.\n\n# Management of poor prognosis\n\nWhat is the clinical and cost effectiveness of managing RA with a poor prognosis (identified as presence of anti-cyclic citrullinated peptide [CCP] antibodies or evidence of erosions on X-ray at diagnosis) with a different strategy from that used for standard management of RA?\n\n## Why this is important\n\nCurrent recommendations suggest all people with RA should be offered the same management; however clinical experience suggests that the condition responds less well in some people and some suffer progressive radiographic damage and impaired function despite standard management. Several factors have been identified in the literature that, if present and identified early in the course of the disease, may predict a poor prognosis (greater radiographic progression). These include anti-CCP antibody positivity and the presence of radiographic erosions at baseline. At present it is unclear whether people with poor prognostic markers should have different management early in the disease, and whether this would improve radiographic and functional (HAQ) outcomes in this group.\n\n# Subcutaneous methotrexate\n\nWhat is the clinical and cost effectiveness of subcutaneous methotrexate compared with oral methotrexate for adults with early onset RA starting a new DMARD?\n\n## Why this is important\n\nMethotrexate is an important drug in the treatment of RA. Subcutaneous administration is an alternative option for people who have side effects with oral treatment. Evidence on the effectiveness of subcutaneous methotrexate is lacking, but its effects may be superior, due to increased bioavailability, and fewer side effects than with oral drugs. Research on subcutaneous methotrexate will inform future guideline recommendations.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.\n\n# Investigations following diagnosis\n\nRecommendations 1.1.5 and 1.1.6\n\n## Why the committee made the recommendations\n\nEvidence showed that anti-cyclic citrullinated peptide (CCP) antibodies and radiographic damage at baseline were both important prognostic factors for subsequent radiographic progression. Anti-CCP antibodies are usually measured and X-rays often taken as part of diagnosis. When this has not been done, the committee agreed that the tests should be performed as soon as possible. The results will inform discussions with the patient about how their rheumatoid arthritis (RA) might progress and reinforce the importance of active monitoring and rapidly seeking specialist care if the disease worsens.\n\nThere was limited evidence on poor function, as measured by the Health Assessment Questionnaire (HAQ), as a prognostic factor. However, the committee agreed that functional ability (measured, for example, by HAQ) should be determined at diagnosis to provide a baseline for assessing response to treatment at the annual review.\n\nEvidence suggests that all people with RA should be offered the same management strategy; however, in the committee's experience some people may respond less well and have more progressive radiographic damage and impaired function. Because the evidence was limited as to whether people with poor prognostic markers should follow a different management strategy to improve radiographic and functional (HAQ) outcomes, the committee agreed to make a research recommendation.\n\n## How the recommendations might affect practice\n\nAnti-CCP antibodies are usually measured so there should be no change in current practice. X-raying the hands and feet and measuring functional ability at baseline reflects current best practice, but not everyone with RA currently has these investigations. There may be an increase in the number of X-rays, especially in units without early inflammatory arthritis clinics, but this is unlikely to have a substantial resource impact.\n\nMeasuring functional ability at baseline will involve a change of practice for some providers, but the cost is low and so this is not expected to have a substantial resource impact.\n\nFull details of the evidence and the committee's discussion are in evidence review B: Risk factors.\n\nReturn to recommendations\n\n# Investigations (ultrasound in diagnosis)\n\n## Why the committee made the research recommendation on ultrasound in diagnosis\n\nUltrasound is not used widely in diagnosing RA, but use is increasing and depends on the clinic and the rheumatologist. Evidence was inconsistent and too limited for the committee to make any recommendation for or against its use in diagnosis. The committee noted that the studies generally included only people with clinically definite synovitis and agreed that ultrasound may be more useful when there is uncertainty about the diagnosis after clinical assessment. They decided to make a research recommendation to inform future guidance on who (if anyone) should have ultrasound to aid diagnosis.\n\nFull details of the evidence and the committee's discussion are in evidence review A: Ultrasound for diagnosis.\n\nReturn to the recommendation for research\n\n# Treat-to-target strategy\n\nRecommendations 1.2.1 to 1.2.3\n\n## Why the committee made the recommendations\n\nEvidence showed that a treat-to-target strategy was more effective than usual care for managing RA and improved outcomes at no additional cost. The committee agreed that this approach was more likely to achieve rapid and sustained disease control.\n\nNo evidence was identified to indicate whether a target of remission or low disease activity was more effective. However, the committee agreed that remission (for example, a DAS28 score of less than 2.6) is the most appropriate target for most people, but for some who are unable to achieve remission despite a treat-to-target approach with appropriate escalation, low disease activity (for example, a DAS28 score of less than 3.2) is acceptable. It was agreed that for those identified as being at risk of poor prognosis, a target of remission may be more appropriate.\n\nNo studies were identified that compared different frequencies of monitoring specifically in people with active disease. The committee noted that the 2009 guideline recommended monthly monitoring and that this was used in some of the studies of a treat-to-target strategy. The committee agreed that monthly monitoring of C-reactive protein (CRP) and disease activity was most appropriate for active disease. This allows dose escalation of disease-modifying anti-rheumatic drugs (DMARDs), checking the need for short-term bridging treatment with glucocorticoids and whether people are tolerating the drug regimen, assessing side effects, providing support and encouraging adherence.\n\nThere was no evidence that people with a poor prognosis should have different management in terms of the treatment target or the frequency of monitoring. However, in the committee's experience RA often responds less well to standard management in this group. The committee agreed that the recommendations on treat-to-target with monthly monitoring should ensure that people with a poor prognosis receive effective treatment, but they decided to make a research recommendation to inform future guidance for managing RA in this group.\n\n## How the recommendations might affect practice\n\nA treat-to-target strategy is current best practice in most NHS settings. The 2016 National Clinical Audit for Rheumatoid Arthritis and Early Inflammatory Arthritis indicated that healthcare professionals set a treatment target for about 90% of their patients. Although the 2018 recommendation specifies a target of remission or low disease activity, rather than a disease level previously agreed with the person, the committee agreed that these are the targets commonly used and so this is unlikely to involve a significant change in practice.\n\nMonthly monitoring was recommended in the 2009 guideline, but the committee acknowledged that many clinics do not monitor active disease this often. A regional survey (Tugnet 2013) reported that about two-thirds of people with RA received monthly CRP monitoring but only a quarter had monthly monitoring of disease activity (with about 40% in dedicated early arthritis clinics) until disease control was achieved. The committee were unsure whether these rates reflected practice across England and noted that practice had improved since the survey was conducted in 2011. However, the committee agreed that monthly monitoring would likely involve a change in practice in some clinics.\n\nFull details of the evidence and the committee's discussion are in evidence review C: Treat-to-target.\n\nReturn to the recommendations\n\n# DMARDs\n\nRecommendations 1.4.1 and 1.4.3\n\n## Why the committee made the recommendations\n\nEvidence showed that starting treatment with more than 1 conventional DMARD (cDMARD) was no more effective than starting with a single cDMARD. The committee agreed that cDMARD monotherapy might have fewer side effects and recommended cDMARD monotherapy as first-line treatment. This differed from the 2009 guideline which recommended combination therapy. The difference is largely a result of inclusion of different evidence and a different approach to analysing that evidence.\n\nMany of the studies included in the 2009 guideline used cDMARDs that are no longer commonly used in UK practice (for example, ciclosporin), and these studies were excluded from the evidence for the 2018 update. In addition, the 2018 update included new evidence published after the 2009 guideline. Further, a different approach to analysing the evidence was taken, with the 2018 update aiming to identify the most effective cDMARD strategy (monotherapy, sequential monotherapy, step-up therapy, step-down therapy or parallel combination therapy) as well as which cDMARD should be used. The 2009 guideline compared treatment strategies only, regardless of the particular cDMARDs, and combined evidence according to treatment strategy.\n\nThe evidence included in the 2018 update was therefore different to that included in 2009 and supported cDMARD monotherapy as first-line treatment.\n\nEvidence from randomised controlled trials (RCTs) in people who had never had a DMARD showed no consistent differences in the effectiveness of methotrexate, leflunomide and sulfasalazine as monotherapies. The drugs also had similar costs. The committee agreed that any of these drugs can be used as first-line treatment.\n\nHydroxychloroquine was less effective, but fewer people stopped treatment because of side effects. The committee agreed that hydroxychloroquine could be considered for people with mild or palindromic disease.\n\nEvidence for different first-line treatment in people with a poor prognosis was limited so the committee decided not to make a separate recommendation for this group. They agreed that the recommendation for dose increases and treating to target (with the aim of keeping disease activity low) should ensure adequate treatment for these people. Given the limited evidence in this area, the committee also decided that the possible benefit of managing RA with a poor prognosis with a different strategy was a priority for future research.\n\nEvidence supported adding another cDMARD when needed (step-up strategy) rather than replacing the cDMARD with another (sequential monotherapy). The committee acknowledged that more side effects were possible with a step-up strategy, but in their experience these could be managed by drug monitoring and were outweighed by the clinical benefit of combination treatment when monotherapy was inadequate. A published economic analysis supported a step-up approach rather than sequential monotherapy.\n\nNo evidence was found for subcutaneous methotrexate, but the committee agreed that the effects may be superior and side effects fewer than with oral cDMARDs. However, because subcutaneous methotrexate is significantly more expensive than other cDMARD options, the committee was not able to recommend this without evidence of clinical benefit and cost effectiveness relative to oral cDMARDs. The committee decided to make a research recommendation to inform future guidance.\n\n## How the recommendations might affect practice\n\nThe 2009 guideline recommended a combination of cDMARDs (including methotrexate and at least 1 other cDMARD) for newly diagnosed RA and emphasised the importance of starting effective cDMARD therapy as soon as possible.\n\nThe 2009 recommendation to start with combination therapy was not widely adopted. The 2016 National Clinical Audit for Rheumatoid Arthritis and Early Inflammatory Arthritis reported that only 46% of people with RA received combination cDMARDs at any time. Currently there is variation in practice regarding the choice of cDMARD(s) and treatment strategy, with many healthcare professionals preferring to start with monotherapy and only use combination therapy when response is inadequate.\n\nThe 2018 recommendations to start with monotherapy and add drugs when the response is inadequate are unlikely to have a substantial impact on practice or resources, as they align with the current approach taken by many healthcare professionals. However, the recommendations should result in a more consistent treatment strategy and reduce the number of people prescribed combination therapy on diagnosis.\n\nThe 2009 guideline recommended methotrexate as one of the first drugs used in combination therapy. The 2018 recommendations do not specify which cDMARD should be used at any stage of treatment. Again, this will be unlikely to have a significant impact on practice, and methotrexate is likely to remain one of the most commonly prescribed drugs.\n\nThe recommendations on dose escalation and reduction have not changed substantially from the 2009 guideline and reflect current clinical practice. The committee clarified that dose reduction and the use of a step-down strategy should only be considered after a person has maintained the treatment target for at least 1\xa0year without the use of glucocorticoids.\n\nFull details of the evidence and the committee's discussion are in evidence review F: DMARDs.\n\nReturn to the recommendations\n\n# Short-term bridging treatment with glucocorticoids\n\nRecommendation 1.4.2\n\n## Why the committee made the recommendation\n\nEvidence from RCTs on the use of short-term bridging treatment with glucocorticoids to relieve symptoms while people are waiting for a new DMARD to take effect was limited. There was some evidence that fewer people withdrew from the studies due to inefficacy or adverse events when they were taking glucocorticoids, although there was no evidence that glucocorticoids were effective in terms of disease activity score, quality of life or function, as studies did not report these outcomes. In the committee's experience people with active arthritis may benefit from the anti-inflammatory effects of glucocorticoids. However, for others with less active disease this additional treatment may not be needed. The committee agreed that short-term glucocorticoids could be considered on a case-by-case basis.\n\nBecause of the lack of good quality evidence, the committee decided to make a research recommendation to determine the effectiveness of short-term glucocorticoids for adults taking a new DMARD, including the most effective regimen.\n\n## How the recommendation might affect practice\n\nMost healthcare professionals offer short-term bridging treatment with glucocorticoids to adults starting a new DMARD. They can continue to offer this but the recommendation encourages them to consider whether this additional treatment is always needed. Therefore this is unlikely to result in additional spending for the NHS.\n\nFull details of the evidence and the committee's discussion are in evidence review H: Glucocorticoids.\n\nReturn to the recommendation\n\n# Symptom control\n\nRecommendations 1.6.1 and 1.6.2\n\n## Why the committee made the recommendations\n\nEvidence suggested that non-steroidal anti-inflammatory drugs (NSAIDs) may offer a small benefit in relieving symptoms for adults with RA (including pain and stiffness). The committee agreed that this was likely to outweigh the increase in gastrointestinal adverse events associated with NSAIDs. To minimise adverse events, the committee agreed that NSAIDs should be used at the lowest doses and for the shortest possible time, with a proton pump inhibitor, and that risk factors for adverse events should be reviewed regularly. The recommendations for analgesic treatment in this guideline replace those in the 2009 guideline.\n\nThere was limited evidence on paracetamol, opioids and tricyclic antidepressants and no evidence for nefopam, gabapentinoids or selective serotonin reuptake inhibitor (SSRI) and SSNRI antidepressants. The committee acknowledged that the 2009 guideline had recommended analgesics other than NSAIDs for pain control. However, the 2009 guideline indicated that the evidence on analgesia other than NSAIDs was 'sparse'. No further evidence on these drugs was identified since the publication of the 2009 guideline. The committee for the 2018 guideline decided to make a research recommendation rather than a practice recommendation on analgesia other than NSAIDs.\n\n## How the recommendations might affect practice\n\nCurrent practice regarding the choice of analgesic is variable, with paracetamol, compound analgesics and NSAIDs all commonly used to control symptoms. Choice of analgesic tends to be based on individual effectiveness as well as the person's risk profile, tolerance, and side effects. In particular, there are some groups of people for whom NSAIDs are unsuitable because of contraindications, comorbidities or tolerability, and other people who are currently benefiting from analgesic drugs other than NSAIDs. The current approach is likely to continue but there may be an increase in prescribing of NSAIDs instead of other analgesic drugs for people with newly diagnosed RA.\n\nFull details of the evidence and the committee's discussion are in evidence review G: Analgesics.\n\nReturn to the recommendations\n\n# Monitoring\n\nRecommendations 1.9.1, 1.9.2, 1.9.4 and 1.9.5\n\n## Why the committee made the recommendations\n\nNo evidence was identified on monitoring frequency once the treatment target has been achieved. However, the committee agreed that once people with RA had achieved the treatment target, and this was sustained at a 6-month follow-up appointment, there was no need for additional routine appointments to be scheduled other than the annual review. All people with RA should have an annual review.\n\nIn people with established RA (RA for at least 2\xa0years), the evidence suggested that patient-initiated rapid access and scheduled medical review every 3 to 6 months were similarly effective. The committee agreed that all adults with RA should have rapid access to specialist care for disease flares, and ongoing drug monitoring.\n\nRandomised controlled evidence did not support using ultrasound for routine monitoring of RA. However, in the committee's experience ultrasound can be useful for monitoring when clinical examination is inconclusive or is inconsistent with other signs of disease activity (for example, pain or markers of inflammation). The committee decided to make a research recommendation to inform future guidance about using ultrasound in these situations.\n\n## How the recommendations might affect practice\n\nThe frequency of monitoring and review appointments for people who have reached the treatment target vary around the country, with some people being seen more often than needed and others not receiving adequate follow-up. The 2018 recommendations are likely to reduce unwarranted variation.\n\nMost people with RA currently have rapid access to specialist care when they have a flare. The 2016 National Clinical Audit for Rheumatoid Arthritis and Early Inflammatory Arthritis reported that 92% of people had access to urgent advice, with 97% of providers running a telephone advice line. Therefore the recommendation will not affect current practice.\n\nUse and availability of ultrasound varies widely across the country and even between healthcare professionals in the same department. Some healthcare professionals use it routinely whereas others use it on a case-by-case basis. The recommendation should reduce the overall use of ultrasound while still allowing its use for selected subgroups.\n\nFull details of the evidence and the committee's discussion are in evidence review E: Frequency of monitoring.\n\nReturn to the recommendations", 'Context': 'Rheumatoid arthritis (RA) is an inflammatory disease largely affecting synovial joints. It typically affects the small joints of the hands and the feet, and usually both sides equally and symmetrically, although any synovial joint can be affected. It is a systemic disease and so can affect the whole body, including the heart, lungs and eyes.\n\nThe incidence of the condition is low, with around 1.5 men and 3.6 women developing RA per 10,000 people per year. The overall occurrence of RA is 2 to 4 times greater in women than men. The peak age of incidence in the UK for both men and women is the 70s, but people of all ages can develop the disease.\n\nDrug management aims to relieve symptoms, as pain relief is the priority for people with RA, and to modify the disease process. Disease modification slows or stops radiological progression, which is closely correlated with progressive functional impairment.\n\nRA can result in a wide range of complications for people with the disease, their carers, the NHS and society in general. The economic impact of this disease includes:\n\ndirect costs to the NHS and associated healthcare support services\n\nindirect costs to the economy, including the effects of early mortality and lost productivity\n\nthe personal impact of RA and subsequent complications for people with RA and their families.\n\nApproximately one-third of people stop work because of the disease within 2\xa0years of onset, and this increases thereafter. Clearly this disease is costly to the UK economy and to individuals.'}
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https://www.nice.org.uk/guidance/ng100
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This guideline covers diagnosing and managing rheumatoid arthritis. It aims to improve quality of life by ensuring that people with rheumatoid arthritis have the right treatment to slow the progression of their condition and control their symptoms. People should also have rapid access to specialist care if their condition suddenly worsens.
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2c7b2967ef0012ba4314ad033a906f18127d9b27
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nice
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Behaviour change: digital and mobile health interventions
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Behaviour change: digital and mobile health interventions
This guideline covers interventions that use a digital or mobile platform to help people eat more healthily, become more active, stop smoking, reduce their alcohol intake or practise safer sex. The interventions include those delivered by text message, apps, wearable devices or the internet. The guideline only includes those that are delivered by the technology itself and not by healthcare professionals using technology to deliver interventions.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity) and safeguarding.
# Developing digital and mobile health interventions
These recommendations support adopting healthy behaviours in the health and lifestyle areas covered in this guideline (eating more healthily, becoming more active, stopping smoking, reducing alcohol intake, practising safer sex).
Refer to the NICE evidence standards framework for digital technologies when developing and evaluating digital and mobile health interventions for behaviour change.
Follow the advisory frameworks for assessment when developing and evaluating digital and mobile health interventions for behaviour change (such as Public Health England's guidance on evaluating digital health products, NHS Digital's digital assessment questions and the Department of Health and Social Care's code of conduct for data-driven health and care technology).
When designing digital and mobile health interventions, use evidence-based behaviour change techniques that help people start and maintain changes. These include: goals and planning, feedback and monitoring, and social support (see NICE's guideline on behaviour change: individual approaches).
Consider designing interventions that allow the user to tailor goals to their own needs.
Do not develop interventions or components that allow people to set unhealthy or dangerous goals, for example goals that would lead to the person being underweight.
Design interventions so they have the flexibility to be:
scaled up
customised for local needs and use.
Make information available about:
how users can check and set preferences for how their personal information and data may be used
when the intervention is likely to use mobile data, and how much mobile data it is likely to use
any additional costs
terms and conditions.
When developing digital and mobile health interventions, involve a wide range of stakeholders, including potential users, as early as possible and throughout development to:
Develop and review the content, structure, interface and flow of the intervention.
Identify the best digital platforms for the target population.
Identify and address any aspects of the intervention that may unintentionally increase inequity and digital exclusion.
Discuss and ensure that users understand who the intervention is for, which behaviour it is trying to change, its aims, any possible harms, the time needed to establish behaviour change and how frequently users are likely to interact with the intervention.
Use feedback from testing and after releasing the intervention to continually improve the intervention.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on developing digital and mobile health interventions .
Full details of the evidence and the committee's discussion are in evidence review A: smoking behaviour, evidence review B: alcohol, evidence review C: diet, physical activity and sedentary behaviour and evidence review D: sexual health behaviour.
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# Commissioning digital and mobile health interventions
These recommendations support adopting healthy behaviours in the health and lifestyle areas covered in this guideline (eating more healthily, becoming more active, stopping smoking, reducing alcohol intake, practising safer sex).
Consider digital and mobile health interventions as options for behaviour change.
If commissioning digital and mobile health interventions, do this as a supplement to existing services, not as a replacement.
Assess whether specific digital and mobile health interventions could meet some of the needs of the local population by using a needs assessment, including the need to address digital exclusion.
Check expert sources (such as the NHS apps library) for any existing evidence-based digital and mobile health interventions that can meet local needs. Do this before commissioning the development of a new one.
Select interventions that meet current frameworks, regulatory advice and evidence standards for the development and use of digital and mobile health interventions (see the NICE evidence standards framework for digital technologies).
If a new digital and mobile health intervention is needed, assess whether a local-level multidisciplinary collaboration, or partnerships with other health and care organisations, would be appropriate to share development costs.
When commissioning digital and mobile health interventions, take into account equality of access as part of an equality impact assessment. For example:
anything that might limit usability of the intervention (such as literacy, sensory impairments and language barriers)
potential related costs for users (such as cost of apps and data usage)
availability of the necessary hardware and operating system
access to the internet, phone signal and data networks (for example in rural communities, closed institutions and detention settings)
protected characteristics and levels of deprivation.
Be aware that interventions without adverts are preferable, but interventions with adverts may help reduce costs for users.
Do not commission digital and mobile health interventions that are funded or developed by the tobacco industry.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on commissioning digital and mobile health interventions .
Full details of the evidence and the committee's discussion are in evidence review A: smoking behaviour, evidence review B: alcohol, evidence review C: diet, physical activity and sedentary behaviour and evidence review D: sexual health behaviour.
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# Using digital and mobile health interventions
These recommendations support adopting healthy behaviours in the health and lifestyle areas covered in this guideline (eating more healthily, becoming more active, stopping smoking, reducing alcohol intake, practising safer sex). These are to support healthcare professionals.
Consider digital and mobile health interventions as an option for behaviour change as an adjunct to existing services. Be aware that their effectiveness is variable.
When discussing the use of a digital or mobile health intervention with the person, take into account:
their preferences and behaviour change goals, and interventions that allow tailoring towards these
their capability, opportunity and motivation for change
their digital, health and reading literacy
the digital platforms available
the aim of the intervention
how frequently and intensely they are willing to use interventions
that some interventions may not have evidence of effectiveness
how it would fit into their current care pathway.
Advise people who may use a digital and mobile health intervention to:
use one from an expert source if available (such as the NHS apps library) because it is likely to have been assessed for safety, effectiveness and data security
check and set preferences for how their personal information and data may be used
be aware of any possible extra costs
check they are willing and able to pay any associated costs
be aware that the intervention may use mobile data after it is downloaded
seek advice from a healthcare professional if they have health concerns while using the intervention
read the terms and conditions.
When advising on the use of a digital and mobile health intervention, take into account whether the content is appropriate for the user and any possible adverse effects. For example, whether the intervention could:
lead to people self-managing with digital interventions when their behaviour could be more effectively modified with existing health or social care services that involve clinical expertise, face-to-face interaction or treatment
prevent vulnerable people from accessing face-to-face services and interventions
have components that could encourage the person to adopt unhealthy behaviours, such as excessive exercise or disordered eating
have a negative impact on some people's mental health, possibly from using social media components
increase anxiety about health and lead people to consult healthcare professionals more often.
For a short explanation of why the committee made these recommendations and how they might affect practice, see rationale and impact section on using digital and mobile health interventions .
Full details of the evidence and the committee's discussion are in evidence review A: smoking behaviour, evidence review B: alcohol, evidence review C: diet, physical activity and sedentary behaviour and evidence review D: sexual health behaviour.
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# Diet and physical activity
Consider digital and mobile health interventions as an option for people who would benefit from improving their diet or increasing their physical activity levels as an adjunct to existing services. Be aware that their effectiveness is variable.
Advise people to use digital and mobile health interventions that include self-monitoring, such as recording by activity trackers, or food or physical activity diaries. This can help the person to review their own progress towards their diet or physical activity goals.
If you are aware that the person is at risk of developing or resuming an eating disorder or another unhealthy behaviour such as excessive exercise, consider interventions that do not include self-monitoring.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on diet and physical activity .
Full details of the evidence and the committee's discussion are in evidence review C: diet, physical activity and sedentary behaviour.
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# Smoking
Consider digital and mobile health interventions as an option to help people stop smoking as an adjunct to existing services. Be aware that their effectiveness is variable.
Advise the person who wants to stop smoking using a digital or mobile health intervention that text message-based interventions with tailored messages may be more effective than other digital and mobile health interventions.
Do not offer digital and mobile health interventions that are known to be funded or developed by the tobacco industry.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on smoking .
Full details of the evidence and the committee's discussion are in evidence review A: smoking behaviour.
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# Alcohol use
Consider digital and mobile health interventions as an option to reduce alcohol intake as an adjunct to existing services. Be aware that their effectiveness is variable.
Advise the person that some interventions may include particular components that suit them better and reduce their alcohol intake more than other components. For example, a component that compares the person's intake with that of their peers (a personalised normative feedback approach).
Advise the person that interventions they interact with multiple times may be better than a one-off intervention, but a one-off intervention is better than no intervention at all.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on alcohol use .
Full details of the evidence and the committee's discussion are in evidence review B: alcohol.
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# Unsafe sexual behaviour
Consider online brief interventions as an option to help reduce unsafe sexual behaviour as an adjunct to existing services. Be aware that their effectiveness is variable.
If advising people to use online brief interventions, consider ones that include videos with set choice points, scripted scenarios or dramatisation.
When advising on the use of online brief interventions, tell the person that some may have sexually explicit content.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on unsafe sexual behaviour .
Full details of the evidence and the committee's discussion are in evidence review D: sexual health behaviour.
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# Terms used in this guideline
This section defines terms that have been used in a particular way for this guideline. For other definitions see the NICE glossary or, for public health and social care terms, the Think Local, Act Personal Care and Support Jargon Buster.
## Choice points
In an interactive scripted scenario, choice points give the person using the intervention options on what the character should do next at key moments. This models how the person would react in a similar situation in real life, and the consequences of their actions. The intervention can give feedback on how choosing differently may help them change their behaviour.
## Characteristics
A characteristic is an attribute that applies to the whole intervention. For example, how often it will be performed, or if it is specific for a group with a certain condition.
## Components
A component is one part of an intervention. For example, a diary that people can use to track their eating habits. Interventions can be made up of many components.
## Digital and mobile health interventions
Digital health interventions are delivered through: hardware and electronic devices, such as smartwatches; software, such as computer programs or apps; and websites. Mobile health interventions can be delivered through phones, for example by texts, apps or interactive voice response calls. These technologies can deliver interventions independently from healthcare professionals, or healthcare professionals can use them to deliver interventions remotely. This guideline covers digital and mobile health interventions delivered by the technology itself and not by healthcare professionals using technology to deliver interventions.
## Digital exclusion
Digital exclusion describes circumstances in which people are unable or do not want to use digital services. This may be because of a lack of digital skills, confidence, motivation or internet access, or the services may not be accessible. See the NHS information on digital exclusion.
## Digital platforms
Examples include apps, computer programs, websites, smartwatches, interactive voice response systems, or texts.
## Disordered eating
Disordered eating describes a range of irregular eating behaviours. These can include symptoms that reflect many but not all of the symptoms of eating disorders, such as anorexia nervosa, bulimia nervosa and binge eating disorder. Examples of disordered eating include fasting or chronic restrained eating, skipping meals, binge eating, self-induced vomiting, restrictive dieting, and laxative or diuretic misuse.
(For further information on eating disorders refer to the NHS information on eating disorders.)
## Excessive exercise
Exercising more than is recommended if it is detrimental to the person's mental, social or physical wellbeing.
## Scaled up
Technology needs to be designed so it has the ability to cope with an increasing number of people or organisations using it across different parts of the country. The digital architecture must be able to support this. How the technology is supported and regulated is different when more people are using it. An intervention that supports few people in one region is a smaller scale intervention than one that supports more people across multiple regions.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Key recommendations for research
## Engaging people with digital and mobile health interventions
How can providers and healthcare professionals identify groups that do not initially engage, or do not stay engaged, with digital and mobile health behaviour change interventions?
## Effective components of behaviour change interventions
What components and characteristics of digital and mobile health behaviour change interventions are most effective, separately and in combination, to achieve behaviour change?
## Effects of behaviour change interventions on low socioeconomic and other underserved groups
What is the effectiveness and cost effectiveness of digital and mobile health behaviour change interventions in low socioeconomic and other underserved groups?
## Populations that will benefit most from digital and mobile health interventions
Are digital and mobile health behaviour change interventions as effective as face-to-face, standard care, or combination approaches for some populations?
## Harms of behaviour change using digital and mobile health interventions
What are the harms and adverse effects associated with different digital and mobile health behaviour change interventions?
For a short explanation of why the committee made the recommendations for research, see the rationale on recommendations for research .
Full details for all of the recommendations for research for this guideline are in evidence review A: smoking behaviour.
Loading. Please wait.# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice.
Sections on developing, commissioning, and using interventions are applicable to the behaviours covered in this guideline.
# Developing digital and mobile health interventions
Recommendations 1.1.1 to 1.1.9
## Why the committee made the recommendations
The committee discussed the lack of evidence surrounding which components and characteristics of interventions would lead to healthy behaviour change in different populations. This is common to all behaviours and is why the recommendations cannot be more specific. The committee made recommendations for research to fill this gap in evidence.
The committee noted that digital and mobile health interventions is a rapidly changing and developing area. As such, they agreed it was important to develop them in line with national supporting frameworks such as the NICE evidence standards framework for digital technologies to ensure they are as effective as possible. In addition, the committee agreed that the government digital service standard could be followed when creating interventions for public services.
The committee discussed the views from expert testimony that said many developers of these interventions do not have a background in healthcare. This is another reason why the committee wanted to stress the importance of using these advisory frameworks, as well as NICE frameworks.
In the committee's experience regarding approaches to behaviour change in general, the specific behaviour change techniques they recommended have been shown to be effective. But based on the evidence, the committee were unable to draw firm conclusions about how effective these techniques are when used with digital and mobile health interventions. However, they agreed that interventions with the listed behaviour change techniques are more likely to be effective than those without them. The conclusions of the committee also agreed with those in the NICE guideline on behaviour change: individual approaches, which notes that behaviour change interventions should include behaviour change techniques including goals and planning, feedback and monitoring, and social support.
The committee discussed and agreed that it is important for those developing interventions to consider their possible future use, which may be on a wide scale or much more localised. They agreed that it was important for interventions to be designed so that they can be scaled up and can be customised for local needs.
The committee agreed that people are more likely to change their behaviour using interventions that allow them to tailor goals to their needs. The evidence showed that interventions have variable effectiveness, and it is not clear which interventions result in positive behaviour change or in whom. So the committee agreed that developers should include tailored goals in interventions but should be transparent about how the interventions tailor more complex goals to people's needs.
NICE looked for evidence on adverse effects but did not find any. Based on expert testimony and their experience, the committee discussed interventions that may allow people to set goals that may be unhealthy for them. They were particularly concerned about the possibility of setting goals that would lead to the person becoming underweight, and the potential for this to cause disordered eating, exacerbate eating disorders or cause relapse. So they emphasised that interventions should not be designed to allow people to do this.
The committee were aware that developers have a responsibility to make information about their interventions clear. This allows people to make informed decisions on the interventions they choose. Some differences, such as ongoing data use after the intervention has been downloaded, are not obvious and may lead to unwanted costs for the user.
Based on limited evidence and expert testimony the committee understood that it can be challenging to get people to use these interventions on an ongoing basis. They agreed that more collaboration between developers, stakeholders and potential users would be likely to produce more useful and engaging interventions.
For example, if people with physical disabilities and sensory impairments or children and young people are given the opportunity to contribute, they are more likely to use the interventions, and the interventions are more likely to be effective. Some users may say how frequently they would prefer to use the intervention. For example, it could be a one-off intervention, multiple brief interventions or interventions that people interact with multiple times.
Owing to the impact of COVID-19, development might be conducted remotely using digital technology. This could mean that people who are not digitally literate may not be well represented. Developers should make efforts to include these people if possible, for example in design or testing.
The committee discussed expert testimony and agreed that interventions may be used differently after they have been released. This may mean components that worked well in development may work differently in real life. They agreed it is important to gather feedback after release to improve the intervention based on real world use.
## How the recommendations might affect practice
Designing interventions that can be scaled up to be used by many people may help reach more people at a lower average cost. Wider implementation would allow local usage patterns to be monitored and services to be standardised between regions.
Developers will need to work with topic experts to develop content that meets evidence standards. This may mean sharing development costs with other organisations, which would help to reduce the resource impact.
Return to recommendations
# Commissioning digital and mobile health interventions
Recommendations 1.2.1 to 1.2.9
## Why the committee made the recommendations
There is inconsistent evidence that digital and mobile health interventions may be effective for behaviour change. There is insufficient evidence to suggest that they can be used instead of other services.
Some services that include face-to-face contact are currently being delivered remotely (such as by phone or video calls) by healthcare professionals while social distancing measures are in place. It is important to keep these services available, whether face to face or remotely delivered, to ensure that digital exclusion does not increase health inequalities.
The committee agreed that it is important that existing services are not simply replaced by a digital or mobile health intervention that may be less effective. There were very few studies that compared digital and mobile health interventions with usual care, which made it difficult to make a reliable comparison. But they recognised that the interventions could be effective for some people. So, they recommended considering them as an adjunct to other individual behaviour change services.
During the COVID-19 pandemic, many face-to-face services are being delivered remotely, such as by phone or video calls. The committee discussed the possible impact of this on the commissioning process, including the possibility that some services may be delivered in this way for an unknown time period, or possibly permanently. Commissioners may need to be aware of this possibility, assess any effects on health and wellbeing or on inequalities, and mitigate this.
The committee discussed the importance of differences in local populations and assessing local needs when commissioning a digital or mobile health intervention. These needs would be routinely assessed by a Joint Strategic Needs Assessment.
They agreed that these new technologies should cater for groups that face inequalities in accessing remotely delivered interventions. For example, by making them accessible for people with learning disabilities, problems with hearing or vision, mobility requirements, neurodevelopmental disorders, cancer, cognitive impairment, or mental health problems.
The committee also agreed that expert sources would only list interventions that have been assessed for safety, effectiveness and data security. So they highlighted the need to check those sources before commissioning any new interventions.
Commissioning the development of new interventions can be costly. By collaborating, trusts, local authorities and developers may be able to reduce costs. Collaboration could also lead to coordinated implementation so the interventions can reach a wider audience. Normal procedures and policies for collaborative working should be followed before starting development and when adapting an existing intervention.
Expert testimony suggested that interventions are often developed independently by either healthcare, policy or digital professionals, not collaboratively. Multidisciplinary teams would ensure that interventions are as useful and relevant as possible.
There was no specific evidence on equalities, but the committee agreed that not everyone may have access to digital and mobile interventions. An equality impact assessment can inform how interventions affect different groups. So, they made a recommendation to ensure that any communication, access and cost issues identified are addressed.
The committee were aware that interventions can contain adverts, some of which may counter the aims of the intervention and harm users. But interventions with adverts may reduce costs, thereby allowing more people to access them. On balance, the committee concluded that the benefits of adverts reducing costs for users outweighed the potential harms of inappropriate adverts.
## How the recommendations might affect practice
Commissioners would use the NICE evidence framework and a needs assessment when choosing digital or mobile interventions.
Networks may be needed for collaboration between regions and people, which may need to be set up if they do not already exist. These networks will help to share costs.
Return to recommendations
# Using digital and mobile health interventions
Recommendations 1.3.1 to 1.3.4
## Why the committee made the recommendations
The committee could not conclude which interventions and for whom digital and mobile health interventions would be effective on their own because of the variable evidence. They also noted that most of the evidence was not compared against current practice. Therefore, the committee agreed that they would not recommend that these interventions replace existing evidence-based services. But they agreed that they may be more suitable for people who want a more discreet tool to help change their behaviour or who cannot get to face-to-face consultations.
During social distancing, many face-to-face services are being delivered remotely, such as by phone or video calls. Digital and mobile interventions can therefore still be used as an adjunct to these services. The committee anticipate there may be a drift from remotely delivered non-digital services to digital-only services. Healthcare professionals should be wary not to push digital and mobile health interventions onto people they are unsuitable for, because this may exacerbate inequalities in some groups.
Based on their experience, the committee agreed that behaviour change is complex. The person's preferences and goals have to be taken into account alongside other considerations, such as in the COM-B model (capability, opportunity and motivation), to identify what type of interventions may be the most beneficial. It is important to discuss motivations because wanting to set unhealthy goals could indicate an underlying cause that needs to be treated.
In addition, if a consultation is conducted remotely during social distancing, healthcare professionals can assess and discuss with the person how comfortable they are with using technology for this purpose. If they are not happy using technology for this, digital or mobile health interventions may not be suitable for them.
Because digital and mobile technology is a fast-moving field, the committee agreed that in any discussions it was best to focus on components and characteristics rather than on specific named individual interventions. This is because individual interventions may become unavailable or their content may change.
The committee agreed with expert testimony that said users, particularly people from vulnerable groups, need to be made aware of certain issues relating to digital and mobile health interventions and how they work. For example, they may use the person's personal data if the person does not opt out of this option. There are many interventions available and the quality varies.
The committee discussed that potential users may trust digital and mobile health interventions more than other (non-health-related) digital and mobile technologies and believe that they are safer to use. So they may not be as alert to data security issues as they would be normally. Therefore, the committee recommended using interventions from an expert source, to reduce the risk to the user.
Data usage is another point to be aware of and is likely to be higher for interventions that continually track activity than those that only use data when they are first downloaded.
They also agreed that using digital and mobile health interventions may lead to some people having limited interaction with healthcare professionals and that this may not be suitable for everyone, in particular those in vulnerable groups. These include people being trafficked and young people who are vulnerable to sexual exploitation. Both groups may be kept hidden by abusers, using these apps instead of a consultation that would expose the person to authorities.
The committee discussed evidence from expert testimony that digital and mobile health interventions can lead to some unintended consequences, specifically to unhealthy behaviours such as disordered eating, excessive exercise or health anxiety.
The committee agreed that it was important to make healthcare professionals aware of these risks to try to mitigate them if possible. This can be done during the consultation when digital and mobile health interventions are first discussed and followed up at future appointments.
## How the recommendations might affect practice
Extra time may be needed for healthcare professionals and users to discuss digital and mobile health interventions as an option for behaviour change. But after the initial consultation, because people use these interventions on their own, healthcare resources may be freed up for other activities. Use of these interventions may also lead to people not taking up other resource-intensive services. This may lead to cost savings. There may be increased costs due to adverse consequences of using the intervention, for example increased consultations related to increased anxiety.
Return to recommendations
# Diet and physical activity
Recommendations 1.4.1 to 1.4.3
## Why the committee made the recommendations
Evidence showed that digital and mobile health interventions may help people to reduce their weight, increase their fruit and vegetable intake and become more physically active. The committee were confident that some interventions may work and some people would benefit from using them. But the evidence was variable, so they were not able to say which interventions would work or in whom. Therefore, they recommended considering these interventions as an option alongside other individual behaviour change services.
During social distancing, many face-to-face services are being delivered remotely, such as by phone or video calls. Digital and mobile interventions can therefore still be used as an adjunct to these services.
The committee discussed evidence and heard from expert testimony that self-monitoring may help people lose weight and become more physically active. This is because it gives people the opportunity to review their own progress towards their diet and physical activity goals. (See also NICE's guideline on behaviour change: individual approaches).
Expert testimony also warned that self-monitoring may be harmful to people who have, or who have previously had, an eating disorder or exercise addiction because it may become excessive. (Self-monitoring is part of disordered eating and excessive exercise.) So the committee agreed that interventions without self-monitoring might be more appropriate for this group.
## How the recommendations might affect practice
Professionals need time and resources to check that potential users are not at risk of harmful behaviours by using these interventions, especially if they contain self-monitoring aspects.
More people using digital or mobile health interventions may mean fewer face-to-face appointments, making resources available for other services and saving costs.
Return to recommendations
# Smoking
Recommendations 1.5.1 to 1.5.3
## Why the committee made the recommendations
There was evidence that digital and mobile health interventions can help people to stop smoking, although it was unclear which interventions and in whom they would work. Most of the evidence did not compare against typical services for smoking cessation in the UK. On the basis of the evidence, the committee recommended considering these interventions as an option alongside other individual behaviour change services.
During social distancing, existing face-to-face services are being delivered remotely, such as by phone or video calls. Digital and mobile interventions can therefore still be used as an adjunct to these services.
The committee discussed the limited evidence that suggested that interventions using tailored text messages may be more effective than other digital and mobile health interventions. They used this and their expertise to agree a recommendation on the use of tailored messages. There was also evidence that using text messages as a supplement to usual care was cost effective.
The committee agreed that interventions developed or funded by the tobacco industry are not appropriate. This is in line with NICE's obligation under Article 5.3 of the World Health Organization Framework Convention on Tobacco Control to protect public health policies from the commercial and other vested interests of the tobacco industry.
## How the recommendations might affect practice
More people using digital or mobile health interventions may mean fewer face-to-face appointments, making resources available for other services and saving costs.
Return to recommendations
# Alcohol use
Recommendations 1.6.1 to 1.6.3
## Why the committee made the recommendations
There was limited evidence that digital and mobile health interventions can help people reduce their alcohol intake. But the committee agreed that some interventions may work and for some people, so they recommended considering them as an option alongside other individual behaviour change services.
During social distancing, existing face-to-face services are being delivered remotely, such as by phone or video calls. Digital and mobile interventions can therefore still be used as an adjunct to these services.
Some evidence showed that presenting people who drink at hazardous levels with details of how much they consume may help to reduce their drinking. Effective components may be different from person to person based on their lifestyle and health.
Limited evidence showed that interventions that people need to interact with several times were more effective than one-off interventions – although a one-off intervention is more effective than doing nothing. Because the committee did not want anyone to be excluded from the advice provided, they made a recommendation to reflect this.
## How the recommendations might affect practice
More people using digital or mobile health interventions may mean fewer face-to-face appointments, making resources available for other services and saving costs.
Return to recommendations
# Unsafe sexual behaviour
Recommendations 1.7.1 to 1.7.3
## Why the committee made the recommendations
The evidence identified covered several populations including adolescents, men who have sex with men, people with HIV and university students. But because it was very limited, the committee agreed that they could not make individual recommendations for each of these groups. Most of the evidence related to online brief interventions (for example, a 15-minute interactive condom use intervention). There was limited evidence that these interventions showed some effectiveness in helping people change their sexual behaviour.
Limited evidence showed that interactive videos can help people change their sexual behaviour. These are scripted scenarios that need the person to take part in the story. Dramatisations, with the person just watching the story, are also effective. The committee agreed that people putting themselves in these 'virtual' situations allows them to experience difficult sexual situations and develop healthy response mechanisms that can be applied in real life. The committee also agreed that this approach is unlikely to be as effective for changing other behaviours because it works well for sexual behaviour in particular.
The committee were aware that some interventions may contain sexually explicit content. They were also aware that some people should not or may not want to view this material. They agreed that raising awareness of this issue would help people choose interventions that are appropriate for them.
The committee agreed that they would only recommend that people consider these interventions, and only as an option alongside other individual behaviour change services, for people who are considered to be Gillick competent (see the Department for Health and Social care's reference guide to consent for examination or treatment for information on Gillick competence).
During social distancing, existing face-to-face services are being delivered remotely, such as by phone or video calls. Digital and mobile interventions can therefore still be used as an adjunct to these services.
## How the recommendations might affect practice
More people using digital or mobile health interventions may mean fewer face-to-face appointments, making resources available for other services and saving costs.
Return to recommendations
# Recommendations for research
## Why the committee made the recommendations
There is limited evidence on why and when people engage with and disengage from digital and mobile health interventions. This is important because initial engagement is lower in people with lower socioeconomic status, and there may be other members of the population not currently visible to services.
The committee agreed that research into ways that healthcare professionals can identify and encourage people to engage with and continue using digital and mobile health interventions is needed (see the recommendation for research on engaging people with digital and mobile health interventions).
The committee was aware that specific components or characteristics may be more effective at changing or targeting specific behaviours. Evidence on this is complex, and digital and mobile health interventions is a rapidly changing field. The committee agreed that research is needed to evaluate the effectiveness of specific components and characteristics (see the recommendation for research on effective components of behaviour change interventions).
There is limited information on the effectiveness of digital and mobile health interventions for different socioeconomic groups, people with disabilities or underserved populations. The committee discussed the potential difficulties with recruitment and possible additional costs associated with reaching underserved populations. They agreed that more information on this topic would help to tackle health inequalities (see the recommendation for research on effects of behaviour change interventions on low socioeconomic and other underserved groups).
The committee agreed that, as the field develops, it will be helpful to know if there are specific groups that may get as much benefit from digital and mobile health interventions used alone as they would from existing services. This question is more significant in light of the current context of the COVID-19 pandemic because the committee expect more people to consider using remote interventions (see the recommendation for research on populations that will benefit most from digital and mobile health interventions).
No published evidence was found on adverse effects or potential harms for any of the behaviour change areas considered. The committee discussed this and heard from expert testimony about potential harms related to digital and mobile health interventions. The committee noted that more published research is needed on harms, adverse effects or unintended consequences (see the recommendation for research on harms of behaviour change using digital and mobile health interventions).# Context
Digital and mobile health interventions, such as apps, online programmes, websites, text messages and wearable devices, are widely used. Using these technologies may help people change their behaviour, which in turn, can help improve their health.
Addressing health-related behaviours such as those relating to physical activity, smoking and alcohol intake can help reduce the risk of developing chronic conditions such as diabetes, cardiovascular diseases, respiratory conditions, cancer and liver disease. Digital and mobile interventions may also help people to self-manage, self-monitor or improve these behaviours and improve their mental, social and emotional wellbeing.
This guideline covers everyone, including children and young people (and their families or carers), who would benefit from changing current unhealthy behaviours. It includes interventions that are delivered by the technology and do not need input from healthcare professionals.
Digital and mobile technology is a fast-moving field, so the guideline did not look at specific digital and mobile health interventions, as these may change or are likely to be updated and superseded. Instead, it assesses the components and characteristics of interventions.
The guideline also doesn't cover people who have already changed their behaviours and want to maintain the change.
This guideline was developed before the COVID-19 pandemic. It is uncertain how practice and consultations will be carried out after the pandemic has ended but it may result in more people using remote consultations. We have highlighted likely impacts on the guideline in the rationale sections, but we have not changed any recommendations as a result of the pandemic or its possible effects on future practice.
The behaviours included in this guideline align with those in NICE's guideline on behaviour change: individual approaches.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity) and safeguarding.\n\n# Developing digital and mobile health interventions\n\nThese recommendations support adopting healthy behaviours in the health and lifestyle areas covered in this guideline (eating more healthily, becoming more active, stopping smoking, reducing alcohol intake, practising safer sex).\n\nRefer to the NICE evidence standards framework for digital technologies when developing and evaluating digital and mobile health interventions for behaviour change.\n\nFollow the advisory frameworks for assessment when developing and evaluating digital and mobile health interventions for behaviour change (such as Public Health England's guidance on evaluating digital health products, NHS Digital's digital assessment questions and the Department of Health and Social Care's code of conduct for data-driven health and care technology).\n\nWhen designing digital and mobile health interventions, use evidence-based behaviour change techniques that help people start and maintain changes. These include: goals and planning, feedback and monitoring, and social support (see NICE's guideline on behaviour change: individual approaches).\n\nConsider designing interventions that allow the user to tailor goals to their own needs.\n\nDo not develop interventions or components that allow people to set unhealthy or dangerous goals, for example goals that would lead to the person being underweight.\n\nDesign interventions so they have the flexibility to be:\n\nscaled up\n\ncustomised for local needs and use.\n\nMake information available about:\n\nhow users can check and set preferences for how their personal information and data may be used\n\nwhen the intervention is likely to use mobile data, and how much mobile data it is likely to use\n\nany additional costs\n\nterms and conditions.\n\nWhen developing digital and mobile health interventions, involve a wide range of stakeholders, including potential users, as early as possible and throughout development to:\n\nDevelop and review the content, structure, interface and flow of the intervention.\n\nIdentify the best digital platforms for the target population.\n\nIdentify and address any aspects of the intervention that may unintentionally increase inequity and digital exclusion.\n\nDiscuss and ensure that users understand who the intervention is for, which behaviour it is trying to change, its aims, any possible harms, the time needed to establish behaviour change and how frequently users are likely to interact with the intervention.\n\nUse feedback from testing and after releasing the intervention to continually improve the intervention.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on developing digital and mobile health interventions\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: smoking behaviour, evidence review B: alcohol, evidence review C: diet, physical activity and sedentary behaviour and evidence review D: sexual health behaviour.\n\nLoading. Please wait.\n\n# Commissioning digital and mobile health interventions\n\nThese recommendations support adopting healthy behaviours in the health and lifestyle areas covered in this guideline (eating more healthily, becoming more active, stopping smoking, reducing alcohol intake, practising safer sex).\n\nConsider digital and mobile health interventions as options for behaviour change.\n\nIf commissioning digital and mobile health interventions, do this as a supplement to existing services, not as a replacement.\n\nAssess whether specific digital and mobile health interventions could meet some of the needs of the local population by using a needs assessment, including the need to address digital exclusion.\n\nCheck expert sources (such as the NHS apps library) for any existing evidence-based digital and mobile health interventions that can meet local needs. Do this before commissioning the development of a new one.\n\nSelect interventions that meet current frameworks, regulatory advice and evidence standards for the development and use of digital and mobile health interventions (see the NICE evidence standards framework for digital technologies).\n\nIf a new digital and mobile health intervention is needed, assess whether a local-level multidisciplinary collaboration, or partnerships with other health and care organisations, would be appropriate to share development costs.\n\nWhen commissioning digital and mobile health interventions, take into account equality of access as part of an equality impact assessment. For example:\n\nanything that might limit usability of the intervention (such as literacy, sensory impairments and language barriers)\n\npotential related costs for users (such as cost of apps and data usage)\n\navailability of the necessary hardware and operating system\n\naccess to the internet, phone signal and data networks (for example in rural communities, closed institutions and detention settings)\n\nprotected characteristics and levels of deprivation.\n\nBe aware that interventions without adverts are preferable, but interventions with adverts may help reduce costs for users.\n\nDo not commission digital and mobile health interventions that are funded or developed by the tobacco industry.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on commissioning digital and mobile health interventions\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: smoking behaviour, evidence review B: alcohol, evidence review C: diet, physical activity and sedentary behaviour and evidence review D: sexual health behaviour.\n\nLoading. Please wait.\n\n# Using digital and mobile health interventions\n\nThese recommendations support adopting healthy behaviours in the health and lifestyle areas covered in this guideline (eating more healthily, becoming more active, stopping smoking, reducing alcohol intake, practising safer sex). These are to support healthcare professionals.\n\nConsider digital and mobile health interventions as an option for behaviour change as an adjunct to existing services. Be aware that their effectiveness is variable.\n\nWhen discussing the use of a digital or mobile health intervention with the person, take into account:\n\ntheir preferences and behaviour change goals, and interventions that allow tailoring towards these\n\ntheir capability, opportunity and motivation for change\n\ntheir digital, health and reading literacy\n\nthe digital platforms available\n\nthe aim of the intervention\n\nhow frequently and intensely they are willing to use interventions\n\nthat some interventions may not have evidence of effectiveness\n\nhow it would fit into their current care pathway.\n\nAdvise people who may use a digital and mobile health intervention to:\n\nuse one from an expert source if available (such as the NHS apps library) because it is likely to have been assessed for safety, effectiveness and data security\n\ncheck and set preferences for how their personal information and data may be used\n\nbe aware of any possible extra costs\n\ncheck they are willing and able to pay any associated costs\n\nbe aware that the intervention may use mobile data after it is downloaded\n\nseek advice from a healthcare professional if they have health concerns while using the intervention\n\nread the terms and conditions.\n\nWhen advising on the use of a digital and mobile health intervention, take into account whether the content is appropriate for the user and any possible adverse effects. For example, whether the intervention could:\n\nlead to people self-managing with digital interventions when their behaviour could be more effectively modified with existing health or social care services that involve clinical expertise, face-to-face interaction or treatment\n\nprevent vulnerable people from accessing face-to-face services and interventions\n\nhave components that could encourage the person to adopt unhealthy behaviours, such as excessive exercise or disordered eating\n\nhave a negative impact on some people's mental health, possibly from using social media components\n\nincrease anxiety about health and lead people to consult healthcare professionals more often.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see rationale and impact section on using digital and mobile health interventions\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: smoking behaviour, evidence review B: alcohol, evidence review C: diet, physical activity and sedentary behaviour and evidence review D: sexual health behaviour.\n\nLoading. Please wait.\n\n# Diet and physical activity\n\nConsider digital and mobile health interventions as an option for people who would benefit from improving their diet or increasing their physical activity levels as an adjunct to existing services. Be aware that their effectiveness is variable.\n\nAdvise people to use digital and mobile health interventions that include self-monitoring, such as recording by activity trackers, or food or physical activity diaries. This can help the person to review their own progress towards their diet or physical activity goals.\n\nIf you are aware that the person is at risk of developing or resuming an eating disorder or another unhealthy behaviour such as excessive exercise, consider interventions that do not include self-monitoring.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on diet and physical activity\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: diet, physical activity and sedentary behaviour.\n\nLoading. Please wait.\n\n# Smoking\n\nConsider digital and mobile health interventions as an option to help people stop smoking as an adjunct to existing services. Be aware that their effectiveness is variable.\n\nAdvise the person who wants to stop smoking using a digital or mobile health intervention that text message-based interventions with tailored messages may be more effective than other digital and mobile health interventions.\n\nDo not offer digital and mobile health interventions that are known to be funded or developed by the tobacco industry.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on smoking\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: smoking behaviour.\n\nLoading. Please wait.\n\n# Alcohol use\n\nConsider digital and mobile health interventions as an option to reduce alcohol intake as an adjunct to existing services. Be aware that their effectiveness is variable.\n\nAdvise the person that some interventions may include particular components that suit them better and reduce their alcohol intake more than other components. For example, a component that compares the person's intake with that of their peers (a personalised normative feedback approach).\n\nAdvise the person that interventions they interact with multiple times may be better than a one-off intervention, but a one-off intervention is better than no intervention at all.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on alcohol use\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B: alcohol.\n\nLoading. Please wait.\n\n# Unsafe sexual behaviour\n\nConsider online brief interventions as an option to help reduce unsafe sexual behaviour as an adjunct to existing services. Be aware that their effectiveness is variable.\n\nIf advising people to use online brief interventions, consider ones that include videos with set choice points, scripted scenarios or dramatisation.\n\nWhen advising on the use of online brief interventions, tell the person that some may have sexually explicit content.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on unsafe sexual behaviour\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: sexual health behaviour.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a particular way for this guideline. For other definitions see the NICE glossary or, for public health and social care terms, the Think Local, Act Personal Care and Support Jargon Buster.\n\n## Choice points\n\nIn an interactive scripted scenario, choice points give the person using the intervention options on what the character should do next at key moments. This models how the person would react in a similar situation in real life, and the consequences of their actions. The intervention can give feedback on how choosing differently may help them change their behaviour.\n\n## Characteristics\n\nA characteristic is an attribute that applies to the whole intervention. For example, how often it will be performed, or if it is specific for a group with a certain condition.\n\n## Components\n\nA component is one part of an intervention. For example, a diary that people can use to track their eating habits. Interventions can be made up of many components.\n\n## Digital and mobile health interventions\n\nDigital health interventions are delivered through: hardware and electronic devices, such as smartwatches; software, such as computer programs or apps; and websites. Mobile health interventions can be delivered through phones, for example by texts, apps or interactive voice response calls. These technologies can deliver interventions independently from healthcare professionals, or healthcare professionals can use them to deliver interventions remotely. This guideline covers digital and mobile health interventions delivered by the technology itself and not by healthcare professionals using technology to deliver interventions.\n\n## Digital exclusion\n\nDigital exclusion describes circumstances in which people are unable or do not want to use digital services. This may be because of a lack of digital skills, confidence, motivation or internet access, or the services may not be accessible. See the NHS information on digital exclusion.\n\n## Digital platforms\n\nExamples include apps, computer programs, websites, smartwatches, interactive voice response systems, or texts.\n\n## Disordered eating\n\nDisordered eating describes a range of irregular eating behaviours. These can include symptoms that reflect many but not all of the symptoms of eating disorders, such as anorexia nervosa, bulimia nervosa and binge eating disorder. Examples of disordered eating include fasting or chronic restrained eating, skipping meals, binge eating, self-induced vomiting, restrictive dieting, and laxative or diuretic misuse.\n\n(For further information on eating disorders refer to the NHS information on eating disorders.)\n\n## Excessive exercise\n\nExercising more than is recommended if it is detrimental to the person's mental, social or physical wellbeing.\n\n## Scaled up\n\nTechnology needs to be designed so it has the ability to cope with an increasing number of people or organisations using it across different parts of the country. The digital architecture must be able to support this. How the technology is supported and regulated is different when more people are using it. An intervention that supports few people in one region is a smaller scale intervention than one that supports more people across multiple regions.", 'Recommendations for research ': 'The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Engaging people with digital and mobile health interventions\n\nHow can providers and healthcare professionals identify groups that do not initially engage, or do not stay engaged, with digital and mobile health behaviour change interventions?\n\n## Effective components of behaviour change interventions\n\nWhat components and characteristics of digital and mobile health behaviour change interventions are most effective, separately and in combination, to achieve behaviour change?\n\n## Effects of behaviour change interventions on low socioeconomic and other underserved groups\n\nWhat is the effectiveness and cost effectiveness of digital and mobile health behaviour change interventions in low socioeconomic and other underserved groups?\n\n## Populations that will benefit most from digital and mobile health interventions\n\nAre digital and mobile health behaviour change interventions as effective as face-to-face, standard care, or combination approaches for some populations?\n\n## Harms of behaviour change using digital and mobile health interventions\n\nWhat are the harms and adverse effects associated with different digital and mobile health behaviour change interventions?\n\nFor a short explanation of why the committee made the recommendations for research, see the rationale on recommendations for research\xa0.\n\nFull details for all of the recommendations for research for this guideline are in evidence review\xa0A: smoking behaviour.\n\nLoading. Please wait.', 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice.\n\nSections on developing, commissioning, and using interventions are applicable to the behaviours covered in this guideline.\n\n# Developing digital and mobile health interventions\n\nRecommendations 1.1.1 to 1.1.9\n\n## Why the committee made the recommendations\n\nThe committee discussed the lack of evidence surrounding which components and characteristics of interventions would lead to healthy behaviour change in different populations. This is common to all behaviours and is why the recommendations cannot be more specific. The committee made recommendations for research to fill this gap in evidence.\n\nThe committee noted that digital and mobile health interventions is a rapidly changing and developing area. As such, they agreed it was important to develop them in line with national supporting frameworks such as the NICE evidence standards framework for digital technologies to ensure they are as effective as possible. In addition, the committee agreed that the government digital service standard could be followed when creating interventions for public services.\n\nThe committee discussed the views from expert testimony that said many developers of these interventions do not have a background in healthcare. This is another reason why the committee wanted to stress the importance of using these advisory frameworks, as well as NICE frameworks.\n\nIn the committee's experience regarding approaches to behaviour change in general, the specific behaviour change techniques they recommended have been shown to be effective. But based on the evidence, the committee were unable to draw firm conclusions about how effective these techniques are when used with digital and mobile health interventions. However, they agreed that interventions with the listed behaviour change techniques are more likely to be effective than those without them. The conclusions of the committee also agreed with those in the NICE guideline on behaviour change: individual approaches, which notes that behaviour change interventions should include behaviour change techniques including goals and planning, feedback and monitoring, and social support.\n\nThe committee discussed and agreed that it is important for those developing interventions to consider their possible future use, which may be on a wide scale or much more localised. They agreed that it was important for interventions to be designed so that they can be scaled up and can be customised for local needs.\n\nThe committee agreed that people are more likely to change their behaviour using interventions that allow them to tailor goals to their needs. The evidence showed that interventions have variable effectiveness, and it is not clear which interventions result in positive behaviour change or in whom. So the committee agreed that developers should include tailored goals in interventions but should be transparent about how the interventions tailor more complex goals to people's needs.\n\nNICE looked for evidence on adverse effects but did not find any. Based on expert testimony and their experience, the committee discussed interventions that may allow people to set goals that may be unhealthy for them. They were particularly concerned about the possibility of setting goals that would lead to the person becoming underweight, and the potential for this to cause disordered eating, exacerbate eating disorders or cause relapse. So they emphasised that interventions should not be designed to allow people to do this.\n\nThe committee were aware that developers have a responsibility to make information about their interventions clear. This allows people to make informed decisions on the interventions they choose. Some differences, such as ongoing data use after the intervention has been downloaded, are not obvious and may lead to unwanted costs for the user.\n\nBased on limited evidence and expert testimony the committee understood that it can be challenging to get people to use these interventions on an ongoing basis. They agreed that more collaboration between developers, stakeholders and potential users would be likely to produce more useful and engaging interventions.\n\nFor example, if people with physical disabilities and sensory impairments or children and young people are given the opportunity to contribute, they are more likely to use the interventions, and the interventions are more likely to be effective. Some users may say how frequently they would prefer to use the intervention. For example, it could be a one-off intervention, multiple brief interventions or interventions that people interact with multiple times.\n\nOwing to the impact of COVID-19, development might be conducted remotely using digital technology. This could mean that people who are not digitally literate may not be well represented. Developers should make efforts to include these people if possible, for example in design or testing.\n\nThe committee discussed expert testimony and agreed that interventions may be used differently after they have been released. This may mean components that worked well in development may work differently in real life. They agreed it is important to gather feedback after release to improve the intervention based on real world use.\n\n## How the recommendations might affect practice\n\nDesigning interventions that can be scaled up to be used by many people may help reach more people at a lower average cost. Wider implementation would allow local usage patterns to be monitored and services to be standardised between regions.\n\nDevelopers will need to work with topic experts to develop content that meets evidence standards. This may mean sharing development costs with other organisations, which would help to reduce the resource impact.\n\nReturn to recommendations\n\n# Commissioning digital and mobile health interventions\n\nRecommendations 1.2.1 to 1.2.9\n\n## Why the committee made the recommendations\n\nThere is inconsistent evidence that digital and mobile health interventions may be effective for behaviour change. There is insufficient evidence to suggest that they can be used instead of other services.\n\nSome services that include face-to-face contact are currently being delivered remotely (such as by phone or video calls) by healthcare professionals while social distancing measures are in place. It is important to keep these services available, whether face to face or remotely delivered, to ensure that digital exclusion does not increase health inequalities.\n\nThe committee agreed that it is important that existing services are not simply replaced by a digital or mobile health intervention that may be less effective. There were very few studies that compared digital and mobile health interventions with usual care, which made it difficult to make a reliable comparison. But they recognised that the interventions could be effective for some people. So, they recommended considering them as an adjunct to other individual behaviour change services.\n\nDuring the COVID-19 pandemic, many face-to-face services are being delivered remotely, such as by phone or video calls. The committee discussed the possible impact of this on the commissioning process, including the possibility that some services may be delivered in this way for an unknown time period, or possibly permanently. Commissioners may need to be aware of this possibility, assess any effects on health and wellbeing or on inequalities, and mitigate this.\n\nThe committee discussed the importance of differences in local populations and assessing local needs when commissioning a digital or mobile health intervention. These needs would be routinely assessed by a Joint Strategic Needs Assessment.\n\nThey agreed that these new technologies should cater for groups that face inequalities in accessing remotely delivered interventions. For example, by making them accessible for people with learning disabilities, problems with hearing or vision, mobility requirements, neurodevelopmental disorders, cancer, cognitive impairment, or mental health problems.\n\nThe committee also agreed that expert sources would only list interventions that have been assessed for safety, effectiveness and data security. So they highlighted the need to check those sources before commissioning any new interventions.\n\nCommissioning the development of new interventions can be costly. By collaborating, trusts, local authorities and developers may be able to reduce costs. Collaboration could also lead to coordinated implementation so the interventions can reach a wider audience. Normal procedures and policies for collaborative working should be followed before starting development and when adapting an existing intervention.\n\nExpert testimony suggested that interventions are often developed independently by either healthcare, policy or digital professionals, not collaboratively. Multidisciplinary teams would ensure that interventions are as useful and relevant as possible.\n\nThere was no specific evidence on equalities, but the committee agreed that not everyone may have access to digital and mobile interventions. An equality impact assessment can inform how interventions affect different groups. So, they made a recommendation to ensure that any communication, access and cost issues identified are addressed.\n\nThe committee were aware that interventions can contain adverts, some of which may counter the aims of the intervention and harm users. But interventions with adverts may reduce costs, thereby allowing more people to access them. On balance, the committee concluded that the benefits of adverts reducing costs for users outweighed the potential harms of inappropriate adverts.\n\n## How the recommendations might affect practice\n\nCommissioners would use the NICE evidence framework and a needs assessment when choosing digital or mobile interventions.\n\nNetworks may be needed for collaboration between regions and people, which may need to be set up if they do not already exist. These networks will help to share costs.\n\nReturn to recommendations\n\n# Using digital and mobile health interventions\n\nRecommendations 1.3.1 to 1.3.4\n\n## Why the committee made the recommendations\n\nThe committee could not conclude which interventions and for whom digital and mobile health interventions would be effective on their own because of the variable evidence. They also noted that most of the evidence was not compared against current practice. Therefore, the committee agreed that they would not recommend that these interventions replace existing evidence-based services. But they agreed that they may be more suitable for people who want a more discreet tool to help change their behaviour or who cannot get to face-to-face consultations.\n\nDuring social distancing, many face-to-face services are being delivered remotely, such as by phone or video calls. Digital and mobile interventions can therefore still be used as an adjunct to these services. The committee anticipate there may be a drift from remotely delivered non-digital services to digital-only services. Healthcare professionals should be wary not to push digital and mobile health interventions onto people they are unsuitable for, because this may exacerbate inequalities in some groups.\n\nBased on their experience, the committee agreed that behaviour change is complex. The person's preferences and goals have to be taken into account alongside other considerations, such as in the COM-B model (capability, opportunity and motivation), to identify what type of interventions may be the most beneficial. It is important to discuss motivations because wanting to set unhealthy goals could indicate an underlying cause that needs to be treated.\n\nIn addition, if a consultation is conducted remotely during social distancing, healthcare professionals can assess and discuss with the person how comfortable they are with using technology for this purpose. If they are not happy using technology for this, digital or mobile health interventions may not be suitable for them.\n\nBecause digital and mobile technology is a fast-moving field, the committee agreed that in any discussions it was best to focus on components and characteristics rather than on specific named individual interventions. This is because individual interventions may become unavailable or their content may change.\n\nThe committee agreed with expert testimony that said users, particularly people from vulnerable groups, need to be made aware of certain issues relating to digital and mobile health interventions and how they work. For example, they may use the person's personal data if the person does not opt out of this option. There are many interventions available and the quality varies.\n\nThe committee discussed that potential users may trust digital and mobile health interventions more than other (non-health-related) digital and mobile technologies and believe that they are safer to use. So they may not be as alert to data security issues as they would be normally. Therefore, the committee recommended using interventions from an expert source, to reduce the risk to the user.\n\nData usage is another point to be aware of and is likely to be higher for interventions that continually track activity than those that only use data when they are first downloaded.\n\nThey also agreed that using digital and mobile health interventions may lead to some people having limited interaction with healthcare professionals and that this may not be suitable for everyone, in particular those in vulnerable groups. These include people being trafficked and young people who are vulnerable to sexual exploitation. Both groups may be kept hidden by abusers, using these apps instead of a consultation that would expose the person to authorities.\n\nThe committee discussed evidence from expert testimony that digital and mobile health interventions can lead to some unintended consequences, specifically to unhealthy behaviours such as disordered eating, excessive exercise or health anxiety.\n\nThe committee agreed that it was important to make healthcare professionals aware of these risks to try to mitigate them if possible. This can be done during the consultation when digital and mobile health interventions are first discussed and followed up at future appointments.\n\n## How the recommendations might affect practice\n\nExtra time may be needed for healthcare professionals and users to discuss digital and mobile health interventions as an option for behaviour change. But after the initial consultation, because people use these interventions on their own, healthcare resources may be freed up for other activities. Use of these interventions may also lead to people not taking up other resource-intensive services. This may lead to cost savings. There may be increased costs due to adverse consequences of using the intervention, for example increased consultations related to increased anxiety.\n\nReturn to recommendations\n\n# Diet and physical activity\n\nRecommendations 1.4.1 to 1.4.3\n\n## Why the committee made the recommendations\n\nEvidence showed that digital and mobile health interventions may help people to reduce their weight, increase their fruit and vegetable intake and become more physically active. The committee were confident that some interventions may work and some people would benefit from using them. But the evidence was variable, so they were not able to say which interventions would work or in whom. Therefore, they recommended considering these interventions as an option alongside other individual behaviour change services.\n\nDuring social distancing, many face-to-face services are being delivered remotely, such as by phone or video calls. Digital and mobile interventions can therefore still be used as an adjunct to these services.\n\nThe committee discussed evidence and heard from expert testimony that self-monitoring may help people lose weight and become more physically active. This is because it gives people the opportunity to review their own progress towards their diet and physical activity goals. (See also NICE's guideline on behaviour change: individual approaches).\n\nExpert testimony also warned that self-monitoring may be harmful to people who have, or who have previously had, an eating disorder or exercise addiction because it may become excessive. (Self-monitoring is part of disordered eating and excessive exercise.) So the committee agreed that interventions without self-monitoring might be more appropriate for this group.\n\n## How the recommendations might affect practice\n\nProfessionals need time and resources to check that potential users are not at risk of harmful behaviours by using these interventions, especially if they contain self-monitoring aspects.\n\nMore people using digital or mobile health interventions may mean fewer face-to-face appointments, making resources available for other services and saving costs.\n\nReturn to recommendations\n\n# Smoking\n\nRecommendations 1.5.1 to 1.5.3\n\n## Why the committee made the recommendations\n\nThere was evidence that digital and mobile health interventions can help people to stop smoking, although it was unclear which interventions and in whom they would work. Most of the evidence did not compare against typical services for smoking cessation in the UK. On the basis of the evidence, the committee recommended considering these interventions as an option alongside other individual behaviour change services.\n\nDuring social distancing, existing face-to-face services are being delivered remotely, such as by phone or video calls. Digital and mobile interventions can therefore still be used as an adjunct to these services.\n\nThe committee discussed the limited evidence that suggested that interventions using tailored text messages may be more effective than other digital and mobile health interventions. They used this and their expertise to agree a recommendation on the use of tailored messages. There was also evidence that using text messages as a supplement to usual care was cost effective.\n\nThe committee agreed that interventions developed or funded by the tobacco industry are not appropriate. This is in line with NICE's obligation under Article 5.3 of the World Health Organization Framework Convention on Tobacco Control to protect public health policies from the commercial and other vested interests of the tobacco industry.\n\n## How the recommendations might affect practice\n\nMore people using digital or mobile health interventions may mean fewer face-to-face appointments, making resources available for other services and saving costs.\n\nReturn to recommendations\n\n# Alcohol use\n\nRecommendations 1.6.1 to 1.6.3\n\n## Why the committee made the recommendations\n\nThere was limited evidence that digital and mobile health interventions can help people reduce their alcohol intake. But the committee agreed that some interventions may work and for some people, so they recommended considering them as an option alongside other individual behaviour change services.\n\nDuring social distancing, existing face-to-face services are being delivered remotely, such as by phone or video calls. Digital and mobile interventions can therefore still be used as an adjunct to these services.\n\nSome evidence showed that presenting people who drink at hazardous levels with details of how much they consume may help to reduce their drinking. Effective components may be different from person to person based on their lifestyle and health.\n\nLimited evidence showed that interventions that people need to interact with several times were more effective than one-off interventions – although a one-off intervention is more effective than doing nothing. Because the committee did not want anyone to be excluded from the advice provided, they made a recommendation to reflect this.\n\n## How the recommendations might affect practice\n\nMore people using digital or mobile health interventions may mean fewer face-to-face appointments, making resources available for other services and saving costs.\n\nReturn to recommendations\n\n# Unsafe sexual behaviour\n\nRecommendations 1.7.1 to 1.7.3\n\n## Why the committee made the recommendations\n\nThe evidence identified covered several populations including adolescents, men who have sex with men, people with HIV and university students. But because it was very limited, the committee agreed that they could not make individual recommendations for each of these groups. Most of the evidence related to online brief interventions (for example, a 15-minute interactive condom use intervention). There was limited evidence that these interventions showed some effectiveness in helping people change their sexual behaviour.\n\nLimited evidence showed that interactive videos can help people change their sexual behaviour. These are scripted scenarios that need the person to take part in the story. Dramatisations, with the person just watching the story, are also effective. The committee agreed that people putting themselves in these 'virtual' situations allows them to experience difficult sexual situations and develop healthy response mechanisms that can be applied in real life. The committee also agreed that this approach is unlikely to be as effective for changing other behaviours because it works well for sexual behaviour in particular.\n\nThe committee were aware that some interventions may contain sexually explicit content. They were also aware that some people should not or may not want to view this material. They agreed that raising awareness of this issue would help people choose interventions that are appropriate for them.\n\nThe committee agreed that they would only recommend that people consider these interventions, and only as an option alongside other individual behaviour change services, for people who are considered to be Gillick competent (see the Department for Health and Social care's reference guide to consent for examination or treatment for information on Gillick competence).\n\nDuring social distancing, existing face-to-face services are being delivered remotely, such as by phone or video calls. Digital and mobile interventions can therefore still be used as an adjunct to these services.\n\n## How the recommendations might affect practice\n\nMore people using digital or mobile health interventions may mean fewer face-to-face appointments, making resources available for other services and saving costs.\n\nReturn to recommendations\n\n# Recommendations for research\n\n## Why the committee made the recommendations\n\nThere is limited evidence on why and when people engage with and disengage from digital and mobile health interventions. This is important because initial engagement is lower in people with lower socioeconomic status, and there may be other members of the population not currently visible to services.\n\nThe committee agreed that research into ways that healthcare professionals can identify and encourage people to engage with and continue using digital and mobile health interventions is needed (see the recommendation for research on engaging people with digital and mobile health interventions).\n\nThe committee was aware that specific components or characteristics may be more effective at changing or targeting specific behaviours. Evidence on this is complex, and digital and mobile health interventions is a rapidly changing field. The committee agreed that research is needed to evaluate the effectiveness of specific components and characteristics (see the recommendation for research on effective components of behaviour change interventions).\n\nThere is limited information on the effectiveness of digital and mobile health interventions for different socioeconomic groups, people with disabilities or underserved populations. The committee discussed the potential difficulties with recruitment and possible additional costs associated with reaching underserved populations. They agreed that more information on this topic would help to tackle health inequalities (see the recommendation for research on effects of behaviour change interventions on low socioeconomic and other underserved groups).\n\nThe committee agreed that, as the field develops, it will be helpful to know if there are specific groups that may get as much benefit from digital and mobile health interventions used alone as they would from existing services. This question is more significant in light of the current context of the COVID-19 pandemic because the committee expect more people to consider using remote interventions (see the recommendation for research on populations that will benefit most from digital and mobile health interventions).\n\nNo published evidence was found on adverse effects or potential harms for any of the behaviour change areas considered. The committee discussed this and heard from expert testimony about potential harms related to digital and mobile health interventions. The committee noted that more published research is needed on harms, adverse effects or unintended consequences (see the recommendation for research on harms of behaviour change using digital and mobile health interventions).", 'Context': "Digital and mobile health interventions, such as apps, online programmes, websites, text messages and wearable devices, are widely used. Using these technologies may help people change their behaviour, which in turn, can help improve their health.\n\nAddressing health-related behaviours such as those relating to physical activity, smoking and alcohol intake can help reduce the risk of developing chronic conditions such as diabetes, cardiovascular diseases, respiratory conditions, cancer and liver disease. Digital and mobile interventions may also help people to self-manage, self-monitor or improve these behaviours and improve their mental, social and emotional wellbeing.\n\nThis guideline covers everyone, including children and young people (and their families or carers), who would benefit from changing current unhealthy behaviours. It includes interventions that are delivered by the technology and do not need input from healthcare professionals.\n\nDigital and mobile technology is a fast-moving field, so the guideline did not look at specific digital and mobile health interventions, as these may change or are likely to be updated and superseded. Instead, it assesses the components and characteristics of interventions.\n\nThe guideline also doesn't cover people who have already changed their behaviours and want to maintain the change.\n\nThis guideline was developed before the COVID-19 pandemic. It is uncertain how practice and consultations will be carried out after the pandemic has ended but it may result in more people using remote consultations. We have highlighted likely impacts on the guideline in the rationale sections, but we have not changed any recommendations as a result of the pandemic or its possible effects on future practice.\n\nThe behaviours included in this guideline align with those in NICE's guideline on behaviour change: individual approaches."}
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https://www.nice.org.uk/guidance/ng183
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This guideline covers interventions that use a digital or mobile platform to help people eat more healthily, become more active, stop smoking, reduce their alcohol intake or practise safer sex. The interventions include those delivered by text message, apps, wearable devices or the internet. The guideline only includes those that are delivered by the technology itself and not by healthcare professionals using technology to deliver interventions.
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9bc08e39587e20b8a1d17e485e784743a791c490
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nice
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Pembrolizumab with axitinib for untreated advanced renal cell carcinoma
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Pembrolizumab with axitinib for untreated advanced renal cell carcinoma
Evidence-based recommendations on pembrolizumab (Keytruda) with axitinib (Inlyta) for untreated advanced renal cell carcinoma in adults.
# Recommendations
Pembrolizumab with axitinib is not recommended, within its marketing authorisation, for untreated advanced renal cell carcinoma in adults.
This recommendation is not intended to affect treatment with pembrolizumab plus axitinib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Current treatment for untreated advanced renal cell carcinoma includes pazopanib, tivozanib or sunitinib. Also, cabozantinib is recommended for patients with intermediate or poor-risk cancer as defined by the International Metastatic Renal Cell Carcinoma Database Consortium. Nivolumab with ipilimumab and avelumab with axitinib are available through the Cancer Drugs Fund. Because they are not established practice, they cannot be comparators in this appraisal.
Short-term clinical trial evidence shows that pembrolizumab with axitinib is more effective than sunitinib for people with untreated renal cell carcinoma, but it is uncertain if there is a long-term benefit. This means the cost-effectiveness estimates are uncertain.
Pembrolizumab with axitinib is not suitable for use in the Cancer Drugs Fund because it is unlikely to be cost effective at its current price (even if the uncertainty about its effectiveness is reduced).
Pembrolizumab with axitinib does not meet NICE's criteria to be a life-extending treatment at the end of life. The cost-effectiveness estimates are higher than what NICE normally considers an acceptable use of NHS resources. Therefore, pembrolizumab with axitinib is not recommended.# Information about pembrolizumab with axitinib
# Marketing authorisation indication
Pembrolizumab (Keytruda, Merck Sharp & Dohme), in combination with axitinib (Inlyta, Pfizer), is indicated 'for the first-line treatment of advanced renal cell carcinoma (RCC) in adults'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price of pembrolizumab is £2,630 per 100-mg vial (excluding VAT; BNF online, assessed January 2020). The cost of a single administration is £5,260. This represents 3 weeks of treatment.The list price of axitinib is £3,517 for 56 × 5-mg tablets (excluding VAT; BNF online, assessed January 2020). This represents about 28 days of treatment.The companies have commercial arrangements for each of the drugs. These make pembrolizumab with axitinib available to the NHS with a discount and would have also applied to this indication if the technology had been recommended. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 4) considered evidence submitted by Merck Sharp & Dohme, a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:
A time horizon of 40 years should be used to capture all relevant benefits and costs that arise from treatment for untreated metastatic renal cell carcinoma (issue 3, see technical report page 27).
Treatment after pembrolizumab with axitinib is likely to include cabozantinib in UK clinical practice (issue 4, see technical report page 29).
The subgroup analysis for the intermediate and poor International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group should be informed by the constant hazard approach network meta-analysis (issue 6, see technical report page 36).The committee recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, table 2, page 49), and took these into account in its decision making. It discussed the following issues (issues 1, 2, 5, 7, 8, and 9), which were outstanding after the technical engagement stage.
# New treatment option
## People with untreated renal cell carcinoma would welcome a new treatment option
In England, kidney cancer is expected to cause about 3,783 deaths every year, with 10,759 new cases per year. Of people with kidney cancer, 80% have renal cell carcinoma. A patient expert explained that treatment with pembrolizumab with axitinib had been positive. This was because their tumour had reduced and there were no notable side effects with the treatment, unlike their experience with other treatment options. Patient experts confirmed that people with untreated renal cell carcinoma felt that the side effects of treatment could substantially affect quality of life. The committee recognised that for advanced renal cell carcinoma there is a high unmet need for both patients and healthcare professionals. Also, there is an unmet need for treating non-clear cell renal cell carcinoma specifically. Overall, an option that improved survival and reduced side effects would be welcomed by patients and clinicians to allow more choice of treatment and individualised care plans.
## If recommended, pembrolizumab with axitinib is likely to affect access to subsequent treatments
The committee considered the current treatment pathway for renal cell carcinoma. First-line options for treating metastatic renal cell carcinoma include tivozanib, sunitinib and pazopanib. Pazopanib is most likely to be used out of these. Avelumab with axitinib is recommended through the Cancer Drugs Fund (CDF). Cabozantinib is only recommended for patients with intermediate or poor risk renal cell carcinoma. Nivolumab with ipilimumab is also only recommended for patients with intermediate or poor risk renal cell carcinoma, through the CDF. Treatment options, in particular cabozantinib, can be difficult to tolerate because of the side effects. Clinical experts expected that patients who are less frail would be offered combination therapy instead of single agents. This is because of enhanced tolerability and a longer duration of disease control when using 2 effective treatments together (noting that the IMDC criteria corresponds to prognosis, rather than a score of frailty). During technical engagement, clinical experts estimated that over 50% of people who had first-line treatment would have subsequent treatment. The CDF clinical lead and the clinical experts explained that if patients have first-line treatment with pembrolizumab (a checkpoint inhibitor) plus axitinib (a tyrosine kinase inhibitor ), then they would be unable to have nivolumab (another checkpoint inhibitor) or axitinib monotherapy later in the treatment pathway. It is likely that subsequent treatment options would then be considered from a combination of current first-line and second-line options. The committee concluded that pembrolizumab with axitinib was likely to have a substantial effect on the care pathway. But, this effect would be similar to that of other immunotherapy combinations for first-line renal cell cancer.
# Clinical evidence
## Clinical evidence from KEYNOTE-426 shows that pembrolizumab with axitinib is more effective than sunitinib for overall and progression-free survival
The clinical evidence came from KEYNOTE‑426, an open-label, randomised phase 3 trial that compared pembrolizumab plus axitinib with sunitinib (median follow up of 12.8 months). The primary outcome measures in KEYNOTE‑426 were overall survival (hazard ratio 0.53; 95% confidence interval 0.38 to 0.74, p=0.00005) and progression-free survival (hazard ratio 0.69; 95% confidence interval 0.57 to 0.84, p=0.00014). Median survival was not reached in either arm. There was no evidence presented comparing pembrolizumab plus axitinib with tivozanib or pazopanib. However, tivozanib and pazopanib were assumed to have equal efficacy and safety to sunitinib. This was in line with previous NICE technology appraisal guidance on:
pazopanib for the first-line treatment of advanced renal cell carcinoma
tivozanib for treating advanced renal cell carcinoma
cabozantinib for untreated advanced renal cell carcinoma
nivolumab with ipilimumab for untreated advanced renal cell carcinoma
avelumab with axitinib for untreated advanced renal cell carcinoma.The committee concluded that pembrolizumab with axitinib was more effective than sunitinib for overall survival and progression-free survival in untreated renal cell carcinoma, but the data are immature.
## The evidence from the company's network meta-analysis for the intermediate and poor-risk subgroup is weak
There was no direct evidence comparing pembrolizumab plus axitinib with cabozantinib for the IMDC intermediate and poor-risk subgroup. The company did a network meta-analysis using data from KEYNOTE‑426 and CABOSUN (a randomised phase 2 trial of cabozantinib compared with sunitinib ). The committee noted the small sample size of CABOSUN. Also, the network meta-analysis did not find a significant difference in progression-free survival or overall survival for the indirect comparison of pembrolizumab plus axitinib with cabozantinib. Overall, the committee considered that the evidence base for the intermediate and poor-risk subgroup was weak.
# Extrapolation of overall survival
## There is no robust evidence to support using different distributions to extrapolate survival for each of the trial arms
Clinical experts expected that pembrolizumab with axitinib would offer a durable response, but they were not certain about the size of the response. They suggested that a different survival trajectory between pembrolizumab with axitinib and sunitinib could be expected. This was because of the differences in the biological mode of action between an immunotherapy and a TKI. The clinical experts explained that immunotherapy was expected to not only attack and kill the cancer cells, but also re-programme the immune system to recognise and adapt to attack and kill future cancer cells. This mode of action differed from a single TKI. The clinical experts expected a durable sustained response after treatment that was not expected with treatment from a single TKI. However, the NICE Decision Support Unit technical support document 14 advises that both arms should have the same extrapolation distribution unless there is substantial justification. There was theoretical justification to use different distributions for each of the trial arms. However, there was no robust evidence to support the argument that the different mode of action of the drugs would result in different survival trajectories. The committee acknowledged that the overall survival data were immature. Therefore, it was appropriate to consider various scenarios presented, including analyses when different distributions were applied. However, the committee concluded that there was no robust evidence to justify using different distributions to extrapolate survival for each of the trial arms.
## The log-logistic distribution used by the company gives optimistic estimates of survival
The committee considered which distribution was the most appropriate to model the overall survival for pembrolizumab with axitinib. The log-logistic distribution used by the company had optimistic survival estimates compared with clinical estimates. The committee also examined the progression-free survival data and survival curves from KEYNOTE‑426, noting that there were data for about 20 months of follow up. It also noted that disease had progressed in most people before 20 months, regardless of treatment. This led the committee to question both the size and length of response, and given this, whether it was valid to assume different survival trajectories for the different treatments. At consultation, the company submitted long-term follow-up data from KEYNOTE‑035. This was a phase 1 study of pembrolizumab with axitinib in advanced untreated renal cell cancer. It suggested treatment effect continued past 5 years (the exact results are confidential and cannot be reported here), supporting using the log-logistic distribution. Given the short follow up in KEYNOTE‑426, clinical experts stated that extrapolation of mature data from other sources (such as KEYNOTE‑035) was important to inform long-term survival estimates. However, the ERG noted that the KEYNOTE‑035 study was not designed to assess overall survival, which was one of a number of secondary outcomes. This, along with the small number of patients in the trial, meant that the results of KEYNOTE-035 should be interpreted with caution. The committee concluded that the survival estimates from the log-logistic distribution in the company base case were optimistic.
## The company economic model is likely to give optimistic survival estimates
To account for age-related increase in mortality, overall survival was capped at the general population mortality rates in the company model. For pembrolizumab with axitinib, this change happened at around 20 years and suggested that about 17% of people were 'cured'. The committee asked the company whether it had examined cure fractions or if it had considered a 'cure' model to estimate survival. The company confirmed that cure fractions had not been considered in the economic modelling and did not intend to do a 'mixture' cure model. The committee concluded that overall survival for pembrolizumab and axitinib may have been overestimated. This was because switching to the same mortality as the general population at about 20 years was likely to be overly optimistic.
## The Weibull distribution gives pessimistic survival estimates
The Weibull curve was the ERG and technical team's preferred distribution for extrapolating overall survival for both pembrolizumab with axitinib and sunitinib. The committee heard from clinical experts that a rising hazard rate, which was a characteristic of the chosen Weibull distribution, was not expected for people who had pembrolizumab with axitinib. Therefore, the committee agreed that the chosen Weibull distribution was likely to give pessimistic survival estimates.
## There is considerable uncertainty in the survival estimates because of the immaturity of the data
The committee concluded that the most plausible survival estimates were likely to fall within the range created by the log-logistic and Weibull distribution used in the company base case and the ERG and technical team base cases, respectively. At consultation, the company submitted new analyses using the exponential distribution to estimate overall survival for both pembrolizumab with axitinib and sunitinib. The company considered this approach unfavourable to pembrolizumab with axitinib. In this distribution, long-term survival estimates fell within the range considered plausible by the committee and a smaller proportion of patients were predicted to be 'cured'. The ERG maintained its initial preference for the Weibull distribution but noted that the exponential was also plausible. The committee agreed to take both the log-logistic and exponential distributions into account in its decision making. However, it noted that considerable uncertainty remained because of the immaturity of the evidence.
# Treatment effect duration
## There is not enough evidence to assume a lifetime treatment effect so treatment benefit waning effects should be applied
The committee acknowledged that assumptions about treatment effect duration would affect expected survival. Clinical experts explained that there could be a long-term response with continued use of a TKI, but it would not be a durable response and would stop when treatment was stopped. Immunotherapy was expected to provide a durable response after stopping the treatment because of its mode of action but this has not yet been confirmed with clinical evidence. One clinical expert estimated that this could happen in around 15% of people having pembrolizumab with axitinib. Expert opinion on long-term survival also varied, with between 35% and 50% of people estimated to be alive 5 years after starting treatment. There was a large amount of uncertainty surrounding the estimates at 10 years and 20 years. Although the committee thought a durable response was possible, immaturity of the data meant that this was based on clinical opinion, scientific reasoning and anecdotal evidence. The committee noted that in previous NICE appraisals of checkpoint inhibitors when length of treatment was capped at 2 years, the committee:
did not assume lifetime treatment benefit
examined various analyses of treatment benefit waning effects, including those that have benefit waning at 1 year and 3 years after stopping treatment (the '2+1' and '2+3' analyses in terms of time since starting treatment).Given the short follow up for KEYNOTE-426, the committee concluded that the treatment effect duration was uncertain. It agreed that there was not enough evidence to assume a lifetime treatment effect. Therefore, treatment benefit waning effects should be applied in the economic model.
## Because of the immaturity of data, it is appropriate to consider a 5-year waning effect scenario to estimate cost effectiveness
There was a 2-year stopping rule in the economic model for pembrolizumab. Treatment with axitinib continued until second-line treatment was needed, for example, because of disease progression. Based on long-term follow-up data from other checkpoint inhibitors, the committee found it reasonable to assume some duration of response. However, it agreed that it could not generalise the size of this effect from one cancer to another. It also recalled that there were only data for about 20 months of follow up from KEYNOTE-426. It considered scenarios when the treatment effect stopped after 3 years, 5 years and 10 years (that is, treatment effect continued to 1 year, 3 years and 8 years after stopping pembrolizumab). The committee noted that there could be uncertainty in the economic model if treatment waning effects were applied in a scenario with continued axitinib treatment, or in scenarios when there was an implicit assumption of cure in the model. Therefore, the scenario analyses were interpreted with caution. The committee concluded that the immaturity of the data made any estimation of treatment waning effect highly uncertain. But, it accepted scenarios when a waning effect was applied after 5 years.
## A treatment waning effect should be applied to all people having pembrolizumab with axitinib, regardless of treatment response
At consultation, the company provided a scenario to model treatment effect waning after 5 years, based on individual responses to pembrolizumab with axitinib in the KEYNOTE-426 trial. People whose disease responded to treatment were modelled so that they were assumed to have the base-case hazard rate. A waning effect was only applied to people whose disease did not respond to treatment (16.2% of the full population). For these people, there was a gradual decrease in hazard rate for progression-free and overall survival between years 5 and 10. After this hazard rates equalled that of sunitinib. The ERG was unclear why the waning effect had only been applied to people whose disease did not respond, given that for most people disease had progressed after 5 years. It stated that applying a treatment waning effect to the entire population was appropriate and provided a scenario using this method. The committee concluded that a treatment waning effect should be applied to all patients having pembrolizumab with axitinib, regardless of treatment response.
# Applying a 2-year stopping rule
## It is appropriate to apply a 2-year stopping rule for pembrolizumab
In KEYNOTE-426, the maximum pembrolizumab treatment duration was 2 years from the first dose, when treatment must be stopped. This was not reflected in the summary of product characteristics, which states that treatment should continue until disease progression or unacceptable toxicity. For pembrolizumab for other indications, a 2‑year stopping rule was applied. The committee noted that the 2‑year stopping rule was included in company's economic model, and concluded that it was appropriate. KEYNOTE-426 allowed treatment to stop and restart within the 35 cycles. It also allowed for another 17 cycles of retreatment because of relapse if the patient had stopped at 35 cycles or stopped because of complete remission. Clinical experts noted that these patients were those most likely to have an ongoing treatment effect, so retreatment rates were expected to be low. The committee noted that the follow up of 20 months was shorter than the 2‑year stopping rule. So, KEYNOTE‑426 did not give any information about the likely impact of the 2‑year stopping rule on effectiveness, the proportion of patients who would restart treatment with pembrolizumab after having had 35 cycles, or the effectiveness of retreatment. The committee concluded that a 2‑year treatment stopping rule in line with the clinical- and cost-effectiveness evidence was appropriate. However, it was uncertain how this might work in the NHS if the technology were recommended.
## The company's retreatment scenario is not generalisable to renal cell cancer
At consultation, the company presented retreatment data from a later data cut of KEYNOTE‑426 (results are confidential and cannot be presented here). The company discouraged modelling of retreatment because of insufficient evidence and a lack of robust statistical methods to account for bias and confounders. However, it presented a scenario to show the effect on the incremental cost-effectiveness ratio (ICER). A cost was applied to 4.8% of the full population. This was based on pembrolizumab retreatment rates seen in the phase 3 KEYNOTE‑006 and KEYNOTE‑010 trials for melanoma and non-small-cell lung cancer, respectively. Clinical experts noted that the immaturity of the data meant that retreatment had little impact on the effectiveness estimates. However, the committee shared the ERG's concerns that these data were collected in different cancer types and used pembrolizumab as a monotherapy. It concluded that the company's retreatment rate was not generalisable to renal cell cancer and the scenario presented was not appropriate for decision making.
# Health-related quality of life
## Post-progression utility values from both the published literature and KEYNOTE-426 are acceptable for decision making
Clinical experts confirmed that markers of disease progression, such as tumour size, may not have a strong correlation with quality of life. This suggests that a time-to-death approach to estimate health-related quality of life could be reasonable. The committee compared the utility values used for the progression-free and progressed states with those using the time-to-death approach in the company base case. The company also provided a scenario when utilities were calculated by progression status and differentiated by treatment. They were higher for pembrolizumab with axitinib than those calculated for sunitinib for each respective health state. The committee noted the decrement in quality of life between the progression-free and progressed states. It considered how the utility data were collected in KEYNOTE‑426. Findings from all the methods to analyse utility data may be biased and give overly optimistic estimates. This is because data collection on health-related quality of life stopped shortly after progression. This may have led to informative censoring bias and uncertainty in estimates for health-related quality of life at the end stages of disease. Clinical experts commented that they would expect post-progression quality of life to be influenced by subsequent-line treatments and this may be higher than estimated using the study data. Patient experts confirmed that patients might feel the need to complete the questionnaire with more positive responses to be able to continue treatment. The committee concluded that, without further data, post-progression utility values from both the published literature and KEYNOTE-426 were acceptable for decision making.
## It is unclear whether an age-related decrement to health-related quality of life is appropriate because of uncertainty in overall survival estimates
The committee did not comment further on the appropriateness of including or excluding an age-related decrement to the model. This was because overall survival estimates were highly uncertain. However, findings from both scenarios (with and without age-related decrements) were considered in the committee's decision making.
# Cost-effectiveness estimate
## The most plausible ICER is above the acceptable range
The cost-effectiveness results are commercial in confidence and cannot be reported here. The committee considered all scenarios from the company, ERG and technical team to establish when pembrolizumab with axitinib could be considered cost effective. It agreed that the company's original base-case ICER was likely to be optimistic because of using the log-logistic distribution for extrapolation and applying a lifetime treatment effect. Also, when using either the log-logistic or exponential distribution, every scenario presented was above the normally acceptable range, taking into account all commercial arrangements. This applied to both the overall renal cell carcinoma population and the intermediate and poor-risk subgroup when using either the company's or ERG's assumptions of treatment waning effect. However, the technical team and ERG base-case ICERs were likely to be pessimistic, because they used the Weibull distribution in the extrapolation of survival (see section 3.8). ICERs of alternative scenarios provided by the technical team and the ERG also did not fall below £30,000 per quality-adjusted life year (QALY) gained. These scenarios included all commercial arrangements added to the analyses for either the overall renal cell carcinoma population or for the intermediate and poor-risk subgroup. The committee concluded that the most plausible ICER was within the range presented by the company base case and the technical team base case. So, the most plausible ICER was above the range normally considered cost effective.
# End of life
## Pembrolizumab with axitinib does not meet the criteria to be considered as a life-extending treatment at the end of life
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The committee, ERG and company agreed that pembrolizumab with axitinib does not meet end-of-life criteria for the overall renal cell carcinoma population. The first end-of-life criterion (that treatment is indicated for patients with a short life expectancy, normally less than 24 months) in the intermediate and poor-risk group was not met. This was because the median overall survival in the sunitinib arm of CHECKMATE‑214 was 26 months, with the mean value likely to be higher. Overall survival for the poor-risk group could not be estimated from the economic model because it was not considered as a distinct subgroup. The committee noted that the CABOSUN trial included few patients who had poor-risk disease (15 for cabozantinib and 15 for sunitinib). This meant an overall survival estimate for cabozantinib, the standard of care in this population, would be highly uncertain. The committee concluded there was no evidence to support that the first end-of-life criterion was met in any of the IMDC risk groups. Therefore, pembrolizumab with axitinib did not meet the criteria to be considered as a life-extending treatment at the end of life.
# Cancer Drugs Fund
## Pembrolizumab with axitinib does not meet the criteria to be considered for inclusion in the CDF
The committee discussed the arrangements for the CDF agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum):
The modelling of overall survival data was uncertain. There was no evidence to confirm that pembrolizumab with axitinib would have a durable response and the size of response is highly uncertain. Further information could reduce this uncertainty, in particular:
the number of people who complete 2 years of therapy or stop because of complete remission
the proportion of these 2 groups that relapse and when they do
the response to retreatment.
The company stated that further data cuts were expected from KEYNOTE‑426 that could provide another 3.5 years of follow-up data (giving around 5 years' data in total) in the typical CDF timeframe of 2 years. Further analysis using these data would help reduce uncertainty on the fraction of people 'cured' for use in a 'mixture' cure model.
The committee considered whether further information about progression-free survival would be useful to collect through the CDF. If everyone's disease had progressed by the end of the CDF data collection period, then a long-term immunotherapeutic effect with pembrolizumab would be less likely.
There was no plausible potential for routine use because all plausible ICERs were above £30,000 per QALY gained when commercial arrangements were included in the analyses.The committee concluded that pembrolizumab with axitinib did not meet the criteria to be considered for inclusion in the CDF.
# Innovation
## The benefits of pembrolizumab with axitinib can be captured in the cost-effectiveness analysis
The company and clinical experts considered that pembrolizumab with axitinib was innovative. They noted pembrolizumab with axitinib had a notable survival benefit and expected that the treatment would have a durable response. A clinical expert commented that, observationally, the technology seemed to have an improved adverse event profile when compared with other combination treatments. The committee agreed that these were important potential benefits of pembrolizumab with axitinib. However, it had not been presented with evidence of any additional benefits that could not be captured in the QALY measurements.
# Other factors
## There are no equality issues relevant to the recommendations
No equality or social value judgement issues were identified.
# Conclusion
## Pembrolizumab with axitinib is not recommended
The committee concluded that the most plausible ICER, when commercial discounts were taken into account, was above the range that NICE normally considers to be a cost-effective use of NHS resources. It therefore concluded that pembrolizumab with axitinib is not recommended for untreated advanced renal cell carcinoma.
|
{'Recommendations': "Pembrolizumab with axitinib is not recommended, within its marketing authorisation, for untreated advanced renal cell carcinoma in adults.\n\nThis recommendation is not intended to affect treatment with pembrolizumab plus axitinib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nCurrent treatment for untreated advanced renal cell carcinoma includes pazopanib, tivozanib or sunitinib. Also, cabozantinib is recommended for patients with intermediate or poor-risk cancer as defined by the International Metastatic Renal Cell Carcinoma Database Consortium. Nivolumab with ipilimumab and avelumab with axitinib are available through the Cancer Drugs Fund. Because they are not established practice, they cannot be comparators in this appraisal.\n\nShort-term clinical trial evidence shows that pembrolizumab with axitinib is more effective than sunitinib for people with untreated renal cell carcinoma, but it is uncertain if there is a long-term benefit. This means the cost-effectiveness estimates are uncertain.\n\nPembrolizumab with axitinib is not suitable for use in the Cancer Drugs Fund because it is unlikely to be cost effective at its current price (even if the uncertainty about its effectiveness is reduced).\n\nPembrolizumab with axitinib does not meet NICE's criteria to be a life-extending treatment at the end of life. The cost-effectiveness estimates are higher than what NICE normally considers an acceptable use of NHS resources. Therefore, pembrolizumab with axitinib is not recommended.", 'Information about pembrolizumab with axitinib': "# Marketing authorisation indication\n\nPembrolizumab (Keytruda, Merck Sharp & Dohme), in combination with axitinib (Inlyta, Pfizer), is indicated 'for the first-line treatment of advanced renal cell carcinoma (RCC) in adults'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price of pembrolizumab is £2,630 per 100-mg vial (excluding VAT; BNF online, assessed January\xa02020). The cost of a single administration is £5,260. This represents 3\xa0weeks of treatment.The list price of axitinib is £3,517 for 56 × 5-mg tablets (excluding VAT; BNF online, assessed January\xa02020). This represents about 28\xa0days of treatment.The companies have commercial arrangements for each of the drugs. These make pembrolizumab with axitinib available to the NHS with a discount and would have also applied to this indication if the technology had been recommended. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa04) considered evidence submitted by Merck Sharp & Dohme, a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:\n\nA time horizon of 40\xa0years should be used to capture all relevant benefits and costs that arise from treatment for untreated metastatic renal cell carcinoma (issue\xa03, see technical report page\xa027).\n\nTreatment after pembrolizumab with axitinib is likely to include cabozantinib in UK clinical practice (issue\xa04, see technical report page\xa029).\n\nThe subgroup analysis for the intermediate and poor International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group should be informed by the constant hazard approach network meta-analysis (issue\xa06, see technical report page\xa036).The committee recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, table\xa02, page\xa049), and took these into account in its decision making. It discussed the following issues (issues\xa01, 2, 5, 7, 8, and 9), which were outstanding after the technical engagement stage.\n\n# New treatment option\n\n## People with untreated renal cell carcinoma would welcome a new treatment option\n\nIn England, kidney cancer is expected to cause about 3,783\xa0deaths every year, with 10,759 new cases per year. Of people with kidney cancer, 80% have renal cell carcinoma. A patient expert explained that treatment with pembrolizumab with axitinib had been positive. This was because their tumour had reduced and there were no notable side effects with the treatment, unlike their experience with other treatment options. Patient experts confirmed that people with untreated renal cell carcinoma felt that the side effects of treatment could substantially affect quality of life. The committee recognised that for advanced renal cell carcinoma there is a high unmet need for both patients and healthcare professionals. Also, there is an unmet need for treating non-clear cell renal cell carcinoma specifically. Overall, an option that improved survival and reduced side effects would be welcomed by patients and clinicians to allow more choice of treatment and individualised care plans.\n\n## If recommended, pembrolizumab with axitinib is likely to affect access to subsequent treatments\n\nThe committee considered the current treatment pathway for renal cell carcinoma. First-line options for treating metastatic renal cell carcinoma include tivozanib, sunitinib and pazopanib. Pazopanib is most likely to be used out of these. Avelumab with axitinib is recommended through the Cancer Drugs Fund (CDF). Cabozantinib is only recommended for patients with intermediate or poor risk renal cell carcinoma. Nivolumab with ipilimumab is also only recommended for patients with intermediate or poor risk renal cell carcinoma, through the CDF. Treatment options, in particular cabozantinib, can be difficult to tolerate because of the side effects. Clinical experts expected that patients who are less frail would be offered combination therapy instead of single agents. This is because of enhanced tolerability and a longer duration of disease control when using 2 effective treatments together (noting that the IMDC criteria corresponds to prognosis, rather than a score of frailty). During technical engagement, clinical experts estimated that over 50% of people who had first-line treatment would have subsequent treatment. The CDF clinical lead and the clinical experts explained that if patients have first-line treatment with pembrolizumab (a checkpoint inhibitor) plus axitinib (a tyrosine kinase inhibitor [TKI]), then they would be unable to have nivolumab (another checkpoint inhibitor) or axitinib monotherapy later in the treatment pathway. It is likely that subsequent treatment options would then be considered from a combination of current first-line and second-line options. The committee concluded that pembrolizumab with axitinib was likely to have a substantial effect on the care pathway. But, this effect would be similar to that of other immunotherapy combinations for first-line renal cell cancer.\n\n# Clinical evidence\n\n## Clinical evidence from KEYNOTE-426 shows that pembrolizumab with axitinib is more effective than sunitinib for overall and progression-free survival\n\nThe clinical evidence came from KEYNOTE‑426, an open-label, randomised phase\xa03 trial that compared pembrolizumab plus axitinib with sunitinib (median follow up of 12.8\xa0months). The primary outcome measures in KEYNOTE‑426 were overall survival (hazard ratio 0.53; 95% confidence interval 0.38 to 0.74, p=0.00005) and progression-free survival (hazard ratio 0.69; 95% confidence interval 0.57 to 0.84, p=0.00014). Median survival was not reached in either arm. There was no evidence presented comparing pembrolizumab plus axitinib with tivozanib or pazopanib. However, tivozanib and pazopanib were assumed to have equal efficacy and safety to sunitinib. This was in line with previous NICE technology appraisal guidance on:\n\npazopanib for the first-line treatment of advanced renal cell carcinoma\n\ntivozanib for treating advanced renal cell carcinoma\n\ncabozantinib for untreated advanced renal cell carcinoma\n\nnivolumab with ipilimumab for untreated advanced renal cell carcinoma\n\navelumab with axitinib for untreated advanced renal cell carcinoma.The committee concluded that pembrolizumab with axitinib was more effective than sunitinib for overall survival and progression-free survival in untreated renal cell carcinoma, but the data are immature.\n\n## The evidence from the company's network meta-analysis for the intermediate and poor-risk subgroup is weak\n\nThere was no direct evidence comparing pembrolizumab plus axitinib with cabozantinib for the IMDC intermediate and poor-risk subgroup. The company did a network meta-analysis using data from KEYNOTE‑426 and CABOSUN (a randomised phase\xa02 trial of cabozantinib [n=79] compared with sunitinib [n=78]). The committee noted the small sample size of CABOSUN. Also, the network meta-analysis did not find a significant difference in progression-free survival or overall survival for the indirect comparison of pembrolizumab plus axitinib with cabozantinib. Overall, the committee considered that the evidence base for the intermediate and poor-risk subgroup was weak.\n\n# Extrapolation of overall survival\n\n## There is no robust evidence to support using different distributions to extrapolate survival for each of the trial arms\n\nClinical experts expected that pembrolizumab with axitinib would offer a durable response, but they were not certain about the size of the response. They suggested that a different survival trajectory between pembrolizumab with axitinib and sunitinib could be expected. This was because of the differences in the biological mode of action between an immunotherapy and a TKI. The clinical experts explained that immunotherapy was expected to not only attack and kill the cancer cells, but also re-programme the immune system to recognise and adapt to attack and kill future cancer cells. This mode of action differed from a single TKI. The clinical experts expected a durable sustained response after treatment that was not expected with treatment from a single TKI. However, the NICE Decision Support Unit technical support document\xa014 advises that both arms should have the same extrapolation distribution unless there is substantial justification. There was theoretical justification to use different distributions for each of the trial arms. However, there was no robust evidence to support the argument that the different mode of action of the drugs would result in different survival trajectories. The committee acknowledged that the overall survival data were immature. Therefore, it was appropriate to consider various scenarios presented, including analyses when different distributions were applied. However, the committee concluded that there was no robust evidence to justify using different distributions to extrapolate survival for each of the trial arms.\n\n## The log-logistic distribution used by the company gives optimistic estimates of survival\n\nThe committee considered which distribution was the most appropriate to model the overall survival for pembrolizumab with axitinib. The log-logistic distribution used by the company had optimistic survival estimates compared with clinical estimates. The committee also examined the progression-free survival data and survival curves from KEYNOTE‑426, noting that there were data for about 20\xa0months of follow up. It also noted that disease had progressed in most people before 20\xa0months, regardless of treatment. This led the committee to question both the size and length of response, and given this, whether it was valid to assume different survival trajectories for the different treatments. At consultation, the company submitted long-term follow-up data from KEYNOTE‑035. This was a phase\xa01 study of pembrolizumab with axitinib in advanced untreated renal cell cancer. It suggested treatment effect continued past 5\xa0years (the exact results are confidential and cannot be reported here), supporting using the log-logistic distribution. Given the short follow up in KEYNOTE‑426, clinical experts stated that extrapolation of mature data from other sources (such as KEYNOTE‑035) was important to inform long-term survival estimates. However, the ERG noted that the KEYNOTE‑035 study was not designed to assess overall survival, which was one of a number of secondary outcomes. This, along with the small number of patients in the trial, meant that the results of KEYNOTE-035 should be interpreted with caution. The committee concluded that the survival estimates from the log-logistic distribution in the company base case were optimistic.\n\n## The company economic model is likely to give optimistic survival estimates\n\nTo account for age-related increase in mortality, overall survival was capped at the general population mortality rates in the company model. For pembrolizumab with axitinib, this change happened at around 20\xa0years and suggested that about 17% of people were 'cured'. The committee asked the company whether it had examined cure fractions or if it had considered a 'cure' model to estimate survival. The company confirmed that cure fractions had not been considered in the economic modelling and did not intend to do a 'mixture' cure model. The committee concluded that overall survival for pembrolizumab and axitinib may have been overestimated. This was because switching to the same mortality as the general population at about 20\xa0years was likely to be overly optimistic.\n\n## The Weibull distribution gives pessimistic survival estimates\n\nThe Weibull curve was the ERG and technical team's preferred distribution for extrapolating overall survival for both pembrolizumab with axitinib and sunitinib. The committee heard from clinical experts that a rising hazard rate, which was a characteristic of the chosen Weibull distribution, was not expected for people who had pembrolizumab with axitinib. Therefore, the committee agreed that the chosen Weibull distribution was likely to give pessimistic survival estimates.\n\n## There is considerable uncertainty in the survival estimates because of the immaturity of the data\n\nThe committee concluded that the most plausible survival estimates were likely to fall within the range created by the log-logistic and Weibull distribution used in the company base case and the ERG and technical team base cases, respectively. At consultation, the company submitted new analyses using the exponential distribution to estimate overall survival for both pembrolizumab with axitinib and sunitinib. The company considered this approach unfavourable to pembrolizumab with axitinib. In this distribution, long-term survival estimates fell within the range considered plausible by the committee and a smaller proportion of patients were predicted to be 'cured'. The ERG maintained its initial preference for the Weibull distribution but noted that the exponential was also plausible. The committee agreed to take both the log-logistic and exponential distributions into account in its decision making. However, it noted that considerable uncertainty remained because of the immaturity of the evidence.\n\n# Treatment effect duration\n\n## There is not enough evidence to assume a lifetime treatment effect so treatment benefit waning effects should be applied\n\nThe committee acknowledged that assumptions about treatment effect duration would affect expected survival. Clinical experts explained that there could be a long-term response with continued use of a TKI, but it would not be a durable response and would stop when treatment was stopped. Immunotherapy was expected to provide a durable response after stopping the treatment because of its mode of action but this has not yet been confirmed with clinical evidence. One clinical expert estimated that this could happen in around 15% of people having pembrolizumab with axitinib. Expert opinion on long-term survival also varied, with between 35% and 50% of people estimated to be alive 5\xa0years after starting treatment. There was a large amount of uncertainty surrounding the estimates at 10 years and 20\xa0years. Although the committee thought a durable response was possible, immaturity of the data meant that this was based on clinical opinion, scientific reasoning and anecdotal evidence. The committee noted that in previous NICE appraisals of checkpoint inhibitors when length of treatment was capped at 2\xa0years, the committee:\n\ndid not assume lifetime treatment benefit\n\nexamined various analyses of treatment benefit waning effects, including those that have benefit waning at 1\xa0year and 3\xa0years after stopping treatment (the '2+1' and '2+3' analyses in terms of time since starting treatment).Given the short follow up for KEYNOTE-426, the committee concluded that the treatment effect duration was uncertain. It agreed that there was not enough evidence to assume a lifetime treatment effect. Therefore, treatment benefit waning effects should be applied in the economic model.\n\n## Because of the immaturity of data, it is appropriate to consider a 5-year waning effect scenario to estimate cost effectiveness\n\nThere was a 2-year stopping rule in the economic model for pembrolizumab. Treatment with axitinib continued until second-line treatment was needed, for example, because of disease progression. Based on long-term follow-up data from other checkpoint inhibitors, the committee found it reasonable to assume some duration of response. However, it agreed that it could not generalise the size of this effect from one cancer to another. It also recalled that there were only data for about 20\xa0months of follow up from KEYNOTE-426. It considered scenarios when the treatment effect stopped after 3\xa0years, 5\xa0years and 10\xa0years (that is, treatment effect continued to 1\xa0year, 3\xa0years and 8\xa0years after stopping pembrolizumab). The committee noted that there could be uncertainty in the economic model if treatment waning effects were applied in a scenario with continued axitinib treatment, or in scenarios when there was an implicit assumption of cure in the model. Therefore, the scenario analyses were interpreted with caution. The committee concluded that the immaturity of the data made any estimation of treatment waning effect highly uncertain. But, it accepted scenarios when a waning effect was applied after 5\xa0years.\n\n## A treatment waning effect should be applied to all people having pembrolizumab with axitinib, regardless of treatment response\n\nAt consultation, the company provided a scenario to model treatment effect waning after 5\xa0years, based on individual responses to pembrolizumab with axitinib in the KEYNOTE-426 trial. People whose disease responded to treatment were modelled so that they were assumed to have the base-case hazard rate. A waning effect was only applied to people whose disease did not respond to treatment (16.2% of the full population). For these people, there was a gradual decrease in hazard rate for progression-free and overall survival between years\xa05 and\xa010. After this hazard rates equalled that of sunitinib. The ERG was unclear why the waning effect had only been applied to people whose disease did not respond, given that for most people disease had progressed after 5\xa0years. It stated that applying a treatment waning effect to the entire population was appropriate and provided a scenario using this method. The committee concluded that a treatment waning effect should be applied to all patients having pembrolizumab with axitinib, regardless of treatment response.\n\n# Applying a 2-year stopping rule\n\n## It is appropriate to apply a 2-year stopping rule for pembrolizumab\n\nIn KEYNOTE-426, the maximum pembrolizumab treatment duration was 2\xa0years from the first dose, when treatment must be stopped. This was not reflected in the summary of product characteristics, which states that treatment should continue until disease progression or unacceptable toxicity. For pembrolizumab for other indications, a 2‑year stopping rule was applied. The committee noted that the 2‑year stopping rule was included in company's economic model, and concluded that it was appropriate. KEYNOTE-426 allowed treatment to stop and restart within the 35\xa0cycles. It also allowed for another 17\xa0cycles of retreatment because of relapse if the patient had stopped at 35\xa0cycles or stopped because of complete remission. Clinical experts noted that these patients were those most likely to have an ongoing treatment effect, so retreatment rates were expected to be low. The committee noted that the follow up of 20\xa0months was shorter than the 2‑year stopping rule. So, KEYNOTE‑426 did not give any information about the likely impact of the 2‑year stopping rule on effectiveness, the proportion of patients who would restart treatment with pembrolizumab after having had 35\xa0cycles, or the effectiveness of retreatment. The committee concluded that a 2‑year treatment stopping rule in line with the clinical- and cost-effectiveness evidence was appropriate. However, it was uncertain how this might work in the NHS if the technology were recommended.\n\n## The company's retreatment scenario is not generalisable to renal cell cancer\n\nAt consultation, the company presented retreatment data from a later data cut of KEYNOTE‑426 (results are confidential and cannot be presented here). The company discouraged modelling of retreatment because of insufficient evidence and a lack of robust statistical methods to account for bias and confounders. However, it presented a scenario to show the effect on the incremental cost-effectiveness ratio (ICER). A cost was applied to 4.8% of the full population. This was based on pembrolizumab retreatment rates seen in the phase\xa03 KEYNOTE‑006 and KEYNOTE‑010 trials for melanoma and non-small-cell lung cancer, respectively. Clinical experts noted that the immaturity of the data meant that retreatment had little impact on the effectiveness estimates. However, the committee shared the ERG's concerns that these data were collected in different cancer types and used pembrolizumab as a monotherapy. It concluded that the company's retreatment rate was not generalisable to renal cell cancer and the scenario presented was not appropriate for decision making.\n\n# Health-related quality of life\n\n## Post-progression utility values from both the published literature and KEYNOTE-426 are acceptable for decision making\n\nClinical experts confirmed that markers of disease progression, such as tumour size, may not have a strong correlation with quality of life. This suggests that a time-to-death approach to estimate health-related quality of life could be reasonable. The committee compared the utility values used for the progression-free and progressed states with those using the time-to-death approach in the company base case. The company also provided a scenario when utilities were calculated by progression status and differentiated by treatment. They were higher for pembrolizumab with axitinib than those calculated for sunitinib for each respective health state. The committee noted the decrement in quality of life between the progression-free and progressed states. It considered how the utility data were collected in KEYNOTE‑426. Findings from all the methods to analyse utility data may be biased and give overly optimistic estimates. This is because data collection on health-related quality of life stopped shortly after progression. This may have led to informative censoring bias and uncertainty in estimates for health-related quality of life at the end stages of disease. Clinical experts commented that they would expect post-progression quality of life to be influenced by subsequent-line treatments and this may be higher than estimated using the study data. Patient experts confirmed that patients might feel the need to complete the questionnaire with more positive responses to be able to continue treatment. The committee concluded that, without further data, post-progression utility values from both the published literature and KEYNOTE-426 were acceptable for decision making.\n\n## It is unclear whether an age-related decrement to health-related quality of life is appropriate because of uncertainty in overall survival estimates\n\nThe committee did not comment further on the appropriateness of including or excluding an age-related decrement to the model. This was because overall survival estimates were highly uncertain. However, findings from both scenarios (with and without age-related decrements) were considered in the committee's decision making.\n\n# Cost-effectiveness estimate\n\n## The most plausible ICER is above the acceptable range\n\nThe cost-effectiveness results are commercial in confidence and cannot be reported here. The committee considered all scenarios from the company, ERG and technical team to establish when pembrolizumab with axitinib could be considered cost effective. It agreed that the company's original base-case ICER was likely to be optimistic because of using the log-logistic distribution for extrapolation and applying a lifetime treatment effect. Also, when using either the log-logistic or exponential distribution, every scenario presented was above the normally acceptable range, taking into account all commercial arrangements. This applied to both the overall renal cell carcinoma population and the intermediate and poor-risk subgroup when using either the company's or ERG's assumptions of treatment waning effect. However, the technical team and ERG base-case ICERs were likely to be pessimistic, because they used the Weibull distribution in the extrapolation of survival (see section 3.8). ICERs of alternative scenarios provided by the technical team and the ERG also did not fall below £30,000 per quality-adjusted life year (QALY) gained. These scenarios included all commercial arrangements added to the analyses for either the overall renal cell carcinoma population or for the intermediate and poor-risk subgroup. The committee concluded that the most plausible ICER was within the range presented by the company base case and the technical team base case. So, the most plausible ICER was above the range normally considered cost effective.\n\n# End of life\n\n## Pembrolizumab with axitinib does not meet the criteria to be considered as a life-extending treatment at the end of life\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The committee, ERG and company agreed that pembrolizumab with axitinib does not meet end-of-life criteria for the overall renal cell carcinoma population. The first end-of-life criterion (that treatment is indicated for patients with a short life expectancy, normally less than 24\xa0months) in the intermediate and poor-risk group was not met. This was because the median overall survival in the sunitinib arm of CHECKMATE‑214 was 26\xa0months, with the mean value likely to be higher. Overall survival for the poor-risk group could not be estimated from the economic model because it was not considered as a distinct subgroup. The committee noted that the CABOSUN trial included few patients who had poor-risk disease (15 for cabozantinib and 15 for sunitinib). This meant an overall survival estimate for cabozantinib, the standard of care in this population, would be highly uncertain. The committee concluded there was no evidence to support that the first end-of-life criterion was met in any of the IMDC risk groups. Therefore, pembrolizumab with axitinib did not meet the criteria to be considered as a life-extending treatment at the end of life.\n\n# Cancer Drugs Fund\n\n## Pembrolizumab with axitinib does not meet the criteria to be considered for inclusion in the CDF\n\nThe committee discussed the arrangements for the CDF agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum):\n\nThe modelling of overall survival data was uncertain. There was no evidence to confirm that pembrolizumab with axitinib would have a durable response and the size of response is highly uncertain. Further information could reduce this uncertainty, in particular:\n\n\n\nthe number of people who complete 2\xa0years of therapy or stop because of complete remission\n\nthe proportion of these 2 groups that relapse and when they do\n\nthe response to retreatment.\n\n\n\nThe company stated that further data cuts were expected from KEYNOTE‑426 that could provide another 3.5\xa0years of follow-up data (giving around 5\xa0years' data in total) in the typical CDF timeframe of 2\xa0years. Further analysis using these data would help reduce uncertainty on the fraction of people 'cured' for use in a 'mixture' cure model.\n\nThe committee considered whether further information about progression-free survival would be useful to collect through the CDF. If everyone's disease had progressed by the end of the CDF data collection period, then a long-term immunotherapeutic effect with pembrolizumab would be less likely.\n\nThere was no plausible potential for routine use because all plausible ICERs were above £30,000 per QALY gained when commercial arrangements were included in the analyses.The committee concluded that pembrolizumab with axitinib did not meet the criteria to be considered for inclusion in the CDF.\n\n# Innovation\n\n## The benefits of pembrolizumab with axitinib can be captured in the cost-effectiveness analysis\n\nThe company and clinical experts considered that pembrolizumab with axitinib was innovative. They noted pembrolizumab with axitinib had a notable survival benefit and expected that the treatment would have a durable response. A clinical expert commented that, observationally, the technology seemed to have an improved adverse event profile when compared with other combination treatments. The committee agreed that these were important potential benefits of pembrolizumab with axitinib. However, it had not been presented with evidence of any additional benefits that could not be captured in the QALY measurements.\n\n# Other factors\n\n## There are no equality issues relevant to the recommendations\n\nNo equality or social value judgement issues were identified.\n\n# Conclusion\n\n## Pembrolizumab with axitinib is not recommended\n\nThe committee concluded that the most plausible ICER, when commercial discounts were taken into account, was above the range that NICE normally considers to be a cost-effective use of NHS resources. It therefore concluded that pembrolizumab with axitinib is not recommended for untreated advanced renal cell carcinoma."}
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https://www.nice.org.uk/guidance/ta650
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Evidence-based recommendations on pembrolizumab (Keytruda) with axitinib (Inlyta) for untreated advanced renal cell carcinoma in adults.
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211253f998193a196f6ada5500593cbc70ff1361
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nice
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Naldemedine for treating opioid-induced constipation
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Naldemedine for treating opioid-induced constipation
Evidence-based recommendations on naldemedine (Rizmoic) for treating opioid-induced constipation in adults who have had laxative treatment.
# Recommendations
Naldemedine is recommended, within its marketing authorisation, as an option for treating opioid-induced constipation in adults who have had laxative treatment.
Why the committee made these recommendations
The treatment of opioid-induced constipation depends on whether the opioid is the only cause of the constipation (pure opioid-induced constipation) or if there are other contributing factors (mixed aetiology constipation). Treatment may include a peripherally acting mu-opioid receptor antagonist (PAMORA) alone. But, commonly a PAMORA and a conventional laxative are used together. Naldemedine is an oral PAMORA for adults who have had laxative treatment.
The clinical evidence shows that naldemedine increases the frequency of bowel movements compared with no treatment and other PAMORAs.
The cost-effectiveness evidence includes naldemedine in several clinical scenarios, for both pure opioid-induced constipation and mixed aetiology constipation. In all scenarios, the most likely cost-effectiveness results are within what NICE normally considers an acceptable use of NHS resources. Therefore, naldemedine is recommended for opioid-induced constipation in adults who have had laxative treatment.# Information about naldemedine
# Marketing authorisation indication
Naldemedine (Rizmoic, Shionogi) has a marketing authorisation in the UK for 'the treatment of opioid-induced constipation in adult patients who have previously been treated with a laxative'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price of a 28-tablet pack of naldemedine is £41.72 (excluding VAT; BNF online, accessed March 2020). The cost of a course of treatment depends on the duration of opioid-induced constipation needing treatment. Costs may vary in different settings because of negotiated procurement discounts.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Shionogi, a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:
Combination standard laxatives are recommended for mixed aetiology constipation, when initial laxative therapy has been tried (see technical report, issue 1, page 14).
Opioid-induced constipation often happens at the same time as other causes of constipation (mixed aetiology constipation) in people with both non-cancer and cancer pain. In these circumstances, naldemedine is suitable for managing the opioid-induced component of mixed aetiology constipation (see technical report, issue 1, page 14).
Laxative-inadequate response is an artificial definition not used in clinical practice and has been removed from the treatment pathway. The company positioning of naldemedine in the relevant subgroups in the treatment pathway is now clear (see technical report, issue 2, page 15).
Rescue medication should be included in both the naldemedine and comparator groups. Cost-effectiveness analyses include the intention-to-treat (ITT) population and can be considered relevant for decision making (see technical report, issue 3, page 16).
The results of the COMPOSE trials can be generalised to England. Naldemedine is likely to be equally effective in people with non-cancer and cancer pain who have opioid-induced constipation (see technical report, issue 5, page 19).
The committee recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, table 11, page 25), and took these into account in its decision making. It discussed the following issues, including issues 4 and 6 from the technical report, which remained unresolved after the technical engagement stage.
# New treatment option
## People with opioid-induced constipation would welcome a new treatment option
Opioid receptors are present in the gastrointestinal tract. When opioids bind to these receptors they can disrupt normal gastrointestinal function, usually resulting in opioid-induced constipation. Treatment for opioid-induced constipation could be a single treatment with a peripherally acting mu-opioid receptor antagonist (PAMORA) such as oral naloxegol or subcutaneous methylnaltrexone. But it commonly involves a combination of a PAMORA and a conventional laxative. Naldemedine is an alternative oral PAMORA taken as a single daily dose. The clinical expert explained that opioid-induced constipation is very common in people with non-cancer and cancer pain, and continues regardless of the type of opioid used. The expert estimated that over 80% of patients with cancer pain will have opioid-induced constipation, while the prevalence is likely to be lower in patients with non-cancer pain. The clinical expert also highlighted that in clinical practice, many patients taking a PAMORA have mixed aetiology constipation and so need a combination treatment to target the different causes of constipation. For some patients the burden of opioid-induced constipation on quality of life is greater than the pain that needs an opioid. This often means patients stop opioid treatment. The clinical expert said that a key benefit of a PAMORA is that patients can have a normal stool, while those taking conventional laxatives often experience a continual back and forth of being constipated and then having diarrhoea. This is a huge burden for both patients and carers in terms of continually managing bowel function. The committee concluded that people with opioid-induced constipation would welcome a new treatment that improves their constipation symptoms and quality of life.
# Comparators
## There are several relevant comparators including no treatment, laxatives, naloxegol and methylnaltrexone
The clinical expert confirmed that all relevant comparators had been included in the key subpopulations modelled by the company (see section 3.4, table 1). The clinical expert explained that the available PAMORAs are subcutaneous methylnaltrexone and oral naloxegol. The committee was informed that methylnaltrexone is primarily used to treat severe cases of constipation when a response is needed quickly, before switching to an oral treatment. The comparators included:
naloxegol for people with opioid-induced constipation
methylnaltrexone for people with opioid-induced constipation and cancer pain
laxatives for people with mixed aetiology constipation
no treatment for people with opioid-induced constipation or mixed aetiology constipation.The committee also discussed the value of conventional laxatives in managing opioid-induced constipation. The clinical expert explained that because of the way opioids cause constipation and the way conventional laxatives work, there is very little evidence to support the use of conventional laxatives for treating opioid-induced constipation. The committee concluded that all relevant comparators had been included in the correct subpopulations' analyses.
# Response in the COMPOSE trials
## Naldemedine is clinically effective compared with placebo and there are more clinical benefits for patients than considered in the trials
The company submission included 4 pivotal randomised trials (COMPOSE-1, -2 -3 and -4) and 3 supportive open-label safety studies (COMPOSE-5, -6 and -7). The primary outcome for COMPOSE-1, -2 and -4 was the proportion of people who had spontaneous bowel movements. For COMPOSE-3, the primary outcome was measures of treatment-emergent adverse events. The proportion of people who had spontaneous bowel movements was significantly greater in the naldemedine arm compared with placebo for COMPOSE-1, -2 and -4:
COMPOSE-1: naldemedine 48%, placebo 35%, percentage change 13.0% (95% confidence interval 4.8 to 21.2).
COMPOSE -2: naldemedine 53%, placebo 34%, percentage change 18.9% (95% CI 10.8 to 27.0).
COMPOSE-4: naldemedine 71%, placebo 34%, percentage change 36.8% (95% CI 23.7 to 49.9).The committee discussed the response rates in the COMPOSE trials and noted that there was response in both the naldemedine and placebo groups. The clinical expert explained that pure opioid-induced constipation should respond to a PAMORA (including naloxegol and methylnaltrexone). Because the response rates in the COMPOSE trials were not 100%, this suggests that patients having naldemedine had mixed aetiology constipation. The expert explained that many other factors other than opioid use can contribute to constipation. These include gastrointestinal pathology, other medications including antiemetics and painkillers, level of mobility and diet. These causes of constipation would not respond to a PAMORA and in some cases would not respond to a conventional laxative. The clinical expert also explained that the frequency of bowel motions is not as important to patients as other symptoms of opioid-induced constipation such as bloating, straining and incomplete evacuations, which affect the patient's quality of life. Opioids may also affect other functions in the gut, causing symptoms such as nausea and gastroparesis. The expert explained that PAMORAs not only increase the frequency of bowel movements but also help to manage these other side effects of opioids. The committee concluded that the increase in quality of life for people whose constipation had a response to naldemedine compared with placebo includes relief of other opioid-induced symptoms, which may be directly or indirectly related to constipation. It also concluded that naldemedine is more clinically effective compared with placebo and there are more clinical benefits for patients than considered in the trials.
# Subpopulations included in the economic model
## The key subpopulations (0 to 4) reflect the clinical pathway in NHS practice and were relevant for decision making
The committee considered several key subpopulations revised by the company after clarification stage and after technical engagement. The committee agreed that subpopulations 1 to 4 reflect the clinical pathway in NHS practice (see table 1 below).
Subpopulation
Intervention
Comparator
Source
: OIC, patients with non-cancer pain
Naldemedine with or without a rescue laxative
Placebo with or without a rescue laxative
COMPOSE-1 and COMPOSE-2 (ITT)
: OIC and mixed aetiology constipation, patients with non-cancer pain
Naldemedine with or without a laxative and with or without a rescue laxative
Placebo with or without a laxative and with or without a rescue laxative
COMPOSE-3 (ITT)
: mixed aetiology constipation, patients with non-cancer pain
Naldemedine plus stable laxative with or without a rescue laxative
Placebo plus stable laxative with or without a rescue laxative
COMPOSE-3 (ITT stable laxative subgroup)
: OIC, patients with non-cancer pain
Naldemedine with or without a rescue laxative
Naloxegol with or without a rescue laxative
ITC from Luthra et al. 2018
: OIC, patients with cancer pain
Naldemedine with or without a rescue laxative
Methylnaltrexone (SC) with or without a rescue laxative
ITC based on COMPOSE-4 and Bull et al. 2015
Abbreviations: ITC, indirect treatment comparison; ITT, intention-to-treat analysis; OIC, opioid-induced constipation; SC, subcutaneous injection.
The committee discussed the clinical plausibility of the various subpopulations modelled by the company. The clinical expert confirmed that the key subpopulations 0 to 4 reflected NHS practice. The clinical expert explained that standard practice in England often involves patients starting therapy with a conventional laxative, which will often remain as part of the treatment regimen in both pure opioid-induced constipation and mixed aetiology constipation. When there is a poor response, a PAMORA would be considered in addition to the conventional laxative, and response to therapy would be monitored. The experience of the clinical expert indicated varying NHS practice, and limited use of the NICE technology appraisal guidance on naloxegol for treating opioid-induced constipation. The committee agreed that subpopulations 0 to 4 reflected naldemedine in clinical practice and were relevant for decision making.
# Indirect treatment comparisons
## The indirect treatment comparisons for subpopulations 3 and 4 are relevant for decision making
The company submission did not include any direct evidence comparing naldemedine with any of the active comparators (naloxegol and methylnaltrexone). It included the results from an indirect treatment comparison comparing naloxegol with naldemedine (relative risk 0.79 ) which informed subpopulation 3, based on an independent publication by Luthra et al. (2018). Also, the company included the results from an indirect treatment comparison comparing methylnaltrexone with naldemedine (RR 0.88 ). This informed subpopulation 4, based on the COMPOSE-4 trial and a randomised controlled trial by Bull et al. (2015). The company did not provide the methods used to combine the data from the trials in the indirect treatment comparison for subpopulation 4 after technical engagement. The company also highlighted that they did not have the input data for the indirect treatment comparison used to inform subpopulation 3. Therefore, the ERG was unable to assess the appropriateness of the indirect treatment comparison analyses or verify the results. After technical engagement, the ERG did several probabilistic sensitivity analyses and concluded that the uncertainty in the indirect treatment comparisons were unlikely to have a large effect on the cost-effectiveness results. For subpopulation 4, the ERG noted that methylnaltrexone is much more expensive than naldemedine. So, even if methylnaltrexone was much more effective, naldemedine would still be cost effective. The clinical expert noted that as subpopulations 3 and 4 did not include a direct comparison of these PAMORAs with naldemedine, it was difficult to determine whether there was a true difference between treatments. The committee concluded that any uncertainty was likely to have a small effect on the cost-effectiveness results for these subpopulations. It therefore considered that the indirect treatment comparisons for subpopulations 3 and 4 were relevant for decision making.
# Assumptions in the economic model
## Stopping treatment for constipation that does not respond is an appropriate assumption in the model
The company's economic model structure was based on the model considered in NICE's technology appraisal guidance on naloxegol. This consisted of a decision-tree structure for the first cycle followed by a Markov-structure from the second cycle onwards. Patients enter the Markov model at either opioid-induced constipation or non-opioid-induced constipation (when having treatment) health states, with a cycle length of 4 weeks and time horizon of up to 5 years. The company made several structural assumptions in their economic model, based on the NICE technology appraisal guidance, including for stopping treatment. Patients were assumed to stop treatment with naldemedine if their constipation had not responded by week 4 or had responded but they then experienced a reoccurrence of opioid-induced constipation. After stopping treatment, people whose constipation had not responded were assumed to not resume treatment across the 5-year time horizon of the economic model. The committee discussed loss of treatment response and the clinical likelihood of having only 1 possibility of response to naldemedine. The clinical expert explained that patients with pure opioid-induced constipation often develop mixed aetiology constipation, meaning response to a PAMORA may reduce. However, the clinical expert explained that for people with pure opioid-induced constipation, a PAMORA should not stop working and people should not develop a tolerance. Any loss of efficacy is normally because of a change in the patient's underlying condition rather than because of the PAMORA itself. The committee discussed the effect of assuming that treatment would be stopped on the estimates of cost effectiveness. It noted that the company had modelled naldemedine across various time horizons between 1 and 5 years. For most subpopulations, the incremental cost-effectiveness ratios (ICERs) increased slightly with a shorter time horizon. The ERG also noted that their clinical expert confirmed the appropriateness of assuming that treatment would be stopped for people whose constipation does not respond, or those who lost response. The committee recognised that stopping treatment for constipation that stops responding to naldemedine is plausible in clinical practice and is an appropriate assumption for the model.
# Extrapolation of treatment response
## Choice of survival distribution has a minimal effect on the ICERs for each subpopulation
The company submission included the probabilities for loss of treatment response to naldemedine, which were based on extrapolated time-to-event data from the relevant trials (see section 3.4, table 1). The company did not explore the clinical plausibility of their preferred parametric curves to model loss of treatment response at the clarification stage or after technical engagement. Instead, it highlighted that for all subpopulations, the choice of survival distribution has a minimal effect on the ICERs for each subpopulation. The ERG agreed with the choice of parametric curve in the company submission for subpopulations 1 to 4 but concluded that the Gompertz model was more appropriate for subpopulation 0. This was based on clinical opinion, which suggests that loss of response is likely to plateau at a certain level. The committee was aware that the choice of the curve has a minimal effect on the ICERs for all the subpopulations. It agreed that, while the clinical plausibility of the time-to-event curves is not known and that it would have been helpful for the company to provide this information, the effect on the ICERs is likely to be small.
# Utility values in the economic model
## The ICERs are sensitive to treatment-specific utility values and it is acceptable to include these in the economic model
The EQ-5D was not used in the COMPOSE trials, and so utility values from NICE's technology appraisal guidance on naloxegol were used. The company used treatment-specific utilities for the non-opioid-induced constipation (when having treatment) health state in the base case. The ERG noted that each health state should be homogeneous enough that the utility does not differ between different treatments. Therefore, it would have preferred a refined Markov model to which health state-specific utility values could be applied. The ERG's clinical expert did not expect differences in quality of life between people having naldemedine or naloxegol. The committee was aware that the ICER was sensitive to assuming treatment-specific utilities. Using health state-specific utilities increased the company's base case ICERs for subpopulations 0, 1 and 2 to £28,131, £27,484 and £15,020 per quality-adjusted life year (QALY) gained, respectively. The ERG noted that while it was not ideal to use treatment-specific utilities, the non-opioid-induced constipation (when having treatment) health state was probably quite heterogeneous in terms of spontaneous bowel movements. The committee agreed that using treatment-specific utilities was reasonable based on the approach in the technology appraisal guidance on naloxegol, and on the clinical expert opinion that naldemedine would improve a range of opioid-induced side effects, in addition to increases in spontaneous bowel movements seen in the COMPOSE trials. The committee noted that the company's model may not have captured these additional health benefits of naldemedine, and therefore accepted the use of treatment-specific utilities in the economic model.
# Cost-effectiveness estimates
## The most plausible ICER is likely to be below £20,000 per QALY gained for all subpopulations
NICE's guide to the methods of technology appraisal notes that above a most plausible ICER of £20,000 per QALY gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. Because of the uncertainty in the indirect treatment comparisons and the impact on the choice of utility values, the committee agreed that an acceptable ICER would be below £20,000 per QALY gained. The committee recognised that the company's cost-effectiveness estimates for naldemedine using treatment-specific utility values were below £20,000 per QALY gained for all subpopulations (see table 2 below) and considered this to be a cost-effective use of NHS resources.
Subpopulation
Incremental costs
Incremental QALYs
ICER
(per QALY gained)
Subpopulation 0
Subpopulation 1
Subpopulation 2
Subpopulation 3
Subpopulation 4
Naldemedine is dominant (it is more effective and costs less than comparators)
The ICERs in table 2 have been calculated using incremental costs and QALYs from the company's economic model.
The committee noted that the use of health state-specific utilities increased the ICERs for some of the subpopulations above this range, but that these were still under £30,000 per QALY gained. The committee was also persuaded that using health state-specific utilities did not capture all the broader benefits of treatment with naldemedine as highlighted by the clinical expert. If these were taken into account, the ICERs were likely to be under £20,000 per QALY gained. The committee was reassured by the results of the ERG's probabilistic sensitivity analysis for subpopulation 1. This indicated that naldemedine had probabilities of being cost effective of 74.8% and 86.3% at £20,000 and £30,000 per QALY gained, respectively. The committee agreed that treatment with naldemedine will likely result in an ICER below £20,000 per QALY gained compared with the relevant comparators for all the subpopulations.
# Other factors
## There are no equality issues relevant to the recommendations
No equality or social value judgement issues were identified.
## The benefits of naldemedine are captured in the cost-effectiveness analysis
The company considered naldemedine to be innovative because of its permanent binding capacity and higher receptor affinity compared with other PAMORAs. The committee agreed that these were important benefits of naldemedine. But, it concluded that it had not been presented with evidence of any additional benefits that could not be captured in the QALYs.
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{'Recommendations': 'Naldemedine is recommended, within its marketing authorisation, as an option for treating opioid-induced constipation in adults who have had laxative treatment.\n\nWhy the committee made these recommendations\n\nThe treatment of opioid-induced constipation depends on whether the opioid is the only cause of the constipation (pure opioid-induced constipation) or if there are other contributing factors (mixed aetiology constipation). Treatment may include a peripherally acting mu-opioid receptor antagonist (PAMORA) alone. But, commonly a PAMORA and a conventional laxative are used together. Naldemedine is an oral PAMORA for adults who have had laxative treatment.\n\nThe clinical evidence shows that naldemedine increases the frequency of bowel movements compared with no treatment and other PAMORAs.\n\nThe cost-effectiveness evidence includes naldemedine in several clinical scenarios, for both pure opioid-induced constipation and mixed aetiology constipation. In all scenarios, the most likely cost-effectiveness results are within what NICE normally considers an acceptable use of NHS resources. Therefore, naldemedine is recommended for opioid-induced constipation in adults who have had laxative treatment.', 'Information about naldemedine': "# Marketing authorisation indication\n\nNaldemedine (Rizmoic, Shionogi) has a marketing authorisation in the UK for 'the treatment of opioid-induced constipation in adult patients who have previously been treated with a laxative'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price of a 28-tablet pack of naldemedine is £41.72 (excluding VAT; BNF online, accessed March 2020). The cost of a course of treatment depends on the duration of opioid-induced constipation needing treatment. Costs may vary in different settings because of negotiated procurement discounts.", 'Committee discussion': "The appraisal committee (section 5) considered evidence submitted by Shionogi, a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:\n\nCombination standard laxatives are recommended for mixed aetiology constipation, when initial laxative therapy has been tried (see technical report, issue\xa01, page\xa014).\n\nOpioid-induced constipation often happens at the same time as other causes of constipation (mixed aetiology constipation) in people with both non-cancer and cancer pain. In these circumstances, naldemedine is suitable for managing the opioid-induced component of mixed aetiology constipation (see technical report, issue\xa01, page\xa014).\n\nLaxative-inadequate response is an artificial definition not used in clinical practice and has been removed from the treatment pathway. The company positioning of naldemedine in the relevant subgroups in the treatment pathway is now clear (see technical report, issue\xa02, page\xa015).\n\nRescue medication should be included in both the naldemedine and comparator groups. Cost-effectiveness analyses include the intention-to-treat (ITT) population and can be considered relevant for decision making (see technical report, issue\xa03, page\xa016).\n\nThe results of the COMPOSE trials can be generalised to England. Naldemedine is likely to be equally effective in people with non-cancer and cancer pain who have opioid-induced constipation (see technical report, issue\xa05, page\xa019).\n\nThe committee recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, table\xa011, page\xa025), and took these into account in its decision making. It discussed the following issues, including issues\xa04 and\xa06 from the technical report, which remained unresolved after the technical engagement stage.\n\n# New treatment option\n\n## People with opioid-induced constipation would welcome a new treatment option\n\nOpioid receptors are present in the gastrointestinal tract. When opioids bind to these receptors they can disrupt normal gastrointestinal function, usually resulting in opioid-induced constipation. Treatment for opioid-induced constipation could be a single treatment with a peripherally acting mu-opioid receptor antagonist (PAMORA) such as oral naloxegol or subcutaneous methylnaltrexone. But it commonly involves a combination of a PAMORA and a conventional laxative. Naldemedine is an alternative oral PAMORA taken as a single daily dose. The clinical expert explained that opioid-induced constipation is very common in people with non-cancer and cancer pain, and continues regardless of the type of opioid used. The expert estimated that over 80% of patients with cancer pain will have opioid-induced constipation, while the prevalence is likely to be lower in patients with non-cancer pain. The clinical expert also highlighted that in clinical practice, many patients taking a PAMORA have mixed aetiology constipation and so need a combination treatment to target the different causes of constipation. For some patients the burden of opioid-induced constipation on quality of life is greater than the pain that needs an opioid. This often means patients stop opioid treatment. The clinical expert said that a key benefit of a PAMORA is that patients can have a normal stool, while those taking conventional laxatives often experience a continual back and forth of being constipated and then having diarrhoea. This is a huge burden for both patients and carers in terms of continually managing bowel function. The committee concluded that people with opioid-induced constipation would welcome a new treatment that improves their constipation symptoms and quality of life.\n\n# Comparators\n\n## There are several relevant comparators including no treatment, laxatives, naloxegol and methylnaltrexone\n\nThe clinical expert confirmed that all relevant comparators had been included in the key subpopulations modelled by the company (see section\xa03.4, table\xa01). The clinical expert explained that the available PAMORAs are subcutaneous methylnaltrexone and oral naloxegol. The committee was informed that methylnaltrexone is primarily used to treat severe cases of constipation when a response is needed quickly, before switching to an oral treatment. The comparators included:\n\nnaloxegol for people with opioid-induced constipation\n\nmethylnaltrexone for people with opioid-induced constipation and cancer pain\n\nlaxatives for people with mixed aetiology constipation\n\nno treatment for people with opioid-induced constipation or mixed aetiology constipation.The committee also discussed the value of conventional laxatives in managing opioid-induced constipation. The clinical expert explained that because of the way opioids cause constipation and the way conventional laxatives work, there is very little evidence to support the use of conventional laxatives for treating opioid-induced constipation. The committee concluded that all relevant comparators had been included in the correct subpopulations' analyses.\n\n# Response in the COMPOSE trials\n\n## Naldemedine is clinically effective compared with placebo and there are more clinical benefits for patients than considered in the trials\n\nThe company submission included 4 pivotal randomised trials (COMPOSE-1, -2 -3 and -4) and 3 supportive open-label safety studies (COMPOSE-5, -6 and -7). The primary outcome for COMPOSE-1, -2 and\xa0-4 was the proportion of people who had spontaneous bowel movements. For COMPOSE-3, the primary outcome was measures of treatment-emergent adverse events. The proportion of people who had spontaneous bowel movements was significantly greater in the naldemedine arm compared with placebo for COMPOSE-1, -2 and\xa0-4:\n\nCOMPOSE-1: naldemedine 48%, placebo 35%, percentage change 13.0% (95% confidence interval [CI] 4.8 to 21.2).\n\nCOMPOSE -2: naldemedine 53%, placebo 34%, percentage change 18.9% (95% CI 10.8 to 27.0).\n\nCOMPOSE-4: naldemedine 71%, placebo 34%, percentage change 36.8% (95% CI 23.7 to 49.9).The committee discussed the response rates in the COMPOSE trials and noted that there was response in both the naldemedine and placebo groups. The clinical expert explained that pure opioid-induced constipation should respond to a PAMORA (including naloxegol and methylnaltrexone). Because the response rates in the COMPOSE trials were not 100%, this suggests that patients having naldemedine had mixed aetiology constipation. The expert explained that many other factors other than opioid use can contribute to constipation. These include gastrointestinal pathology, other medications including antiemetics and painkillers, level of mobility and diet. These causes of constipation would not respond to a PAMORA and in some cases would not respond to a conventional laxative. The clinical expert also explained that the frequency of bowel motions is not as important to patients as other symptoms of opioid-induced constipation such as bloating, straining and incomplete evacuations, which affect the patient's quality of life. Opioids may also affect other functions in the gut, causing symptoms such as nausea and gastroparesis. The expert explained that PAMORAs not only increase the frequency of bowel movements but also help to manage these other side effects of opioids. The committee concluded that the increase in quality of life for people whose constipation had a response to naldemedine compared with placebo includes relief of other opioid-induced symptoms, which may be directly or indirectly related to constipation. It also concluded that naldemedine is more clinically effective compared with placebo and there are more clinical benefits for patients than considered in the trials.\n\n# Subpopulations included in the economic model\n\n## The key subpopulations (0 to 4) reflect the clinical pathway in NHS practice and were relevant for decision making\n\nThe committee considered several key subpopulations revised by the company after clarification stage and after technical engagement. The committee agreed that subpopulations 1 to 4 reflect the clinical pathway in NHS practice (see table\xa01 below).\n\nSubpopulation\n\nIntervention\n\nComparator\n\nSource\n\n: OIC, patients with non-cancer pain\n\nNaldemedine with or without a rescue laxative\n\nPlacebo with or without a rescue laxative\n\nCOMPOSE-1 and COMPOSE-2 (ITT)\n\n: OIC and mixed aetiology constipation, patients with non-cancer pain\n\nNaldemedine with or without a laxative and with or without a rescue laxative\n\nPlacebo with or without a laxative and with or without a rescue laxative\n\nCOMPOSE-3 (ITT)\n\n: mixed aetiology constipation, patients with non-cancer pain\n\nNaldemedine plus stable laxative with or without a rescue laxative\n\nPlacebo plus stable laxative with or without a rescue laxative\n\nCOMPOSE-3 (ITT stable laxative subgroup)\n\n: OIC, patients with non-cancer pain\n\nNaldemedine with or without a rescue laxative\n\nNaloxegol with or without a rescue laxative\n\nITC from Luthra et al. 2018\n\n: OIC, patients with cancer pain\n\nNaldemedine with or without a rescue laxative\n\nMethylnaltrexone (SC) with or without a rescue laxative\n\nITC based on COMPOSE-4 and Bull et al. 2015\n\nAbbreviations: ITC, indirect treatment comparison; ITT, intention-to-treat analysis; OIC, opioid-induced constipation; SC, subcutaneous injection.\n\nThe committee discussed the clinical plausibility of the various subpopulations modelled by the company. The clinical expert confirmed that the key subpopulations 0 to 4 reflected NHS practice. The clinical expert explained that standard practice in England often involves patients starting therapy with a conventional laxative, which will often remain as part of the treatment regimen in both pure opioid-induced constipation and mixed aetiology constipation. When there is a poor response, a PAMORA would be considered in addition to the conventional laxative, and response to therapy would be monitored. The experience of the clinical expert indicated varying NHS practice, and limited use of the NICE technology appraisal guidance on naloxegol for treating opioid-induced constipation. The committee agreed that subpopulations\xa00 to\xa04 reflected naldemedine in clinical practice and were relevant for decision making.\n\n# Indirect treatment comparisons\n\n## The indirect treatment comparisons for subpopulations 3 and 4 are relevant for decision making\n\nThe company submission did not include any direct evidence comparing naldemedine with any of the active comparators (naloxegol and methylnaltrexone). It included the results from an indirect treatment comparison comparing naloxegol with naldemedine (relative risk [RR] 0.79 [95% CI 0.63 to 0.99]) which informed subpopulation\xa03, based on an independent publication by Luthra et al. (2018). Also, the company included the results from an indirect treatment comparison comparing methylnaltrexone with naldemedine (RR 0.88 [95% CI 0.71, 1.06]). This informed subpopulation\xa04, based on the COMPOSE-4 trial and a randomised controlled trial by Bull et al. (2015). The company did not provide the methods used to combine the data from the trials in the indirect treatment comparison for subpopulation\xa04 after technical engagement. The company also highlighted that they did not have the input data for the indirect treatment comparison used to inform subpopulation\xa03. Therefore, the ERG was unable to assess the appropriateness of the indirect treatment comparison analyses or verify the results. After technical engagement, the ERG did several probabilistic sensitivity analyses and concluded that the uncertainty in the indirect treatment comparisons were unlikely to have a large effect on the cost-effectiveness results. For subpopulation\xa04, the ERG noted that methylnaltrexone is much more expensive than naldemedine. So, even if methylnaltrexone was much more effective, naldemedine would still be cost effective. The clinical expert noted that as subpopulations\xa03 and\xa04 did not include a direct comparison of these PAMORAs with naldemedine, it was difficult to determine whether there was a true difference between treatments. The committee concluded that any uncertainty was likely to have a small effect on the cost-effectiveness results for these subpopulations. It therefore considered that the indirect treatment comparisons for subpopulations\xa03 and\xa04 were relevant for decision making.\n\n# Assumptions in the economic model\n\n## Stopping treatment for constipation that does not respond is an appropriate assumption in the model\n\nThe company's economic model structure was based on the model considered in NICE's technology appraisal guidance on naloxegol. This consisted of a decision-tree structure for the first cycle followed by a Markov-structure from the second cycle onwards. Patients enter the Markov model at either opioid-induced constipation or non-opioid-induced constipation (when having treatment) health states, with a cycle length of 4\xa0weeks and time horizon of up to 5\xa0years. The company made several structural assumptions in their economic model, based on the NICE technology appraisal guidance, including for stopping treatment. Patients were assumed to stop treatment with naldemedine if their constipation had not responded by week\xa04 or had responded but they then experienced a reoccurrence of opioid-induced constipation. After stopping treatment, people whose constipation had not responded were assumed to not resume treatment across the 5-year time horizon of the economic model. The committee discussed loss of treatment response and the clinical likelihood of having only 1 possibility of response to naldemedine. The clinical expert explained that patients with pure opioid-induced constipation often develop mixed aetiology constipation, meaning response to a PAMORA may reduce. However, the clinical expert explained that for people with pure opioid-induced constipation, a PAMORA should not stop working and people should not develop a tolerance. Any loss of efficacy is normally because of a change in the patient's underlying condition rather than because of the PAMORA itself. The committee discussed the effect of assuming that treatment would be stopped on the estimates of cost effectiveness. It noted that the company had modelled naldemedine across various time horizons between 1\xa0and 5\xa0years. For most subpopulations, the incremental cost-effectiveness ratios (ICERs) increased slightly with a shorter time horizon. The ERG also noted that their clinical expert confirmed the appropriateness of assuming that treatment would be stopped for people whose constipation does not respond, or those who lost response. The committee recognised that stopping treatment for constipation that stops responding to naldemedine is plausible in clinical practice and is an appropriate assumption for the model.\n\n# Extrapolation of treatment response\n\n## Choice of survival distribution has a minimal effect on the ICERs for each subpopulation\n\nThe company submission included the probabilities for loss of treatment response to naldemedine, which were based on extrapolated time-to-event data from the relevant trials (see section\xa03.4, table\xa01). The company did not explore the clinical plausibility of their preferred parametric curves to model loss of treatment response at the clarification stage or after technical engagement. Instead, it highlighted that for all subpopulations, the choice of survival distribution has a minimal effect on the ICERs for each subpopulation. The ERG agreed with the choice of parametric curve in the company submission for subpopulations\xa01 to\xa04 but concluded that the Gompertz model was more appropriate for subpopulation\xa00. This was based on clinical opinion, which suggests that loss of response is likely to plateau at a certain level. The committee was aware that the choice of the curve has a minimal effect on the ICERs for all the subpopulations. It agreed that, while the clinical plausibility of the time-to-event curves is not known and that it would have been helpful for the company to provide this information, the effect on the ICERs is likely to be small.\n\n# Utility values in the economic model\n\n## The ICERs are sensitive to treatment-specific utility values and it is acceptable to include these in the economic model\n\nThe EQ-5D was not used in the COMPOSE trials, and so utility values from NICE's technology appraisal guidance on naloxegol were used. The company used treatment-specific utilities for the non-opioid-induced constipation (when having treatment) health state in the base case. The ERG noted that each health state should be homogeneous enough that the utility does not differ between different treatments. Therefore, it would have preferred a refined Markov model to which health state-specific utility values could be applied. The ERG's clinical expert did not expect differences in quality of life between people having naldemedine or naloxegol. The committee was aware that the ICER was sensitive to assuming treatment-specific utilities. Using health state-specific utilities increased the company's base case ICERs for subpopulations\xa00, 1 and 2 to £28,131, £27,484 and £15,020 per quality-adjusted life year (QALY) gained, respectively. The ERG noted that while it was not ideal to use treatment-specific utilities, the non-opioid-induced constipation (when having treatment) health state was probably quite heterogeneous in terms of spontaneous bowel movements. The committee agreed that using treatment-specific utilities was reasonable based on the approach in the technology appraisal guidance on naloxegol, and on the clinical expert opinion that naldemedine would improve a range of opioid-induced side effects, in addition to increases in spontaneous bowel movements seen in the COMPOSE trials. The committee noted that the company's model may not have captured these additional health benefits of naldemedine, and therefore accepted the use of treatment-specific utilities in the economic model.\n\n# Cost-effectiveness estimates\n\n## The most plausible ICER is likely to be below £20,000 per QALY gained for all subpopulations\n\nNICE's guide to the methods of technology appraisal notes that above a most plausible ICER of £20,000 per QALY gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. Because of the uncertainty in the indirect treatment comparisons and the impact on the choice of utility values, the committee agreed that an acceptable ICER would be below £20,000 per QALY gained. The committee recognised that the company's cost-effectiveness estimates for naldemedine using treatment-specific utility values were below £20,000 per QALY gained for all subpopulations (see table\xa02 below) and considered this to be a cost-effective use of NHS resources.\n\nSubpopulation\n\nIncremental costs\n\nIncremental QALYs\n\nICER\n\n(per QALY gained)\n\nSubpopulation 0\n\n£275.11\n\n\n\n£12,556\n\nSubpopulation 1\n\n£838.46\n\n\n\n£12,489\n\nSubpopulation 2\n\n£788.59\n\n\n\n£9,462\n\nSubpopulation 3\n\n£73.72\n\n\n\n£3,649\n\nSubpopulation 4\n\n-£3,356\n\n\n\nNaldemedine is dominant (it is more effective and costs less than comparators)\n\nThe ICERs in table 2 have been calculated using incremental costs and QALYs from the company's economic model.\n\nThe committee noted that the use of health state-specific utilities increased the ICERs for some of the subpopulations above this range, but that these were still under £30,000 per QALY gained. The committee was also persuaded that using health state-specific utilities did not capture all the broader benefits of treatment with naldemedine as highlighted by the clinical expert. If these were taken into account, the ICERs were likely to be under £20,000 per QALY gained. The committee was reassured by the results of the ERG's probabilistic sensitivity analysis for subpopulation\xa01. This indicated that naldemedine had probabilities of being cost effective of 74.8% and 86.3% at £20,000 and £30,000 per QALY gained, respectively. The committee agreed that treatment with naldemedine will likely result in an ICER below £20,000 per QALY gained compared with the relevant comparators for all the subpopulations.\n\n# Other factors\n\n## There are no equality issues relevant to the recommendations\n\nNo equality or social value judgement issues were identified.\n\n## The benefits of naldemedine are captured in the cost-effectiveness analysis\n\nThe company considered naldemedine to be innovative because of its permanent binding capacity and higher receptor affinity compared with other PAMORAs. The committee agreed that these were important benefits of naldemedine. But, it concluded that it had not been presented with evidence of any additional benefits that could not be captured in the QALYs."}
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https://www.nice.org.uk/guidance/ta651
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Evidence-based recommendations on naldemedine (Rizmoic) for treating opioid-induced constipation in adults who have had laxative treatment.
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b693259da49335e552d14c4ab51603647fbd1728
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nice
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Transcranial magnetic stimulation for auditory hallucinations
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Transcranial magnetic stimulation for auditory hallucinations
Evidence-based recommendations on transcranial magnetic stimulation for auditory hallucinations. This involves stimulating the brain with pulses of electromagnetic energy.
# Recommendations
Evidence on the safety of transcranial magnetic stimulation for auditory hallucinations is adequate and raises no major safety concerns. However, evidence on its efficacy is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.
Further research should be in the form of randomised controlled trials and should use well described treatment protocols. Studies should report details of patient selection including specific psychopathology, underlying disease and other treatments, the area of brain treated and the imaging used to target it, and long-term outcomes for at least 1 year.# The condition, current treatments and procedure
# The condition
Auditory hallucinations are when you hear sounds that do not exist (such as hearing voices). They are often symptoms of mental health problems such as schizophrenia, bipolar disorder, major depression and post-traumatic stress disorder. However, they may also be symptoms of temporal lobe epilepsy, dementia, neurological infections and brain tumours. And they are sometimes caused by lack of sleep, extreme hunger, or the use of recreational or prescribed drugs.
# Current treatments
The treatment options for auditory hallucinations depend on the underlying cause. For example, antipsychotic medication may help with hallucinations for people living with schizophrenia. Some people find strategies such as learning to understand their voices, taking control and keeping busy are helpful in managing the condition.
# The procedure
Transcranial magnetic stimulation is typically done with the patient awake and sitting in a chair. The operator places an electromagnetic coil against the scalp, over a specific region of the brain, usually the left temporoparietal area. Pulses of electrical current in the coil generate rapidly pulsating magnetic fields that pass through the skull and meninges and into the targeted area of the brain. The magnetic field is relatively powerful but short lived (milliseconds). The precise mechanism of action is unclear but it produces both excitatory and inhibitory effects on cortical neurons. The amount of stimulation and the target area is adjusted for each patient. Treatment usually comprises daily or twice daily sessions lasting about 20 minutes. The number of sessions varies but it could be up to 30 sessions. The aim is to stop or reduce the auditory hallucinations.
Stimulation can be repetitive, with pulses of magnetic energy delivered at various frequencies or stimulus intensities. In the standard repetitive technique, individual pulses are repeated at a pre-set interval (repetition of pulses). In the theta-burst technique, short bursts of pulses are repeated at a pre-set interval (repetition of bursts). In the deep repetitive technique, deeper and broader brain regions are stimulated than in the standard technique.
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{'Recommendations': 'Evidence on the safety of transcranial magnetic stimulation for auditory hallucinations is adequate and raises no major safety concerns. However, evidence on its efficacy is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nFurther research should be in the form of randomised controlled trials and should use well described treatment protocols. Studies should report details of patient selection including specific psychopathology, underlying disease and other treatments, the area of brain treated and the imaging used to target it, and long-term outcomes for at least 1\xa0year.', 'The condition, current treatments and procedure': '# The condition\n\nAuditory hallucinations are when you hear sounds that do not exist (such as hearing voices). They are often symptoms of mental health problems such as schizophrenia, bipolar disorder, major depression and post-traumatic stress disorder. However, they may also be symptoms of temporal lobe epilepsy, dementia, neurological infections and brain tumours. And they are sometimes caused by lack of sleep, extreme hunger, or the use of recreational or prescribed drugs.\n\n# Current treatments\n\nThe treatment options for auditory hallucinations depend on the underlying cause. For example, antipsychotic medication may help with hallucinations for people living with schizophrenia. Some people find strategies such as learning to understand their voices, taking control and keeping busy are helpful in managing the condition.\n\n# The procedure\n\nTranscranial magnetic stimulation is typically done with the patient awake and sitting in a chair. The operator places an electromagnetic coil against the scalp, over a specific region of the brain, usually the left temporoparietal area. Pulses of electrical current in the coil generate rapidly pulsating magnetic fields that pass through the skull and meninges and into the targeted area of the brain. The magnetic field is relatively powerful but short lived (milliseconds). The precise mechanism of action is unclear but it produces both excitatory and inhibitory effects on cortical neurons. The amount of stimulation and the target area is adjusted for each patient. Treatment usually comprises daily or twice daily sessions lasting about 20\xa0minutes. The number of sessions varies but it could be up to\xa030\xa0sessions. The aim is to stop or reduce the auditory hallucinations.\n\nStimulation can be repetitive, with pulses of magnetic energy delivered at various frequencies or stimulus intensities. In the standard repetitive technique, individual pulses are repeated at a pre-set interval (repetition of pulses). In the theta-burst technique, short bursts of pulses are repeated at a pre-set interval (repetition of bursts). In the deep repetitive technique, deeper and broader brain regions are stimulated than in the standard technique.'}
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https://www.nice.org.uk/guidance/ipg680
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Evidence-based recommendations on transcranial magnetic stimulation for auditory hallucinations. This involves stimulating the brain with pulses of electromagnetic energy.
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21b3256be72db52aafa5baee79a4aaf64db00680
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nice
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Polatuzumab vedotin with rituximab and bendamustine for treating relapsed or refractory diffuse large B-cell lymphoma
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Polatuzumab vedotin with rituximab and bendamustine for treating relapsed or refractory diffuse large B-cell lymphoma
Evidence-based recommendations on polatuzumab vedotin (Polivy) with rituximab and bendamustine for treating relapsed or refractory diffuse large B-cell lymphoma in adults who cannot have a haematopoietic stem cell transplant.
# Recommendations
Polatuzumab vedotin with rituximab and bendamustine is recommended, within its marketing authorisation, as an option for treating relapsed or refractory diffuse large B‑cell lymphoma in adults who cannot have a haematopoietic stem cell transplant. It is recommended only if the company provides polatuzumab vedotin according to the commercial arrangement.
Why the committee made these recommendations
There is no standard treatment for relapsed or refractory diffuse large B‑cell lymphoma in people who cannot have a haematopoietic stem cell transplant. They could be offered rituximab with bendamustine, although this is not standard care in the NHS. Clinical evidence shows that people having polatuzumab vedotin plus rituximab and bendamustine have more time before their disease gets worse than people having rituximab and bendamustine alone. It also suggests that they live longer.
Polatuzumab vedotin plus rituximab and bendamustine is considered to be a life-extending treatment at the end of life. The cost-effectiveness estimates are within the range that NICE considers an acceptable use of NHS resources. Therefore, polatuzumab vedotin plus rituximab and bendamustine is recommended.# Information about polatuzumab vedotin
# Marketing authorisation indication
Polatuzumab vedotin (Polivy, Roche) in combination with bendamustine and rituximab is indicated for 'the treatment of adult patients with relapsed or refractory diffuse large B‑cell lymphoma (DLBCL) who are not candidates for haematopoietic stem cell transplant'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The cost per item from the company's submission is £11,060 per 140‑mg vial (excluding VAT; British national formulary online accessed July 2020). The company estimates that the average cost of a course of treatment is £50,416.
The company has a commercial arrangement. This makes polatuzumab vedotin available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Roche, a review of this submission by the evidence review group (ERG), the technical report developed through engagement with stakeholders, the responses to the appraisal consultation document and the ERG's review of the company's consultation response. See the committee papers for full details of the evidence.
The appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:
There are no known safety or efficacy issues with using the lyophilised formulation of polatuzumab vedotin instead of the liquid formulation. The committee noted that the company is to supply polatuzumab vedotin in its lyophilised formulation whereas data from the clinical trial were generated with a liquid formulation. The committee considers that this is a regulatory issue.
Polatuzumab vedotin meets the criteria to be considered a life-extending treatment at the end of life because the prognosis of untreated patients is poor (median 10 months estimated by the company) and extension of life is greater than 3 months.It recognised that there were remaining areas of uncertainty associated with the analyses presented and took these into account in its decision making. It discussed the following issues, which were outstanding after the technical engagement stage.
# Clinical need and treatment pathway
## There is a high unmet need for effective treatments
Diffuse large B‑cell lymphoma is an aggressive disease. Symptoms usually develop rapidly and progress quickly. The disease is treated with the aim of cure, but it is refractory to treatment or relapses after initial treatment in up to 50% of patients. The patient expert explained that the prognosis for patients with relapsed or refractory disease is extremely poor with median survival of less than 1 year. Patients can be extremely unwell for many months and often spend many weeks in hospital. The clinical and patient experts explained that relapsed or refractory disease is treated using salvage chemotherapy followed by a haematopoietic stem cell transplant if the person is fit enough for intensive therapy. People who are not fit enough to have a transplant, or whose disease relapses after a transplant, are offered low-intensity chemotherapy regimens. The clinical and patient experts explained that there is a high unmet clinical need in this group of patients for an alternative to palliative care, or regimens with poor outcomes or unacceptable toxicities. The patient expert also highlighted the psychological effects of relapsed or refractory disease for both the patient and their carers, with patients experiencing insomnia, anxiety and a constant fear of relapse and death. The committee concluded that relapsed or refractory diffuse large B‑cell lymphoma is a devastating condition with a poor prognosis and that patients have a high unmet need for effective treatments with manageable side effects.
## There is no standard of care for treating the disease in people who cannot have a haematopoietic stem cell transplant
Polatuzumab vedotin has a conditional marketing authorisation in combination with bendamustine and rituximab for treating relapsed or refractory diffuse large B‑cell lymphoma in adults who cannot have a haematopoietic stem cell transplant. The clinical experts explained that this encompasses 3 main groups of people who:
are older and/or have co-morbidities and would not be fit enough to have a stem cell transplant
have had a stem cell transplant but whose disease then relapsed again
are fit enough for a stem cell transplant but their disease is not sufficiently in remission to proceed with this.The clinical experts explained that there is no standard of care for patients with relapsed or refractory disease who are not able to have a transplant. A number of low-intensity chemotherapy regimens (with or without rituximab, depending on the amount the patient has already had) are currently used, but there is no evidence to show that one regimen is better than another. The committee concluded that there is no standard of care for relapsed or refractory disease in people who cannot have a haematopoietic stem cell transplant.
## Rituximab with bendamustine is a reasonable proxy for standard of care
The comparators for polatuzumab vedotin in the NICE scope were rituximab with 1 or more chemotherapy agents, including rituximab with bendamustine (the comparator in the clinical trial). Direct evidence for polatuzumab vedotin compared with the other rituximab and chemotherapy combinations listed in the scope is not available, and the company and the ERG agreed that a network could not be constructed to inform an indirect comparison. The committee therefore considered whether rituximab with bendamustine could be considered a reasonable proxy for standard of care in the NHS. The clinical experts explained that rituximab with bendamustine is not commonly used to treat diffuse large B‑cell lymphoma in the UK, and it is not routinely funded. However, it is standard of care in other indications such as chronic lymphocytic leukaemia. The clinical experts explained that there is a lack of information on the relative effectiveness of different treatments used in relapsed or refractory diffuse large B‑cell lymphoma. However, rituximab with bendamustine would not be expected to have inferior efficacy or tolerability to other treatments and therefore it would be reasonable to use it as a proxy for standard care. The committee concluded that rituximab with bendamustine is a reasonable proxy for standard of care in the NHS in relapsed or refractory diffuse large B‑cell lymphoma when a haematopoietic stem cell transplant is not an option.
# Clinical evidence
## The GO29365 trial is generalisable to UK clinical practice
The clinical evidence came from trial GO29365. This was a multicentre, randomised, open-label trial of polatuzumab vedotin with rituximab and bendamustine, compared with rituximab with bendamustine alone, in patients with relapsed or refractory disease. Because the trial was open label, patients and their healthcare professionals were aware of treatment allocation. The trial was small (40 patients were randomised to each arm) and 3 patients were from the UK. The clinical experts explained that the trial population was broadly reflective of the population seen in UK clinical practice in terms of age and previous treatments including haematopoietic stem cell transplants. The committee noted the ERG's comment that non-white people were underrepresented in the trial. However, the clinical experts explained that ethnicity is not a factor when considering efficacy or toxicity. The committee also noted the ERG's comment that most patients had an Eastern Cooperative Oncology Group (ECOG) status of 0 or 1. The clinical experts explained that 14 of the 80 people in the trial had an ECOG status of 2, which is consistent with how polatuzumab vedotin would be used in clinical practice. The committee concluded that trial GO29365 is generalisable to the UK.
## The company's adjustments for imbalances between the treatment arms are appropriate
The ERG highlighted that there were imbalances between treatment arms in some prognostic factors such as bulky disease and International Prognostic Index (IPI) score. More people had bulky disease in the comparator arm than in the polatuzumab vedotin arm (37.5% compared with 25%), which could favour polatuzumab vedotin. Conversely, more people in the polatuzumab arm had a lower (more favourable) IPI score (22.5% compared with 7.5% had a score of 0 to 1), which could also favour polatuzumab vedotin. The committee heard from the clinical experts that it was difficult to determine the importance of these imbalances given the small patient numbers involved. The company acknowledged the imbalance of these prognostic factors in its response to technical engagement and conducted multivariable regression and propensity score weighted regression models to adjust the progression-free survival and overall survival for the imbalances. The ERG considered that the company's methods of adjustment were appropriate, with a range of methods tested in sensitivity analyses. The committee concluded that the company's adjustments for the imbalances between the treatment arms were appropriate.
## Polatuzumab vedotin is a promising new treatment
The primary outcome of trial G029365 was complete disease response as judged on PET-CT. Polatuzumab vedotin with bendamustine and rituximab led to a statistically significant 22.5 percentage point greater complete response rate than rituximab and bendamustine alone (95% confidence interval 2.62 to 40.22, p=0.0261). There were also statistically significant benefits in the secondary outcomes of progression-free survival and overall survival. When the company adjusted the results for imbalances in prognostic factors between the 2 arms (see section 3.5) the progression-free survival and overall-survival benefits remained but were less than in the trial. The committee noted that these adjusted estimates were used in the company's updated model that was submitted in response to technical engagement. The committee noted that the progression-free survival data from trial G029365 are mature but heard from the company that further overall-survival data are expected within the next 2 years. The committee concluded that polatuzumab vedotin is a promising new treatment and that the evidence from the trial to date suggests that it extends both progression-free survival and overall survival.
## There is a lack of robust long-term evidence on remission and cure
The company assumed that a proportion of patients having polatuzumab vedotin who are progression free at 2 years are 'cured' from the disease, because it considered that a high complete response rate is associated with improved outcomes in diffuse large B‑cell lymphoma. The committee considered whether this assumption is clinically plausible. It noted the company's comments that at 30‑month follow up, 23% of patients in the polatuzumab vedotin arm were in disease remission (8 complete, 1 partial) compared with 5% in the rituximab with bendamustine arm. The committee heard from the clinical experts that it is too early to say whether polatuzumab vedotin will be a curative treatment. However, at least for the first-line treatment of diffuse large B‑cell lymphoma, long-term survival may be improved when there has been an ongoing complete response lasting more than 24 months, and this is independent of the treatment used. The clinical experts explained that the evidence so far is suggestive of improved long-term survival in a small cohort of patients with relapsed or refractory disease. They also explained that patients who have had several lines of therapy might have improved long-term survival or be 'cured' but would be unlikely to have exactly the same risk of mortality as the general population. This is because some patients would relapse and the treatments themselves can affect long-term survival. The clinical experts estimated that 2-year survival with existing treatments such as rituximab and bendamustine would be around 5% to 10%, although there is no robust data to inform this estimate. In response to the appraisal consultation document the company provided data from a later data cut on progression-free survival and overall survival, which included 1 further event in the polatuzumab vedotin arm. The committee agreed that further follow up would establish the amount of long-term benefit of both treatments. It concluded that there is a lack of robust evidence on long-term remission and cure with polatuzumab vedotin in patients with relapsed or refractory disease. However, the data from the trial so far suggest that a small proportion of people may have a durable response that could indicate cure.
# The company's economic model
## The assumptions about cure in the company's cure-mixture model are highly uncertain
The company presented a 3-state partitioned survival model to estimate the cost effectiveness of polatuzumab vedotin plus rituximab and bendamustine compared with rituximab and bendamustine alone. The company and the ERG used different methods to extrapolate progression-free survival and overall survival and this was the key driver of the cost-effectiveness results. The company used a cure-mixture model, which assumed that the population consisted of 2 groups: a 'cured' population and a population whose disease would progress. About two-thirds of those who were progression-free at 2 years were considered 'cured'. These 'cured' patients had an increased relative risk of mortality (standardised mortality ratio of 1.41) compared to the general population from the start of the model. They were assumed to use no healthcare resources after 3 years and were assigned general population utilities adjusted for age and gender. The company's initial base case used a generalised gamma cure-mixture model. In response to the appraisal consultation document, the company updated its base-case model to a log-normal cure-mixture model. The committee considered whether the company's approach in using a cure-mixture model was appropriate. It noted that the ERG had several concerns about the approach, including the lack of a plateau in the Kaplan–Meier curve for progression-free survival. A plateau would be expected for a treatment that is curative. The ERG also considered that smoothed hazard plots for overall survival and progression-free survival do not suggest a 'cure', and that the company's model overestimates progression-free survival in the intervention arm and underestimates it in the comparator arm towards the end of follow up. The ERG also highlighted NICE's technology appraisal guidance on axicabtagene ciloleucel and tisagenlecleucel. These used cure-mixture models, in which the Kaplan–Meier curves for progression-free survival and overall survival plateaued towards the end of follow up. The committee agreed with the ERG's concerns about the company's modelling approach. It considered that the cure rate assumed by the company was not sufficiently justified because it was based on 2-year progression-free survival in a small trial that only had 40 people in each arm. Also, progression-free survival may not be appropriate for estimating long-term remission. In response to the appraisal consultation document the company presented sensitivity analyses with varied cure rates. The committee considered that it was unclear which of the assumed cure rates was most plausible or how these rates were derived. The clinical experts explained that the assumed rates for the polatuzumab vedotin arm were at the top end of the range of estimates of long-term survival. The committee concluded that there was insufficient evidence to justify assuming a cured proportion from the outset of the model and that the estimate of a cure rate was highly uncertain.
## The probabilistic results from the company's cure-mixture model are implausible and the model is not suitable for decision making
The probabilistic analysis for the company's cure-mixture model estimated that the number of life years gained in the comparator arm with bendamustine and rituximab is more than 2 years. The committee noted that the model included discount rates and, therefore, the true value would be higher. The committee agreed that this seemed unrealistic and inconsistent with clinical opinion and would cast doubt on whether polatuzumab vedotin meets the end of life criteria. The committee agreed that the company's probabilistic analysis for its cure-mixture model lacked face validity. Because of this and the uncertainty around the cure rates (see section 3.8), the committee concluded that the company's cure-mixture model was not suitable for decision making.
## Standard parametric survival modelling is preferred
Because of concerns about the lack of robust long-term evidence to support the cure assumption, the ERG used standard independent parametric survival modelling to extrapolate progression-free survival and overall survival. The committee considered that the ERG's analyses were a more standard approach, noting that they also captured long-term survival. However, it was concerned that the proportion of people predicted to be alive at 5 or 10 years was substantially higher than the proportion predicted to be progression free at the same time points, indicating that some patients had long-term survival with progressed disease. The committee considered that this was not consistent with the comments from clinical experts that survival is associated with an ongoing complete response. In response to the appraisal consultation document, the company presented a scenario analysis using a standard independent parametric survival model with a generalised gamma distribution. The ERG also presented 2 additional scenario analyses that assumed a generalised gamma distribution for progression-free survival and either a log-logistic or log-normal distribution for overall survival. The ERG explained that the difference between the analyses was the method of extrapolating overall survival and that all other parameters were the same. The committee appreciated that the new analyses resulted in a smaller difference in the number of people predicted to be alive at 5 or 10 years and progression‑free at the same time points, compared with the ERG's base case. It concluded that the revised standard parametric modelling was appropriate.
## The company's assumption of a maximum of 6 cycles of treatment is appropriate
The company's model assumes a maximum of 6 cycles of treatment in line with the licence for polatuzumab vedotin and the protocol for trial GO29365. The committee heard from the clinical experts that a maximum of 6 cycles of treatment would be given in clinical practice. However, the ERG had concerns about whether this was appropriate because 5% of patients appeared to have more than 6 cycles in trial GO29365, based on the company's Kaplan–Meier curve for time to off-treatment. The company explained that no patients had more than 6 cycles in the trial, but the time to off-treatment curve is not 0 after 4.15 months (the time point corresponding to 6 cycles) because some patients had delayed doses of treatment. The ERG considered that it was not clear how the time to off-treatment curve was constructed and how the delayed doses were included in the company's calculations. Therefore, the ERG's revised base case included drug costs for patients who had delayed doses of polatuzumab vedotin. The committee noted that this change had a small effect on the cost-effectiveness results, increasing the incremental cost-effectiveness ratio (ICER) by less than £2,000 per quality-adjusted life year (QALY) gained. The committee concluded that this was not a key driver of the results and that the company's approach was appropriate because it reflected clinical practice and the marketing authorisation for polatuzumab vedotin.
## The company's modelling of background mortality is appropriate
The company initially used an individual patient-level approach based on the age distribution in the trial for modelling background mortality. However, the ERG used a single age cohort-based modelling approach in its revised base case. This was consistent with the methods used for modelling progression-free survival and overall survival, which the committee agreed were appropriate. In response to the appraisal consultation document, the company updated its base-case model using the committee's preferred assumption of a single-age cohort of 69 years. The committee concluded that the company's single-age cohort approach was appropriate for modelling background mortality in its updated base case.
# Health-related quality of life
## The utility values are uncertain, but not a driver of the model results
Health-related quality of life was not directly measured in trial GO29365. The company's base-case utility values were estimated from the ZUMA-1 trial based on a small sample of patients with mixed histology lymphoma, using the EQ-5D-5L. The ERG identified some alternative utility sources but did not consider these to be any better than those used by the company. In response to technical engagement the company highlighted that the values chosen for its base case produced the most conservative ICER estimates. The ERG considered that the small variation in the ICERs shows that the utility values are not major drivers of the model results. The committee concluded that even though the company had used the best available data there was considerable uncertainty about the utility values, but these are not a key driver of the cost-effectiveness results for this appraisal. However it was disappointed that no health-related quality of life data were available from trial GO29365, and it did not endorse the approach of basing utility values for large B‑cell lymphoma on data from the ZUMA-1 trial.
# Cost-effectiveness estimate
## Polatuzumab vedotin with rituximab and bendamustine is cost effective compared with rituximab and bendamustine alone
Following consultation, the company submitted cost-effectiveness analyses incorporating an updated commercial arrangement. The committee considered that the most plausible ICER would be derived from a standard parametric survival model (see section 3.10). It noted that the probabilistic and deterministic ICERs from the company's standard parametric model and the ERG's standard parametric analyses (£35,663 to £48,839 per QALY gained) were within the range normally considered a cost-effective use of NHS resources for life-extending treatments at the end of life. Therefore, the committee concluded that polatuzumab vedotin could be recommended for routine use in the NHS.
# Conclusion
## Polatuzumab vedotin with rituximab and bendamustine is recommended for relapsed or refractory diffuse large B-cell lymphoma
There is a high unmet need for effective treatments in relapsed and refractory diffuse large B‑cell lymphoma. Clinical trial evidence shows that polatuzumab vedotin with rituximab and bendamustine increases progression-free survival and overall survival compared with rituximab and bendamustine alone. The committee agreed that all plausible cost-effectiveness estimates were within the range considered to be cost effective for life-extending treatments at the end of life. Therefore, polatuzumab vedotin with rituximab and bendamustine is recommended for relapsed or refractory diffuse large B-cell lymphoma in adults who cannot have a haematopoietic stem cell transplant.
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{'Recommendations': 'Polatuzumab vedotin with rituximab and bendamustine is recommended, within its marketing authorisation, as an option for treating relapsed or refractory diffuse large B‑cell lymphoma in adults who cannot have a haematopoietic stem cell transplant. It is recommended only if the company provides polatuzumab vedotin according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nThere is no standard treatment for relapsed or refractory diffuse large B‑cell lymphoma in people who cannot have a haematopoietic stem cell transplant. They could be offered rituximab with bendamustine, although this is not standard care in the NHS. Clinical evidence shows that people having polatuzumab vedotin plus rituximab and bendamustine have more time before their disease gets worse than people having rituximab and bendamustine alone. It also suggests that they live longer.\n\nPolatuzumab vedotin plus rituximab and bendamustine is considered to be a life-extending treatment at the end of life. The cost-effectiveness estimates are within the range that NICE considers an acceptable use of NHS resources. Therefore, polatuzumab vedotin plus rituximab and bendamustine is recommended.', 'Information about polatuzumab vedotin': "# Marketing authorisation indication\n\nPolatuzumab vedotin (Polivy, Roche) in combination with bendamustine and rituximab is indicated for 'the treatment of adult patients with relapsed or refractory diffuse large B‑cell lymphoma (DLBCL) who are not candidates for haematopoietic stem cell transplant'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe cost per item from the company's submission is £11,060 per 140‑mg vial (excluding VAT; British national formulary online accessed July 2020). The company estimates that the average cost of a course of treatment is £50,416.\n\nThe company has a commercial arrangement. This makes polatuzumab vedotin available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section 5) considered evidence submitted by Roche, a review of this submission by the evidence review group (ERG), the technical report developed through engagement with stakeholders, the responses to the appraisal consultation document and the ERG's review of the company's consultation response. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:\n\nThere are no known safety or efficacy issues with using the lyophilised formulation of polatuzumab vedotin instead of the liquid formulation. The committee noted that the company is to supply polatuzumab vedotin in its lyophilised formulation whereas data from the clinical trial were generated with a liquid formulation. The committee considers that this is a regulatory issue.\n\nPolatuzumab vedotin meets the criteria to be considered a life-extending treatment at the end of life because the prognosis of untreated patients is poor (median 10\xa0months estimated by the company) and extension of life is greater than 3\xa0months.It recognised that there were remaining areas of uncertainty associated with the analyses presented and took these into account in its decision making. It discussed the following issues, which were outstanding after the technical engagement stage.\n\n# Clinical need and treatment pathway\n\n## There is a high unmet need for effective treatments\n\nDiffuse large B‑cell lymphoma is an aggressive disease. Symptoms usually develop rapidly and progress quickly. The disease is treated with the aim of cure, but it is refractory to treatment or relapses after initial treatment in up to 50% of patients. The patient expert explained that the prognosis for patients with relapsed or refractory disease is extremely poor with median survival of less than 1\xa0year. Patients can be extremely unwell for many months and often spend many weeks in hospital. The clinical and patient experts explained that relapsed or refractory disease is treated using salvage chemotherapy followed by a haematopoietic stem cell transplant if the person is fit enough for intensive therapy. People who are not fit enough to have a transplant, or whose disease relapses after a transplant, are offered low-intensity chemotherapy regimens. The clinical and patient experts explained that there is a high unmet clinical need in this group of patients for an alternative to palliative care, or regimens with poor outcomes or unacceptable toxicities. The patient expert also highlighted the psychological effects of relapsed or refractory disease for both the patient and their carers, with patients experiencing insomnia, anxiety and a constant fear of relapse and death. The committee concluded that relapsed or refractory diffuse large B‑cell lymphoma is a devastating condition with a poor prognosis and that patients have a high unmet need for effective treatments with manageable side effects.\n\n## There is no standard of care for treating the disease in people who cannot have a haematopoietic stem cell transplant\n\nPolatuzumab vedotin has a conditional marketing authorisation in combination with bendamustine and rituximab for treating relapsed or refractory diffuse large B‑cell lymphoma in adults who cannot have a haematopoietic stem cell transplant. The clinical experts explained that this encompasses 3\xa0main groups of people who:\n\nare older and/or have co-morbidities and would not be fit enough to have a stem cell transplant\n\nhave had a stem cell transplant but whose disease then relapsed again\n\nare fit enough for a stem cell transplant but their disease is not sufficiently in remission to proceed with this.The clinical experts explained that there is no standard of care for patients with relapsed or refractory disease who are not able to have a transplant. A number of low-intensity chemotherapy regimens (with or without rituximab, depending on the amount the patient has already had) are currently used, but there is no evidence to show that one regimen is better than another. The committee concluded that there is no standard of care for relapsed or refractory disease in people who cannot have a haematopoietic stem cell transplant.\n\n## Rituximab with bendamustine is a reasonable proxy for standard of care\n\nThe comparators for polatuzumab vedotin in the NICE scope were rituximab with 1\xa0or more chemotherapy agents, including rituximab with bendamustine (the comparator in the clinical trial). Direct evidence for polatuzumab vedotin compared with the other rituximab and chemotherapy combinations listed in the scope is not available, and the company and the ERG agreed that a network could not be constructed to inform an indirect comparison. The committee therefore considered whether rituximab with bendamustine could be considered a reasonable proxy for standard of care in the NHS. The clinical experts explained that rituximab with bendamustine is not commonly used to treat diffuse large B‑cell lymphoma in the UK, and it is not routinely funded. However, it is standard of care in other indications such as chronic lymphocytic leukaemia. The clinical experts explained that there is a lack of information on the relative effectiveness of different treatments used in relapsed or refractory diffuse large B‑cell lymphoma. However, rituximab with bendamustine would not be expected to have inferior efficacy or tolerability to other treatments and therefore it would be reasonable to use it as a proxy for standard care. The committee concluded that rituximab with bendamustine is a reasonable proxy for standard of care in the NHS in relapsed or refractory diffuse large B‑cell lymphoma when a haematopoietic stem cell transplant is not an option.\n\n# Clinical evidence\n\n## The GO29365\xa0trial is generalisable to UK clinical practice\n\nThe clinical evidence came from trial\xa0GO29365. This was a multicentre, randomised, open-label trial of polatuzumab vedotin with rituximab and bendamustine, compared with rituximab with bendamustine alone, in patients with relapsed or refractory disease. Because the trial was open label, patients and their healthcare professionals were aware of treatment allocation. The trial was small (40\xa0patients were randomised to each arm) and 3\xa0patients were from the UK. The clinical experts explained that the trial population was broadly reflective of the population seen in UK clinical practice in terms of age and previous treatments including haematopoietic stem cell transplants. The committee noted the ERG's comment that non-white people were underrepresented in the trial. However, the clinical experts explained that ethnicity is not a factor when considering efficacy or toxicity. The committee also noted the ERG's comment that most patients had an Eastern Cooperative Oncology Group (ECOG) status of\xa00\xa0or\xa01. The clinical experts explained that 14\xa0of the 80\xa0people in the trial had an ECOG status of\xa02, which is consistent with how polatuzumab vedotin would be used in clinical practice. The committee concluded that trial\xa0GO29365 is generalisable to the UK.\n\n## The company's adjustments for imbalances between the treatment arms are appropriate\n\nThe ERG highlighted that there were imbalances between treatment arms in some prognostic factors such as bulky disease and International Prognostic Index (IPI) score. More people had bulky disease in the comparator arm than in the polatuzumab vedotin arm (37.5% compared with 25%), which could favour polatuzumab vedotin. Conversely, more people in the polatuzumab arm had a lower (more favourable) IPI score (22.5% compared with 7.5% had a score of 0\xa0to\xa01), which could also favour polatuzumab vedotin. The committee heard from the clinical experts that it was difficult to determine the importance of these imbalances given the small patient numbers involved. The company acknowledged the imbalance of these prognostic factors in its response to technical engagement and conducted multivariable regression and propensity score weighted regression models to adjust the progression-free survival and overall survival for the imbalances. The ERG considered that the company's methods of adjustment were appropriate, with a range of methods tested in sensitivity analyses. The committee concluded that the company's adjustments for the imbalances between the treatment arms were appropriate.\n\n## Polatuzumab vedotin is a promising new treatment\n\nThe primary outcome of trial\xa0G029365 was complete disease response as judged on PET-CT. Polatuzumab vedotin with bendamustine and rituximab led to a statistically significant 22.5\xa0percentage point greater complete response rate than rituximab and bendamustine alone (95%\xa0confidence interval 2.62 to 40.22, p=0.0261). There were also statistically significant benefits in the secondary outcomes of progression-free survival and overall survival. When the company adjusted the results for imbalances in prognostic factors between the 2\xa0arms (see section 3.5) the progression-free survival and overall-survival benefits remained but were less than in the trial. The committee noted that these adjusted estimates were used in the company's updated model that was submitted in response to technical engagement. The committee noted that the progression-free survival data from trial\xa0G029365 are mature but heard from the company that further overall-survival data are expected within the next 2\xa0years. The committee concluded that polatuzumab vedotin is a promising new treatment and that the evidence from the trial to date suggests that it extends both progression-free survival and overall survival.\n\n## There is a lack of robust long-term evidence on remission and cure\n\nThe company assumed that a proportion of patients having polatuzumab vedotin who are progression free at 2\xa0years are 'cured' from the disease, because it considered that a high complete response rate is associated with improved outcomes in diffuse large B‑cell lymphoma. The committee considered whether this assumption is clinically plausible. It noted the company's comments that at 30‑month follow up, 23% of patients in the polatuzumab vedotin arm were in disease remission (8\xa0complete, 1\xa0partial) compared with 5% in the rituximab with bendamustine arm. The committee heard from the clinical experts that it is too early to say whether polatuzumab vedotin will be a curative treatment. However, at least for the first-line treatment of diffuse large B‑cell lymphoma, long-term survival may be improved when there has been an ongoing complete response lasting more than 24\xa0months, and this is independent of the treatment used. The clinical experts explained that the evidence so far is suggestive of improved long-term survival in a small cohort of patients with relapsed or refractory disease. They also explained that patients who have had several lines of therapy might have improved long-term survival or be 'cured' but would be unlikely to have exactly the same risk of mortality as the general population. This is because some patients would relapse and the treatments themselves can affect long-term survival. The clinical experts estimated that 2-year survival with existing treatments such as rituximab and bendamustine would be around 5% to 10%, although there is no robust data to inform this estimate. In response to the appraisal consultation document the company provided data from a later data cut on progression-free survival and overall survival, which included 1 further event in the polatuzumab vedotin arm. The committee agreed that further follow up would establish the amount of long-term benefit of both treatments. It concluded that there is a lack of robust evidence on long-term remission and cure with polatuzumab vedotin in patients with relapsed or refractory disease. However, the data from the trial so far suggest that a small proportion of people may have a durable response that could indicate cure.\n\n# The company's economic model\n\n## The assumptions about cure in the company's cure-mixture model are highly uncertain\n\nThe company presented a 3-state partitioned survival model to estimate the cost effectiveness of polatuzumab vedotin plus rituximab and bendamustine compared with rituximab and bendamustine alone. The company and the ERG used different methods to extrapolate progression-free survival and overall survival and this was the key driver of the cost-effectiveness results. The company used a cure-mixture model, which assumed that the population consisted of 2\xa0groups: a 'cured' population and a population whose disease would progress. About two-thirds of those who were progression-free at 2\xa0years were considered 'cured'. These 'cured' patients had an increased relative risk of mortality (standardised mortality ratio of 1.41) compared to the general population from the start of the model. They were assumed to use no healthcare resources after 3\xa0years and were assigned general population utilities adjusted for age and gender. The company's initial base case used a generalised gamma cure-mixture model. In response to the appraisal consultation document, the company updated its base-case model to a log-normal cure-mixture model. The committee considered whether the company's approach in using a cure-mixture model was appropriate. It noted that the ERG had several concerns about the approach, including the lack of a plateau in the Kaplan–Meier curve for progression-free survival. A plateau would be expected for a treatment that is curative. The ERG also considered that smoothed hazard plots for overall survival and progression-free survival do not suggest a 'cure', and that the company's model overestimates progression-free survival in the intervention arm and underestimates it in the comparator arm towards the end of follow up. The ERG also highlighted NICE's technology appraisal guidance on axicabtagene ciloleucel and tisagenlecleucel. These used cure-mixture models, in which the Kaplan–Meier curves for progression-free survival and overall survival plateaued towards the end of follow up. The committee agreed with the ERG's concerns about the company's modelling approach. It considered that the cure rate assumed by the company was not sufficiently justified because it was based on 2-year progression-free survival in a small trial that only had 40\xa0people in each arm. Also, progression-free survival may not be appropriate for estimating long-term remission. In response to the appraisal consultation document the company presented sensitivity analyses with varied cure rates. The committee considered that it was unclear which of the assumed cure rates was most plausible or how these rates were derived. The clinical experts explained that the assumed rates for the polatuzumab vedotin arm were at the top end of the range of estimates of long-term survival. The committee concluded that there was insufficient evidence to justify assuming a cured proportion from the outset of the model and that the estimate of a cure rate was highly uncertain.\n\n## The probabilistic results from the company's cure-mixture model are implausible and the model is not suitable for decision making\n\nThe probabilistic analysis for the company's cure-mixture model estimated that the number of life years gained in the comparator arm with bendamustine and rituximab is more than 2\xa0years. The committee noted that the model included discount rates and, therefore, the true value would be higher. The committee agreed that this seemed unrealistic and inconsistent with clinical opinion and would cast doubt on whether polatuzumab vedotin meets the end of life criteria. The committee agreed that the company's probabilistic analysis for its cure-mixture model lacked face validity. Because of this and the uncertainty around the cure rates (see section 3.8), the committee concluded that the company's cure-mixture model was not suitable for decision making.\n\n## Standard parametric survival modelling is preferred\n\nBecause of concerns about the lack of robust long-term evidence to support the cure assumption, the ERG used standard independent parametric survival modelling to extrapolate progression-free survival and overall survival. The committee considered that the ERG's analyses were a more standard approach, noting that they also captured long-term survival. However, it was concerned that the proportion of people predicted to be alive at 5 or 10\xa0years was substantially higher than the proportion predicted to be progression free at the same time points, indicating that some patients had long-term survival with progressed disease. The committee considered that this was not consistent with the comments from clinical experts that survival is associated with an ongoing complete response. In response to the appraisal consultation document, the company presented a scenario analysis using a standard independent parametric survival model with a generalised gamma distribution. The ERG also presented 2\xa0additional scenario analyses that assumed a generalised gamma distribution for progression-free survival and either a log-logistic or log-normal distribution for overall survival. The ERG explained that the difference between the analyses was the method of extrapolating overall survival and that all other parameters were the same. The committee appreciated that the new analyses resulted in a smaller difference in the number of people predicted to be alive at 5 or 10\xa0years and progression‑free at the same time points, compared with the ERG's base case. It concluded that the revised standard parametric modelling was appropriate.\n\n## The company's assumption of a maximum of 6\xa0cycles of treatment is appropriate\n\nThe company's model assumes a maximum of 6\xa0cycles of treatment in line with the licence for polatuzumab vedotin and the protocol for trial\xa0GO29365. The committee heard from the clinical experts that a maximum of 6\xa0cycles of treatment would be given in clinical practice. However, the ERG had concerns about whether this was appropriate because 5% of patients appeared to have more than 6\xa0cycles in trial\xa0GO29365, based on the company's Kaplan–Meier curve for time to off-treatment. The company explained that no patients had more than 6\xa0cycles in the trial, but the time to off-treatment curve is not 0 after 4.15\xa0months (the time point corresponding to 6\xa0cycles) because some patients had delayed doses of treatment. The ERG considered that it was not clear how the time to off-treatment curve was constructed and how the delayed doses were included in the company's calculations. Therefore, the ERG's revised base case included drug costs for patients who had delayed doses of polatuzumab vedotin. The committee noted that this change had a small effect on the cost-effectiveness results, increasing the incremental cost-effectiveness ratio (ICER) by less than £2,000 per quality-adjusted life year (QALY) gained. The committee concluded that this was not a key driver of the results and that the company's approach was appropriate because it reflected clinical practice and the marketing authorisation for polatuzumab vedotin.\n\n## The company's modelling of background mortality is appropriate\n\nThe company initially used an individual patient-level approach based on the age distribution in the trial for modelling background mortality. However, the ERG used a single age cohort-based modelling approach in its revised base case. This was consistent with the methods used for modelling progression-free survival and overall survival, which the committee agreed were appropriate. In response to the appraisal consultation document, the company updated its base-case model using the committee's preferred assumption of a single-age cohort of 69\xa0years. The committee concluded that the company's single-age cohort approach was appropriate for modelling background mortality in its updated base case.\n\n# Health-related quality of life\n\n## The utility values are uncertain, but not a driver of the model results\n\nHealth-related quality of life was not directly measured in trial\xa0GO29365. The company's base-case utility values were estimated from the ZUMA-1 trial based on a small sample of patients with mixed histology lymphoma, using the EQ-5D-5L. The ERG identified some alternative utility sources but did not consider these to be any better than those used by the company. In response to technical engagement the company highlighted that the values chosen for its base case produced the most conservative ICER estimates. The ERG considered that the small variation in the ICERs shows that the utility values are not major drivers of the model results. The committee concluded that even though the company had used the best available data there was considerable uncertainty about the utility values, but these are not a key driver of the cost-effectiveness results for this appraisal. However it was disappointed that no health-related quality of life data were available from trial\xa0GO29365, and it did not endorse the approach of basing utility values for large B‑cell lymphoma on data from the ZUMA-1 trial.\n\n# Cost-effectiveness estimate\n\n## Polatuzumab vedotin with rituximab and bendamustine is cost effective compared with rituximab and bendamustine alone\n\nFollowing consultation, the company submitted cost-effectiveness analyses incorporating an updated commercial arrangement. The committee considered that the most plausible ICER would be derived from a standard parametric survival model (see section 3.10). It noted that the probabilistic and deterministic ICERs from the company's standard parametric model and the ERG's standard parametric analyses (£35,663 to £48,839 per QALY gained) were within the range normally considered a cost-effective use of NHS resources for life-extending treatments at the end of life. Therefore, the committee concluded that polatuzumab vedotin could be recommended for routine use in the NHS.\n\n# Conclusion\n\n## Polatuzumab vedotin with rituximab and bendamustine is recommended for relapsed or refractory diffuse large B-cell lymphoma\n\nThere is a high unmet need for effective treatments in relapsed and refractory diffuse large B‑cell lymphoma. Clinical trial evidence shows that polatuzumab vedotin with rituximab and bendamustine increases progression-free survival and overall survival compared with rituximab and bendamustine alone. The committee agreed that all plausible cost-effectiveness estimates were within the range considered to be cost effective for life-extending treatments at the end of life. Therefore, polatuzumab vedotin with rituximab and bendamustine is recommended for relapsed or refractory diffuse large B-cell lymphoma in adults who cannot have a haematopoietic stem cell transplant."}
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https://www.nice.org.uk/guidance/ta649
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Evidence-based recommendations on polatuzumab vedotin (Polivy) with rituximab and bendamustine for treating relapsed or refractory diffuse large B-cell lymphoma in adults who cannot have a haematopoietic stem cell transplant.
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8636b721126fad208098895d47579192f513d1f6
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nice
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Neuropathic pain in adults: pharmacological management in non-specialist settings
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Neuropathic pain in adults: pharmacological management in non-specialist settings
This guideline covers managing neuropathic pain (nerve pain) with pharmacological treatments (drugs) in adults in non-specialist settings. It aims to improve quality of life for people with conditions such as neuralgia, shingles and diabetic neuropathy by reducing pain and promoting increased participation in all aspects of daily living. The guideline sets out how drug treatments for neuropathic pain differ from traditional pain management.
# Introduction
Pain is an unpleasant sensory and emotional experience that can have a significant impact on a person's quality of life, general health, psychological health, and social and economic wellbeing. The International Association for the Study of Pain (IASP 2011) defines neuropathic pain as 'pain caused by a lesion or disease of the somatosensory nervous system'. Central neuropathic pain is defined as 'pain caused by a lesion or disease of the central somatosensory nervous system', and peripheral neuropathic pain is defined as 'pain caused by a lesion or disease of the peripheral somatosensory nervous system'.
Neuropathic pain is very challenging to manage because of the heterogeneity of its aetiologies, symptoms and underlying mechanisms (Beniczky et al. 2005). There is often uncertainty regarding the nature and exact location of a lesion or health condition associated with neuropathic pain, particularly in non-specialist settings. Examples of common conditions that have peripheral neuropathic pain as a symptom are painful diabetic neuropathy, post-herpetic neuralgia, trigeminal neuralgia, post-surgical chronic neuropathic pain, and neuropathic cancer pain (such as, chemotherapy-induced neuropathy, neuropathy secondary to tumour antigens, or caused by direct invasion or compression of neural structures). Examples of conditions that can cause central neuropathic pain include stroke, spinal cord injury and multiple sclerosis. Neuropathic pain can be intermittent or constant, and spontaneous or provoked. Typical descriptions of the pain include terms such as shooting, stabbing, like an electric shock, burning, tingling, tight, numb, prickling, itching and a sensation of pins and needles. People may also describe symptoms of allodynia (pain caused by a stimulus that does not normally provoke pain), hyperalgesia (an increased response to a stimulus that is normally painful), anaesthesia dolorosa (pain felt in an anaesthetic area or region), and sensory gain or loss (IASP 2011).
A review of the epidemiology of chronic pain found that there is still no accurate estimate available for the population prevalence of neuropathic pain (Smith et al. 2012). For example, the prevalence of neuropathic pain overall has been estimated to be between 6% and 8%, from postal surveys in France (Bouhassira 2008) and the UK (Torrance 2006). However, these estimates came from studies using different questionnaires. Other condition-specific studies have also mirrored the heterogeneous nature of neuropathic pain. For example, painful diabetic neuropathy is estimated to affect between 16% and 26% of people with diabetes (Jensen et al. 2006; Ziegler 2008). Prevalence estimates for post‑herpetic neuralgia range from 8% to 19% of people with herpes zoster when defined as pain at 1 month after rash onset, and 8% when defined as pain at 3 months after rash onset (Schmader 2002).
The development of chronic pain after surgery is also fairly common, with estimates of prevalence ranging from 10% to 50% after many common operations (Shipton 2008). This pain is severe in between 2% and 10% of this subgroup of patients, and many of the clinical features closely resemble those of neuropathic pain (Jung et al. 2004; Mikkelsen et al. 2004; Kehlet et al. 2006). Furthermore, a study of 362,693 computerised records in primary care from the Netherlands estimated the annual incidence of neuropathic pain in the general population to be almost 1% (Dieleman et al. 2008). This considerable variability in estimates of the prevalence and incidence of neuropathic pain and similar conditions from general population studies is likely to be because of differences in the definitions of neuropathic pain, methods of assessment and patient selection (Smith and Torrance 2010, Smith et al. 2012).
A number of pharmacological treatments can be used to manage neuropathic pain outside of specialist pain management services. However, there is considerable variation in how treatment is initiated, the dosages used and the order in which drugs are introduced, whether therapeutic doses are achieved and whether there is correct sequencing of therapeutic classes. A further issue is that a number of commonly used treatments are unlicensed for treating neuropathic pain, which may limit their use. These factors may lead to inadequate pain control, with considerable morbidity.
Commonly used pharmacological treatments include antidepressants (tricyclic antidepressants , selective serotonin reuptake inhibitors and serotonin–norepinephrine reuptake inhibitors ), antiepileptic (anticonvulsant) drugs, topical treatments and opioid analgesics. In addition to their potential benefits, all of these drug classes are associated with various adverse effects.
This short clinical guideline aims to improve the care of adults with neuropathic pain by making evidence-based recommendations on the pharmacological management of neuropathic pain outside of specialist pain management services. A further aim is to ensure that people who require specialist assessment and interventions are referred appropriately and in a timely fashion to a specialist pain management service and/or other condition‑specific services.
# Drug recommendations
For all drugs, recommendations are based on evidence of clinical and cost effectiveness and reflect whether their use for the management of neuropathic pain is a good use of NHS resources. This guideline should be used in conjunction with clinical judgement and decision-making appropriate for the individual patient.
The guideline will assume that prescribers will use a drug's summary of product characteristics (SPC) and the British National Formulary (BNF) to inform decisions made with individual patients (this includes obtaining information on special warnings, precautions for use, contraindications and adverse effects of pharmacological treatments).
This guideline recommends some drugs for indications for which they do not have a UK marketing authorisation at the date of publication, if there is good evidence to support that use. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. The patient (or those with authority to give consent on their behalf) should provide informed consent, which should be documented. See the General Medical Council's Good practice in prescribing and managing medicines and devices (2013). Where recommendations have been made for the use of drugs outside their licensed indications (off-label use), these drugs are marked with a footnote in the recommendations.
# Healthcare setting for this guideline
The recommendations in this clinical guideline are for the pharmacological management of neuropathic pain in non-specialist settings only. The Guideline Development Group acknowledged that there are other pharmacological and non-pharmacological treatments that will be of benefit to people with neuropathic pain, within different care pathways in different settings.
# Terms used in this guideline
## Condition-specific service
A condition-specific service is a specialist service that provides treatment for the underlying health condition that is causing neuropathic pain. Examples include neurology, diabetology and oncology services.
## Non-specialist settings
These are primary and secondary care services that do not provide specialist pain services. Non-specialist settings include general practice, general community care and hospital care.
## Participation
The World Health Organization ICF (International Classification of Functioning, Disability and Health, 2001) defines participation as 'A person's involvement in a life situation.' It includes the following domains: learning and applying knowledge, general tasks and demands, mobility, self-care, domestic life, interpersonal interactions and relationships, major life areas, community, and social and civil life.
## Specialist pain services
These are those that that provide comprehensive assessment and multi-modal management of all types of pain, including neuropathic pain.# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.
# List of all recommendations
## Key principles of care
For guidance on safe prescribing and managing withdrawal of antidepressants and dependence-forming medicines, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.
When agreeing a treatment plan with the person, take into account their concerns and expectations, and discuss:
the severity of the pain, and its impact on lifestyle, daily activities (including sleep disturbance) and participation
the underlying cause of the pain and whether this condition has deteriorated
why a particular pharmacological treatment is being offered
the benefits and possible adverse effects of pharmacological treatments, taking into account any physical or psychological problems, and concurrent medications
the importance of dosage titration and the titration process, providing the person with individualised information and advice
coping strategies for pain and for possible adverse effects of treatment
non-pharmacological treatments, for example, physical and psychological therapies (which may be offered through a rehabilitation service) and surgery (which may be offered through specialist services).For more information about involving people in decisions and supporting adherence, see the NICE guideline on medicines adherence.
Consider referring the person to a specialist pain service and/or a condition-specific service at any stage, including at initial presentation and at the regular clinical reviews (see recommendation 1.1.6), if:
they have severe pain or
their pain significantly limits their lifestyle, daily activities (including sleep disturbance) and participation or
their underlying health condition has deteriorated.
Continue existing treatments for people whose neuropathic pain is already effectively managed, taking into account the need for regular clinical reviews (see recommendation 1.1.6).
When introducing a new treatment, take into account any overlap with the old treatments to avoid deterioration in pain control.
After starting or changing a treatment, carry out an early clinical review of dosage titration, tolerability and adverse effects to assess the suitability of the chosen treatment.
Carry out regular clinical reviews to assess and monitor the effectiveness of the treatment. Each review should include an assessment of:
pain control
impact on lifestyle, daily activities (including sleep disturbance) and participation
physical and psychological wellbeing
adverse effects
continued need for treatment.
When withdrawing or switching treatment, taper the withdrawal regimen to take account of dosage and any discontinuation symptoms.
## Treatment
For guidance on safe prescribing and managing withdrawal of antidepressants and dependence-forming medicines, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.
For advice on treating sciatica, see the NICE guideline on low back pain and sciatica and the September 2020 update information.
Offer a choice of amitriptyline, duloxetine, gabapentin or pregabalin as initial treatment for neuropathic pain (except trigeminal neuralgia). See additional information for more on duloxetine, gabapentin and pregabalin.
If the initial treatment is not effective or is not tolerated, offer one of the remaining 3 drugs, and consider switching again if the second and third drugs tried are also not effective or not tolerated.
Consider tramadol only if acute rescue therapy is needed (see recommendation 1.1.12 about long‑term use).
Consider capsaicin cream for people with localised neuropathic pain who wish to avoid, or who cannot tolerate, oral treatments. See additional information for more on capsaicin cream.
Do not start the following to treat neuropathic pain in non-specialist settings, unless advised by a specialist to do so:
cannabis sativa extract
capsaicin patch
lacosamide
lamotrigine
levetiracetam
morphine
-xcarbazepine
topiramate
tramadol (this is referring to long-term use; see recommendation 1.1.10 for short-term use)
venlafaxinesodium valproate (follow the MHRA safety advice on valproate use by women and girls and antiepileptic drugs in pregnancy). December 2022: The MHRA has issued new safety advice on risks associated with valproate for anyone under 55.
Offer carbamazepine as initial treatment for trigeminal neuralgia. Follow the MHRA safety advice on antiepileptic drugs in pregnancy.
If initial treatment with carbamazepine is not effective, is not tolerated or is contraindicated, consider seeking expert advice from a specialist and consider early referral to a specialist pain service or a condition-specific service.# Additional information
# Recommendation 1.1.8
In November 2013, duloxetine was licensed for diabetic peripheral neuropathic pain only, and gabapentin was licensed for peripheral neuropathic pain only, so use for other conditions was off label. See NICE's information on prescribing medicines.
Pregabalin and gabapentin are Class C controlled substances (under the Misuse of Drugs Act 1971) and Schedule 3 under the Misuse of Drugs Regulations 2001. Evaluate patients carefully for a history of drug abuse before prescribing and observe patients for development of signs of abuse and dependence (MHRA, Drug Safety Update April 2019).
Follow the MHRA safety advice on pregabalin in pregnancy.
Return to recommendation 1.1.8
# Recommendation 1.1.11
In November 2013), capsaicin cream (Axsain) was licensed for post-herpetic neuralgia and painful diabetic peripheral polyneuropathy only, so use for other conditions was off label. The SPC states that this should only be used for painful diabetic peripheral polyneuropathy 'under the direct supervision of a hospital consultant who has access to specialist resources'. See NICE's information on prescribing medicines.
Return to recommendation 1.1.11# Research recommendations
The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future.
# Monotherapy versus combination therapy for treating neuropathic pain
What is the clinical effectiveness, cost effectiveness and tolerability of pharmacological monotherapy compared with combination therapy for treating neuropathic pain?
## Why this is important
Combination therapy is commonly prescribed for neuropathic pain. It may also be a helpful option as a stepwise approach if initially used drugs are insufficient at reducing pain. Combination therapy may also result in better tolerability because smaller doses of individual drugs are often used when combined with other drugs. However, there is a lack of trial evidence comparing the clinical and cost effectiveness and tolerability of different drug combinations. Further research should be conducted as described in table 1 below.
Criterion
Explanation
Population
Adults with a diagnosis of neuropathic pain. Neuropathic pain conditions include:
Central neuropathic pain/central pain
Complex regional pain syndromes
Compression neuropathies/nerve compression syndromes
Facial neuralgia
HIV-related neuropathy
Mixed neuropathic pain
Multiple sclerosis
Neurogenic pain
Neuropathic cancer pain/cancer pain
Neuropathic pain
Painful diabetic neuropathy/diabetic neuropathy
Peripheral nerve injury
Peripheral nervous system disease/neuropathies
Phantom limb pain
Polyneuropathies
Post-amputation pain
Post-herpetic neuralgia
Post-stroke pain
Post-treatment/post-surgery/post-operative pain
Radiculopathies/radicular pain
Spinal cord diseases
Spinal cord injury
Trigeminal neuralgia
Intervention(s)
Pharmacological agents as monotherapy or combination therapy. The pharmacological agents include:
Amitriptyline
Clomipramine
Dosulepin (dothiepin)
Doxepin
Imipramine
Lofepramine
Nortriptyline
Trimipramine
Citalopram
Escitalopram
Fluoxetine
Paroxetine
Sertraline
Duloxetine
Mirtazapine
Reboxetine
Trazodone
Venlafaxine
Carbamazepine
Gabapentin
Lacosamide
Lamotrigine
Levetiracetam
Oxcarbazepine
Phenytoin
Pregabalin
Valproate
Topiramate
Buprenorphine
Co-codamol
Co-dydramol
Dihydrocodeine
Fentanyl
Morphine
Oxycodone
Oxycodone with naloxone
Tapentadol
Tramadol
Cannabis sativa extract
Flecainide
-HT1-receptor agonists
Topical capsaicin
Topical lidocaine
Comparator(s)
Any of the above listed pharmacological agents as monotherapy compared with any combinations of the above listed pharmacological agents as combination therapy.
Outcome(s)
Patient-reported global improvement (on a 7-point scale)
Patient-reported improvement in daily physical and emotional functioning including sleep (on a 9-point scale)
At least 30% and 50% pain reduction (on a 11-point Numerical rating scale scale)
Mean change from baseline pain scores (on a 11-NRS scale)
Withdrawal due to adverse effects of the pharmacological agents Adverse effects of the pharmacological agents
HRQoL (for example, EQ-5D, WHOQoL- BREF and London Handicap Scale)
Study design
Parallel triple-blinded randomised controlled trial of at least 12‑weeks' study period (they should not have enriched enrolment).
All participants should have a 'wash-out' period after assessment for inclusion in the study and before randomisation.
Baseline pain scores between arms should be equal and clearly documented.
Concomitant medications should not be allowed or should be restricted and maintained at a stable dose in the study. Difference in concomitant pain medication usage at baseline should be clearly described in each trial arm, including details of the number of patients on different drugs.
Rescue pain medications should either not be allowed or, if used, their use should be accurately documented.
# Relationship between symptoms, cause of neuropathic pain and its treatment
Is response to pharmacological treatment predicted more reliably by underlying aetiology or by symptom characteristics?
## Why this is important
There is little evidence about whether certain symptoms that present in healthcare settings, or whether different neuropathic pain conditions with different aetiologies, respond differently to different treatments. Current evidence is typically focused on particular conditions and is limited to particular drugs. Further research should be conducted as described in table 2 below.
Criterion
Explanation
Population
Adults with a diagnosis of neuropathic pain. Neuropathic pain conditions include:
Central neuropathic pain/central pain
Complex regional pain syndromes
Compression neuropathies/nerve compression syndromes
Facial neuralgia
HIV-related neuropathy
Mixed neuropathic pain
Multiple sclerosis
Neurogenic pain
Neuropathic cancer pain/cancer pain
Neuropathic pain
Painful diabetic neuropathy/diabetic neuropathy
Peripheral nerve injury
Peripheral nervous system disease/neuropathies
Phantom limb pain
Polyneuropathies
Post-amputation pain
Post-herpetic neuralgia
Post-stroke pain
Post-treatment/post-surgery/post-operative pain
Radiculopathies/radicular pain
Spinal cord diseases
Spinal cord injury
Trigeminal neuralgia
Intervention(s)
Any pharmacological agents as monotherapy or combination therapy (see research recommendation B1).
Comparator(s)
Same pharmacological agents chosen as the main treatments of interest but compare the treatment response across different groups of participants with different neuropathic pain conditions or underlying aetiology.
Outcome(s)
Patient-reported global improvement (on a 7-point scale)
Patient-reported improvement in daily physical and emotional functioning including sleep (on a 9-point scale)
At least 30% and 50% pain reduction (on a 11-NRS scale)
Mean change from baseline pain scores (on a 11-NRS scale)
Withdrawal due to adverse effects of the pharmacological agents Adverse effects of the pharmacological agents
HRQoL (for example, EQ-5D, WHOQoL- BREF and London Handicap Scale)
Study design
Prospective cohort study
All participants should have a 'wash-out' period before assessment for inclusion in the study.
Baseline pain scores between arms should be equal and clearly documented.
Concomitant medications should not be allowed, or should be restricted and maintained at stable dose during the study. Difference in concomitant pain medication usage at baseline should be clearly described in each trial arm, including details of the number of patients on different drugs.
Rescue pain medications either not be allowed or, if used, their use should be accurately documented.
# Carbamazepine for treating trigeminal neuralgia
What is the clinical and cost effectiveness of carbamazepine as initial treatment for trigeminal neuralgia compared with other pharmacological treatments?
## Why this is important
Carbamazepine has been the standard treatment for trigeminal neuralgia since the 1960s. Despite the lack of trial evidence, it is perceived by clinicians to be efficacious. Further research should be conducted as described in table 3 below.
Criterion
Explanation
Population
Adults with a diagnosis of trigeminal neuralgia.
Intervention(s)
Carbamazepine as monotherapy.
Comparator(s)
Any of the below listed pharmacological agents as monotherapy or combinations. The pharmacological agents include:
Amitriptyline
Clomipramine
Dosulepin (dothiepin)
Doxepin
Imipramine
Lofepramine
Nortriptyline
Trimipramine
Citalopram
Escitalopram
Fluoxetine
Paroxetine
Sertraline
Duloxetine
Mirtazapine
Reboxetine
Trazodone
Venlafaxine
Carbamazepine
Gabapentin
Lacosamide
Lamotrigine
Levetiracetam
Oxcarbazepine
Phenytoin
Pregabalin
Valproate
Topiramate
Buprenorphine
Co-codamol
Co-dydramol
Dihydrocodeine
Fentanyl
Morphine
Oxycodone
Oxycodone with naloxone
Tapentadol
Tramadol
Cannabis sativa extract
Flecainide
-HT1-receptor agonists
Topical capsaicin
Topical lidocaine
Outcome(s)
Patient-reported global improvement (on a 7-point scale)
Patient-reported improvement in daily physical and emotional functioning including sleep (on a 9-point scale)
At least 30% and 50% pain reduction (on a 11-NRS scale)
Mean change from baseline pain scores (on a 11-NRS scale)
Withdrawal due to adverse effects of the pharmacological agents Adverse effects of the pharmacological agents
HRQoL (for example, EQ-5D, WHOQoL- BREF and London Handicap Scale)
Study design
Parallel triple-blinded randomised controlled trial of at least 12 weeks' study period (they should not have enriched enrolment).
All participants should have a 'wash-out' period after assessment for inclusion in the study and before randomisation.
Baseline pain scores between arms should be equal and clearly documented.
Concomitant medications should not be allowed or should be restricted and maintained at a stable dose during the study. Difference in concomitant pain medication usage at baseline should be clearly described in each trial arm, including details of the number of patients on different drugs.
Rescue pain medications either not be allowed or, if used, their use should be accurately documented.
# Factors affecting participation and quality of life
What are the key factors, including additional care and support, that influence participation and quality of life in people with neuropathic pain?
## Why this is important
There is evidence suggesting that people with neuropathic pain experience poorer physical and mental health than people with other forms of pain, even when adjusted for pain intensity. The discrepancy between pain intensity and quality of life implies that other, unrecognisable factors are important for people with neuropathic pain and that these factors may influence their daily activities and participation. Further research should be conducted as described in table 4 below.
Criterion
Explanation
Population
Adults with a diagnosis of neuropathic pain. Neuropathic pain conditions include:
Central neuropathic pain/central pain
Complex regional pain syndromes
Compression neuropathies/nerve compression syndromes
Facial neuralgia
HIV-related neuropathy
Mixed neuropathic pain
Multiple sclerosis
Neurogenic pain
Neuropathic cancer pain/cancer pain
Neuropathic pain
Painful diabetic neuropathy/diabetic neuropathy
Peripheral nerve injury
Peripheral nervous system disease/neuropathies
Phantom limb pain
Polyneuropathies
Post-amputation pain
Post-herpetic neuralgia
Post-stroke pain
Post-treatment/post-surgery/post-operative pain
Radiculopathies/radicular pain*
Spinal cord diseases
Spinal cord injury
Trigeminal neuralgia
Note: radiculopathies/radicular pain is now within the NICE guideline on low back pain and sciatica.
Intervention(s)
Any important factors, including elements of additional care and support that are perceived as important by adults with neuropathic pain to improve their daily participation.
Comparator(s)
Non-applicable.
Outcome(s)
HRQoL (for example, EQ-5D, WHOQoL- BREF)
Measurements of participation (for example, the London Handicap Scale)
Satisfaction
Patient experiences
Study design
Qualitative research or structured/semi-structured survey questionnaire.
# Impact of drug-related adverse effects on cost effectiveness and quality of life
What is the impact of drug-related adverse effects on health economics and quality of life in neuropathic pain?
## Why this is important
Pharmacological agents for neuropathic pain are associated with various adverse effects. However, there is little evidence about how this affects cost of the quality of life of patients receiving treatment. Further research should be conducted as described in table 5 below.
Criterion
Explanation
Population
Adults with a diagnosis of neuropathic pain. Neuropathic pain conditions include:
Central neuropathic pain/central pain
Complex regional pain syndromes
Compression neuropathies/nerve compression syndromes
Facial neuralgia
HIV-related neuropathy
Mixed neuropathic pain
Multiple sclerosis
Neurogenic pain
Neuropathic cancer pain/cancer pain
Neuropathic pain
Painful diabetic neuropathy/diabetic neuropathy
Peripheral nerve injury
Peripheral nervous system disease/neuropathies
Phantom limb pain
Polyneuropathies
Post-amputation pain
Post-herpetic neuralgia
Post-stroke pain
Post-treatment/post-surgery/post-operative pain
Radiculopathies/radicular pain*
Spinal cord diseases
Spinal cord injury
Trigeminal neuralgia
Note: radiculopathies/radicular pain is now within the NICE guideline on low back pain and sciatica.
Intervention(s)
Any pharmacological treatment for neuropathic pain, alone or in combination (see research recommendation B1)
Comparator(s)
N/A
Outcome(s)
HRQoL (EQ-5D as well as any condition-specific instruments) in people experiencing adverse effects and people experiencing none
Resource-use and costs in people experiencing adverse effects and people experiencing none
Study design
Case–control study
This research should be performed in a cohort of people receiving a variety of pharmacological treatments for neuropathic pain. Those experiencing adverse effects should be matched with those experiencing none, and their HRQoL and resource-use/costs compared. Matching should be performed using as many modifiers of HRQoL as possible, including age, sex and underlying diagnosis.
Analysis of single, named adverse events and also of people experiencing any serious adverse effect (those leading to discontinuation of the medication in question) would be valuable.
# Potential for dependence associated with pharmacological drugs for neuropathic pain
Is there a potential for dependence associated with pharmacological agents for neuropathic pain?
## Why this is important
There has been some suggestion that some pharmacological agents for neuropathic pain are associated with increased potential for misuse. However, there had not been enough high-quality evidence to adequately explore this issue. Further research should be conducted as described in table 6 below.
Criterion
Explanation
Population
Adults with a diagnosis of neuropathic pain. Neuropathic pain conditions include:
Central neuropathic pain/central pain
Complex regional pain syndromes
Compression neuropathies/nerve compression syndromes
Facial neuralgia
HIV-related neuropathy
Mixed neuropathic pain
Multiple sclerosis
Neurogenic pain
Neuropathic cancer pain/cancer pain
Neuropathic pain
Painful diabetic neuropathy/diabetic neuropathy
Peripheral nerve injury
Peripheral nervous system disease/neuropathies
Phantom limb pain
Polyneuropathies
Post-amputation pain
Post-herpetic neuralgia
Post-stroke pain
Post-treatment/post-surgery/post-operative pain
Radiculopathies/radicular pain
Spinal cord diseases
Spinal cord injury
Trigeminal neuralgia
Intervention(s)
Any pharmacological treatment for neuropathic pain, alone or in combination (see research recommendation B1)
Comparator(s)
Any other pharmacological treatment for neuropathic pain, alone or in combination (see research recommendation B1)
Outcome(s)
Drug dependence (including withdrawal symptoms)
Drug abuse or drug misuse
Study design
Long-term follow-up from a randomised controlled trial (minimum 6 months) or community-based observational studies.
For trials:
Intention to observe dependency and misuse should be made in the study protocol and monitored throughout the study period.
All participants should have a 'wash-out' period after assessment for inclusion in the study and before randomisation.
Baseline pain scores between arms should be equal and clearly documented.
Concomitant medications should not be allowed or should be restricted and maintained at a stable dose in the study. Difference in concomitant pain medication usage at baseline should be clearly described in each trial arm, including details of the number of patients on different drugs.
Rescue pain medications should either not be allowed or, if used, their use should be accurately documented.
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{'Introduction': "Pain is an unpleasant sensory and emotional experience that can have a significant impact on a person's quality of life, general health, psychological health, and social and economic wellbeing. The International Association for the Study of Pain (IASP 2011) defines neuropathic pain as 'pain caused by a lesion or disease of the somatosensory nervous system'. Central neuropathic pain is defined as 'pain caused by a lesion or disease of the central somatosensory nervous system', and peripheral neuropathic pain is defined as 'pain caused by a lesion or disease of the peripheral somatosensory nervous system'.\n\nNeuropathic pain is very challenging to manage because of the heterogeneity of its aetiologies, symptoms and underlying mechanisms (Beniczky et al. 2005). There is often uncertainty regarding the nature and exact location of a lesion or health condition associated with neuropathic pain, particularly in non-specialist settings. Examples of common conditions that have peripheral neuropathic pain as a symptom are painful diabetic neuropathy, post-herpetic neuralgia, trigeminal neuralgia, post-surgical chronic neuropathic pain, and neuropathic cancer pain (such as, chemotherapy-induced neuropathy, neuropathy secondary to tumour antigens, or caused by direct invasion or compression of neural structures). Examples of conditions that can cause central neuropathic pain include stroke, spinal cord injury and multiple sclerosis. Neuropathic pain can be intermittent or constant, and spontaneous or provoked. Typical descriptions of the pain include terms such as shooting, stabbing, like an electric shock, burning, tingling, tight, numb, prickling, itching and a sensation of pins and needles. People may also describe symptoms of allodynia (pain caused by a stimulus that does not normally provoke pain), hyperalgesia (an increased response to a stimulus that is normally painful), anaesthesia dolorosa (pain felt in an anaesthetic [numb] area or region), and sensory gain or loss (IASP 2011).\n\nA review of the epidemiology of chronic pain found that there is still no accurate estimate available for the population prevalence of neuropathic pain (Smith et al. 2012). For example, the prevalence of neuropathic pain overall has been estimated to be between 6% and 8%, from postal surveys in France (Bouhassira 2008) and the UK (Torrance 2006). However, these estimates came from studies using different questionnaires. Other condition-specific studies have also mirrored the heterogeneous nature of neuropathic pain. For example, painful diabetic neuropathy is estimated to affect between 16% and 26% of people with diabetes (Jensen et al. 2006; Ziegler 2008). Prevalence estimates for post‑herpetic neuralgia range from 8% to 19% of people with herpes zoster when defined as pain at 1\xa0month after rash onset, and 8% when defined as pain at 3\xa0months after rash onset (Schmader 2002).\n\nThe development of chronic pain after surgery is also fairly common, with estimates of prevalence ranging from 10% to 50% after many common operations (Shipton 2008). This pain is severe in between 2% and 10% of this subgroup of patients, and many of the clinical features closely resemble those of neuropathic pain (Jung et al. 2004; Mikkelsen et al. 2004; Kehlet et al. 2006). Furthermore, a study of 362,693 computerised records in primary care from the Netherlands estimated the annual incidence of neuropathic pain in the general population to be almost 1% (Dieleman et al. 2008). This considerable variability in estimates of the prevalence and incidence of neuropathic pain and similar conditions from general population studies is likely to be because of differences in the definitions of neuropathic pain, methods of assessment and patient selection (Smith and Torrance 2010, Smith et al. 2012).\n\nA number of pharmacological treatments can be used to manage neuropathic pain outside of specialist pain management services. However, there is considerable variation in how treatment is initiated, the dosages used and the order in which drugs are introduced, whether therapeutic doses are achieved and whether there is correct sequencing of therapeutic classes. A further issue is that a number of commonly used treatments are unlicensed for treating neuropathic pain, which may limit their use. These factors may lead to inadequate pain control, with considerable morbidity.\n\nCommonly used pharmacological treatments include antidepressants (tricyclic antidepressants [TCAs], selective serotonin reuptake inhibitors [SSRIs] and serotonin–norepinephrine reuptake inhibitors [SNRIs]), antiepileptic (anticonvulsant) drugs, topical treatments and opioid analgesics. In addition to their potential benefits, all of these drug classes are associated with various adverse effects.\n\nThis short clinical guideline aims to improve the care of adults with neuropathic pain by making evidence-based recommendations on the pharmacological management of neuropathic pain outside of specialist pain management services. A further aim is to ensure that people who require specialist assessment and interventions are referred appropriately and in a timely fashion to a specialist pain management service and/or other condition‑specific services.\n\n# Drug recommendations\n\nFor all drugs, recommendations are based on evidence of clinical and cost effectiveness and reflect whether their use for the management of neuropathic pain is a good use of NHS resources. This guideline should be used in conjunction with clinical judgement and decision-making appropriate for the individual patient.\n\nThe guideline will assume that prescribers will use a drug's summary of product characteristics (SPC) and the British National Formulary (BNF) to inform decisions made with individual patients (this includes obtaining information on special warnings, precautions for use, contraindications and adverse effects of pharmacological treatments).\n\nThis guideline recommends some drugs for indications for which they do not have a UK marketing authorisation at the date of publication, if there is good evidence to support that use. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. The patient (or those with authority to give consent on their behalf) should provide informed consent, which should be documented. See the General Medical Council's Good practice in prescribing and managing medicines and devices (2013). Where recommendations have been made for the use of drugs outside their licensed indications (off-label use), these drugs are marked with a footnote in the recommendations.\n\n# Healthcare setting for this guideline\n\nThe recommendations in this clinical guideline are for the pharmacological management of neuropathic pain in non-specialist settings only. The Guideline Development Group acknowledged that there are other pharmacological and non-pharmacological treatments that will be of benefit to people with neuropathic pain, within different care pathways in different settings.\n\n# Terms used in this guideline\n\n## Condition-specific service\n\nA condition-specific service is a specialist service that provides treatment for the underlying health condition that is causing neuropathic pain. Examples include neurology, diabetology and oncology services.\n\n## Non-specialist settings\n\nThese are primary and secondary care services that do not provide specialist pain services. Non-specialist settings include general practice, general community care and hospital care.\n\n## Participation\n\nThe World Health Organization ICF (International Classification of Functioning, Disability and Health, 2001) defines participation as 'A person's involvement in a life situation.' It includes the following domains: learning and applying knowledge, general tasks and demands, mobility, self-care, domestic life, interpersonal interactions and relationships, major life areas, community, and social and civil life.\n\n## Specialist pain services\n\nThese are those that that provide comprehensive assessment and multi-modal management of all types of pain, including neuropathic pain.", 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThe following guidance is based on the best available evidence. The full\xa0guideline gives details of the methods and the evidence used to develop the guidance.\n\n# List of all recommendations\n\n## Key principles of care\n\nFor guidance on safe prescribing and managing withdrawal of antidepressants and dependence-forming medicines, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.\n\nWhen agreeing a treatment plan with the person, take into account their concerns and expectations, and discuss:\n\nthe severity of the pain, and its impact on lifestyle, daily activities (including sleep disturbance) and participation\n\nthe underlying cause of the pain and whether this condition has deteriorated\n\nwhy a particular pharmacological treatment is being offered\n\nthe benefits and possible adverse effects of pharmacological treatments, taking into account any physical or psychological problems, and concurrent medications\n\nthe importance of dosage titration and the titration process, providing the person with individualised information and advice\n\ncoping strategies for pain and for possible adverse effects of treatment\n\nnon-pharmacological treatments, for example, physical and psychological therapies (which may be offered through a rehabilitation service) and surgery (which may be offered through specialist services).For more information about involving people in decisions and supporting adherence, see the NICE guideline on medicines adherence.\n\nConsider referring the person to a specialist pain service and/or a condition-specific service at any stage, including at initial presentation and at the regular clinical reviews (see recommendation 1.1.6), if:\n\nthey have severe pain or\n\ntheir pain significantly limits their lifestyle, daily activities (including sleep disturbance) and participation or\n\ntheir underlying health condition has deteriorated.\n\nContinue existing treatments for people whose neuropathic pain is already effectively managed, taking into account the need for regular clinical reviews (see recommendation 1.1.6).\n\nWhen introducing a new treatment, take into account any overlap with the old treatments to avoid deterioration in pain control.\n\nAfter starting or changing a treatment, carry out an early clinical review of dosage titration, tolerability and adverse effects to assess the suitability of the chosen treatment.\n\nCarry out regular clinical reviews to assess and monitor the effectiveness of the treatment. Each review should include an assessment of:\n\npain control\n\nimpact on lifestyle, daily activities (including sleep disturbance) and participation\n\nphysical and psychological wellbeing\n\nadverse effects\n\ncontinued need for treatment.\n\nWhen withdrawing or switching treatment, taper the withdrawal regimen to take account of dosage and any discontinuation symptoms.\n\n## Treatment\n\nFor guidance on safe prescribing and managing withdrawal of antidepressants and dependence-forming medicines, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.\n\nFor advice on treating sciatica, see the NICE guideline on low back pain and sciatica and the September 2020 update information.\n\nOffer a choice of amitriptyline, duloxetine, gabapentin or pregabalin as initial treatment for neuropathic pain (except trigeminal neuralgia). See additional information for more on duloxetine, gabapentin and pregabalin.\n\nIf the initial treatment is not effective or is not tolerated, offer one of the remaining 3 drugs, and consider switching again if the second and third drugs tried are also not effective or not tolerated.\n\nConsider tramadol only if acute rescue therapy is needed (see recommendation 1.1.12 about long‑term use).\n\nConsider capsaicin cream for people with localised neuropathic pain who wish to avoid, or who cannot tolerate, oral treatments. See additional information for more on capsaicin cream.\n\nDo not start the following to treat neuropathic pain in non-specialist settings, unless advised by a specialist to do so:\n\ncannabis sativa extract\n\ncapsaicin patch\n\nlacosamide\n\nlamotrigine\n\nlevetiracetam\n\nmorphine\n\noxcarbazepine\n\ntopiramate\n\ntramadol (this is referring to long-term use; see recommendation 1.1.10 for short-term use)\n\nvenlafaxinesodium valproate (follow the MHRA safety advice on valproate use by women and girls and antiepileptic drugs in pregnancy). [amended 2018]December 2022: The MHRA has issued new safety advice on risks associated with valproate for anyone under 55.\n\nOffer carbamazepine as initial treatment for trigeminal neuralgia. Follow the MHRA safety advice on antiepileptic drugs in pregnancy. [amended 2021]\n\nIf initial treatment with carbamazepine is not effective, is not tolerated or is contraindicated, consider seeking expert advice from a specialist and consider early referral to a specialist pain service or a condition-specific service.", 'Additional information': "# Recommendation 1.1.8\n\nIn November 2013, duloxetine was licensed for diabetic peripheral neuropathic pain only, and gabapentin was licensed for peripheral neuropathic pain only, so use for other conditions was off label. See NICE's information on prescribing medicines.\n\nPregabalin and gabapentin are Class C controlled substances (under the Misuse of Drugs Act 1971) and Schedule 3 under the Misuse of Drugs Regulations 2001. Evaluate patients carefully for a history of drug abuse before prescribing and observe patients for development of signs of abuse and dependence (MHRA, Drug Safety Update April 2019).\n\nFollow the MHRA safety advice on pregabalin in pregnancy.\n\nReturn to recommendation 1.1.8\n\n# Recommendation 1.1.11\n\nIn November 2013), capsaicin cream (Axsain) was licensed for post-herpetic neuralgia and painful diabetic peripheral polyneuropathy only, so use for other conditions was off label. The SPC states that this should only be used for painful diabetic peripheral polyneuropathy 'under the direct supervision of a hospital consultant who has access to specialist resources'. See NICE's information on prescribing medicines.\n\nReturn to recommendation 1.1.11", 'Research recommendations': "The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future.\n\n# Monotherapy versus combination therapy for treating neuropathic pain\n\nWhat is the clinical effectiveness, cost effectiveness and tolerability of pharmacological monotherapy compared with combination therapy for treating neuropathic pain?\n\n## Why this is important\n\nCombination therapy is commonly prescribed for neuropathic pain. It may also be a helpful option as a stepwise approach if initially used drugs are insufficient at reducing pain. Combination therapy may also result in better tolerability because smaller doses of individual drugs are often used when combined with other drugs. However, there is a lack of trial evidence comparing the clinical and cost effectiveness and tolerability of different drug combinations. Further research should be conducted as described in table 1 below.\n\nCriterion\n\nExplanation\n\nPopulation\n\nAdults with a diagnosis of neuropathic pain. Neuropathic pain conditions include:\n\nCentral neuropathic pain/central pain\n\nComplex regional pain syndromes\n\nCompression neuropathies/nerve compression syndromes\n\nFacial neuralgia\n\nHIV-related neuropathy\n\nMixed neuropathic pain\n\nMultiple sclerosis\n\nNeurogenic pain\n\nNeuropathic cancer pain/cancer pain\n\nNeuropathic pain\n\nPainful diabetic neuropathy/diabetic neuropathy\n\nPeripheral nerve injury\n\nPeripheral nervous system disease/neuropathies\n\nPhantom limb pain\n\nPolyneuropathies\n\nPost-amputation pain\n\nPost-herpetic neuralgia\n\nPost-stroke pain\n\nPost-treatment/post-surgery/post-operative pain\n\nRadiculopathies/radicular pain\n\nSpinal cord diseases\n\nSpinal cord injury\n\nTrigeminal neuralgia\n\nIntervention(s)\n\nPharmacological agents as monotherapy or combination therapy. The pharmacological agents include:\n\nAmitriptyline\n\nClomipramine\n\nDosulepin (dothiepin)\n\nDoxepin\n\nImipramine\n\nLofepramine\n\nNortriptyline\n\nTrimipramine\n\nCitalopram\n\nEscitalopram\n\nFluoxetine\n\nParoxetine\n\nSertraline\n\nDuloxetine\n\nMirtazapine\n\nReboxetine\n\nTrazodone\n\nVenlafaxine\n\nCarbamazepine\n\nGabapentin\n\nLacosamide\n\nLamotrigine\n\nLevetiracetam\n\nOxcarbazepine\n\nPhenytoin\n\nPregabalin\n\nValproate\n\nTopiramate\n\nBuprenorphine\n\nCo-codamol\n\nCo-dydramol\n\nDihydrocodeine\n\nFentanyl\n\nMorphine\n\nOxycodone\n\nOxycodone with naloxone\n\nTapentadol\n\nTramadol\n\nCannabis sativa extract\n\nFlecainide\n\n-HT1-receptor agonists\n\nTopical capsaicin\n\nTopical lidocaine\n\nComparator(s)\n\nAny of the above listed pharmacological agents as monotherapy compared with any combinations of the above listed pharmacological agents as combination therapy.\n\nOutcome(s)\n\nPatient-reported global improvement (on a 7-point scale)\n\nPatient-reported improvement in daily physical and emotional functioning including sleep (on a 9-point scale)\n\nAt least 30% and 50% pain reduction (on a 11-point Numerical rating scale [NRS] scale)\n\nMean change from baseline pain scores (on a 11-NRS scale)\n\nWithdrawal due to adverse effects of the pharmacological agents Adverse effects of the pharmacological agents\n\nHRQoL (for example, EQ-5D, WHOQoL- BREF and London Handicap Scale)\n\nStudy design\n\nParallel triple-blinded randomised controlled trial of at least 12‑weeks' study period (they should not have enriched enrolment).\n\nAll participants should have a 'wash-out' period after assessment for inclusion in the study and before randomisation.\n\nBaseline pain scores between arms should be equal and clearly documented.\n\nConcomitant medications should not be allowed or should be restricted and maintained at a stable dose in the study. Difference in concomitant pain medication usage at baseline should be clearly described in each trial arm, including details of the number of patients on different drugs.\n\nRescue pain medications should either not be allowed or, if used, their use should be accurately documented.\n\n# Relationship between symptoms, cause of neuropathic pain and its treatment\n\nIs response to pharmacological treatment predicted more reliably by underlying aetiology or by symptom characteristics?\n\n## Why this is important\n\nThere is little evidence about whether certain symptoms that present in healthcare settings, or whether different neuropathic pain conditions with different aetiologies, respond differently to different treatments. Current evidence is typically focused on particular conditions and is limited to particular drugs. Further research should be conducted as described in table 2 below.\n\nCriterion\n\nExplanation\n\nPopulation\n\nAdults with a diagnosis of neuropathic pain. Neuropathic pain conditions include:\n\nCentral neuropathic pain/central pain\n\nComplex regional pain syndromes\n\nCompression neuropathies/nerve compression syndromes\n\nFacial neuralgia\n\nHIV-related neuropathy\n\nMixed neuropathic pain\n\nMultiple sclerosis\n\nNeurogenic pain\n\nNeuropathic cancer pain/cancer pain\n\nNeuropathic pain\n\nPainful diabetic neuropathy/diabetic neuropathy\n\nPeripheral nerve injury\n\nPeripheral nervous system disease/neuropathies\n\nPhantom limb pain\n\nPolyneuropathies\n\nPost-amputation pain\n\nPost-herpetic neuralgia\n\nPost-stroke pain\n\nPost-treatment/post-surgery/post-operative pain\n\nRadiculopathies/radicular pain\n\nSpinal cord diseases\n\nSpinal cord injury\n\nTrigeminal neuralgia\n\nIntervention(s)\n\nAny pharmacological agents as monotherapy or combination therapy (see research recommendation B1).\n\nComparator(s)\n\nSame pharmacological agents chosen as the main treatments of interest but compare the treatment response across different groups of participants with different neuropathic pain conditions or underlying aetiology.\n\nOutcome(s)\n\nPatient-reported global improvement (on a 7-point scale)\n\nPatient-reported improvement in daily physical and emotional functioning including sleep (on a 9-point scale)\n\nAt least 30% and 50% pain reduction (on a 11-NRS scale)\n\nMean change from baseline pain scores (on a 11-NRS scale)\n\nWithdrawal due to adverse effects of the pharmacological agents Adverse effects of the pharmacological agents\n\nHRQoL (for example, EQ-5D, WHOQoL- BREF and London Handicap Scale)\n\nStudy design\n\nProspective cohort study\n\nAll participants should have a 'wash-out' period before assessment for inclusion in the study.\n\nBaseline pain scores between arms should be equal and clearly documented.\n\nConcomitant medications should not be allowed, or should be restricted and maintained at stable dose during the study. Difference in concomitant pain medication usage at baseline should be clearly described in each trial arm, including details of the number of patients on different drugs.\n\nRescue pain medications either not be allowed or, if used, their use should be accurately documented.\n\n# Carbamazepine for treating trigeminal neuralgia\n\nWhat is the clinical and cost effectiveness of carbamazepine as initial treatment for trigeminal neuralgia compared with other pharmacological treatments?\n\n## Why this is important\n\nCarbamazepine has been the standard treatment for trigeminal neuralgia since the 1960s. Despite the lack of trial evidence, it is perceived by clinicians to be efficacious. Further research should be conducted as described in table 3 below.\n\nCriterion\n\nExplanation\n\nPopulation\n\nAdults with a diagnosis of trigeminal neuralgia.\n\nIntervention(s)\n\nCarbamazepine as monotherapy.\n\nComparator(s)\n\nAny of the below listed pharmacological agents as monotherapy or combinations. The pharmacological agents include:\n\nAmitriptyline\n\nClomipramine\n\nDosulepin (dothiepin)\n\nDoxepin\n\nImipramine\n\nLofepramine\n\nNortriptyline\n\nTrimipramine\n\nCitalopram\n\nEscitalopram\n\nFluoxetine\n\nParoxetine\n\nSertraline\n\nDuloxetine\n\nMirtazapine\n\nReboxetine\n\nTrazodone\n\nVenlafaxine\n\nCarbamazepine\n\nGabapentin\n\nLacosamide\n\nLamotrigine\n\nLevetiracetam\n\nOxcarbazepine\n\nPhenytoin\n\nPregabalin\n\nValproate\n\nTopiramate\n\nBuprenorphine\n\nCo-codamol\n\nCo-dydramol\n\nDihydrocodeine\n\nFentanyl\n\nMorphine\n\nOxycodone\n\nOxycodone with naloxone\n\nTapentadol\n\nTramadol\n\nCannabis sativa extract\n\nFlecainide\n\n-HT1-receptor agonists\n\nTopical capsaicin\n\nTopical lidocaine\n\nOutcome(s)\n\nPatient-reported global improvement (on a 7-point scale)\n\nPatient-reported improvement in daily physical and emotional functioning including sleep (on a 9-point scale)\n\nAt least 30% and 50% pain reduction (on a 11-NRS scale)\n\nMean change from baseline pain scores (on a 11-NRS scale)\n\nWithdrawal due to adverse effects of the pharmacological agents Adverse effects of the pharmacological agents\n\nHRQoL (for example, EQ-5D, WHOQoL- BREF and London Handicap Scale)\n\nStudy design\n\nParallel triple-blinded randomised controlled trial of at least 12\xa0weeks' study period (they should not have enriched enrolment).\n\nAll participants should have a 'wash-out' period after assessment for inclusion in the study and before randomisation.\n\nBaseline pain scores between arms should be equal and clearly documented.\n\nConcomitant medications should not be allowed or should be restricted and maintained at a stable dose during the study. Difference in concomitant pain medication usage at baseline should be clearly described in each trial arm, including details of the number of patients on different drugs.\n\nRescue pain medications either not be allowed or, if used, their use should be accurately documented.\n\n# Factors affecting participation and quality of life\n\nWhat are the key factors, including additional care and support, that influence participation and quality of life in people with neuropathic pain?\n\n## Why this is important\n\nThere is evidence suggesting that people with neuropathic pain experience poorer physical and mental health than people with other forms of pain, even when adjusted for pain intensity. The discrepancy between pain intensity and quality of life implies that other, unrecognisable factors are important for people with neuropathic pain and that these factors may influence their daily activities and participation. Further research should be conducted as described in table 4 below.\n\nCriterion\n\nExplanation\n\nPopulation\n\nAdults with a diagnosis of neuropathic pain. Neuropathic pain conditions include:\n\nCentral neuropathic pain/central pain\n\nComplex regional pain syndromes\n\nCompression neuropathies/nerve compression syndromes\n\nFacial neuralgia\n\nHIV-related neuropathy\n\nMixed neuropathic pain\n\nMultiple sclerosis\n\nNeurogenic pain\n\nNeuropathic cancer pain/cancer pain\n\nNeuropathic pain\n\nPainful diabetic neuropathy/diabetic neuropathy\n\nPeripheral nerve injury\n\nPeripheral nervous system disease/neuropathies\n\nPhantom limb pain\n\nPolyneuropathies\n\nPost-amputation pain\n\nPost-herpetic neuralgia\n\nPost-stroke pain\n\nPost-treatment/post-surgery/post-operative pain\n\nRadiculopathies/radicular pain*\n\nSpinal cord diseases\n\nSpinal cord injury\n\nTrigeminal neuralgia\n\nNote: radiculopathies/radicular pain is now within the NICE guideline on low back pain and sciatica.\n\nIntervention(s)\n\nAny important factors, including elements of additional care and support that are perceived as important by adults with neuropathic pain to improve their daily participation.\n\nComparator(s)\n\nNon-applicable.\n\nOutcome(s)\n\nHRQoL (for example, EQ-5D, WHOQoL- BREF)\n\nMeasurements of participation (for example, the London Handicap Scale)\n\nSatisfaction\n\nPatient experiences\n\nStudy design\n\nQualitative research or structured/semi-structured survey questionnaire.\n\n# Impact of drug-related adverse effects on cost effectiveness and quality of life\n\nWhat is the impact of drug-related adverse effects on health economics and quality of life in neuropathic pain?\n\n## Why this is important\n\nPharmacological agents for neuropathic pain are associated with various adverse effects. However, there is little evidence about how this affects cost of the quality of life of patients receiving treatment. Further research should be conducted as described in table 5 below.\n\nCriterion\n\nExplanation\n\nPopulation\n\nAdults with a diagnosis of neuropathic pain. Neuropathic pain conditions include:\n\nCentral neuropathic pain/central pain\n\nComplex regional pain syndromes\n\nCompression neuropathies/nerve compression syndromes\n\nFacial neuralgia\n\nHIV-related neuropathy\n\nMixed neuropathic pain\n\nMultiple sclerosis\n\nNeurogenic pain\n\nNeuropathic cancer pain/cancer pain\n\nNeuropathic pain\n\nPainful diabetic neuropathy/diabetic neuropathy\n\nPeripheral nerve injury\n\nPeripheral nervous system disease/neuropathies\n\nPhantom limb pain\n\nPolyneuropathies\n\nPost-amputation pain\n\nPost-herpetic neuralgia\n\nPost-stroke pain\n\nPost-treatment/post-surgery/post-operative pain\n\nRadiculopathies/radicular pain*\n\nSpinal cord diseases\n\nSpinal cord injury\n\nTrigeminal neuralgia\n\nNote: radiculopathies/radicular pain is now within the NICE guideline on low back pain and sciatica.\n\nIntervention(s)\n\nAny pharmacological treatment for neuropathic pain, alone or in combination (see research recommendation B1)\n\nComparator(s)\n\nN/A\n\nOutcome(s)\n\nHRQoL (EQ-5D as well as any condition-specific instruments) in people experiencing adverse effects and people experiencing none\n\nResource-use and costs in people experiencing adverse effects and people experiencing none\n\nStudy design\n\nCase–control study\n\nThis research should be performed in a cohort of people receiving a variety of pharmacological treatments for neuropathic pain. Those experiencing adverse effects should be matched with those experiencing none, and their HRQoL and resource-use/costs compared. Matching should be performed using as many modifiers of HRQoL as possible, including age, sex and underlying diagnosis.\n\nAnalysis of single, named adverse events and also of people experiencing any serious adverse effect (those leading to discontinuation of the medication in question) would be valuable.\n\n# Potential for dependence associated with pharmacological drugs for neuropathic pain\n\nIs there a potential for dependence associated with pharmacological agents for neuropathic pain?\n\n## Why this is important\n\nThere has been some suggestion that some pharmacological agents for neuropathic pain are associated with increased potential for misuse. However, there had not been enough high-quality evidence to adequately explore this issue. Further research should be conducted as described in table 6 below.\n\nCriterion\n\nExplanation\n\nPopulation\n\nAdults with a diagnosis of neuropathic pain. Neuropathic pain conditions include:\n\nCentral neuropathic pain/central pain\n\nComplex regional pain syndromes\n\nCompression neuropathies/nerve compression syndromes\n\nFacial neuralgia\n\nHIV-related neuropathy\n\nMixed neuropathic pain\n\nMultiple sclerosis\n\nNeurogenic pain\n\nNeuropathic cancer pain/cancer pain\n\nNeuropathic pain\n\nPainful diabetic neuropathy/diabetic neuropathy\n\nPeripheral nerve injury\n\nPeripheral nervous system disease/neuropathies\n\nPhantom limb pain\n\nPolyneuropathies\n\nPost-amputation pain\n\nPost-herpetic neuralgia\n\nPost-stroke pain\n\nPost-treatment/post-surgery/post-operative pain\n\nRadiculopathies/radicular pain\n\nSpinal cord diseases\n\nSpinal cord injury\n\nTrigeminal neuralgia\n\nIntervention(s)\n\nAny pharmacological treatment for neuropathic pain, alone or in combination (see research recommendation B1)\n\nComparator(s)\n\nAny other pharmacological treatment for neuropathic pain, alone or in combination (see research recommendation B1)\n\nOutcome(s)\n\nDrug dependence (including withdrawal symptoms)\n\nDrug abuse or drug misuse\n\nStudy design\n\nLong-term follow-up from a randomised controlled trial (minimum 6\xa0months) or community-based observational studies.\n\nFor trials:\n\nIntention to observe dependency and misuse should be made in the study protocol and monitored throughout the study period.\n\nAll participants should have a 'wash-out' period after assessment for inclusion in the study and before randomisation.\n\nBaseline pain scores between arms should be equal and clearly documented.\n\nConcomitant medications should not be allowed or should be restricted and maintained at a stable dose in the study. Difference in concomitant pain medication usage at baseline should be clearly described in each trial arm, including details of the number of patients on different drugs.\n\nRescue pain medications should either not be allowed or, if used, their use should be accurately documented."}
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https://www.nice.org.uk/guidance/cg173
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This guideline covers managing neuropathic pain (nerve pain) with pharmacological treatments (drugs) in adults in non-specialist settings. It aims to improve quality of life for people with conditions such as neuralgia, shingles and diabetic neuropathy by reducing pain and promoting increased participation in all aspects of daily living. The guideline sets out how drug treatments for neuropathic pain differ from traditional pain management.
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f82cad6c8efb13c0cd3cc64169cc89ef400e657f
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nice
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Insect bites and stings: antimicrobial prescribing
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Insect bites and stings: antimicrobial prescribing
This guideline sets out an antimicrobial prescribing strategy for insect and spider bites and stings in adults, young people and children aged 72 hours and over, including those that occurred while travelling outside the UK. It aims to limit antibiotic use and reduce antibiotic resistance.
# Recommendations
# Managing insect bites and stings
## Assessment and advice
Be aware that:
a rapid-onset skin reaction from an insect bite or sting is likely to be an inflammatory or allergic reaction, rather than an infection
most insect bites or stings will not need antibiotics.
Assess the type and severity of the insect bite or stings to identify:
a local inflammatory or allergic skin reaction
erythema migrans (bullseye rash), a sign of Lyme disease (see the NICE guideline on Lyme disease)
symptoms or signs of an infection
a systemic reaction (see the recommendations on referral and seeking specialist advice).
Advise people with an insect bite or sting that:
a community pharmacist can advise about self‑care treatments
skin redness and itching are common and may last for up to 10 days
it is unlikely that the skin will become infected
avoiding scratching may reduce inflammation and the risk of infection
they should seek medical help if symptoms worsen rapidly or significantly at any time, or they become systemically unwell.
For people with a known or suspected tick bite, follow the NICE guideline on Lyme disease.
For a short explanation of why the committee made these recommendations, see the rationale section on assessment and advice .
For more details, see the evidence review.
Loading. Please wait.
## Treating a local inflammatory or allergic skin reaction
Do not offer an antibiotic for an insect bite or sting in people who do not have symptoms or signs of an infection.
Be aware that people may wish to consider oral antihistamines (in people aged over 1 year) to help relieve itching, even though there is uncertainty about their effectiveness in managing insect bites or stings. Some antihistamines cause sedation, which may help at night.
## Treating an infected insect bite or sting
For people with an insect bite or sting who have symptoms or signs of an infection, see the recommendations on choice of antibiotic in the NICE guideline on cellulitis and erysipelas.
For a short explanation of why the committee made these recommendations, see the rationale section on treatment .
For more details, see the summary of the evidence.
Loading. Please wait.
## Reassessment
Reassess people with an insect bite or sting if:
symptoms or signs of an infection develop (see the NICE guideline on cellulitis and erysipelas)
their condition worsens rapidly or significantly, or they become systemically unwell
they have severe pain out of proportion to the wound, which may indicate the presence of toxin‑producing bacteria.
When reassessing people with an insect bite or sting, take account of other possible diagnoses such as Lyme disease (see the NICE guideline on Lyme disease).
## Referral and seeking specialist advice
Refer people with an insect bite or sting to hospital if they have symptoms or signs suggesting a more serious illness or condition, such as a systemic allergic reaction (see the NICE guideline on anaphylaxis).
Consider referral or seeking specialist advice for people with an insect bite or sting if:
they are systemically unwell
they are severely immunocompromised, and have symptoms or signs of an infection
they have had a previous systemic allergic reaction to the same type of bite or sting
it is in the mouth or throat, or around the eyes
it has been caused by an unusual or exotic insect
they have fever or persisting lesions associated with a bite or sting that occurred while travelling outside the UK.
For a short explanation of why the committee made these recommendations, see the rationale section on referral and seeking specialist advice .
For more details, see the evidence review.
Loading. Please wait.
# Terms used in the guideline
## Cellulitis and erysipelas
Infections of the tissues under the skin (subcutaneous), which usually result from a contaminated break in the skin. Both conditions are characterised by acute localised inflammation and oedema. The lesions are more superficial in erysipelas and have a well-defined, raised margin.
## Erythema migrans
Erythema migrans is an expanding rash often seen in the early stage of Lyme disease, and can also (but less commonly) be caused by southern tick-associated rash illness. It usually becomes visible from 1 to 4 weeks (but can appear from 3 days to 3 months) after a tick bite and lasts for several weeks.
## Insect bite or sting
For the purpose of this guideline, 'insect bites' also includes bites from spiders and ticks. Insects may bite with their mouthparts when feeding or defending themselves. Stings come from bees, wasps and hornets and are used only for defence.# Rationales
The recommendations in this guideline are based on the evidence identified and the experience of the committee.
# Assessment and advice
## Why the committee made the recommendations
Recommendations 1.1.1 to 1.1.4
Most insect bites and stings can be treated at home with simple first aid, with advice from a community pharmacist. Prescribers are unlikely to be involved even when, rarely, symptoms may last for up to 10 days. This is because secondary bacterial infection is rare. The committee agreed that, usually, knowing what caused the bite or sting is unlikely to change how it is treated.
The committee also noted that redness, itchiness, or pain and swelling after an insect bite or sting is much more likely to be an inflammatory or allergic reaction rather than an infection, especially when there is a rapid onset. They recognised that inflammation after an insect bite or sting may appear like an infection but does not mean that antibiotics are needed. The committee noted that the extent of redness from an insect bite or sting may be less visible on darker skin tones, and healthcare professionals should take this into account when assessing insect bites.
The committee agreed that it was important to prompt people to think about whether the bite may be a tick bite, and to check whether erythema migrans is present. This is so that a known or suspected tick bite can be managed appropriately in line with the NICE guideline on Lyme disease.
Return to the recommendations
# Treatment
## Why the committee made the recommendations
Recommendations 1.1.5 to 1.1.7
Although biting insects can carry bacteria on their mouthparts, most infected bites are likely to be secondary bacterial infections that arise from scratching the bite lesion. Symptoms and signs of infection most likely indicate cellulitis and should be treated with antibiotics in line with the NICE guideline on cellulitis and erysipelas.
There is limited evidence with high uncertainty for the use of oral antihistamines in reducing lesion size and itchiness from mosquito bites. However, based on their experience, the committee agreed that oral antihistamines may help to relieve itching. Although the included study of oral antihistamines compared with placebo included only children who were aged 2 years and over, the committee acknowledged that oral antihistamines are also an option for adults and children under 2 years. Not all antihistamines are licensed for treating insect bites and stings, and not all antihistamines are licensed in young children. The committee also discussed the use of sedating antihistamines in children, noting that the BNF for children states: 'sedating antihistamines are occasionally useful when insomnia is associated with urticaria and pruritus'.
No evidence was found for other self-care treatments that are often used in practice (such as topical corticosteroids, topical antihistamines and analgesics). However, studies published before the year 2000 that compared these treatments were not included in the literature search. Given the range of potential self-care treatments and differences in licensed indications, the committee concluded that a community pharmacist is ideally placed to advise people about managing an insect bite or sting at home.
For more detail, see the summary of the evidence on oral antihistamines for uninfected mosquito bites in adults and antihistamines for uninfected mosquito bites in children.
Return to the recommendations
# Referral and seeking specialist advice
## Why the committee made the recommendations
Recommendations 1.1.10 to 1.1.11
Insect bites and stings are the second most common cause of serious allergic reactions, so the committee agreed that people with symptoms or signs of a serious allergic reaction should be referred for urgent care.
It is also important to consider referral or seeking specialist advice in the following situations:
people who have had a previous systemic allergic reaction to the same type of bite or sting because a serious allergic reaction is more likely
people with a bite or sting in the mouth or throat, or around the eyes
people with a bite or sting from an unusual or exotic insect or spider, because management may be different (for example, certain spider bites can lead to tissue necrosis)
people with fever or persistent lesions after an insect bite or sting from outside the UK because this may indicate a more serious illness such as rickettsia or malaria.
Return to the recommendations# Context
An insect bite or sting often causes a small, red lump on the skin, which may be painful and itchy. Secondary bacterial infection is unlikely; it is unclear which causative organisms are most common.# Summary of the evidence
This is a summary of the evidence. For full details, see the evidence review.
The evidence included:
randomised controlled trial in adults with extensive cellulitis caused by an arthropod bite (Friedland et al. 2012)
systematic review of double-blind crossover randomised controlled trials of oral antihistamines in people with uninfected mosquito bites (Foex et al. 2006)
double-blind crossover randomised controlled trials of oral antihistamines in people with uninfected mosquito bites (Karpinnen et al. 2006 and Karpinnen et al. 2012)
retrospective study (Dyachenko and Rozenman 2006) of treatments in people with an uninfected bite (confirmed or presumed to be caused by a brown recluse spider).
Randomised controlled trial evidence was only identified for the effectiveness of oral antihistamines in adults and children with mosquito bites and for intravenous antibiotics in adults with an infected arthropod (of undefined species) bite. Only 1 of the randomised controlled trials included people with a secondary infection of their bite and this was a subgroup of people with an infected arthropod bite from a larger trial.
No evidence was identified for antibiotics in children and young people.
# Antibiotics for infected arthropod bites in adults
Based on clinical response at day 3, there was no statistically significant difference in the clinical effectiveness of intravenous ceftaroline compared with intravenous vancomycin plus intravenous aztreonam (Friedland et al. 2012) in adults with extensive cellulitis caused by an arthropod bite. No adverse effect data were reported.
# Oral antihistamines for uninfected mosquito bites in adults
## Cetirizine 10 mg once or twice daily compared with placebo
There was no statistically significant difference in median mosquito bite lesion size at 10 minutes, 60 minutes, 12 hours or 24 hours with cetirizine compared with placebo. In 2 studies, there was a statistically significant difference in median mosquito bite lesion size at 15 minutes compared with placebo (but no statistically significant difference was seen in a third study).
There was no statistically significant difference in pruritus after mosquito bite exposure at 10 minutes, 30 minutes, 90 minutes, 24 hours, 48 hours, 5 days or 7 to 10 days with cetirizine compared with placebo. However, there was a statistically significant reduction in mean or median pruritus scores at other time points: 15 minutes, 60 minutes, 12 hours, and at days 3, 4 and 6.
There was no statistically significant difference in adverse effects (mild to severe sedation, headache, emesis or arthralgia) at follow up.
In 1 study, 7 of 9 people preferred cetirizine 10 mg twice daily (1 preferred placebo and the other had no preference).
## Levocetirizine 5 mg once daily compared with placebo
There was a statistically significant reduction in both median mosquito bite lesion size and median pruritus scores at 15 minutes, and in delayed bite lesions at 24 hours.
There was no statistically significant difference in adverse effects (mild to moderate somnolence) at follow up.
## Loratadine 10 mg once daily compared with placebo
There was no statistically significant difference in median mosquito bite lesion size or median pruritus scores at 15 minutes.
There was no statistically significant difference in adverse effects (mild to moderate sedation) at follow up.
## Rupatadine 10 mg once daily compared with placebo
There was a statistically significant difference in median mosquito bite lesion size at 15 minutes, but no statistically significant difference in delayed bite lesion size at 24 hours. There was also a statistically significant reduction in median pruritus scores at 15 minutes but no statistically significant difference for delayed bite reaction pruritis at 24 hours.
Adverse effects (sedation) were statistically significantly increased at follow up.
# Antihistamines for uninfected mosquito bites in children
## Loratadine 0.3 mg/kg once daily compared with placebo
There was a statistically significant reduction in median bite lesion size at 15 minutes and 24 hours but no statistically significant difference at 2 hours and 6 hours. There was also a statistically significant reduction in median pruritus score at 15 minutes.
There was no statistically significant difference in adverse effects (mild gastrointestinal pain and diarrhoea) at follow up.
# Treatments for uninfected brown recluse spider bites
A single-centre retrospective study (Dyachenko and Rozenman 2006) reported data for 52 people with an uninfected bite that was confirmed or presumed to be caused by a brown recluse spider. The study included people aged 9 to 66 years; results were not broken down by age.
All patients had prophylactic antibiotics (92.3% had cefalexin; no further details given), rest, cold compression and elevation. Most patients (92.3%) had prednisolone and an antihistamine (no further details given), and 21 patients (40.4%) had a non-steroidal anti-inflammatory drug. All the outcomes were assessed as being of very low quality.
The authors concluded that none of the treatments prevented necrotic lesions, and their role in time to healing and length of hospital stay was unclear.
See the evidence review for more information.
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{'Recommendations': "# Managing insect bites and stings\n\n## Assessment and advice\n\nBe aware that:\n\na rapid-onset skin reaction from an insect bite or sting is likely to be an inflammatory or allergic reaction, rather than an infection\n\nmost insect bites or stings will not need antibiotics.\n\nAssess the type and severity of the insect bite or stings to identify:\n\na local inflammatory or allergic skin reaction\n\nerythema migrans (bullseye rash), a sign of Lyme disease (see the NICE guideline on Lyme disease)\n\nsymptoms or signs of an infection\n\na systemic reaction (see the recommendations on referral and seeking specialist advice).\n\nAdvise people with an insect bite or sting that:\n\na community pharmacist can advise about self‑care treatments\n\nskin redness and itching are common and may last for up to 10\xa0days\n\nit is unlikely that the skin will become infected\n\navoiding scratching may reduce inflammation and the risk of infection\n\nthey should seek medical help if symptoms worsen rapidly or significantly at any time, or they become systemically unwell.\n\nFor people with a known or suspected tick bite, follow the NICE guideline on Lyme disease.\n\nFor a short explanation of why the committee made these recommendations, see the rationale section on assessment and advice\xa0.\n\nFor more details, see the evidence review.\n\nLoading. Please wait.\n\n## Treating a local inflammatory or allergic skin reaction\n\nDo not offer an antibiotic for an insect bite or sting in people who do not have symptoms or signs of an infection.\n\nBe aware that people may wish to consider oral antihistamines (in people aged over 1\xa0year) to help relieve itching, even though there is uncertainty about their effectiveness in managing insect bites or stings. Some antihistamines cause sedation, which may help at night.\n\n## Treating an infected insect bite or sting\n\nFor people with an insect bite or sting who have symptoms or signs of an infection, see the recommendations on choice of antibiotic in the NICE guideline on cellulitis and erysipelas.\n\nFor a short explanation of why the committee made these recommendations, see the rationale section on treatment\xa0.\n\nFor more details, see the summary of the evidence.\n\nLoading. Please wait.\n\n## Reassessment\n\nReassess people with an insect bite or sting if:\n\nsymptoms or signs of an infection develop (see the NICE guideline on cellulitis and erysipelas)\n\ntheir condition worsens rapidly or significantly, or they become systemically unwell\n\nthey have severe pain out of proportion to the wound, which may indicate the presence of toxin‑producing bacteria.\n\nWhen reassessing people with an insect bite or sting, take account of other possible diagnoses such as Lyme disease (see the NICE guideline on Lyme disease).\n\n## Referral and seeking specialist advice\n\nRefer people with an insect bite or sting to hospital if they have symptoms or signs suggesting a more serious illness or condition, such as a systemic allergic reaction (see the NICE guideline on anaphylaxis).\n\nConsider referral or seeking specialist advice for people with an insect bite or sting if:\n\nthey are systemically unwell\n\nthey are severely immunocompromised, and have symptoms or signs of an infection\n\nthey have had a previous systemic allergic reaction to the same type of bite or sting\n\nit is in the mouth or throat, or around the eyes\n\nit has been caused by an unusual or exotic insect\n\nthey have fever or persisting lesions associated with a bite or sting that occurred while travelling outside the UK.\n\nFor a short explanation of why the committee made these recommendations, see the rationale section on referral and seeking specialist advice\xa0.\n\nFor more details, see the evidence review.\n\nLoading. Please wait.\n\n# Terms used in the guideline\n\n## Cellulitis and erysipelas\n\nInfections of the tissues under the skin (subcutaneous), which usually result from a contaminated break in the skin. Both conditions are characterised by acute localised inflammation and oedema. The lesions are more superficial in erysipelas and have a well-defined, raised margin.\n\n## Erythema migrans\n\nErythema migrans is an expanding rash often seen in the early stage of Lyme disease, and can also (but less commonly) be caused by southern tick-associated rash illness. It usually becomes visible from 1 to\xa04\xa0weeks (but can appear from 3\xa0days to 3\xa0months) after a tick bite and lasts for several weeks.\n\n## Insect bite or sting\n\nFor the purpose of this guideline, 'insect bites' also includes bites from spiders and ticks. Insects may bite with their mouthparts when feeding or defending themselves. Stings come from bees, wasps and hornets and are used only for defence.", 'Rationales': "The recommendations in this guideline are based on the evidence identified and the experience of the committee.\n\n# Assessment and advice\n\n## Why the committee made the recommendations\n\nRecommendations 1.1.1 to 1.1.4\n\nMost insect bites and stings can be treated at home with simple first aid, with advice from a community pharmacist. Prescribers are unlikely to be involved even when, rarely, symptoms may last for up to 10\xa0days. This is because secondary bacterial infection is rare. The committee agreed that, usually, knowing what caused the bite or sting is unlikely to change how it is treated.\n\nThe committee also noted that redness, itchiness, or pain and swelling after an insect bite or sting is much more likely to be an inflammatory or allergic reaction rather than an infection, especially when there is a rapid onset. They recognised that inflammation after an insect bite or sting may appear like an infection but does not mean that antibiotics are needed. The committee noted that the extent of redness from an insect bite or sting may be less visible on darker skin tones, and healthcare professionals should take this into account when assessing insect bites.\n\nThe committee agreed that it was important to prompt people to think about whether the bite may be a tick bite, and to check whether erythema migrans is present. This is so that a known or suspected tick bite can be managed appropriately in line with the NICE guideline on Lyme disease.\n\nReturn to the recommendations\n\n# Treatment\n\n## Why the committee made the recommendations\n\nRecommendations 1.1.5 to 1.1.7\n\nAlthough biting insects can carry bacteria on their mouthparts, most infected bites are likely to be secondary bacterial infections that arise from scratching the bite lesion. Symptoms and signs of infection most likely indicate cellulitis and should be treated with antibiotics in line with the NICE guideline on cellulitis and erysipelas.\n\nThere is limited evidence with high uncertainty for the use of oral antihistamines in reducing lesion size and itchiness from mosquito bites. However, based on their experience, the committee agreed that oral antihistamines may help to relieve itching. Although the included study of oral antihistamines compared with placebo included only children who were aged 2\xa0years and over, the committee acknowledged that oral antihistamines are also an option for adults and children under 2\xa0years. Not all antihistamines are licensed for treating insect bites and stings, and not all antihistamines are licensed in young children. The committee also discussed the use of sedating antihistamines in children, noting that the BNF for children states: 'sedating antihistamines are occasionally useful when insomnia is associated with urticaria and pruritus'.\n\nNo evidence was found for other self-care treatments that are often used in practice (such as topical corticosteroids, topical antihistamines and analgesics). However, studies published before the year 2000 that compared these treatments were not included in the literature search. Given the range of potential self-care treatments and differences in licensed indications, the committee concluded that a community pharmacist is ideally placed to advise people about managing an insect bite or sting at home.\n\nFor more detail, see the summary of the evidence on oral antihistamines for uninfected mosquito bites in adults and antihistamines for uninfected mosquito bites in children.\n\nReturn to the recommendations\n\n# Referral and seeking specialist advice\n\n## Why the committee made the recommendations\n\nRecommendations 1.1.10 to 1.1.11\n\nInsect bites and stings are the second most common cause of serious allergic reactions, so the committee agreed that people with symptoms or signs of a serious allergic reaction should be referred for urgent care.\n\nIt is also important to consider referral or seeking specialist advice in the following situations:\n\npeople who have had a previous systemic allergic reaction to the same type of bite or sting because a serious allergic reaction is more likely\n\npeople with a bite or sting in the mouth or throat, or around the eyes\n\npeople with a bite or sting from an unusual or exotic insect or spider, because management may be different (for example, certain spider bites can lead to tissue necrosis)\n\npeople with fever or persistent lesions after an insect bite or sting from outside the UK because this may indicate a more serious illness such as rickettsia or malaria.\n\nReturn to the recommendations", 'Context': 'An insect bite or sting often causes a small, red lump on the skin, which may be painful and itchy. Secondary bacterial infection is unlikely; it is unclear which causative organisms are most common.', 'Summary of the evidence': 'This is a summary of the evidence. For full details, see the evidence review.\n\nThe evidence included:\n\nrandomised controlled trial in adults with extensive cellulitis caused by an arthropod bite (Friedland et al. 2012)\n\nsystematic review of double-blind crossover randomised controlled trials of oral antihistamines in people with uninfected mosquito bites (Foex et al. 2006)\n\ndouble-blind crossover randomised controlled trials of oral antihistamines in people with uninfected mosquito bites (Karpinnen et al. 2006 and Karpinnen et al. 2012)\n\nretrospective study (Dyachenko and Rozenman 2006) of treatments in people with an uninfected bite (confirmed or presumed to be caused by a brown recluse spider).\n\nRandomised controlled trial evidence was only identified for the effectiveness of oral antihistamines in adults and children with mosquito bites and for intravenous antibiotics in adults with an infected arthropod (of undefined species) bite. Only 1\xa0of the randomised controlled trials included people with a secondary infection of their bite and this was a subgroup of people with an infected arthropod bite from a larger trial.\n\nNo evidence was identified for antibiotics in children and young people.\n\n# Antibiotics for infected arthropod bites in adults\n\nBased on clinical response at day\xa03, there was no statistically significant difference in the clinical effectiveness of intravenous ceftaroline compared with intravenous vancomycin plus intravenous aztreonam (Friedland et al. 2012) in adults with extensive cellulitis caused by an arthropod bite. No adverse effect data were reported.\n\n# Oral antihistamines for uninfected mosquito bites in adults\n\n## Cetirizine 10\xa0mg once or twice daily compared with placebo\n\nThere was no statistically significant difference in median mosquito bite lesion size at 10\xa0minutes, 60\xa0minutes, 12\xa0hours or 24\xa0hours with cetirizine compared with placebo. In 2\xa0studies, there was a statistically significant difference in median mosquito bite lesion size at 15\xa0minutes compared with placebo (but no statistically significant difference was seen in a third study).\n\nThere was no statistically significant difference in pruritus after mosquito bite exposure at 10\xa0minutes, 30\xa0minutes, 90\xa0minutes, 24\xa0hours, 48\xa0hours, 5\xa0days or 7\xa0to 10\xa0days with cetirizine compared with placebo. However, there was a statistically significant reduction in mean or median pruritus scores at other time points: 15\xa0minutes, 60\xa0minutes, 12\xa0hours, and at days\xa03, 4\xa0and\xa06.\n\nThere was no statistically significant difference in adverse effects (mild to severe sedation, headache, emesis or arthralgia) at follow up.\n\nIn 1\xa0study, 7\xa0of 9\xa0people preferred cetirizine 10\xa0mg twice daily (1\xa0preferred placebo and the other had no preference).\n\n## Levocetirizine 5\xa0mg once daily compared with placebo\n\nThere was a statistically significant reduction in both median mosquito bite lesion size and median pruritus scores at 15\xa0minutes, and in delayed bite lesions at 24\xa0hours.\n\nThere was no statistically significant difference in adverse effects (mild to moderate somnolence) at follow up.\n\n## Loratadine 10\xa0mg once daily compared with placebo\n\nThere was no statistically significant difference in median mosquito bite lesion size or median pruritus scores at 15\xa0minutes.\n\nThere was no statistically significant difference in adverse effects (mild to moderate sedation) at follow up.\n\n## Rupatadine 10\xa0mg once daily compared with placebo\n\nThere was a statistically significant difference in median mosquito bite lesion size at 15\xa0minutes, but no statistically significant difference in delayed bite lesion size at 24\xa0hours. There was also a statistically significant reduction in median pruritus scores at 15\xa0minutes but no statistically significant difference for delayed bite reaction pruritis at 24\xa0hours.\n\nAdverse effects (sedation) were statistically significantly increased at follow up.\n\n# Antihistamines for uninfected mosquito bites in children\n\n## Loratadine 0.3\xa0mg/kg once daily compared with placebo\n\nThere was a statistically significant reduction in median bite lesion size at 15\xa0minutes and 24\xa0hours but no statistically significant difference at 2\xa0hours and 6\xa0hours. There was also a statistically significant reduction in median pruritus score at 15\xa0minutes.\n\nThere was no statistically significant difference in adverse effects (mild gastrointestinal pain and diarrhoea) at follow up.\n\n# Treatments for uninfected brown recluse spider bites\n\nA single-centre retrospective study (Dyachenko and Rozenman 2006) reported data for 52\xa0people with an uninfected bite that was confirmed or presumed to be caused by a brown recluse spider. The study included people aged 9\xa0to 66\xa0years; results were not broken down by age.\n\nAll patients had prophylactic antibiotics (92.3% had cefalexin; no further details given), rest, cold compression and elevation. Most patients (92.3%) had prednisolone and an antihistamine (no further details given), and 21\xa0patients (40.4%) had a non-steroidal anti-inflammatory drug. All the outcomes were assessed as being of very low quality.\n\nThe authors concluded that none of the treatments prevented necrotic lesions, and their role in time to healing and length of hospital stay was unclear.\n\nSee the evidence review for more information.'}
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https://www.nice.org.uk/guidance/ng182
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This guideline sets out an antimicrobial prescribing strategy for insect and spider bites and stings in adults, young people and children aged 72 hours and over, including those that occurred while travelling outside the UK. It aims to limit antibiotic use and reduce antibiotic resistance.
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cd99eff4f2696e5a1e817b7e40a5eadcf02a28f1
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nice
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Axonics sacral neuromodulation system for treating refractory overactive bladder
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Axonics sacral neuromodulation system for treating refractory overactive bladder
Evidence-based recommendations on Axonics sacral neuromodulation system for treating refractory overactive bladder.
# Recommendations
Evidence supports the case for adopting Axonics sacral neuromodulation (SNM) system for treating refractory overactive bladder in the NHS. Axonics SNM system improves symptoms and quality of life. It also has a longer battery life than the non-rechargeable system used in NHS clinical practice.
Axonics SNM system should be considered as an option for people with refractory overactive bladder, that is, when conservative treatment or treatment with medicine has not worked, in line with NICE's guidelines on urinary incontinence and pelvic organ prolapse and lower urinary tract symptoms. Axonics SNM system is small and does not need to be removed for most types of MRI scans, so it may be useful for people with a low body mass index (BMI) or when an MRI is likely.
Cost modelling estimates that, over 15 years, Axonics SNM system is cost saving compared with the non-rechargeable system by about £6,025 per person. Cost savings are estimated to begin 6 years after implant. This is because the device needs to be replaced less frequently than the non-rechargeable system, assuming Axonics has a life span of at least 15 years. For more details, see the NICE resource impact statement.
Why the committee made these recommendations
Axonics SNM system uses electrical impulses to stimulate the sacral nerves in the pelvic floor or groin area, to help bladder control. The system is implanted surgically and has a small stimulator that uses a rechargeable battery. Axonics SNM system should be considered when other medicines and treatments do not work.
Axonics SNM system has a longer battery life than the non-rechargeable system used in NHS practice. This means that it needs replacing less frequently, so people need surgery less often. Also, the small size and shape of the stimulator makes it more suitable for people with a lower BMI than the larger, non-rechargeable system. If people need an MRI, the system does not need to be removed, which means surgery to replace it would not be needed.
Evidence from clinical trials shows that Axonics SNM system improves symptoms of overactive bladder and quality of life.
The cost analysis suggests that using Axonics SNM system may lead to cost savings, but this depends on the length of time the battery lasts. The battery is expected to last at least 6 years, at which point it is estimated that Axonics SNM system becomes cost saving to the NHS.# The technology
# Technology
Axonics sacral neuromodulation (SNM) system stimulates the sacral nerve through an implantable pulse generator implanted subcutaneously in the upper buttock. Lead electrodes implanted through the corresponding sacral foramen transmit pulses from the stimulator to the sacral nerves. The stimulator is powered by a rechargeable battery.A handheld remote control activates the stimulator, adjusts the stimulation amplitude, and checks the battery status. A wireless charger, attachable to the skin over the implanted stimulator, is used to charge the stimulator. The company claims that the battery needs recharging every 1 to 2 weeks for 30 minutes to 1 hour. The implanted device is programmed by a clinician in an outpatient setting using a portable tablet. Axonics SNM system received a CE mark as a class 3 medical device in June 2016.
# Innovative aspects
The rechargeable battery that powers the stimulator has an expected life span of at least 15 years, which the company claims is longer than the comparable non-rechargeable device. The stimulator is compatible with MRI and is smaller than existing non-rechargeable SNM devices, making it more suitable for people with a low body mass index.
# Intended use
The Axonics SNM system is intended to treat symptoms of overactive bladder, urinary retention and chronic faecal incontinence, specifically when conservative treatment and treatment with medicine have not worked or are not suitable. Urinary retention and faecal incontinence are outside the scope of this evaluation. The decision to treat with SNM therapy using the Axonics SNM system is made by a multidisciplinary team, including surgeons, specialist nurses and physiotherapists, together with the person having the treatment. Axonics SNM system is implanted by surgeons specialising in bladder dysfunction. Limited surgical and patient training is needed.
# Costs
The Axonics SNM device costs £9,660 for the permanent implant.
For more details, see the website for Axonics SNM system.# Evidence
# Clinical evidence
## The main clinical evidence comes from 2 single-arm trials
Two studies met the inclusion criteria defined by the scope:
ARTISAN‑SNM (McCrery 2019 and Lane 2020; n=129 patients), which included 19 centres in the US and Europe (the Netherlands, Belgium, France and the UK) and had a follow up of 12 months.
RELAX‑OAB (Blok 2018a and b, Blok 2019a and c; n=51 patients), which included 7 centres in Europe (the Netherlands, Belgium, France and the UK) and had a follow up of 2 years. Both studies were non-comparative, before and after, intra-patient, observational studies reporting patient outcomes as a change from baseline. Both studies had design and reporting weaknesses. The company also submitted evidence for the non-rechargeable comparator system.
## The population and definitions of response to therapy and test response vary in both studies
ARTISAN‑SNM included people with urinary urge incontinence. Response to therapy was defined as at least a 50% reduction in urinary urge incontinence (episodes of urinary leaks) per day according to 3‑day urinary diary entries at 6 months. RELAX‑OAB included people with urinary urge incontinence (n=37) and all except one had symptoms of urinary frequency (n=50). Although not considered a primary outcome, response to therapy in RELAX‑OAB was defined as at least a 50% reduction in episodes of urinary leaks for people with urinary urge incontinence. For people with urinary frequency in RELAX‑OAB, response to therapy was defined as at least a 50% reduction in voids or reduction to fewer than 8 voids per day. ARTISAN‑SNM defined test response as symptoms responding to therapy at 1 month after implant. RELAX‑OAB defined test response as symptoms responding to therapy at 2 weeks or 1 month after implant.
## Clinical outcome data show that Axonics SNM system is effective at improving symptoms of overactive bladder
ARTISAN‑SNM reported a statistically significant reduction in:
mean daily urinary urge incontinence (episodes of urinary leaks) from 5.6±0.3 at baseline to 1.3±0.2 after 6 months, and 1.4±0.3 at 1 year (p<0.0001)
urinary frequency episodes (average voids per day) from 11.6±0.3 at baseline to 8.7±0.2 at 6 months (p<0.0001).RELAX‑OAB reported a reduction in:
mean daily urinary urge incontinence (episodes of urinary leaks) from 8.3±0.8 at baseline to 1.8±0.5 after 1 year (p<0.001) and to 1.7±0.5 at 2 years (p<0.0001)
urinary frequency episodes (average voids per day) from 14.3±1.1 at baseline to 8.0±0.5 at 1 year (p<0.001) and 7.3±0.4 at 2 years (p<0.0001).The evidence suggests that symptoms of urinary urge incontinence were more likely to improve than urinary frequency symptoms, but this depended on how improvement was defined. The clinical effectiveness of Axonics sacral neuromodulation (SNM) system was not assessed beyond 2 years.
## Studies report an improved quality of life
Both studies reported scores for the domains of the quality-of-life measure ICIQ‑OABqol before and after treatment. ARTISAN‑SNM reported an average score improvement of 34 points at 1 year and RELAX‑OAB reported an average improvement of 29 points at 2 years. Absolute before and after quality-of-life scores were not reported.
## It is likely the battery life of Axonics SNM system will last at least 15 years
Because there was no long-term clinical evidence, a second independent external assessment centre (Newcastle EAC) assessed the company's technical data supporting the claimed 15‑year life span for the battery and the device's compatibility with MRI. The EAC concluded that, if moderate or typical stimulus is maintained for the lifetime of the battery, it is likely that the battery will exceed its claimed life span of 15 years. No evidence was submitted to explore the potential effect of lead migration (that is, when the lead moves from where it was inserted) or if the lead breaks. Minor lead migrations can be compensated for by increasing the stimulus, but major lead migration and breakage need to be corrected by surgery.
# Cost evidence
## The company's de novo cost model estimates that Axonics SNM system is cost saving in people with symptoms of overactive bladder
The de novo cost analysis used a Markov model adapted from a previously published model (Noblett 2017) to compare the rechargeable Axonics SNM system with the non-rechargeable system in people with overactive bladder. Most clinical parameters in Noblett 2017 are derived from the 12‑month Insite trial (Noblett 2016). The de novo model involved a quarterly progression between 3 health states (on SNM therapy, stopping therapy and death). The model assumed equivalent clinical effectiveness, therapy stopping rates and rate of adverse events for both the rechargeable and non-rechargeable systems, so the same inputs were used for both arms. Results showed that over a 15‑year time horizon, using Axonics SNM system in this population is cost saving by £6,038 per person.
## The EAC's model includes costs for post-procedure adverse events and the same rate of surgical site infection for Axonics SNM system and the comparator
The EAC considered that the study central to the company's model (Noblett 2017) had potentially serious limitations in reporting data sources. It noted that it was difficult to identify data stated in the model from the referenced papers. This limitation was partly addressed by an updated reference list submitted by the company. In the EAC's base case, clinical equivalence was not assumed so data on therapy stopping rate and lead migration were taken from Axonics SNM studies for the rechargeable SNM arm of the model. The company model assumed that all adverse events happen in the same cycle as the implant procedure. This was revised because lead migration, lead breakage and pain may not be related to the procedure and may continue throughout the life of the model. The assumption that the implant procedure would need an inpatient admission was changed to a day-case surgery, based on expert advice. A further revision was made to the cost model after consultation to apply the same rate of surgical site infection for both Axonics SNM system and the non-rechargeable comparator (1%).
## It is estimated that Axonics SNM remains cost saving after the EAC's revisions to the model
In the EAC's preferred base case, Axonics SNM system was associated with an estimated cost saving of £6,025 per person over 15 years. A one-way sensitivity analysis showed that the timing of device replacement is a key driver of the cost savings. Threshold analysis showed that Axonics SNM system becomes cost saving when the life span of the technology is 6 years or longer.# Committee discussion
# Clinical-effectiveness overview
## There is a new rechargeable SNM system but it is not an appropriate comparator for this evaluation
A new rechargeable sacral neuromodulation (SNM) system, InterStim Micro (Medtronic), was launched in the UK when Axonics SNM system was being assessed. The clinical experts explained that InterStim Micro was not yet widely used in the NHS so had not been accepted as standard NHS practice. The external assessment centre (EAC) reported that there was currently no published evidence on InterStim Micro for treating symptoms of overactive bladder. The committee concluded that the appropriate comparator for the Axonics SNM system in this evaluation remained the non-rechargeable SNM system.
## Axonics SNM system is clinically effective and improves quality of life
The committee noted the non-comparative evidence from 2 studies (ARTISAN‑SNM and RELAX‑OAB) and testimony from a patient survey. Some patients described the technology as 'completely life changing', others felt in control of their condition. The clinical experts said that Axonics SNM system improves symptoms and quality of life. They noted that the test phase programming for both devices was different and that Axonics SNM system had 2 programs available during the test period. The Axonics SNM system permanent implant has 1 program, whereas the standard non-rechargeable SNM system has 4 default programs that a patient can switch across remotely. All programs for both Axonics SNM system and the standard non-rechargeable SNM system can be optimised for individual patients. The permanent implantation procedure is similar for both devices. The committee concluded that Axonics improves symptoms of overactive bladder and quality of life.
## The 15-year battery life of the Axonics SNM system is plausible
The committee noted that there was a lack of long-term follow-up data from the existing studies that validated the company's claim of extended battery life in real-world use. The technical expert explained that battery longevity depends on the recharge interval, charging regime and discharge profile. Newcastle EAC did an assessment of accelerated battery bench testing data submitted by the company. Based on this and expert advice, the committee concluded that it was plausible that the Axonics SNM battery would last 15 years for a person who needs typical stimulus (2.1 milliampere) to manage their symptoms. No data on battery failure were submitted and the committee was also advised that the recharge interval depended on stimulation parameters. Also, some devices may fail within the 15‑year life span if stimulus current of up to 4 milliampere is needed to manage symptoms. Mild cases of lead migration were noted as a possible cause of changes in stimulus current. The committee further considered that evidence from RELAX‑OAB showed that stimulation amplitude increased up to 3 months after the device was implanted. But, in the longer term, once the lead settles in the body, amplitude may stabilise or decrease. The committee concluded that even though evidence on battery life was limited, it was plausible that the battery would last at least 6 years and possibly beyond 15 years.
## Desensitisation may occur with Axonics SNM system, but this is unlikely to be different to the non-rechargeable system
The clinical experts explained that it was difficult to predict what proportion of people had symptoms that would stop responding over the 15‑year life span of the Axonics SNM system. They stated that all treatments for overactive bladder are associated with some level of decline in response. This could be because of the person's lifestyle, loss of efficacy, break in circuit or anticipated changes in the stimulation delivered. Clinical experts advised that a therapy break may be recommended to assess if people should continue to use SNM therapy (rechargeable or non-rechargeable). The committee noted that long-term therapy breaks (for desensitisation or pregnancy) may reduce the rechargeable battery life, but evidence of this was not available. The committee concluded that although desensitisation may occur, this is unlikely to be different with Axonics SNM system than with the non-rechargeable system.
# Side effects and adverse events
## There are no reports of serious adverse events with Axonics SNM system
There was no evidence on adverse events beyond 2 years. The most common minor device-related adverse events related to discomfort associated with stimulation. Clinical experts agreed that discomfort with stimulation can usually be corrected with reprogramming. The committee concluded that no serious adverse events had been reported with Axonics SNM system.
# NHS considerations overview
## No other medicine or treatments should be needed with Axonics SNM system
The clinical experts explained that Axonics SNM system is usually used in their practice as a third-line therapy after conservative treatment and treatment with medicine have not worked, which is in line with NICE's guidelines on urinary incontinence and pelvic organ prolapse and lower urinary tract symptoms. They explained that SNM is normally expected to be the only therapy needed to improve symptoms of overactive bladder, but occasionally it may become less effective because of desensitisation. If so, medicine may be needed to control symptoms before making a decision to remove the SNM system. The committee concluded that no other treatments (including medicine) for overactive bladder should be needed with Axonics SNM system, unless symptoms are no longer adequately controlled.
# Other patient benefits or issues
## Axonics SNM system may benefit people with protected characteristics under the Equality Act 2010
Overactive bladder is common in women who have been pregnant or who are postmenopausal. It is more common in older people, people with obesity and may be common in disabled people. The instructions state that Axonics SNM system is contraindicated for patients who are unable to operate it. So, the technology may not be suitable for all patients, which could include some disabled people or people with cognitive impairment. The clinical experts explained that the device can be recharged by a carer. The committee noted that when a carer is not available to help with recharging Axonics SNM system, the option of a non-rechargeable SNM system would still be available.
## Axonics SNM system has advantages for people with low body mass index or who are likely to need an MRI scan
The clinical experts said that the smaller size of the Axonics SNM system compared with the non-rechargeable device makes it more suitable for people with low body mass index. Axonics SNM system is conditionally safe to be used with 1.5T and 3T full-body and head coil MRI. The MRI compatibility of the device means that most people with overactive bladder who may need future MRI scanning do not need to have their device removed, avoiding replacement surgery. This consideration was also relevant to people with chronic conditions such as multiple sclerosis, who are likely to need regular MRI scans.
## Patient choice is key to deciding whether to use a rechargeable SNM system
The clinical experts explained that people are told about the advantages and disadvantages of the rechargeable and non-rechargeable systems before a device is implanted. These include uncertainty about device longevity and possible causes for device failure. The longer battery life of Axonics SNM system may appeal to a person using the device. The committee concluded that this is ultimately the person's decision.
## Axonics SNM system is easy to use
Clinical experts stated that Axonics SNM system is easy to use, for the person and the healthcare professional, and needs little in the way of additional training. They also explained that the implant procedure for the Axonics SNM system is minimally invasive and no more complex than for the non-rechargeable device. A clinical expert explained that people with memory problems may prefer the non-rechargeable device but that people with mild cognitive impairment may be able to have an Axonics SNM system if support is available. The committee concluded that Axonics SNM system could be used by most people, particularly if a carer can help.
# Cost modelling overview
## The EAC's revised cost model is plausible
The committee accepted the EAC's preferred cost model, which showed that Axonics SNM system becomes cost saving at 6 years after implant. The committee acknowledged the uncertainties in extrapolating data collected over 2 years to a 15‑year time horizon but considered this approach to be suitable for decision making. The committee acknowledged that the failure to include the cost of battery disposal in the cost modelling was a limitation.
## The risk of device failure after 1 year should be shared with the company
The company explained that the device warranty lasts for 12 months. The clinical experts explained that people are advised to include their device in insurance policies to cover loss of, or damage to, the remote or charger. The committee considered that, based on the company's confidence in the longevity of the device and the results of the cost modelling, the warranty should be extended by the company to at least 6 years.
## The rates of surgical site infection should be 1% for both Axonics SNM system and the non-rechargeable system
After consultation, the EAC investigated if other parameters and scenarios affected the cost modelling. The rate of surgical site infection used in the model, which had been different for the Axonics SNM system than the non-rechargeable SNM system, was changed to 1% for both groups. The clinical experts explained that in practice, rates of surgical site infection are low, and they had not seen an obvious difference in surgical site infection rates between Axonics SNM system and the non-rechargeable SNM system. The committee concluded that the rates of surgical site infection used in the model should be the same for both the intervention and comparator technologies. It agreed that 1% was appropriate given the low rate of surgical site infection in clinical practice.
## Fewer pain-related events and no cost for the clinician programmer should be included in the cost modelling for Axonics SNM system
After consultation, the committee considered the suggested changes to the model. The clinical experts explained that Axonics SNM system was smaller than the non-rechargeable system, so it was reasonable to assume that people would have fewer pain-related events. Also, the company explained that the clinician programmer is provided free of charge, so it was correct that no cost for this was included in the model. The committee concluded that fewer pain-related events and no cost for the clinician programmer were appropriate assumptions in the cost modelling.
## An appropriate estimate for the lifespan of the non-rechargeable SNM system is 4.4 years
The committee considered the possible effect of a longer lifespan for the non-rechargeable comparator SNM system on the cost-effectiveness modelling. But the clinical experts explained that 4.4 years accurately reflected their own clinical experiences. The committee concluded that an estimated lifespan of 4.4 years for the non-rechargeable SNM system was appropriate for the cost-effectiveness modelling.
# Main cost drivers
## Time to device replacement is key
The EAC's sensitivity analyses identified time to device replacement as a key driver of cost savings. The committee concluded that Axonics SNM system is cost saving only if it lasts longer than the non-rechargeable device.
# Cost savings
## Axonics SNM system is cost saving compared with standard care, but more evidence is needed about the battery life beyond 6 years
The EAC's revised cost modelling estimated that over 15 years, using Axonics SNM system for managing refractory overactive bladder is associated with an estimated cost saving of £6,025 per person in the base case. It showed that cost savings depended on the battery life of Axonics SNM system lasting longer than around 6 years after implant. A battery life of more than 6 years increased the amount of cost savings progressively from 6 years after implant. The committee noted that there was some uncertainty about the battery life beyond 6 years, because there was little published evidence about this. Taking into account Newcastle EAC's technical assessment and expert advice, the committee agreed that the battery is likely to last for at least 6 years. It concluded that Axonics SNM system is cost saving compared with standard care. However, the maximum level of cost savings is uncertain without more evidence about the battery life beyond 6 years.
# Further research
## Further research and collecting registry data would help address uncertainties
Further evidence on the long-term clinical effectiveness, quality-of-life benefits and the device longevity of Axonics SNM system in people with refractory overactive bladder would be welcomed. It is recommended that clinicians routinely collect clinical and procedural outcome data on SNM systems, including Axonics. Ideally this should be a national registry set up with a professional society.
|
{'Recommendations': "Evidence supports the case for adopting Axonics sacral neuromodulation (SNM) system for treating refractory overactive bladder in the NHS. Axonics SNM system improves symptoms and quality of life. It also has a longer battery life than the non-rechargeable system used in NHS clinical practice.\n\nAxonics SNM system should be considered as an option for people with refractory overactive bladder, that is, when conservative treatment or treatment with medicine has not worked, in line with NICE's guidelines on urinary incontinence and pelvic organ prolapse and lower urinary tract symptoms. Axonics SNM system is small and does not need to be removed for most types of MRI scans, so it may be useful for people with a low body mass index (BMI) or when an MRI is likely.\n\nCost modelling estimates that, over 15\xa0years, Axonics SNM system is cost saving compared with the non-rechargeable system by about £6,025 per person. Cost savings are estimated to begin 6\xa0years after implant. This is because the device needs to be replaced less frequently than the non-rechargeable system, assuming Axonics has a life span of at least 15\xa0years. For more details, see the NICE resource impact statement.\n\nWhy the committee made these recommendations\n\nAxonics SNM system uses electrical impulses to stimulate the sacral nerves in the pelvic floor or groin area, to help bladder control. The system is implanted surgically and has a small stimulator that uses a rechargeable battery. Axonics SNM system should be considered when other medicines and treatments do not work.\n\nAxonics SNM system has a longer battery life than the non-rechargeable system used in NHS practice. This means that it needs replacing less frequently, so people need surgery less often. Also, the small size and shape of the stimulator makes it more suitable for people with a lower BMI than the larger, non-rechargeable system. If people need an MRI, the system does not need to be removed, which means surgery to replace it would not be needed.\n\nEvidence from clinical trials shows that Axonics SNM system improves symptoms of overactive bladder and quality of life.\n\nThe cost analysis suggests that using Axonics SNM system may lead to cost savings, but this depends on the length of time the battery lasts. The battery is expected to last at least 6\xa0years, at which point it is estimated that Axonics SNM system becomes cost saving to the NHS.", 'The technology': '# Technology\n\nAxonics sacral neuromodulation (SNM) system stimulates the sacral nerve through an implantable pulse generator implanted subcutaneously in the upper buttock. Lead electrodes implanted through the corresponding sacral foramen transmit pulses from the stimulator to the sacral nerves. The stimulator is powered by a rechargeable battery.A handheld remote control activates the stimulator, adjusts the stimulation amplitude, and checks the battery status. A wireless charger, attachable to the skin over the implanted stimulator, is used to charge the stimulator. The company claims that the battery needs recharging every 1\xa0to 2\xa0weeks for 30\xa0minutes to 1\xa0hour. The implanted device is programmed by a clinician in an outpatient setting using a portable tablet. Axonics SNM system received a CE\xa0mark as a class\xa03 medical device in June\xa02016.\n\n# Innovative aspects\n\nThe rechargeable battery that powers the stimulator has an expected life span of at least 15\xa0years, which the company claims is longer than the comparable non-rechargeable device. The stimulator is compatible with MRI and is smaller than existing non-rechargeable SNM devices, making it more suitable for people with a low body mass index.\n\n# Intended use\n\nThe Axonics SNM system is intended to treat symptoms of overactive bladder, urinary retention and chronic faecal incontinence, specifically when conservative treatment and treatment with medicine have not worked or are not suitable. Urinary retention and faecal incontinence are outside the scope of this evaluation. The decision to treat with SNM therapy using the Axonics SNM system is made by a multidisciplinary team, including surgeons, specialist nurses and physiotherapists, together with the person having the treatment. Axonics SNM system is implanted by surgeons specialising in bladder dysfunction. Limited surgical and patient training is needed.\n\n# Costs\n\nThe Axonics SNM device costs £9,660 for the permanent implant.\n\nFor more details, see the website for Axonics SNM system.', 'Evidence': "# Clinical evidence\n\n## The main clinical evidence comes from 2\xa0single-arm trials\n\nTwo studies met the inclusion criteria defined by the scope:\n\nARTISAN‑SNM (McCrery 2019 and Lane 2020; n=129 patients), which included 19\xa0centres in the US and Europe (the Netherlands, Belgium, France and the UK) and had a follow up of 12\xa0months.\n\nRELAX‑OAB (Blok 2018a and b, Blok 2019a and c; n=51 patients), which included 7\xa0centres in Europe (the Netherlands, Belgium, France and the UK) and had a follow up of 2\xa0years. Both studies were non-comparative, before and after, intra-patient, observational studies reporting patient outcomes as a change from baseline. Both studies had design and reporting weaknesses. The company also submitted evidence for the non-rechargeable comparator system.\n\n## The population and definitions of response to therapy and test response vary in both studies\n\nARTISAN‑SNM included people with urinary urge incontinence. Response to therapy was defined as at least a 50% reduction in urinary urge incontinence (episodes of urinary leaks) per day according to 3‑day urinary diary entries at 6\xa0months. RELAX‑OAB included people with urinary urge incontinence (n=37) and all except one had symptoms of urinary frequency (n=50). Although not considered a primary outcome, response to therapy in RELAX‑OAB was defined as at least a 50% reduction in episodes of urinary leaks for people with urinary urge incontinence. For people with urinary frequency in RELAX‑OAB, response to therapy was defined as at least a 50% reduction in voids or reduction to fewer than 8\xa0voids per day. ARTISAN‑SNM defined test response as symptoms responding to therapy at 1\xa0month after implant. RELAX‑OAB defined test response as symptoms responding to therapy at 2\xa0weeks or 1\xa0month after implant.\n\n## Clinical outcome data show that Axonics SNM system is effective at improving symptoms of overactive bladder\n\nARTISAN‑SNM reported a statistically significant reduction in:\n\nmean daily urinary urge incontinence (episodes of urinary leaks) from 5.6±0.3 at baseline to 1.3±0.2 after 6\xa0months, and 1.4±0.3 at 1\xa0year (p<0.0001)\n\nurinary frequency episodes (average voids per day) from 11.6±0.3 at baseline to 8.7±0.2 at 6\xa0months (p<0.0001).RELAX‑OAB reported a reduction in:\n\nmean daily urinary urge incontinence (episodes of urinary leaks) from 8.3±0.8 at baseline to 1.8±0.5 after 1\xa0year (p<0.001) and to 1.7±0.5 at 2\xa0years (p<0.0001)\n\nurinary frequency episodes (average voids per day) from 14.3±1.1 at baseline to 8.0±0.5 at 1\xa0year (p<0.001) and 7.3±0.4 at 2\xa0years (p<0.0001).The evidence suggests that symptoms of urinary urge incontinence were more likely to improve than urinary frequency symptoms, but this depended on how improvement was defined. The clinical effectiveness of Axonics sacral neuromodulation (SNM) system was not assessed beyond 2\xa0years.\n\n## Studies report an improved quality of life\n\nBoth studies reported scores for the domains of the quality-of-life measure ICIQ‑OABqol before and after treatment. ARTISAN‑SNM reported an average score improvement of 34\xa0points at 1\xa0year and RELAX‑OAB reported an average improvement of 29\xa0points at 2\xa0years. Absolute before and after quality-of-life scores were not reported.\n\n## It is likely the battery life of Axonics SNM system will last at least 15\xa0years\n\nBecause there was no long-term clinical evidence, a second independent external assessment centre (Newcastle EAC) assessed the company's technical data supporting the claimed 15‑year life span for the battery and the device's compatibility with MRI. The EAC concluded that, if moderate or typical stimulus is maintained for the lifetime of the battery, it is likely that the battery will exceed its claimed life span of 15\xa0years. No evidence was submitted to explore the potential effect of lead migration (that is, when the lead moves from where it was inserted) or if the lead breaks. Minor lead migrations can be compensated for by increasing the stimulus, but major lead migration and breakage need to be corrected by surgery.\n\n# Cost evidence\n\n## The company's de novo cost model estimates that Axonics SNM system is cost saving in people with symptoms of overactive bladder\n\nThe de novo cost analysis used a Markov model adapted from a previously published model (Noblett 2017) to compare the rechargeable Axonics SNM system with the non-rechargeable system in people with overactive bladder. Most clinical parameters in Noblett 2017 are derived from the 12‑month Insite trial (Noblett 2016). The de novo model involved a quarterly progression between 3\xa0health states (on SNM therapy, stopping therapy and death). The model assumed equivalent clinical effectiveness, therapy stopping rates and rate of adverse events for both the rechargeable and non-rechargeable systems, so the same inputs were used for both arms. Results showed that over a 15‑year time horizon, using Axonics SNM system in this population is cost saving by £6,038 per person.\n\n## The EAC's model includes costs for post-procedure adverse events and the same rate of surgical site infection for Axonics SNM system and the comparator\n\nThe EAC considered that the study central to the company's model (Noblett 2017) had potentially serious limitations in reporting data sources. It noted that it was difficult to identify data stated in the model from the referenced papers. This limitation was partly addressed by an updated reference list submitted by the company. In the EAC's base case, clinical equivalence was not assumed so data on therapy stopping rate and lead migration were taken from Axonics SNM studies for the rechargeable SNM arm of the model. The company model assumed that all adverse events happen in the same cycle as the implant procedure. This was revised because lead migration, lead breakage and pain may not be related to the procedure and may continue throughout the life of the model. The assumption that the implant procedure would need an inpatient admission was changed to a day-case surgery, based on expert advice. A further revision was made to the cost model after consultation to apply the same rate of surgical site infection for both Axonics SNM system and the non-rechargeable comparator\xa0(1%).\n\n## It is estimated that Axonics SNM remains cost saving after the EAC's revisions to the model\n\nIn the EAC's preferred base case, Axonics SNM system was associated with an estimated cost saving of £6,025 per person over 15\xa0years. A one-way sensitivity analysis showed that the timing of device replacement is a key driver of the cost savings. Threshold analysis showed that Axonics SNM system becomes cost saving when the life span of the technology is 6\xa0years or longer.", 'Committee discussion': "# Clinical-effectiveness overview\n\n## There is a new rechargeable SNM system but it is not an appropriate comparator for this evaluation\n\nA new rechargeable sacral neuromodulation (SNM) system, InterStim Micro (Medtronic), was launched in the UK when Axonics SNM system was being assessed. The clinical experts explained that InterStim Micro was not yet widely used in the NHS so had not been accepted as standard NHS practice. The external assessment centre (EAC) reported that there was currently no published evidence on InterStim Micro for treating symptoms of overactive bladder. The committee concluded that the appropriate comparator for the Axonics SNM system in this evaluation remained the non-rechargeable SNM system.\n\n## Axonics SNM system is clinically effective and improves quality of life\n\nThe committee noted the non-comparative evidence from 2\xa0studies (ARTISAN‑SNM and RELAX‑OAB) and testimony from a patient survey. Some patients described the technology as 'completely life changing', others felt in control of their condition. The clinical experts said that Axonics SNM system improves symptoms and quality of life. They noted that the test phase programming for both devices was different and that Axonics SNM system had 2\xa0programs available during the test period. The Axonics SNM system permanent implant has 1\xa0program, whereas the standard non-rechargeable SNM system has 4\xa0default programs that a patient can switch across remotely. All programs for both Axonics SNM system and the standard non-rechargeable SNM system can be optimised for individual patients. The permanent implantation procedure is similar for both devices. The committee concluded that Axonics improves symptoms of overactive bladder and quality of life.\n\n## The 15-year battery life of the Axonics SNM system is plausible\n\nThe committee noted that there was a lack of long-term follow-up data from the existing studies that validated the company's claim of extended battery life in real-world use. The technical expert explained that battery longevity depends on the recharge interval, charging regime and discharge profile. Newcastle EAC did an assessment of accelerated battery bench testing data submitted by the company. Based on this and expert advice, the committee concluded that it was plausible that the Axonics SNM battery would last 15\xa0years for a person who needs typical stimulus (2.1\xa0milliampere) to manage their symptoms. No data on battery failure were submitted and the committee was also advised that the recharge interval depended on stimulation parameters. Also, some devices may fail within the 15‑year life span if stimulus current of up to 4\xa0milliampere is needed to manage symptoms. Mild cases of lead migration were noted as a possible cause of changes in stimulus current. The committee further considered that evidence from RELAX‑OAB showed that stimulation amplitude increased up to 3\xa0months after the device was implanted. But, in the longer term, once the lead settles in the body, amplitude may stabilise or decrease. The committee concluded that even though evidence on battery life was limited, it was plausible that the battery would last at least 6\xa0years and possibly beyond 15\xa0years.\n\n## Desensitisation may occur with Axonics SNM system, but this is unlikely to be different to the non-rechargeable system\n\nThe clinical experts explained that it was difficult to predict what proportion of people had symptoms that would stop responding over the 15‑year life span of the Axonics SNM system. They stated that all treatments for overactive bladder are associated with some level of decline in response. This could be because of the person's lifestyle, loss of efficacy, break in circuit or anticipated changes in the stimulation delivered. Clinical experts advised that a therapy break may be recommended to assess if people should continue to use SNM therapy (rechargeable or non-rechargeable). The committee noted that long-term therapy breaks (for desensitisation or pregnancy) may reduce the rechargeable battery life, but evidence of this was not available. The committee concluded that although desensitisation may occur, this is unlikely to be different with Axonics SNM system than with the non-rechargeable system.\n\n# Side effects and adverse events\n\n## There are no reports of serious adverse events with Axonics SNM system\n\nThere was no evidence on adverse events beyond 2\xa0years. The most common minor device-related adverse events related to discomfort associated with stimulation. Clinical experts agreed that discomfort with stimulation can usually be corrected with reprogramming. The committee concluded that no serious adverse events had been reported with Axonics SNM system.\n\n# NHS considerations overview\n\n## No other medicine or treatments should be needed with Axonics SNM system\n\nThe clinical experts explained that Axonics SNM system is usually used in their practice as a third-line therapy after conservative treatment and treatment with medicine have not worked, which is in line with NICE's guidelines on urinary incontinence and pelvic organ prolapse and lower urinary tract symptoms. They explained that SNM is normally expected to be the only therapy needed to improve symptoms of overactive bladder, but occasionally it may become less effective because of desensitisation. If so, medicine may be needed to control symptoms before making a decision to remove the SNM system. The committee concluded that no other treatments (including medicine) for overactive bladder should be needed with Axonics SNM system, unless symptoms are no longer adequately controlled.\n\n# Other patient benefits or issues\n\n## Axonics SNM system may benefit people with protected characteristics under the Equality Act\xa02010\n\nOveractive bladder is common in women who have been pregnant or who are postmenopausal. It is more common in older people, people with obesity and may be common in disabled people. The instructions state that Axonics SNM system is contraindicated for patients who are unable to operate it. So, the technology may not be suitable for all patients, which could include some disabled people or people with cognitive impairment. The clinical experts explained that the device can be recharged by a carer. The committee noted that when a carer is not available to help with recharging Axonics SNM system, the option of a non-rechargeable SNM system would still be available.\n\n## Axonics SNM system has advantages for people with low body mass index or who are likely to need an MRI scan\n\nThe clinical experts said that the smaller size of the Axonics SNM system compared with the non-rechargeable device makes it more suitable for people with low body mass index. Axonics SNM system is conditionally safe to be used with 1.5T and 3T full-body and head coil MRI. The MRI compatibility of the device means that most people with overactive bladder who may need future MRI scanning do not need to have their device removed, avoiding replacement surgery. This consideration was also relevant to people with chronic conditions such as multiple sclerosis, who are likely to need regular MRI scans.\n\n## Patient choice is key to deciding whether to use a rechargeable SNM system\n\nThe clinical experts explained that people are told about the advantages and disadvantages of the rechargeable and non-rechargeable systems before a device is implanted. These include uncertainty about device longevity and possible causes for device failure. The longer battery life of Axonics SNM system may appeal to a person using the device. The committee concluded that this is ultimately the person's decision.\n\n## Axonics SNM system is easy to use\n\nClinical experts stated that Axonics SNM system is easy to use, for the person and the healthcare professional, and needs little in the way of additional training. They also explained that the implant procedure for the Axonics SNM system is minimally invasive and no more complex than for the non-rechargeable device. A clinical expert explained that people with memory problems may prefer the non-rechargeable device but that people with mild cognitive impairment may be able to have an Axonics SNM system if support is available. The committee concluded that Axonics SNM system could be used by most people, particularly if a carer can help.\n\n# Cost modelling overview\n\n## The EAC's revised cost model is plausible\n\nThe committee accepted the EAC's preferred cost model, which showed that Axonics SNM system becomes cost saving at 6\xa0years after implant. The committee acknowledged the uncertainties in extrapolating data collected over 2\xa0years to a 15‑year time horizon but considered this approach to be suitable for decision making. The committee acknowledged that the failure to include the cost of battery disposal in the cost modelling was a limitation.\n\n## The risk of device failure after 1\xa0year should be shared with the company\n\nThe company explained that the device warranty lasts for 12\xa0months. The clinical experts explained that people are advised to include their device in insurance policies to cover loss of, or damage to, the remote or charger. The committee considered that, based on the company's confidence in the longevity of the device and the results of the cost modelling, the warranty should be extended by the company to at least 6\xa0years.\n\n## The rates of surgical site infection should be 1% for both Axonics SNM system and the non-rechargeable system\n\nAfter consultation, the EAC investigated if other parameters and scenarios affected the cost modelling. The rate of surgical site infection used in the model, which had been different for the Axonics SNM system than the non-rechargeable SNM system, was changed to 1% for both groups. The clinical experts explained that in practice, rates of surgical site infection are low, and they had not seen an obvious difference in surgical site infection rates between Axonics SNM system and the non-rechargeable SNM system. The committee concluded that the rates of surgical site infection used in the model should be the same for both the intervention and comparator technologies. It agreed that 1% was appropriate given the low rate of surgical site infection in clinical practice.\n\n## Fewer pain-related events and no cost for the clinician programmer should be included in the cost modelling for Axonics SNM system\n\nAfter consultation, the committee considered the suggested changes to the model. The clinical experts explained that Axonics SNM system was smaller than the non-rechargeable system, so it was reasonable to assume that people would have fewer pain-related events. Also, the company explained that the clinician programmer is provided free of charge, so it was correct that no cost for this was included in the model. The committee concluded that fewer pain-related events and no cost for the clinician programmer were appropriate assumptions in the cost modelling.\n\n## An appropriate estimate for the lifespan of the non-rechargeable SNM system is 4.4\xa0years\n\nThe committee considered the possible effect of a longer lifespan for the non-rechargeable comparator SNM system on the cost-effectiveness modelling. But the clinical experts explained that 4.4\xa0years accurately reflected their own clinical experiences. The committee concluded that an estimated lifespan of 4.4\xa0years for the non-rechargeable SNM system was appropriate for the cost-effectiveness modelling.\n\n# Main cost drivers\n\n## Time to device replacement is key\n\nThe EAC's sensitivity analyses identified time to device replacement as a key driver of cost savings. The committee concluded that Axonics SNM system is cost saving only if it lasts longer than the non-rechargeable device.\n\n# Cost savings\n\n## Axonics SNM system is cost saving compared with standard care, but more evidence is needed about the battery life beyond 6\xa0years\n\nThe EAC's revised cost modelling estimated that over 15\xa0years, using Axonics SNM system for managing refractory overactive bladder is associated with an estimated cost saving of £6,025 per person in the base case. It showed that cost savings depended on the battery life of Axonics SNM system lasting longer than around 6\xa0years after implant. A battery life of more than 6\xa0years increased the amount of cost savings progressively from 6\xa0years after implant. The committee noted that there was some uncertainty about the battery life beyond 6\xa0years, because there was little published evidence about this. Taking into account Newcastle EAC's technical assessment and expert advice, the committee agreed that the battery is likely to last for at least 6\xa0years. It concluded that Axonics SNM system is cost saving compared with standard care. However, the maximum level of cost savings is uncertain without more evidence about the battery life beyond 6\xa0years.\n\n# Further research\n\n## Further research and collecting registry data would help address uncertainties\n\nFurther evidence on the long-term clinical effectiveness, quality-of-life benefits and the device longevity of Axonics SNM system in people with refractory overactive bladder would be welcomed. It is recommended that clinicians routinely collect clinical and procedural outcome data on SNM systems, including Axonics. Ideally this should be a national registry set up with a professional society."}
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https://www.nice.org.uk/guidance/mtg50
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Evidence-based recommendations on Axonics sacral neuromodulation system for treating refractory overactive bladder.
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0078db838440a002cd69c108438558e5be00cecd
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nice
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Implantable cardiac monitors to detect atrial fibrillation after cryptogenic stroke
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Implantable cardiac monitors to detect atrial fibrillation after cryptogenic stroke
Evidence-based recommendations on implantable cardiac monitors to detect atrial fibrillation after cryptogenic stroke.
# Recommendations
Reveal LINQ is recommended as an option to help to detect atrial fibrillation after cryptogenic stroke, including transient ischaemic attacks (TIA), only if:
non-invasive electrocardiogram (ECG) monitoring has been done and
a cardiac arrhythmic cause of stroke is still suspected.
Clinicians should consider if disabled people may need support from a carer to help set up the MyCareLink Patient Monitor, to ensure data from Reveal LINQ are transmitted for review.
There is not enough evidence to recommend the routine adoption of BioMonitor 2‑AF (or its successor device BIOMONITOR III) or Confirm Rx to help to detect atrial fibrillation after cryptogenic stroke. Further research is recommended to assess the diagnostic yield (a measure of how many people with atrial fibrillation are diagnosed) of these devices for atrial fibrillation when used in people who have had a cryptogenic stroke (see section 5.1).
Why the committee made these recommendations
After a cryptogenic stroke (a stroke with no identified cause), implantable cardiac monitors can be used for long-term monitoring to identify people with atrial fibrillation if this is thought to have been a cause of the stroke. Clinical trial evidence shows that using Reveal devices increases the detection of atrial fibrillation in people who have had a cryptogenic stroke (including TIA). If people then have an oral anticoagulant medicine, it is also likely to reduce the number of further strokes or TIAs compared with not using implantable cardiac monitors. How much this reduces strokes or TIAs is not known. There are other uncertainties about the impact of using the device in the NHS, such as how many times it produces a false positive alert (that is, incorrectly identifies atrial fibrillation).
However, even after considering these uncertainties, the committee concluded that Reveal LINQ is still likely to be a cost-effective use of NHS resources, if it's used after non-invasive ECG and no other cause for the stroke has been found. There is an unmet need for people who have had a cryptogenic stroke because there is no other option for long-term monitoring for suspected atrial fibrillation. Therefore Reveal LINQ is recommended for use in the NHS.
There's not enough evidence to show if using Confirm Rx or BioMonitor 2‑AF (or any previous versions of the technologies) increases atrial fibrillation detection compared with not using implantable cardiac monitors in people who have had a cryptogenic stroke. The evidence from Reveal devices cannot be used to make decisions about Confirm Rx or BioMonitor 2‑AF. This is because the devices use different algorithms to identify potential atrial fibrillation episodes and it's not certain that they will show similar performance in detecting atrial fibrillation when used in people who have had a cryptogenic stroke. Further research is needed to find out if these devices are clinically and cost effective. Therefore they are not recommended for routine adoption in the NHS.# The diagnostic tests
# Clinical need and practice
## Atrial fibrillation
Atrial fibrillation is a type of arrhythmia that causes an irregular or abnormally fast heart rate. It is the most common arrhythmia. When someone has atrial fibrillation, the upper chambers of their heart (the atria) beat irregularly, which makes the heart less effective at moving blood into the ventricles. This can cause clots to form in the blood, which may cause a stroke. The abnormal electrical impulses in the heart muscle that cause atrial fibrillation can be persistent, permanent or intermittent. Paroxysmal atrial fibrillation involves intermittent episodes that usually last less than 2 days and stop without treatment.
## Cryptogenic stroke
Cryptogenic strokes (including transient ischaemic attack ) have no identified probable cause after diagnostic assessment, and account for around 15% to 40% of ischaemic strokes. When people have treatment for stroke, they are tested for atrial fibrillation. However, if they have paroxysmal atrial fibrillation, it may not happen during the initial assessment, or during subsequent diagnostic tests. Further longer-term testing can potentially detect it, for example by using heart rhythm monitors that can be worn, or implanted. These continuously monitor the heart's electrical activity while a person goes about their daily routine.
# The interventions
Implantable cardiac monitors are also known as implantable loop recorders or insertable cardiac monitors. They monitor heart rhythm for longer than heart rhythm monitors that are worn externally (for example, Holter monitors) and can therefore be used for long-term monitoring (potentially over years, rather than days) for suspected atrial fibrillation. Implantable cardiac monitors can identify atrial fibrillation and could be particularly helpful for identifying paroxysmal atrial fibrillation in people who have had a cryptogenic stroke. If people are diagnosed with atrial fibrillation, they can then be offered anticoagulant therapy to reduce the risk of having another stroke or TIA.
The monitors are implanted under the skin of the person's chest using a small incision under local anaesthetic. They can continuously monitor heart rhythm for several years, and they record information if the device detects an arrhythmia. The devices use algorithms based on electrocardiogram (ECG) features to detect potential atrial fibrillation. The algorithm parameters can be varied to adjust the ECG features identified and flagged as potential atrial fibrillation. Recorded ECGs are remotely transmitted to clinicians, who determine if the person has had atrial fibrillation. They then decide to either continue to monitor or to treat.
## BioMonitor 2-AF (Biotronik SE & Co KG)
The BioMonitor 2‑AF system consists of:
a BioMonitor 2‑AF insertable cardiac monitor (dimensions 88 mm × 15 mm × 6 mm)
an optional Remote Assistant for patient-activated recordings
a remote monitoring system (a CardioMessenger Smart transmitter), which sends data to the Biotronik Home Monitoring Service Centre through a cellular phone network
a Renamic programmer for the insertable cardiac monitor.
BioMonitor 2‑AF is implanted using a Fast Insertion Tool (FIT) accessory kit. First an incision of at least 1.5 cm is made. Then the FIT 1 tool is used to form a pocket for the device under the skin, and the FIT 2 is used to implant and position the device. The battery life of the device is estimated as 4 years, assuming data are sent from the device once a day. The company says that clinicians should decide whether to remove the device once it is no longer in use.
The BioMonitor 2‑AF continuously monitors heart rhythm and ECGs are automatically recorded when atrial fibrillation is detected. Atrial fibrillation is detected based on irregular RR intervals (the interval between heartbeats), absence of P waves and atrial rate greater than 300 beats per minute. Parameters for sensing settings can be adjusted to vary the sensitivity of atrial fibrillation detection. There are also standard settings for parameters, such as atrial fibrillation sensitivity (described in the product manual). BioMonitor 2‑AF can also detect other cardiac arrhythmias such as high ventricular rate, asystole, bradycardia, and sudden ventricular rate drop.
Recordings made by BioMonitor 2‑AF are automatically and wirelessly sent to a transmitter unit every day. Data are encrypted and sent anonymously to the Biotronik Home Monitoring Service Centre over mobile phone networks. Data are stored in Germany and can be accessed by clinicians through an online platform. Automatic alerts are sent to clinicians when a reading is received that meets pre-defined criteria. Clinicians review readings to make a final diagnosis.
## BIOMONITOR III (Biotronik SE & Co KG)
During the assessment phase for this guidance, the manufacturer of BioMonitor 2‑AF launched BIOMONITOR III, a new implantable cardiac monitor device, which supersedes the existing version. The new device uses the same algorithm to detect atrial fibrillation as the BioMonitor 2‑AF. The predicted battery life and cost are also the same. The device is smaller and lighter than the BioMonitor 2‑AF and can be used with a patient app.
## Confirm Rx Insertable Cardiac Monitor (Abbott Medical UK)
The Confirm Rx system consists of:
a Confirm Rx Insertable Cardiac Monitor (dimensions 49.0 mm × 9.4 mm × 3.1 mm)
a remote monitoring system (the myMerlin application installed on a smartphone or tablet) and the Merlin.net Patient Care Network (PCN)
a Merlin Patient Care System and a magnet (to interrogate and program the insertable cardiac monitor).
Confirm Rx is implanted using proprietary insertion and incision tools. The device is implanted under local anaesthetic through a small cut made using the incision tool. The insertion tool is then used to implant the device under the skin. The battery life of the device is estimated as 2 years, assuming an average of 1 automatically detected episode a day and 1 patient-activated episode a month.
Heart rhythm is continuously monitored by Confirm Rx, and ECGs are automatically recorded when atrial fibrillation is detected. Confirm Rx assesses 3 aspects of ECG trace to identify potential atrial fibrillation: regularity of rhythm pattern, variance of RR intervals and how sudden the onset of arrhythmia is. All 3 tests must indicate atrial fibrillation to trigger episode recording. The settings used by the device to detect atrial fibrillation can be varied; for example, to set the length of episode needed to trigger a recording. Confirm Rx also detects bradyarrhythmias, tachyarrhythmias and pauses.
Recordings made by Confirm Rx are transmitted using Bluetooth to a smartphone or tablet with the myMerlin app. The app can be downloaded from the company's website. The company says that the app automatically reads data from the implanted device and sends the data to a database using a cellular or Wi-Fi network during the night. It recommends that a smartphone or tablet with the app installed is kept by the person's bedside at night to allow data transmission. Confirm Rx encrypts its wireless communications and only transmits to a single authenticated and paired myMerlin app at any given time. Emails or SMS notifications can be sent to alert that a recording has been sent. Clinicians can then access transmitted ECG recordings on the Merlin.net PCN by logging on with a User ID and password. Access to the Merlin.net PCN is restricted to authorised users set by the clinic administrator.
## Reveal LINQ Insertable Cardiac Monitoring System (Medtronic Limited)
The Reveal LINQ Insertable Cardiac Monitoring System consists of:
a Reveal LINQ Insertable Cardiac Monitor device (dimensions 45 mm × 7 mm × 4 mm)
an optional Reveal Patient Assistant handheld device, which is held over the implanted Reveal LINQ monitor by the user to start an ECG recording or mark an event on the ECG record
a remote monitoring system (a bedside MyCareLink Patient Monitor), which sends data to the MyCareLink network cloud storage facility
a MyCareLink Programmer, which is a portable computer system used by a healthcare professional to program the devices.
Reveal LINQ is implanted using proprietary incision and insertion tools. The incision tool makes a small opening in the skin (less than 1 cm) and the insertion tool is used to make a small pocket for the device and to implant it under the skin.
Reveal LINQ continuously monitors heart rhythm and identifies potential atrial fibrillation episodes from the person's ECG trace using an algorithm. An ECG trace is assessed in 2‑minute windows which are considered positive if atrial fibrillation is present for longer than a programmable threshold. If the algorithm detects a potential episode of atrial fibrillation, the ECG trace is stored. The device can also be programmed to only store episodes that persist for a set period of time (6, 10, 20, 30 or 60 minutes). Total atrial fibrillation is also calculated, consisting of all 2‑minute windows in which atrial fibrillation was present for longer than the threshold value. Reveal LINQ can also detect tachyarrhythmia, bradyarrhythmia or pause episodes. The device contains an accelerometer to allow changes in patient activity over time to be monitored.
Rhythm abnormalities recorded by Reveal LINQ are wirelessly transmitted to the MyCareLink Patient Monitor and then sent to a CareLink server in the Netherlands. Transmitted and stored data are encrypted. A care alert is sent to clinicians when the device detects a rhythm abnormality. They can access the data through the CareLink website using a password protected log-in. Alternatively, daily notifications of cardiac activity can be sent. The device also sends alerts if the battery is low. If the device is unable to communicate with CareLink it registers as disconnected.
The company also offers a triage and monitoring service (FOCUSON) to review ECG recordings made by Reveal LINQ. ECGs are reviewed by cardiologists and ECG technicians at a Monitoring and Triaging Service Centre. Any clinically relevant cases requiring clinical action or escalation are notified to the NHS clinician by phone or email. Detected episodes are categorised by colour (red, amber or green). The company says that red events are notified on the same working day from when the transmission reaches the CareLink Network service. Amber events are notified by email by the next working day, and green events are aggregated and notified in a weekly email.
# The comparator
## No further testing after outpatient external ambulatory ECG monitoring
The clinical experts said that if no atrial fibrillation is detected by an external ambulatory ECG monitor, the person is unlikely to have any further monitoring for atrial fibrillation, unless an implantable cardiac monitor is available. Undetected atrial fibrillation may be later identified if it causes symptoms (for example, palpitations), incidentally when someone's pulse is checked (for example, when blood pressure is taken), or on investigation after a recurrent stroke or TIA. Therefore the comparator is no further monitoring.# Evidence
The diagnostics advisory committee considered evidence from several sources on implantable cardiac monitors (BioMonitor 2‑AF, Confirm Rx and Reveal LINQ) to assess for suspected paroxysmal atrial fibrillation in people who have had a cryptogenic stroke. Full details of all the evidence are in the committee papers.
# Clinical effectiveness
The external assessment group (EAG) did a systematic review to identify evidence on the clinical effectiveness and diagnostic accuracy of implantable cardiac monitors to detect suspected atrial fibrillation after cryptogenic stroke. The devices reviewed were:
BioMonitor 2‑AF
Confirm Rx
Reveal LINQ.
Studies were included if they assessed the devices in people who had had a cryptogenic stroke or cryptogenic transient ischaemic attack (TIA), and paroxysmal atrial fibrillation was suspected. Because of the small number of studies identified, the requirement for at least 24 hours of outpatient external ambulatory electrocardiogram (ECG) monitoring without atrial fibrillation detection before the devices were implanted (as per current practice) was not applied. Also, data from earlier versions of the devices were considered.
Because only 1 study (the CRYSTAL‑AF randomised controlled trial) met the EAG's initial eligibility criteria, the EAG relaxed the study inclusion criteria to consider single-arm observational studies. The EAG did not change the population inclusion criteria because it considered that data from non-cryptogenic stroke populations would not represent the device's performance in people with cryptogenic stroke or TIA. This is because non-cryptogenic stroke populations have different incidence rates of atrial fibrillation. However, the EAG provided a summary of studies highlighted by the device manufacturers that were not done in a cryptogenic stroke population. The EAG further highlighted that the patient population, duration of monitoring and the type of atrial fibrillation would affect estimates of device performance.
## Comparative studies
One study (reported in 6 publications) compared the effectiveness of using 1 of the devices with conventional follow up: the CRYSTAL‑AF study. This was an open-label, parallel group randomised controlled trial that used Reveal XT (an earlier version of Reveal LINQ). The XT model is larger. The EAG said that evidence from diagnostic accuracy studies (see sections 3.48 and 3.49) suggests that Reveal LINQ has better specificity and sensitivity than the XT, is easier to implant and causes fewer complications.
People aged 40 or older who had a recent episode of cryptogenic symptomatic TIA or recent episode of cryptogenic ischaemic stroke had Reveal XT (n=221) or conventional follow-up care (n=220). People with TIA were only enrolled if they had a visible lesion on MRI or CT that fitted the symptoms of the TIA, and at least 1 of the following symptoms: speech problems, limb weakness or hemianopsia. Follow up in the control group was ECG monitoring at the discretion of the site investigator. The study was done in 55 centres across 14 countries in Europe (none in the UK), Canada and the US. The EAG said that there were similar numbers of withdrawals between the 2 arms (except for crossovers, see section 3.12). Data were collected for up to 36 months of follow up, but relatively few people reached this point (24 in each arm). Mean duration of follow up was 20.3 months for Reveal XT and 19.2 months for conventional follow-up care.
The EAG noted that, although there were no significant differences in baseline characteristics between study arms, there were differences in the numbers of people with patent foramen ovale and history of prior stroke. However, these were small and unlikely to be because of systematic issues with randomisation. The clinical experts said that the population was slightly younger than people expected to be eligible for an implantable cardiac monitor in the UK. Also, a higher proportion of TIA (rather than stroke) would be expected in clinical practice (closer to 20%, instead of about 9% seen in each of the study arms). All patients would be expected to be taking an antiplatelet agent (about 96% in each arm were using an antiplatelet agent at baseline).
The EAG's clinical experts said that the tests used in the trial to define a stroke as cryptogenic were broadly the same as what would be done in the NHS. Pre-enrolment screening for atrial fibrillation was Holter monitoring for 71.2% of people (median duration of 23 hours, interquartile range 21 hours to 24 hours), and the remaining people had inpatient telemetry monitoring only. The EAG said that this meant almost 30% of people did not have any outpatient ECG monitoring (as specified in the scope) and that not all patients who did have outpatient ECG monitoring had it for at least 24 hours.
This trial was sponsored by Medtronic, manufacturers of the device used in the study. The EAG said that the authors of publications for this study reported employment, grants and personal fees from this company. The EAG considered that this was the most robust clinical evidence for Reveal LINQ, even though it relates to an earlier version of the device.
## Non-comparative studies
Comparative data were not identified for BioMonitor 2‑AF, Confirm Rx or the current Reveal LINQ version. Therefore, the EAG reviewed single-arm observational studies in cryptogenic stroke (including TIA) populations to identify available data on these devices. Biotronik submitted a technical validation report comparing the accuracy of BioMonitor 2‑AF with Reveal LINQ during consultation (see section 3.21).
Twenty six observational studies (reported in 60 publications) were found. All but 1 study assessed either Reveal LINQ or Reveal XT. In 1 study (Israel et al. 2017), 13% of people used the BioMonitor (an earlier version of BioMonitor 2‑AF), but results were not reported by device. The EAG said that these studies therefore do not provide any data for BioMonitor 2‑AF or Confirm Rx, but that they did supplement data from the CRYSTAL‑AF study.
Sample sizes in the studies ranged from 14 to 1,247. Only 1 study (Cotter et al. 2013) was done in the UK. Most studies (17) were prospective single-arm observational studies. There were 5 retrospective studies (Asaithambi et al. 2018, Chalfoun et al. 2016, Heckle et al. 2018, Li et al. 2018 and Salahuddin et al. 2015). One did not report a clear methodology (Cotter et al. 2013). Ritter et al. (2013) did a within-patient comparison of Reveal XT and 7-day Holter ECG monitoring. Choe et al. (2015) used the CRYSTAL‑AF dataset to predict how many cases of atrial fibrillation detected by Reveal XT would have been detected by shorter length intermittent ECG monitoring strategies using simulations. Ziegler et al. (2017) presented data from a registry of people who had Reveal LINQ and used simulations to predict how many people with atrial fibrillation detected by the device would have been identified by shorter (non-continuous) ECG monitoring.
## Quality assessment of studies
The CRYSTAL‑AF study was assessed using the Cochrane risk of bias 2.0 tool. The full quality assessment is in the diagnostics assessment report starting from page 28. There was some concern about risk of bias because the trial was open-label and not all people had the randomised intervention required by the study protocol (5.4% of people assigned to Reveal XT got conventional follow up; 2.7% of people assigned conventional follow up got Reveal XT). Also, device implantation was delayed for 11.5% of people who had Reveal XT (median length of delay was 6 days, interquartile range 1 day to 32 days). The EAG noted that results were analysed by intention-to-treat population, which included patients who did not have Reveal XT, received it late, or crossed over to conventional follow up. This means the estimated benefit of having the device may be underestimated. Delays in implanting Reveal XT were mostly short and unlikely to affect outcomes. The EAG said that the lack of blinding was unlikely to affect relative atrial fibrillation detection rates between groups. It noted that only a small number of people were followed up after 12 months, so the 24‑month and 36‑month results are likely to be less reliable than results from 6 months and 12 months, but the direction of this bias is unclear.
The EAG said that it was not able to formally quality assess the 26 additional studies identified that were not randomised controlled trials. However, it considered them all to be at high risk of bias because of their single-arm designs. Because of heterogeneity between the studies, the EAG did not consider it appropriate to pool results from these studies. This included the model of device used, detection settings, patient characteristics, rigour of stroke assessment, severity of index stroke, definition and adjudication of atrial fibrillation, and length of follow up.
## Evidence on ability to detect atrial fibrillation
Atrial fibrillation detection rate at 6 months was the CRYSTAL‑AF study's primary outcome (episodes had to last more than 30 seconds). At 6 months, 19 people were diagnosed with atrial fibrillation in the Reveal XT arm and 3 people in the conventional follow-up arm. More atrial fibrillation was detected with Reveal XT at all time points (see table 1). Reveal XT increased atrial fibrillation detection across all pre-specified subgroups (age, sex, race or ethnic group, index event, presence or absence of patent foramen ovale, and CHADS2 score), with no significant interactions. Most people who had atrial fibrillation detected by Reveal XT were asymptomatic (34 out of the 42 detected by 36 months). Estimated detection rates are higher in the 36‑month Kaplan–Meier analysis because of the non-informative censoring (that is, people who dropped out for reasons unrelated to the study) of patients lost to follow up (atrial fibrillation detection rate estimated as 30% with Reveal XT and 3% with conventional follow up).
Months
Reveal XT: cumulative number of patients with AF detected
(n )
Conventional follow up: cumulative number of patients with AF detected
(n )
Abbreviations: AF, atrial fibrillation; ITT, intention to treat.
All 26 observational studies reported atrial fibrillation detection rate. Detection rates varied widely, ranging from 6.7% to 40.9% (length of monitoring varied between studies). Several studies reported atrial fibrillation detection rates over multiple time points. The EAG said that the studies generally show that a minority of patients are diagnosed in the first month (about 10% of those detected by 1 year). Around 70% to 80% (of the total number of people with atrial fibrillation detected in a study) are diagnosed by 6 months, and a small number after a year of monitoring. All or most of the detected atrial fibrillation in the observational studies (when stated) were asymptomatic, as in CRYSTAL‑AF.
Two observational studies estimated how many atrial fibrillation episodes would have been detected by intermittent ECG monitoring. These used datasets generated by Reveal XT (in CRYSTAL‑AF; Choe et al. 2015) or Reveal LINQ (from a large registry of patients with the device ; Ziegler et al. 2017). The studies assumed Reveal devices had 100% sensitivity. The studies estimated that even the best intermittent ECG monitoring strategies would detect less than a third of atrial fibrillation detected by Reveal devices.
CRYSTAL‑AF did not report any results for the detection of other cardiac pathologies.
Five non-comparative observational studies reported incidental detection of other arrhythmias. The EAG said that the proportion of patients detected with other arrhythmias is about 10% of the total number of people in a study. This mainly consists of bigeminy, pause and bradycardia. Two studies reported the breakdown of arrhythmias and gave rates of 1% (atrial flutter, cardiac arrest, sick sinus node, bigeminy, ventricular tachycardia) to 7% to 8% (atrioventricular block and ventricular extra systole). Full details are on page 51 of the diagnostics assessment report. The studies did not say if the other detected arrhythmias were treated, or if outcomes were improved because these arrhythmias were identified. Also, because these were non-comparative studies, the extent of any increase in detection compared with conventional follow up could not be determined.
No data relevant to this outcome were reported in CRYSTAL‑AF.
Two non-comparative observational studies reported the proportion of episodes detected by the devices that were not verified as atrial fibrillation by a clinician. Li et al. (2018) reported 79.7% for Reveal LINQ and Israel et al. (2017) reported that over 90% of detected episodes were not confirmed by review (Reveal XT and BioMonitor). The EAG noted that Medtronic had said that the number of false positive alerts varies depending on the device model used, and the configuration for detection (including episode duration) that is programmed by the operator. Data on device accuracy (for all devices) in non-cryptogenic stroke populations from studies identified by manufacturers are presented later (see section 3.41).
During the first consultation on this guidance, the manufacturer of the BioMonitor 2‑AF submitted an unpublished technical validation report comparing the accuracy of the Reveal LINQ and BioMonitor devices. This was done by replaying ECG data recorded by a Holter monitor in a previous trial into the sensing electrodes of the Reveal LINQ and BioMonitor devices. The report stated that because the atrial fibrillation detection algorithm of the BioMonitor 2‑AF and BIOMONITOR III are the same, the results are applicable to both devices. People enrolled in the original trial had documented atrial fibrillation episodes or symptoms attributable to atrial fibrillation, were scheduled for catheter ablation or had had it, but were still experiencing atrial fibrillation-related symptoms. Of the participants, 70% had a history of paroxysmal atrial fibrillation. The rest had a history of persistent atrial fibrillation. However, the EAG highlighted that the report also stated that people with long-standing persistent or permanent atrial fibrillation were excluded. The EAG pointed out that this was contradictory and meant that the characteristics of the population in the study were not clear. At consultation on the draft guidance, BioMonitor's manufacturer commented that all ECG data fed into the devices as part of the study were for less than 48 hours. It said that therefore they represented paroxysmal atrial fibrillation episodes only. In the study, atrial fibrillation episodes detected, or not, by clinician assessment of the Holter monitor ECG trace was used to classify true and false positives and false negative atrial fibrillation episodes detected by the Reveal LINQ and BioMonitor. Atrial fibrillation episode sensitivity for BioMonitor and Reveal LINQ were 78.0% and 79.0% respectively. Patient-averaged positive predictive values were 98.7% for BioMonitor and 99.7% for Reveal LINQ.
## Evidence on clinical outcomes
The EAG said that atrial fibrillation was detected in only 5 people in the conventional follow-up arm of CRYSTAL‑AF (and none after 24 months; see table 1). This means it is difficult to make any conclusions about the effect of using Reveal XT from the median time to atrial fibrillation detection data. Atrial fibrillation was detected in more people with longer follow up, and therefore the median time to detection also increased. There was a greater increase in the median time to atrial fibrillation detection with Reveal XT compared with conventional follow up across all time points. The EAG said that the low detection rate of atrial fibrillation in the conventional follow-up arm was the likely cause of this difference.
There were 18 observational studies that reported time from device insertion to atrial fibrillation detection. Average follow up ranged from 7 months to 20 months, and median time to first atrial fibrillation detection had a wide range, from 21 days to 217 days. When reported, interquartile ranges also showed high variability within studies.
No data were reported in CRYSTAL‑AF or the observational studies.
No data were reported in CRYSTAL‑AF or the observational studies.
Most people diagnosed with atrial fibrillation using Reveal XT started having an oral anticoagulant (more than 90%) in the CRYSTAL‑AF study. The reasons people did not start on anticoagulants after being diagnosed with atrial fibrillation were not clear. The EAG noted that some people who were not diagnosed with atrial fibrillation in the trial were also started on anticoagulants. Reasons for this were not provided.
Seven observational studies (Asaithambi et al. 2018, Carrazco et al. 2018, Christensen et al. 2014, Etgen et al. 2013, Li et al. 2018, Merce et al. 2013 and Seow et al. 2018) reported that uptake of anticoagulants for people with atrial fibrillation detected by Reveal XT or LINQ was high: between 83.3% and 100%.
No data were reported in CRYSTAL‑AF or the observational studies.
No incidence of Reveal XT failure was reported in CRYSTAL‑AF. The device had to be removed early because of infection or pocket erosion from 5 out of 208 (2.4%) people by 36 months.
Three non-comparative observational studies reported how many devices were removed during follow up. In Christensen et al. (2014), Reveal XT was removed prematurely in 5.7% people because of skin reactions and discomfort. A further 3.4% of people chose to have the device removed after more than 1 year without atrial fibrillation being detected. In Asaithambi et al. (2018), 2.6% of people chose to have Reveal LINQ removed, and for 0.9% of people the devices migrated or fell out. In Ritter et al. (2013), study participants were offered removal of Reveal XT once atrial fibrillation was detected. But they did not report how many of the 30% of removals were because of this, or for other reasons such as discomfort.
No data were reported in CRYSTAL‑AF or the observational studies.
No data were reported in CRYSTAL‑AF or the observational studies.
In CRYSTAL‑AF, a non-significant trend of fewer recurrent events (stroke or TIA) in the Reveal XT arm was reported (see table 2). The study was not powered for this outcome. It is not clear if the recurrent stroke or TIA events occurred in people who were diagnosed with atrial fibrillation or not.
Month
Reveal XT (n=221): people having another stroke or TIA(n )
Conventional follow up (n=220): people having another stroke or TIA(n )
Hazard ratio(95% CI)
Not reported
(0.22 to 1.80)
(0.30 to 1.97)
Abbreviations: CI, confidence interval; TIA, transient ischaemic attack.
Of the studies, 6 non-comparative observational studies reported variable incidences of secondary stroke or TIA in people with an implantable cardiac monitor: from 0% to 14.6%.
No data were reported in CRYSTAL‑AF or the observational studies.
The EAG said that the incidence of device-related adverse effects (such as pain and infection) was relatively low for people who had Reveal XT implanted in CRYSTAL‑AF. However, adverse events did lead to the device being removed in 2.4% of patients. The proportion of people with serious adverse events was slightly higher for Reveal XT (30.8%) than conventional follow up (27.9%). More people had non-serious adverse events in the Reveal XT arm (18.6%) than in the conventional follow-up arm (4.1%). No details of these events were reported, and the EAG said that it was unclear why there was a difference between the study arms. Reveal XT is larger than Reveal LINQ.
For 5 non-comparative observational studies, there were no complications from the procedure or insertion site reported at follow up (length of follow up was not specified). These were Merce et al. (2013), Reinke et al. (2018) and Ritter et al. (2013) for Reveal XT; Poli et al. (2016) for Reveal LINQ and XT; and Israel et al. (2017) for Reveal XT and BioMonitor.
No data were reported in CRYSTAL‑AF or the observational studies.
## Evidence on patient-reported outcomes
Health-related quality of life data were collected in CRYSTAL‑AF using the EuroQol 5-Dimensions (EQ-5D) tool. Unpublished data were provided by the company as academic in confidence so they cannot be reported here.
No data were reported in CRYSTAL‑AF or the observational studies.
## Evidence from non-cryptogenic stroke populations
The EAG provided a narrative summary of studies in non-cryptogenic stroke populations identified by manufacturers of the devices. These studies were not done in populations who had exclusively had a cryptogenic stroke or TIA although some were in a 'mixed population' (less than 50% of the study population had a cryptogenic stroke or TIA and subgroup analysis was not provided). All studies were either single-arm observational studies or assessed the diagnostic accuracy of the devices compared with Holter monitoring. The EAG highlighted that the performance of the devices depends on the patient population, atrial fibrillation incidence rate, and the type of atrial fibrillation. Therefore, the results from these studies do not necessarily represent the devices' performance in people with cryptogenic stroke.
The EAG did not do a full systematic literature search to validate the inclusion of the studies. This was because of time constraints and concerns about the applicability of results to the cryptogenic stroke population. The EAG said that the data may have study selection bias as well as clinical heterogeneity caused by the variation in the patient populations of each of the studies.
The company said the Detect AF study (Nölker et al. 2016) was potentially relevant for assessing Confirm Rx. The EAG noted that the device used in Detect AF was the Confirm model DM2102. This is an older and larger model of Confirm Rx. The EAG was unsure how the software in this earlier version compared with the current Confirm Rx.
Detect AF was a prospective observational study. It assessed the diagnostic accuracy of the Confirm system in detecting atrial fibrillation compared with Holter monitoring (reference standard) with simultaneous use of the devices. In per-patient analysis, sensitivity of the Confirm system was 100%, positive predictive value was 64.0%, specificity was 85.7% and negative predictive value was 100%. Most of the episodes of atrial fibrillation detected by the Confirm system but not confirmed by the Holter monitor were because of irregular sinus rhythms. No adverse events associated with the device were reported.
The EAG discussed 5 single-arm prospective observational studies (in 8 publications) provided by Biotronik. Three of these studies (which included data on diagnostic accuracy) were unpublished and were provided as academic or commercial in confidence so details cannot be reported here.
Reinsch et al. (2018) reported that BioMonitor 2 was successfully implanted in a catheterisation laboratory with a median time from first cut to final suture of 8 minutes (interquartile range 7 minutes to 10 minutes). Ooi et al. (2017) reported that all insertions of the device were made on first attempt in a catheterisation laboratory with a median time of 9 minutes (interquartile range 5 minutes to 14 minutes). Ooi et al. reported that 1 pocket infection occurred when using the device. Reinsch et al. reported that no devices implanted in the study migrated, and 1 person needed the device removing because of device-related pocket infection. Another patient complained of slight discomfort.
Reinsch et al. reported results from patient satisfaction surveys. Of the respondents, 7% reported moderate to severe pain and 20% reported mild pain within 24 hours of device insertion. One person reported a moderate impairment in daily life. Of the respondents, 63% said that the cosmetic result was 'very satisfying' and 30% said 'satisfying'.
The EAG discussed 5 studies highlighted by the company. Two compared the diagnostic accuracy of Reveal devices (per-patient analysis) with Holter monitoring for detecting atrial fibrillation (Hindricks et al. 2010 and Sanders et al. 2016). In Hindricks et al. (2010), Reveal XT was used (the XPECT trial). Another study (Puerefellner et al. 2014) used data from this trial and recalculated accuracy estimates when changes were made to the atrial fibrillation detection algorithm. This incorporated data on P waves when classifying patients, and this algorithm change was applied in Reveal LINQ. Sanders et al. (2016) used Reveal LINQ. A subsequent study (Puerefellner et al. 2018) was published using this dataset (and the XPECT data) to calculate the accuracy of a modified algorithm for detecting atrial fibrillation (using the TruRhythm algorithm that has now been incorporated in the device). Data on the diagnostic accuracy reported in these studies are shown in table 3.
Measure
XPECT study
Hindricks et al. 2010
(Reveal XT)
XPECT dataset
Puerefellner et al. 2014
(Reveal XT with P-sense enhancement)
LINQ usability study
Sanders et al. 2016
(Reveal LINQ)
LINQ usability dataset
Puerefellner et al. 2018
(Reveal LINQ with adaptive P-sense; TruRhythm)
Sensitivity (%)
Specificity (%)
Positive predictive value (%)
Negative predictive value (%)
Accuracy (%)
Positive predictive value, negative predictive value and accuracy for the XPECT dataset calculated by the EAG using data in Puerefellner et al. (2014).
The EAG said that the studies showed improved detection of atrial fibrillation by Reveal LINQ compared with Reveal XT. Changes made to the algorithm also improved detection. But the results should be interpreted with caution because these studies were not done in people who had had a cryptogenic stroke. However, the EAG said that these data suggest that Reveal LINQ is likely to be as effective as Reveal XT, if not better, at detecting atrial fibrillation. Therefore, the clinical data from CRYSTAL‑AF (which uses the Reveal XT) could be a conservative estimate of the clinical effectiveness of the device.
Mittal et al. (2015) reported adverse event data from 2 observational studies that used Reveal LINQ. An infection occurred in 1.5% of people, an adverse event in 4.0% and a serious adverse event in 1.1%.
The EAG identified 8 potentially relevant ongoing studies from searches of trial registries and electronic databases, in addition to company submissions. There are 3 ongoing randomised controlled trials assessing Reveal LINQ. Of these, 1 is in people with cryptogenic stroke. This is a Canadian randomised trial comparing the clinical and cost effectiveness of Reveal LINQ with external loop recording in 300 people who have had cryptogenic stroke. It was estimated to complete in December 2019 (PERDIEM; NCT02428140). One ongoing study identified is assessing Confirm Rx: the SMART registry (NCT03505801). This is a post-approval study planned for at least 2,000 patients with Confirm Rx across multiple indications, with a planned subgroup analysis for cryptogenic stroke. Completion was expected during 2019. At consultation on the draft guidance, a stakeholder submitted a recent conference abstract (Yokokawa et al. 2019). The abstract gave only limited methodological detail. In this study, people were randomised to have either Confirm Rx or Reveal LINQ implanted (n=80; 52 had cryptogenic stroke but no subgroup analysis was provided). The abstract reported that 28 of 51 atrial fibrillation events (55%) were detected accurately by Reveal LINQ and 131 of 301 atrial fibrillation events (44%) were accurately detected by Confirm Rx (p=0.13).
# Cost effectiveness
## Systematic review of cost-effectiveness evidence
The EAG did a systematic review to identify any published economic evaluations of implantable cardiac monitors to detect atrial fibrillation in people with cryptogenic stroke. There were 5 studies that met the EAG inclusion criteria. Of these, 2 assessed the cost effectiveness of Reveal XT compared with standard care monitoring (DeAngelis et al. 2016 and Diamantopoulos et al. 2016). Another study assessed BioMonitor 2‑AF (Maervoet et al. 2017; further details provided as unpublished report and model by the device manufacturer as commercial in confidence), and 2 studies did not indicate which implantable cardiac monitor was being assessed (Quiroz et al. 2017 and Thijs et al. 2018). Only 1 study (Diamantopoulos et al. 2016) was based on an NHS payer perspective and was discussed in the diagnostics assessment report.
This study was a cost–utility analysis. It compared use of Reveal XT in people who have had a cryptogenic stroke or TIA with conventional follow up, as assessed in the CRYSTAL‑AF study. A Markov model structure was used with 3 main health states for atrial fibrillation status: free, detected and undetected. The deterministic base case produced an incremental cost-effectiveness ratio (ICER) of £17,175 per quality-adjusted life year (QALY) gained for Reveal XT compared with standard care (£2,587 higher costs, 0.151 additional QALYs). The probabilistic ICER was lower.
The EAG considered that results from this model were potentially unreliable because there was uncertainty about how parameters in the model had been estimated. The estimation of treatment effects by indirect comparison, atrial fibrillation incidence and detection rates used in the analysis were particularly unclear. The study authors used indirect comparisons to estimate hazard ratios for the benefit of anticoagulants on the occurrence of ischaemic stroke, bleeding events, intracranial haemorrhages, extracranial haemorrhages and mortality. The EAG tried to verify these figures but was unable to because there were insufficient details in the publication about how the indirect comparisons were done and how publications that informed the analysis were identified. The EAG also considered that estimation of some of the hazard ratios could be flawed. For example, the authors estimated a hazard ratio to adjust mortality in the model, but the source data used are based on standardised mortality ratios. Furthermore, people without atrial fibrillation detected were assumed to be offered aspirin, but the EAG's clinical experts said that clopidogrel would be used as an antiplatelet treatment.
The EAG developed a de novo economic model to assess the cost effectiveness of using implantable cardiac monitors (BioMonitor 2‑AF, Confirm Rx or Reveal LINQ) to assess for suspected paroxysmal atrial fibrillation in people who have had a cryptogenic stroke (including TIA).
The EAG developed a 2-stage economic model. The first stage (an Excel model developed by the EAG) modelled people having either monitoring for suspected paroxysmal atrial fibrillation after a cryptogenic stroke (including TIA) with the implantable cardiac monitors or conventional follow up. Everyone starts the model having antiplatelet therapy (clopidogrel) for stroke prevention. At every 3‑month cycle in the model, a proportion of people have atrial fibrillation. For people with an implantable cardiac monitor, all cases of atrial fibrillation are detected, and treatment is switched to anticoagulants (atrial fibrillation detected). For people with conventional follow up, a proportion of people with atrial fibrillation are detected (and switch to anticoagulants) but most are not (atrial fibrillation undetected) and remain on antiplatelet therapy.
For the subsequent long-term anticoagulation model, the EAG adapted a published economic model to model the long-term effect of people with detected atrial fibrillation (anticoagulant treatment) or undetected atrial fibrillation (remain on antiplatelet therapy with clopidogrel). This is the 'adapted direct oral anticoagulant (DOAC) model' (Sterne et al. 2017 and Welton et al. 2017). People enter the model after having atrial fibrillation in an 'atrial fibrillation well' state. After this, clinical events can occur. These are TIA, ischaemic stroke, intracranial haemorrhage, myocardial infarction, clinically relevant (extracranial) bleed or systemic embolism (multiple events can happen to one person over the course of the model). The risks of these events happening in the model were based on a population with a history of ischaemic stroke and paroxysmal atrial fibrillation. The model structure is the same for people with detected and undetected atrial fibrillation. However, the probability of the events happening depends on the treatment used (anticoagulants or antiplatelet therapy).
The population in the model was people who had had a cryptogenic stroke (including TIA), when there was suspected paroxysmal atrial fibrillation. These people had had at least 24 hours of outpatient external ambulatory ECG monitoring that had not detected atrial fibrillation. Characteristics were based on the population in the CRYSTAL‑AF study, with a mean age of 61 years and about 65% people assumed to be men.
In the model, the EAG used data from the control arm of CRYSTAL‑AF for the comparator. People in the study were assessed at scheduled visits (every 3 months) and unscheduled visits if they were having symptoms of atrial fibrillation. Tests included ECGs and Holter monitoring (for 24 hours, 48 hours or 7 days).
## Model inputs
Diagnostic yield data from CRYSTAL‑AF were used for the number of people with atrial fibrillation detected by an implantable cardiac monitor or by conventional follow up. No equivalent data were identified for BioMonitor 2‑AF or Confirm Rx (or the current Reveal LINQ version). Therefore, the EAG assumed equal efficacy for all devices. A published model (Sterne et al. 2017 and Welton et al. 2017; the 'adapted DOAC' model) was used to model longer-term clinical outcomes for people with atrial fibrillation that is detected (treatment with an anticoagulant) or not detected (treatment with an antiplatelet drug). Outcomes included were ischaemic stroke, myocardial infarction, TIA, systemic embolism, clinically relevant extracranial bleed, intracranial haemorrhage and all-cause mortality.
All costs in the model were valued in 2018, in UK pounds sterling. Device costs are shown in table 4.
Device
Unit cost (£ excluding VAT)
BioMonitor 2‑AF
Confirm Rx
Reveal LINQ
Medtronic also offers an optional triage service for use with Reveal LINQ (FOCUSON) that was included in scenario analyses. There were 2 cost options included: £187 per patient per year or £374 per patient per device. The EAG did not include the cost of reviewing alerts generated by the devices in the base case.
In the base case, the EAG estimated the cost of implanting the devices as £24.17. This was based on advice from the clinical experts about the staff involved (cardiologist and nurse) and time taken for the procedure (10 minutes). The cost of removing the devices was assumed to be £238, based on NHS reference costs schedule 2017/18 (EY13Z – removal of electrocardiography loop recorder, outpatient setting, treatment function code 320). Costs associated with adverse events from implanting the devices were not included in the EAG's analysis.
The EAG based costs for the comparator on the conventional follow-up arm of CRYSTAL‑AF. Costs per cycle in the model were calculated based on the proportion of people having testing every 3 months or no testing in the study. The unit cost of monitoring was £141, based on the NHS reference costs schedule 2017/18 (HRG code EY51Z – ECG monitoring or stress testing ). The EAG assumed that people with an implantable cardiac monitor will have 1 face-to-face follow up a month after the procedure and then will be remotely monitored. For people in the conventional follow-up arm who do not have atrial fibrillation detected, follow-up appointments are assumed to happen after 1, 3, 6 and 12 months, based on clinical expert advice. If atrial fibrillation is detected, a follow-up appointment is assumed to discuss treatment. The cost of an initial follow up (£163.36) and subsequent follow up (£128.05) were taken from NHS reference costs.
The costs of DOACs and clopidogrel were taken from the BNF September 2018 to March 2019 edition. Costs of acute and chronic health events were taken from NHS reference costs or Luengo-Fernandez et al. (2013).
## Health-related quality of life and QALY decrements
The EAG did a systematic review to identify relevant utility values to update the adapted DOAC model. There were 2 papers (Berg et al. 2010 and Luengo-Fernandez et al. 2013) with relevant utility values for ischaemic stroke, intracranial haemorrhage, myocardial infarction and TIA events. These were included in the model and were used to update the adapted DOAC model. The utility value used for people with atrial fibrillation in a 'well' health state (that is, when no clinical events such as stroke have occurred) was 0.78 (Berg et al. 2010). The duration of disutility for an acute event was assumed to be 3 months (1 model cycle).
## Base-case assumptions
The following assumptions (in addition to those described in previous sections) were applied in the base-case analysis:
The prevalence of atrial fibrillation in this population was equal to the detection rate in CRYSTAL‑AF.
Reveal LINQ was as good as Reveal XT (the device used in CRYSTAL‑AF) for detecting atrial fibrillation.
BioMonitor 2‑AF and Confirm Rx were equivalent to Reveal XT or Reveal LINQ for detecting atrial fibrillation.
The detection of atrial fibrillation was capped at 3 years for BioMonitor 2‑AF even though the manufacturer said the battery life is expected to be 4 years. This was because atrial fibrillation detection data were only available for 3 years of follow up.
Atrial fibrillation detection was capped at 2 years for Confirm Rx because this is the expected battery life of the device, and the clinical experts advised that devices are unlikely to be replaced once a battery expires.
After 3 years, detection rates of atrial fibrillation are the same in both the implantable cardiac monitors and conventional follow-up arms.
Once atrial fibrillation was detected, all patients accepted anticoagulation.
DOACs were the only anticoagulation therapies offered (use of warfarin was investigated in a scenario analysis).
## Base-case results
During the first consultation on this guidance, errors were identified in the economic model. NICE commissioned a review of the model by the NICE Decision Support Unit (DSU) who validated the coding and corrected a further minor error. The updated cost-effectiveness results produced by the DSU were provided for the third committee meeting (see table 5 for deterministic results). Probabilistic results (shown in section 3.72) and deterministic results were similar.
Type of monitoring
Total costs (£)
Total QALYs
Incremental costs (£)
Incremental QALYs
ICER (£)
Conventional follow up
Reveal LINQ
BioMonitor 2‑AF
Confirm Rx
Abbreviations: ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life year.
The ICERs in table 5 were produced by separate comparisons of each of the 3 implantable cardiac monitors with conventional follow up. The lower number of QALYs generated by Confirm Rx is because the battery is assumed to last 2 years, rather than 3 years. The EAG noted that if BioMonitor 2‑AF battery life was 4 years, rather than 3 years, as assumed in the model, the device might detect more cases of atrial fibrillation than are captured in the analyses.
The fully incremental analysis is shown in table 6. The EAG advised that the BioMonitor 2‑AF and Confirm Rx results should be viewed with caution because they are based on a strong assumption of equivalence with Reveal LINQ. The difference in costs between BioMonitor 2‑AF and Reveal LINQ is because of the difference in costs of the devices alone.
Type of monitoring
Total costs (£)
Total QALYs
Incremental costs (£)
Incremental QALYs
ICER (£)
Conventional follow up
Reveal LINQ
Dominated
BioMonitor 2‑AF
Confirm Rx
Dominated
Abbreviations: ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life year. Dominated means that using the device costs more but produced fewer, or the same number of, QALYs than the comparator.
## Scenario analyses
The EAG did some scenario analysis to assess the effect of some of the assumptions made in the model. Selected results are shown in table 7.
Scenario
Reveal LINQ ICER
(£ compared with conventional follow up)
BioMonitor 2‑AF ICER
(£ compared with conventional follow up)
Confirm Rx ICER
(£ compared with conventional follow up)
Base case
Addition of FOCUSON triage service provided by Medtronic for Reveal LINQ
Option 1: £187 per patient per year
NA
NA
Addition of FOCUSON triage service provided by Medtronic for Reveal LINQ
Option 2: one-off fee of £374 per patient per device
NA
NA
No monitoring in conventional follow-up arm (monitoring costs and cases of AF detected in the conventional follow-up arm removed)
Abbreviations: AF, atrial fibrillation; DOAC, direct oral anticoagulant; ICER, incremental cost-effectiveness ratio; NA, not applicable.
The DSU provided updated probabilistic sensitivity analysis for the third committee meeting. The ICERs in table 8 were produced by separate comparisons of each of the 3 implantable cardiac monitors with conventional follow up.
Type of monitoring
Total costs (£)
Total QALYs
Incremental costs (£)
Incremental QALYs
ICER (£)
Conventional follow up
Reveal LINQ
BioMonitor 2‑AF
Confirm Rx
Abbreviations: ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life year.
From the cost-effectiveness acceptability curves (each device was compared independently with conventional follow up), at a maximum acceptable ICER of £20,000 per QALY, all 3 devices had an almost 100% probability of being cost effective.# Committee discussion
# Clinical need
## Technologies that improve paroxysmal atrial fibrillation detection after cryptogenic stroke or TIA could have substantial benefits for people
The patient expert told the committee how, when someone has a stroke or transient ischaemic attack (TIA) with no identifiable cause, they can live in fear of having another stroke. This is because they know that the cause of the stroke is not being treated. This can make them anxious and want to visit the GP often for reassurance. Paroxysmal atrial fibrillation is often a cause of cryptogenic stroke. But it's often not detected because it's not present when someone has their initial assessment. If atrial fibrillation is detected, the clinical experts highlighted the importance of offering anticoagulants, rather than antiplatelet therapy, to reduce the risk of a further stroke or TIA. The patient expert explained that people who have had a cryptogenic stroke tend to be younger than people who have had a stroke with a known cause. Therefore, they're more likely to be working and have dependants, such as elderly parents or children. They pointed out the benefits of preventing further strokes, including reducing post-stroke dementia and the psychological impact of sudden illness. The clinical experts said that current practice is to monitor for suspected atrial fibrillation for up to about 14 days at most using Holter monitors if implantable cardiac monitors are not available. A patient expert said that at the moment, monitoring often misses atrial fibrillation in people who have had a stroke, who could benefit from treatment. The committee concluded that identifying the cause of a cryptogenic stroke is important to reduce risk of a further stroke or TIA. Technologies that can identify paroxysmal atrial fibrillation missed by current post-stroke follow-up testing could have substantial benefits for people who have had a cryptogenic stroke.
## Implantable cardiac monitors can reassure people who have had a cryptogenic stroke or TIA, and their carers
The patient expert said that, if atrial fibrillation is suspected after a stroke or TIA, people can often be anxious that new symptoms may be related to the condition, and that they should report them to their doctor. A continuous electrocardiogram (ECG) monitor can reassure people that if they have symptoms, the monitor will detect any atrial fibrillation that caused them, and can be used to confirm or rule out the condition. Because the devices can remotely monitor people, they may need fewer follow-up appointments after a cryptogenic stroke. This could particularly benefit people living in remote areas far from a hospital. The patient expert said that after a stroke people are fatigued for a long time. Travelling to follow-up appointments can be tiring, costly and time-consuming. People may also need to go with a carer to help them and describe symptoms. The committee concluded that implantable cardiac monitors could have quality of life benefits beyond preventing another stroke.
# Clinical effectiveness
## The CRYSTAL-AF study population broadly represents people with cryptogenic stroke in the NHS
The only study identified by the external assessment group (EAG) that compared the effectiveness of using an implantable cardiac monitor with conventional follow up after a cryptogenic stroke was the CRYSTAL‑AF study. The clinical experts said that it's important that non-invasive ECG monitoring is done before an implantable cardiac monitor is considered. They also said that the length of monitoring in the NHS can vary. Holter monitors are typically used for 24 hours to 7 days. Not everyone in CRYSTAL‑AF had outpatient ECG monitoring before having an implantable cardiac monitor fitted. Those who did were monitored for a median of 23 hours. The committee also considered that participants in CRYSTAL‑AF were younger than would be expected for people who have had a stroke (mean age about 61.5 years). However, the clinical experts explained that people with cryptogenic stroke are usually younger than the overall stroke population. The committee concluded that the population in the CRYSTAL‑AF study broadly represented people with cryptogenic stroke who would have an implantable cardiac monitor fitted in the NHS.
## People in the control arm of CRYSTAL-AF may have been tested more for atrial fibrillation than is usual in the NHS
Some people in the control arm of the CRYSTAL‑AF study, who did not have a cardiac monitor implanted, were tested for atrial fibrillation every 3 months using ECG, including Holter monitoring. The clinical experts said that in current practice, the amount of testing for atrial fibrillation varies if an implantable cardiac monitor is not used, but it is likely to be less than in CRYSTAL‑AF. They also said that people may only be tested again for atrial fibrillation if they have another stroke. The committee concluded that testing for atrial fibrillation in the control arm of CRYSTAL‑AF may be more than is done in the NHS, which may underestimate the increased yield of people with atrial fibrillation reported for the intervention arm.
## Reveal XT increases atrial fibrillation detection, but the effect on further stroke or TIA reduction is uncertain
In the CRYSTAL‑AF study, Reveal XT detected more people with atrial fibrillation than conventional follow up (see table 1). There were also fewer strokes or TIAs in the Reveal XT arm of the study (see table 2). However, because of the length of follow up and sample size, the true effect of the device on reducing stroke or TIA incidence is uncertain; the 95% confidence interval for the hazard ratio at 12 months was 0.22 to 1.80. The committee concluded that there was good evidence that Reveal XT detected more people with atrial fibrillation than conventional follow up, and that this was likely to be seen in clinical practice. However, the extent of a subsequent reduction in stroke or TIA occurrence is uncertain.
## CRYSTAL-AF data can be used to assess how well Reveal LINQ detects atrial fibrillation in people who have had a cryptogenic stroke, but not BioMonitor 2‑AF or Confirm Rx
The CRYSTAL‑AF study used Reveal XT, a predecessor model of Reveal LINQ. Changes have been made to the atrial fibrillation detection algorithm that is now used in Reveal LINQ. There was some evidence that suggested this had improved its ability to detect atrial fibrillation. The clinical experts said that the atrial fibrillation detection algorithms in other manufacturers' devices may use the same features of an ECG to detect potential atrial fibrillation. But how these features are used to determine if atrial fibrillation is likely to be present, or to classify an arrythmia as atrial fibrillation or another type of arrythmia, is likely to differ between devices. At consultation, the manufacturer of the BioMonitor submitted an unpublished technical validation report that compared the ability of the BioMonitor 2‑AF and Reveal LINQ to detect atrial fibrillation from a Holter monitor recording (see section 3.21). The EAG commented that this was not a clinical comparison of the devices, which might perform differently when implanted. The study was also not done in a cryptogenic stroke population, where the device may perform differently because of different patient characteristics. The committee noted that the study had a small population size and had not been published and so was not peer reviewed. Clinical experts commented that electrode positioning is different for Holter monitors and implantable cardiac monitors. So the ECG output from a Holter monitor is not the same as the signal that an implantable cardiac monitor receives. The results could therefore be considered to be artificial and not reflect clinical reality. The committee considered that this study did not show that the Reveal LINQ and BioMonitor devices were comparable in detecting atrial fibrillation in a cryptogenic stroke population. The committee concluded that it is feasible that data from Reveal XT are likely to apply to the updated version from the same manufacturer, Reveal LINQ. But there is too much uncertainty over whether the data can be used to show the performance of the BioMonitor 2‑AF or Confirm Rx to detect atrial fibrillation in people who have had a cryptogenic stroke. Therefore, the committee did not accept that evidence from the CRYSTAL‑AF study could be applied to these devices.
# Cost effectiveness
## It is not appropriate to use data from CRYSTAL-AF to model the performance of BioMonitor 2-AF or Confirm Rx
The EAG used diagnostic yield data (a measure of how many people with atrial fibrillation were diagnosed) from the CRYSTAL‑AF study in the economic model for all 3 devices. The committee considered data from this study to be appropriate to assess how well Reveal LINQ detected atrial fibrillation in people who have had a cryptogenic stroke. But it did not think it was appropriate to use it for BioMonitor 2‑AF or Confirm Rx (see section 4.6). In the absence of clinical or comparative data for these devices in people who have had a cryptogenic stroke, the committee concluded that it was not appropriate to consider the cost-effectiveness estimates for BioMonitor 2‑AF or Confirm Rx.
## It is appropriate to use a linked evidence approach to estimate the impact of implantable cardiac monitors on stroke or TIA incidence
Based on data from the CRYSTAL‑AF study, the extent of any reduction in further stroke or TIA as a result of using an implantable cardiac monitor is uncertain (see section 4.5). The EAG used diagnostic yield data from CRYSTAL‑AF to estimate the increase in cases of atrial fibrillation detected by implantable cardiac monitors (compared with conventional follow up). It then used an existing model (Sterne et al. 2017 and Welton et al. 2017) to estimate the effect of subsequent anticoagulant or antiplatelet treatment on the incidence of clinical events such as stroke. The committee considered that the absolute risk of stroke may differ between people with permanent or persistent atrial fibrillation and people with paroxysmal atrial fibrillation. The clinical experts said that people with paroxysmal atrial fibrillation do benefit from anticoagulant treatment. The EAG ran the model with the risks of events adjusted to reflect a secondary stroke population with paroxysmal atrial fibrillation. The committee concluded that there is uncertainty about the impact of using implantable cardiac monitors on the reduction of further strokes or TIAs. But it agreed that, in the absence of long-term data on this, the EAG's approach of linking evidence on the extent of atrial fibrillation detection, the impact of diagnosis on treatment choice, and the effect of treatment on the incidence of subsequent clinical events such as stroke and TIA in the economic model, was suitable for decision making.
## Not including adverse events caused by implanting Reveal LINQ is unlikely to have a large impact on cost-effectiveness estimates
The EAG's economic model did not include the effect of any adverse events caused by implanting the devices. The EAG explained that the proportions of people who had non-serious adverse events was reported in CRYSTAL‑AF, but there were no details on what these events were. Therefore, the EAG could not include any costs or disutilities caused by these events in the model. The clinical and patient experts said that there are some minor issues caused by the devices, such as irritation and pain when they are fitted or removed, or if someone unintentionally exposes the device through the skin, but that these are not common and do not have severe consequences. The committee concluded that not including any adverse events caused by implanting the devices was unlikely to have had a large effect on cost-effectiveness estimates.
## There may be uncaptured benefit in detecting non-atrial fibrillation arrythmia, but the impact of this on patient outcomes is uncertain
The model did not include detection of non-atrial fibrillation arrythmias. There was not much evidence on the number of these arrhythmias detected by the devices, and what evidence there was came from non-comparative observational studies. The clinical experts explained that most asymptomatic non-atrial fibrillation arrythmia detected by the implantable cardiac monitors would not lead to any change in care. The committee concluded that using the devices may increase detection of non-atrial fibrillation arrythmias, but that the extent of this increase, and the clinical significance of these arrythmias and consequent impact on patient outcomes, is highly uncertain.
## The base case may overestimate how much monitoring for atrial fibrillation is done in current practice, which lowers the ICER
The EAG used the control arm of the CRYSTAL‑AF study to model current practice ('conventional follow up'). The committee had earlier concluded that this may include more monitoring for suspected atrial fibrillation than would be done in the NHS (see section 4.4). This may make the increased diagnostic yield of atrial fibrillation for Reveal LINQ in the model a conservative estimate. But it may also mean that the model overestimates the cost of monitoring for atrial fibrillation in current practice. The EAG did a scenario analysis in which no further monitoring for atrial fibrillation was done in current practice (that is, no people with atrial fibrillation were detected or cost of monitoring included). This increased the incremental cost-effectiveness ratio (ICER) for Reveal LINQ by about £1,300 per quality-adjusted life year (QALY) gained. The committee concluded that the EAG's scenario may be too extreme, in that some monitoring is likely to be done in the NHS for people with no implantable cardiac monitor fitted. However, the amount of assessment for atrial fibrillation in current practice is likely to have been overestimated in the base-case model, which lowered the base-case ICER by up to about £1,300 per QALY gained.
## The number of false positive alerts from Reveal LINQ is uncertain, and including this in the economic model increases the base-case ICER
The base-case model did not include the cost of interpreting alerts produced by Reveal LINQ. The EAG explained that this was because of a lack of data on the number of alerts produced by the device. The clinical experts said that the device would produce false positive alerts. Anecdotal evidence differed on the impact of false positive alerts on workload. One clinical expert said that alerts from the devices can generate several hours of work per day for electrophysiologists to review, although this was based largely on alerts from people with syncope. However, another clinical expert said that it takes minimal time to review alerts generated for possible atrial fibrillation (less than 10 seconds), and that the increase in workload for technicians would be minimal. The clinical experts highlighted that the number of alerts can vary widely between people and noted that cardiac physiologists need to triage the alerts. The EAG did 2 scenario analyses that included the costs of an optional triage service for alerts offered by Medtronic for Reveal LINQ. This increased the ICER by about £2,600 to £3,800 per QALY gained, depending on the cost option used. The clinical experts said that the costs used (£187 per patient per year or £374 per patient) are likely to be a realistic estimate and could be considered a reasonable proxy for the costs of triaging alerts in the NHS. The committee concluded that there is uncertainty about the likely number of false alerts that Reveal LINQ generates in people who have had a cryptogenic stroke if used in routine clinical practice, and the impact on services. Including costs for reviewing alerts in the economic model would increase the ICER for Reveal LINQ, although it is uncertain by how much.
## The EAG's model, following DSU review and amendment, is suitable for decision making
At the first committee meeting, the committee was concerned by the difference between the deterministic and probabilistic base-case results provided by the EAG. There was a large difference in the incremental costs and QALYs generated for the devices (compared with conventional follow up) between these analyses. For the second committee meeting, the EAG provided updated analyses in which an error in the model code used to run the probabilistic sensitivity analysis was corrected. The updated base-case probabilistic sensitivity analysis results were now very similar to the deterministic results. At the first committee meeting, the committee was concerned that the model results may not be realistic (lacking face validity) because of the small number of total QALYs generated in the model. At the second committee meeting, the EAG explained that this was because QALYs in the model were only generated by people who had episodes of atrial fibrillation, which was 30% of the total population. No QALYs were considered for the remaining 70% because there would be no difference in the number of QALYs generated between people with implantable cardiac monitors fitted and conventional follow up (and therefore no impact on ICERs). The EAG further explained that the cohort modelled had a starting age of 62, had all had a stroke or TIA, and all had atrial fibrillation. Therefore, they did not consider that the number of QALYs generated was unrealistic. During the first consultation on this guidance, an error was identified in the model. On reviewing the model, the EAG identified another error. NICE commissioned a review of the model by NICE's Decision Support Unit (DSU). The DSU checked the model and corrected another small error. Updated model results were presented at the third committee meeting. The committee concluded that, considering the DSU's review of the model, the corrections made to the model and the explanations provided, the revised model was suitable for decision making.
## The different parameters used in the EAG's and Diamantopoulos et al. models are unlikely to affect decision making
The updated cost-effectiveness estimate for the Reveal LINQ provided for the third meeting was now lower than the results of a previous economic model that also used data from CRYSTAL‑AF (Diamantopoulos et al. 2016; see sections 3.53 and 3.54). The EAG's updated base-case ICER was £10,342 compared with £17,175 per QALY gained for Diamantopoulos et al. and the incremental QALYs were similar (0.14 and 0.15). The EAG explained that the difference between the results of the models was driven by differences in how the impact of anticoagulant treatment was modelled. Because of differences in model structure, the outcomes included, and the mechanisms used to estimate outcomes, the EAG considered a direct comparison of the parameters used in each model to be difficult and potentially not very informative. The DSU's amended version of the EAG's model estimated that the number of strokes that would be avoided by using an implantable cardiac monitor was 52 per 1,000 people with cryptogenic stroke, compared with 40 per 1,000 people estimated by the Diamantopoulos et al. model. The committee recalled that the size of any reduction in further stroke or TIA caused by using the devices was uncertain (see section 4.5). The committee concluded that there was uncertainty about which was the most appropriate approach to modelling the impact of anticoagulant treatment. The acute and post-stroke utilities were lower in the Diamantopoulos et al. model, which would also have contributed to the difference in incremental QALYs between models. At consultation, several stakeholders commented that the underlying model used (reported in Sterne et al.) was developed for a primary stroke population. The EAG explained that they had adjusted parameters in the model (for example, risk of further stroke, TIA, systemic embolism, intracranial haemorrhage and bleeds) for a secondary stroke population. Stakeholders also highlighted that the impact of a secondary, rather than primary, stroke may have been underestimated in the model. For example, the costs of ongoing treatment and impact on someone's health-related quality of life. The committee concluded that there is uncertainty about the most appropriate parameters to use to model the longer-term effects of anticoagulant and antiplatelet treatment in this population, but that the different parameters used in the EAG's and Diamantopoulos et al. models are unlikely to affect decision making.
## The most plausible ICER for Reveal LINQ is likely to be less than £20,000 per QALY gained
The committee only considered cost-effectiveness estimates for Reveal LINQ (see section 4.7). The probabilistic ICER for Reveal LINQ in the EAG's model was almost identical to the deterministic value. The deterministic base case for Reveal LINQ compared with conventional follow up was £10,342 per QALY gained. If assessment for atrial fibrillation in the conventional follow-up arm is removed from the EAG's base-case model, the ICER increases by about £1,300 per QALY gained. However, the assumption that no longer-term monitoring for atrial fibrillation is done in standard monitoring is unlikely (see section 4.11). In addition, costs of reviewing alerts produced by Reveal LINQ were not included in the base-case model. If the cost of a triage service was included, the EAG's base-case ICER increased by about £2,600 to £3,800 per QALY gained (see section 4.12). The committee concluded that there was uncertainty about the most plausible ICER for Reveal LINQ. Including its preferences in the EAG's model would increase the base-case ICER, but this was unlikely to increase to over £20,000 per QALY gained. The committee concluded that the most plausible ICER for Reveal LINQ is likely to be less than £20,000 per QALY gained.
## Reveal LINQ is likely to be a cost-effective use of NHS resources
The committee agreed that Reveal LINQ was likely to be clinically effective because it identifies more people who have atrial fibrillation after a cryptogenic stroke or TIA than current practice. The committee recalled its conclusion that technologies that improve the detection of paroxysmal atrial fibrillation after cryptogenic stroke or TIA could have substantial benefits for patients. In addition, there is an unmet need for longer-term monitoring for atrial fibrillation after a cryptogenic stroke or TIA (see sections 4.1 and 4.2). The committee considered that the most plausible ICER for Reveal LINQ is likely to be less than £20,000 per QALY gained (see section 4.15). Therefore, the committee concluded that Reveal LINQ is likely to be a cost-effective use of NHS resources.
## Reveal LINQ should only be used after non-invasive ECG monitoring has been done
The inclusion criteria for CRYSTAL‑AF included a requirement for a 12‑lead ECG and 24‑hour ECG monitoring for atrial fibrillation detection to establish the diagnosis of cryptogenic stroke (before use of an implantable cardiac monitor). The amount of atrial fibrillation detected in this study population was used for the cost-effectiveness estimates for Reveal LINQ in this assessment. During consultation, stakeholders highlighted that longer duration non-invasive monitors (that is, monitors that are not implanted) are increasingly available and questioned if this would impact the cost effectiveness of Reveal LINQ. The committee recalled that clinical experts had emphasised that Reveal LINQ would only be used after all available non-invasive monitoring had been done. Therefore, these non-invasive monitors were not comparators to implantable cardiac devices. However, longer duration non-invasive monitoring is likely to detect some cases of atrial fibrillation that shorter duration non-invasive monitoring would miss, and therefore there may be a lower yield of people with atrial fibrillation subsequently detected by implantable cardiac monitors. The EAG commented that longer duration non-invasive monitoring of up to a month was unlikely to have a large impact on the cost effectiveness of Reveal LINQ. They based their comment on exploratory model analysis that assumed that anyone with atrial fibrillation in the first month of CRYSTAL‑AF would not have had an implantable cardiac monitor (reducing the diagnostic yield for Reveal LINQ in the model). Clinical experts highlighted that it is important that non-invasive ECG monitoring is done first before Reveal LINQ is considered, and that the type and duration of non-invasive monitoring will vary by local availability across the NHS. The committee concluded that it's important that Reveal LINQ is only used if paroxysmal atrial fibrillation is still suspected after non-invasive ECG monitoring has been done.
## Reveal LINQ should only be used if the device is discussed with patients and they, or a carer, are able to set up the MyCareLink Patient Monitor
The committee noted that clinicians should discuss implanting the device with patients and give advice about the MyCareLink Patient Monitor, which needs to be set up to transmit rhythm abnormalities recorded by Reveal LINQ. The committee noted that disabled people may need a carer to help set up the MyCareLink Patient Monitor to ensure data are transmitted.
# Research considerations
## Further evidence is needed to show the effectiveness of BioMonitor 2-AF and Confirm Rx to detect atrial fibrillation in people with cryptogenic stroke
The committee considered that there was no evidence plausibly showing that BioMonitor 2-AF and Confirm Rx (or previous versions) were as effective as Reveal devices at detecting atrial fibrillation in people with cryptogenic stroke. And the committee noted that it was difficult to get good comparative data on this. Only diagnostic yield data from a Reveal device were available to model cost effectiveness. A randomised controlled trial comparing Reveal LINQ with Confirm Rx was highlighted during consultation (Yokokawa et al. 2019; see section 3.51). Most of the people in the trial had had a cryptogenic stroke. But the study was only available as a conference abstract. Details of the methodology were limited, and it was not clear why the number of events detected in the Reveal LINQ and Confirm Rx arms were so different. Abbott Medical UK, which makes Confirm Rx, said it was not involved in the study and could not give any more information. The committee considered that it did not have enough information to be able to use the study to assess if Reveal LINQ and Confirm Rx had similar effectiveness. However, it concluded that the study did show that it was feasible to do a trial comparing the effectiveness of different implantable cardiac monitors to detect atrial fibrillation in a cryptogenic stroke population.# Recommendations for further research
Further research is recommended to assess the diagnostic yield of the BioMonitor 2‑AF and Confirm Rx (or later devices) for atrial fibrillation when used in people who have had a cryptogenic stroke. The committee noted that existing ongoing research may provide further data for these devices (see section 3.51 and section 4.19).
|
{'Recommendations': "Reveal\xa0LINQ is recommended as an option to help to detect atrial fibrillation after cryptogenic stroke, including transient ischaemic attacks (TIA), only if:\n\nnon-invasive electrocardiogram (ECG) monitoring has been done and\n\na cardiac arrhythmic cause of stroke is still suspected.\n\nClinicians should consider if disabled people may need support from a carer to help set up the MyCareLink Patient Monitor, to ensure data from Reveal\xa0LINQ are transmitted for review.\n\nThere is not enough evidence to recommend the routine adoption of BioMonitor 2‑AF (or its successor device BIOMONITOR\xa0III) or Confirm\xa0Rx to help to detect atrial fibrillation after cryptogenic stroke. Further research is recommended to assess the diagnostic yield (a measure of how many people with atrial fibrillation are diagnosed) of these devices for atrial fibrillation when used in people who have had a cryptogenic stroke (see section\xa05.1).\n\nWhy the committee made these recommendations\n\nAfter a cryptogenic stroke (a stroke with no identified cause), implantable cardiac monitors can be used for long-term monitoring to identify people with atrial fibrillation if this is thought to have been a cause of the stroke. Clinical trial evidence shows that using Reveal\xa0devices increases the detection of atrial fibrillation in people who have had a cryptogenic stroke (including TIA). If people then have an oral anticoagulant medicine, it is also likely to reduce the number of further strokes or TIAs compared with not using implantable cardiac monitors. How much this reduces strokes or TIAs is not known. There are other uncertainties about the impact of using the device in the NHS, such as how many times it produces a false positive alert (that is, incorrectly identifies atrial fibrillation).\n\nHowever, even after considering these uncertainties, the committee concluded that Reveal\xa0LINQ is still likely to be a cost-effective use of NHS resources, if it's used after non-invasive ECG and no other cause for the stroke has been found. There is an unmet need for people who have had a cryptogenic stroke because there is no other option for long-term monitoring for suspected atrial fibrillation. Therefore Reveal\xa0LINQ is recommended for use in the NHS.\n\nThere's not enough evidence to show if using Confirm\xa0Rx or BioMonitor 2‑AF (or any previous versions of the technologies) increases atrial fibrillation detection compared with not using implantable cardiac monitors in people who have had a cryptogenic stroke. The evidence from Reveal devices cannot be used to make decisions about Confirm\xa0Rx or BioMonitor 2‑AF. This is because the devices use different algorithms to identify potential atrial fibrillation episodes and it's not certain that they will show similar performance in detecting atrial fibrillation when used in people who have had a cryptogenic stroke. Further research is needed to find out if these devices are clinically and cost effective. Therefore they are not recommended for routine adoption in the NHS.", 'The diagnostic tests': "# Clinical need and practice\n\n## Atrial fibrillation\n\nAtrial fibrillation is a type of arrhythmia that causes an irregular or abnormally fast heart rate. It is the most common arrhythmia. When someone has atrial fibrillation, the upper chambers of their heart (the atria) beat irregularly, which makes the heart less effective at moving blood into the ventricles. This can cause clots to form in the blood, which may cause a stroke. The abnormal electrical impulses in the heart muscle that cause atrial fibrillation can be persistent, permanent or intermittent. Paroxysmal atrial fibrillation involves intermittent episodes that usually last less than 2\xa0days and stop without treatment.\n\n## Cryptogenic stroke\n\nCryptogenic strokes (including transient ischaemic attack [TIA]) have no identified probable cause after diagnostic assessment, and account for around 15% to 40% of ischaemic strokes. When people have treatment for stroke, they are tested for atrial fibrillation. However, if they have paroxysmal atrial fibrillation, it may not happen during the initial assessment, or during subsequent diagnostic tests. Further longer-term testing can potentially detect it, for example by using heart rhythm monitors that can be worn, or implanted. These continuously monitor the heart's electrical activity while a person goes about their daily routine.\n\n# The interventions\n\nImplantable cardiac monitors are also known as implantable loop recorders or insertable cardiac monitors. They monitor heart rhythm for longer than heart rhythm monitors that are worn externally (for example, Holter monitors) and can therefore be used for long-term monitoring (potentially over years, rather than days) for suspected atrial fibrillation. Implantable cardiac monitors can identify atrial fibrillation and could be particularly helpful for identifying paroxysmal atrial fibrillation in people who have had a cryptogenic stroke. If people are diagnosed with atrial fibrillation, they can then be offered anticoagulant therapy to reduce the risk of having another stroke or TIA.\n\nThe monitors are implanted under the skin of the person's chest using a small incision under local anaesthetic. They can continuously monitor heart rhythm for several years, and they record information if the device detects an arrhythmia. The devices use algorithms based on electrocardiogram (ECG) features to detect potential atrial fibrillation. The algorithm parameters can be varied to adjust the ECG features identified and flagged as potential atrial fibrillation. Recorded ECGs are remotely transmitted to clinicians, who determine if the person has had atrial fibrillation. They then decide to either continue to monitor or to treat.\n\n## BioMonitor 2-AF (Biotronik SE & Co KG)\n\nThe BioMonitor 2‑AF system consists of:\n\na BioMonitor 2‑AF insertable cardiac monitor (dimensions 88\xa0mm × 15\xa0mm × 6\xa0mm)\n\nan optional Remote Assistant for patient-activated recordings\n\na remote monitoring system (a CardioMessenger Smart transmitter), which sends data to the Biotronik Home Monitoring Service Centre through a cellular phone network\n\na Renamic programmer for the insertable cardiac monitor.\n\nBioMonitor 2‑AF is implanted using a Fast Insertion Tool (FIT) accessory kit. First an incision of at least 1.5\xa0cm is made. Then the FIT\xa01 tool is used to form a pocket for the device under the skin, and the FIT\xa02 is used to implant and position the device. The battery life of the device is estimated as 4\xa0years, assuming data are sent from the device once a day. The company says that clinicians should decide whether to remove the device once it is no longer in use.\n\nThe BioMonitor 2‑AF continuously monitors heart rhythm and ECGs are automatically recorded when atrial fibrillation is detected. Atrial fibrillation is detected based on irregular RR intervals (the interval between heartbeats), absence of P waves and atrial rate greater than 300\xa0beats per minute. Parameters for sensing settings can be adjusted to vary the sensitivity of atrial fibrillation detection. There are also standard settings for parameters, such as atrial fibrillation sensitivity (described in the product manual). BioMonitor 2‑AF can also detect other cardiac arrhythmias such as high ventricular rate, asystole, bradycardia, and sudden ventricular rate drop.\n\nRecordings made by BioMonitor 2‑AF are automatically and wirelessly sent to a transmitter unit every day. Data are encrypted and sent anonymously to the Biotronik Home Monitoring Service Centre over mobile phone networks. Data are stored in Germany and can be accessed by clinicians through an online platform. Automatic alerts are sent to clinicians when a reading is received that meets pre-defined criteria. Clinicians review readings to make a final diagnosis.\n\n## BIOMONITOR III (Biotronik SE & Co KG)\n\nDuring the assessment phase for this guidance, the manufacturer of BioMonitor 2‑AF launched BIOMONITOR\xa0III, a new implantable cardiac monitor device, which supersedes the existing version. The new device uses the same algorithm to detect atrial fibrillation as the BioMonitor 2‑AF. The predicted battery life and cost are also the same. The device is smaller and lighter than the BioMonitor 2‑AF and can be used with a patient app.\n\n## Confirm Rx Insertable Cardiac Monitor (Abbott Medical UK)\n\nThe Confirm\xa0Rx system consists of:\n\na Confirm\xa0Rx Insertable Cardiac Monitor (dimensions 49.0\xa0mm × 9.4\xa0mm × 3.1\xa0mm)\n\na remote monitoring system (the myMerlin application installed on a smartphone or tablet) and the Merlin.net Patient Care Network (PCN)\n\na Merlin Patient Care System and a magnet (to interrogate and program the insertable cardiac monitor).\n\nConfirm\xa0Rx is implanted using proprietary insertion and incision tools. The device is implanted under local anaesthetic through a small cut made using the incision tool. The insertion tool is then used to implant the device under the skin. The battery life of the device is estimated as 2\xa0years, assuming an average of 1\xa0automatically detected episode a day and 1\xa0patient-activated episode a month.\n\nHeart rhythm is continuously monitored by Confirm\xa0Rx, and ECGs are automatically recorded when atrial fibrillation is detected. Confirm\xa0Rx assesses 3 aspects of ECG trace to identify potential atrial fibrillation: regularity of rhythm pattern, variance of RR intervals and how sudden the onset of arrhythmia is. All 3 tests must indicate atrial fibrillation to trigger episode recording. The settings used by the device to detect atrial fibrillation can be varied; for example, to set the length of episode needed to trigger a recording. Confirm\xa0Rx also detects bradyarrhythmias, tachyarrhythmias and pauses.\n\nRecordings made by Confirm\xa0Rx are transmitted using Bluetooth to a smartphone or tablet with the myMerlin app. The app can be downloaded from the company's website. The company says that the app automatically reads data from the implanted device and sends the data to a database using a cellular or Wi-Fi network during the night. It recommends that a smartphone or tablet with the app installed is kept by the person's bedside at night to allow data transmission. Confirm\xa0Rx encrypts its wireless communications and only transmits to a single authenticated and paired myMerlin app at any given time. Emails or SMS notifications can be sent to alert that a recording has been sent. Clinicians can then access transmitted ECG recordings on the Merlin.net PCN by logging on with a User ID and password. Access to the Merlin.net PCN is restricted to authorised users set by the clinic administrator.\n\n## Reveal LINQ Insertable Cardiac Monitoring System (Medtronic Limited)\n\nThe Reveal\xa0LINQ Insertable Cardiac Monitoring System consists of:\n\na Reveal\xa0LINQ Insertable Cardiac Monitor device (dimensions 45\xa0mm × 7\xa0mm × 4\xa0mm)\n\nan optional Reveal Patient Assistant handheld device, which is held over the implanted Reveal\xa0LINQ monitor by the user to start an ECG recording or mark an event on the ECG record\n\na remote monitoring system (a bedside MyCareLink Patient Monitor), which sends data to the MyCareLink network cloud storage facility\n\na MyCareLink Programmer, which is a portable computer system used by a healthcare professional to program the devices.\n\nReveal\xa0LINQ is implanted using proprietary incision and insertion tools. The incision tool makes a small opening in the skin (less than 1\xa0cm) and the insertion tool is used to make a small pocket for the device and to implant it under the skin.\n\nReveal\xa0LINQ continuously monitors heart rhythm and identifies potential atrial fibrillation episodes from the person's ECG trace using an algorithm. An ECG trace is assessed in 2‑minute windows which are considered positive if atrial fibrillation is present for longer than a programmable threshold. If the algorithm detects a potential episode of atrial fibrillation, the ECG trace is stored. The device can also be programmed to only store episodes that persist for a set period of time (6, 10, 20, 30 or 60\xa0minutes). Total atrial fibrillation is also calculated, consisting of all 2‑minute windows in which atrial fibrillation was present for longer than the threshold value. Reveal\xa0LINQ can also detect tachyarrhythmia, bradyarrhythmia or pause episodes. The device contains an accelerometer to allow changes in patient activity over time to be monitored.\n\nRhythm abnormalities recorded by Reveal\xa0LINQ are wirelessly transmitted to the MyCareLink Patient Monitor and then sent to a CareLink server in the Netherlands. Transmitted and stored data are encrypted. A care alert is sent to clinicians when the device detects a rhythm abnormality. They can access the data through the CareLink website using a password protected log-in. Alternatively, daily notifications of cardiac activity can be sent. The device also sends alerts if the battery is low. If the device is unable to communicate with CareLink it registers as disconnected.\n\nThe company also offers a triage and monitoring service (FOCUSON) to review ECG recordings made by Reveal\xa0LINQ. ECGs are reviewed by cardiologists and ECG technicians at a Monitoring and Triaging Service Centre. Any clinically relevant cases requiring clinical action or escalation are notified to the NHS clinician by phone or email. Detected episodes are categorised by colour (red, amber or green). The company says that red events are notified on the same working day from when the transmission reaches the CareLink Network service. Amber events are notified by email by the next working day, and green events are aggregated and notified in a weekly email.\n\n# The comparator\n\n## No further testing after outpatient external ambulatory ECG monitoring\n\nThe clinical experts said that if no atrial fibrillation is detected by an external ambulatory ECG monitor, the person is unlikely to have any further monitoring for atrial fibrillation, unless an implantable cardiac monitor is available. Undetected atrial fibrillation may be later identified if it causes symptoms (for example, palpitations), incidentally when someone's pulse is checked (for example, when blood pressure is taken), or on investigation after a recurrent stroke or TIA. Therefore the comparator is no further monitoring.", 'Evidence': "The diagnostics advisory committee considered evidence from several sources on implantable cardiac monitors (BioMonitor 2‑AF, Confirm\xa0Rx and Reveal\xa0LINQ) to assess for suspected paroxysmal atrial fibrillation in people who have had a cryptogenic stroke. Full details of all the evidence are in the committee papers.\n\n# Clinical effectiveness\n\nThe external assessment group (EAG) did a systematic review to identify evidence on the clinical effectiveness and diagnostic accuracy of implantable cardiac monitors to detect suspected atrial fibrillation after cryptogenic stroke. The devices reviewed were:\n\nBioMonitor 2‑AF\n\nConfirm\xa0Rx\n\nReveal\xa0LINQ.\n\nStudies were included if they assessed the devices in people who had had a cryptogenic stroke or cryptogenic transient ischaemic attack (TIA), and paroxysmal atrial fibrillation was suspected. Because of the small number of studies identified, the requirement for at least 24\xa0hours of outpatient external ambulatory electrocardiogram (ECG) monitoring without atrial fibrillation detection before the devices were implanted (as per current practice) was not applied. Also, data from earlier versions of the devices were considered.\n\nBecause only 1 study (the CRYSTAL‑AF randomised controlled trial) met the EAG's initial eligibility criteria, the EAG relaxed the study inclusion criteria to consider single-arm observational studies. The EAG did not change the population inclusion criteria because it considered that data from non-cryptogenic stroke populations would not represent the device's performance in people with cryptogenic stroke or TIA. This is because non-cryptogenic stroke populations have different incidence rates of atrial fibrillation. However, the EAG provided a summary of studies highlighted by the device manufacturers that were not done in a cryptogenic stroke population. The EAG further highlighted that the patient population, duration of monitoring and the type of atrial fibrillation would affect estimates of device performance.\n\n## Comparative studies\n\nOne study (reported in 6 publications) compared the effectiveness of using 1 of the devices with conventional follow up: the CRYSTAL‑AF study. This was an open-label, parallel group randomised controlled trial that used Reveal\xa0XT (an earlier version of Reveal\xa0LINQ). The XT model is larger. The EAG said that evidence from diagnostic accuracy studies (see sections\xa03.48 and\xa03.49) suggests that Reveal\xa0LINQ has better specificity and sensitivity than the XT, is easier to implant and causes fewer complications.\n\nPeople aged 40\xa0or older who had a recent episode of cryptogenic symptomatic TIA or recent episode of cryptogenic ischaemic stroke had Reveal\xa0XT (n=221) or conventional follow-up care (n=220). People with TIA were only enrolled if they had a visible lesion on MRI or CT that fitted the symptoms of the TIA, and at least 1\xa0of the following symptoms: speech problems, limb weakness or hemianopsia. Follow up in the control group was ECG monitoring at the discretion of the site investigator. The study was done in 55 centres across 14 countries in Europe (none in the UK), Canada and the US. The EAG said that there were similar numbers of withdrawals between the 2 arms (except for crossovers, see section\xa03.12). Data were collected for up to 36\xa0months of follow up, but relatively few people reached this point (24 in each arm). Mean duration of follow up was 20.3\xa0months for Reveal\xa0XT and 19.2\xa0months for conventional follow-up care.\n\nThe EAG noted that, although there were no significant differences in baseline characteristics between study arms, there were differences in the numbers of people with patent foramen ovale and history of prior stroke. However, these were small and unlikely to be because of systematic issues with randomisation. The clinical experts said that the population was slightly younger than people expected to be eligible for an implantable cardiac monitor in the UK. Also, a higher proportion of TIA (rather than stroke) would be expected in clinical practice (closer to 20%, instead of about 9% seen in each of the study arms). All patients would be expected to be taking an antiplatelet agent (about 96% in each arm were using an antiplatelet agent at baseline).\n\nThe EAG's clinical experts said that the tests used in the trial to define a stroke as cryptogenic were broadly the same as what would be done in the NHS. Pre-enrolment screening for atrial fibrillation was Holter monitoring for 71.2% of people (median duration of 23\xa0hours, interquartile range 21\xa0hours to 24\xa0hours), and the remaining people had inpatient telemetry monitoring only. The EAG said that this meant almost 30% of people did not have any outpatient ECG monitoring (as specified in the scope) and that not all patients who did have outpatient ECG monitoring had it for at least 24\xa0hours.\n\nThis trial was sponsored by Medtronic, manufacturers of the device used in the study. The EAG said that the authors of publications for this study reported employment, grants and personal fees from this company. The EAG considered that this was the most robust clinical evidence for Reveal\xa0LINQ, even though it relates to an earlier version of the device.\n\n## Non-comparative studies\n\nComparative data were not identified for BioMonitor 2‑AF, Confirm\xa0Rx or the current Reveal\xa0LINQ version. Therefore, the EAG reviewed single-arm observational studies in cryptogenic stroke (including TIA) populations to identify available data on these devices. Biotronik submitted a technical validation report comparing the accuracy of BioMonitor 2‑AF with Reveal\xa0LINQ during consultation (see section\xa03.21).\n\nTwenty six observational studies (reported in 60\xa0publications) were found. All but 1 study assessed either Reveal\xa0LINQ or Reveal\xa0XT. In 1 study (Israel et al. 2017), 13% of people used the BioMonitor (an earlier version of BioMonitor 2‑AF), but results were not reported by device. The EAG said that these studies therefore do not provide any data for BioMonitor 2‑AF or Confirm\xa0Rx, but that they did supplement data from the CRYSTAL‑AF study.\n\nSample sizes in the studies ranged from 14 to 1,247. Only 1 study (Cotter et al. 2013) was done in the UK. Most studies (17) were prospective single-arm observational studies. There were 5 retrospective studies (Asaithambi et al. 2018, Chalfoun et al. 2016, Heckle et al. 2018, Li et al. 2018 and Salahuddin et al. 2015). One did not report a clear methodology (Cotter et\xa0al. 2013). Ritter et al. (2013) did a within-patient comparison of Reveal\xa0XT and 7-day Holter ECG monitoring. Choe et al. (2015) used the CRYSTAL‑AF dataset to predict how many cases of atrial fibrillation detected by Reveal\xa0XT would have been detected by shorter length intermittent ECG monitoring strategies using simulations. Ziegler et al. (2017) presented data from a registry of people who had Reveal\xa0LINQ and used simulations to predict how many people with atrial fibrillation detected by the device would have been identified by shorter (non-continuous) ECG monitoring.\n\n## Quality assessment of studies\n\nThe CRYSTAL‑AF study was assessed using the Cochrane risk of bias 2.0 tool. The full quality assessment is in the diagnostics assessment report starting from page 28. There was some concern about risk of bias because the trial was open-label and not all people had the randomised intervention required by the study protocol (5.4% of people assigned to Reveal\xa0XT got conventional follow up; 2.7% of people assigned conventional follow up got Reveal\xa0XT). Also, device implantation was delayed for 11.5% of people who had Reveal\xa0XT (median length of delay was 6\xa0days, interquartile range 1 day to 32\xa0days). The EAG noted that results were analysed by intention-to-treat population, which included patients who did not have Reveal\xa0XT, received it late, or crossed over to conventional follow up. This means the estimated benefit of having the device may be underestimated. Delays in implanting Reveal\xa0XT were mostly short and unlikely to affect outcomes. The EAG said that the lack of blinding was unlikely to affect relative atrial fibrillation detection rates between groups. It noted that only a small number of people were followed up after 12\xa0months, so the 24‑month and 36‑month results are likely to be less reliable than results from 6\xa0months and 12\xa0months, but the direction of this bias is unclear.\n\nThe EAG said that it was not able to formally quality assess the 26\xa0additional studies identified that were not randomised controlled trials. However, it considered them all to be at high risk of bias because of their single-arm designs. Because of heterogeneity between the studies, the EAG did not consider it appropriate to pool results from these studies. This included the model of device used, detection settings, patient characteristics, rigour of stroke assessment, severity of index stroke, definition and adjudication of atrial fibrillation, and length of follow up.\n\n## Evidence on ability to detect atrial fibrillation\n\nAtrial fibrillation detection rate at 6\xa0months was the CRYSTAL‑AF study's primary outcome (episodes had to last more than 30\xa0seconds). At 6\xa0months, 19 people were diagnosed with atrial fibrillation in the Reveal\xa0XT arm and 3\xa0people in the conventional follow-up arm. More atrial fibrillation was detected with Reveal\xa0XT at all time points (see table\xa01). Reveal\xa0XT increased atrial fibrillation detection across all pre-specified subgroups (age, sex, race or ethnic group, index event, presence or absence of patent foramen ovale, and CHADS2 score), with no significant interactions. Most people who had atrial fibrillation detected by Reveal\xa0XT were asymptomatic (34 out of the 42 detected by 36\xa0months). Estimated detection rates are higher in the 36‑month Kaplan–Meier analysis because of the non-informative censoring (that is, people who dropped out for reasons unrelated to the study) of patients lost to follow up (atrial fibrillation detection rate estimated as 30% with Reveal\xa0XT and 3% with conventional follow up).\n\nMonths\n\nReveal XT: cumulative number of patients with AF detected\n\n(n [% ITT])\n\nConventional follow up: cumulative number of patients with AF detected\n\n(n [% ITT])\n\n\n\n(3.6)\n\n(0.5)\n\n\n\n(8.6)\n\n(1.4)\n\n\n\n(13.1)\n\n(1.8)\n\n\n\n(17.2)\n\n(2.3)\n\n\n\n(19.0)\n\n(2.3)\n\nAbbreviations: AF, atrial fibrillation; ITT, intention to treat.\n\nAll 26 observational studies reported atrial fibrillation detection rate. Detection rates varied widely, ranging from 6.7% to 40.9% (length of monitoring varied between studies). Several studies reported atrial fibrillation detection rates over multiple time points. The EAG said that the studies generally show that a minority of patients are diagnosed in the first month (about 10% of those detected by 1\xa0year). Around 70% to 80% (of the total number of people with atrial fibrillation detected in a study) are diagnosed by 6\xa0months, and a small number after a year of monitoring. All or most of the detected atrial fibrillation in the observational studies (when stated) were asymptomatic, as in CRYSTAL‑AF.\n\nTwo observational studies estimated how many atrial fibrillation episodes would have been detected by intermittent ECG monitoring. These used datasets generated by Reveal\xa0XT (in CRYSTAL‑AF; Choe et al. 2015) or Reveal\xa0LINQ (from a large registry of patients with the device [n=1,247]; Ziegler et al. 2017). The studies assumed Reveal devices had 100% sensitivity. The studies estimated that even the best intermittent ECG monitoring strategies would detect less than a third of atrial fibrillation detected by Reveal devices.\n\nCRYSTAL‑AF did not report any results for the detection of other cardiac pathologies.\n\nFive non-comparative observational studies reported incidental detection of other arrhythmias. The EAG said that the proportion of patients detected with other arrhythmias is about 10% of the total number of people in a study. This mainly consists of bigeminy, pause and bradycardia. Two studies reported the breakdown of arrhythmias and gave rates of 1% (atrial flutter, cardiac arrest, sick sinus node, bigeminy, ventricular tachycardia) to 7% to 8% (atrioventricular block and ventricular extra systole). Full details are on page 51 of the diagnostics assessment report. The studies did not say if the other detected arrhythmias were treated, or if outcomes were improved because these arrhythmias were identified. Also, because these were non-comparative studies, the extent of any increase in detection compared with conventional follow up could not be determined.\n\nNo data relevant to this outcome were reported in CRYSTAL‑AF.\n\nTwo non-comparative observational studies reported the proportion of episodes detected by the devices that were not verified as atrial fibrillation by a clinician. Li et al. (2018) reported 79.7% for Reveal\xa0LINQ and Israel et al. (2017) reported that over 90% of detected episodes were not confirmed by review (Reveal\xa0XT and BioMonitor). The EAG noted that Medtronic had said that the number of false positive alerts varies depending on the device model used, and the configuration for detection (including episode duration) that is programmed by the operator. Data on device accuracy (for all devices) in non-cryptogenic stroke populations from studies identified by manufacturers are presented later (see section\xa03.41).\n\nDuring the first consultation on this guidance, the manufacturer of the BioMonitor 2‑AF submitted an unpublished technical validation report comparing the accuracy of the Reveal\xa0LINQ and BioMonitor devices. This was done by replaying ECG data recorded by a Holter monitor in a previous trial into the sensing electrodes of the Reveal\xa0LINQ and BioMonitor devices. The report stated that because the atrial fibrillation detection algorithm of the BioMonitor 2‑AF and BIOMONITOR\xa0III are the same, the results are applicable to both devices. People enrolled in the original trial had documented atrial fibrillation episodes or symptoms attributable to atrial fibrillation, were scheduled for catheter ablation or had had it, but were still experiencing atrial fibrillation-related symptoms. Of the participants, 70% had a history of paroxysmal atrial fibrillation. The rest had a history of persistent atrial fibrillation. However, the EAG highlighted that the report also stated that people with long-standing persistent or permanent atrial fibrillation were excluded. The EAG pointed out that this was contradictory and meant that the characteristics of the population in the study were not clear. At consultation on the draft guidance, BioMonitor's manufacturer commented that all ECG data fed into the devices as part of the study were for less than 48 hours. It said that therefore they represented paroxysmal atrial fibrillation episodes only. In the study, atrial fibrillation episodes detected, or not, by clinician assessment of the Holter monitor ECG trace was used to classify true and false positives and false negative atrial fibrillation episodes detected by the Reveal\xa0LINQ and BioMonitor. Atrial fibrillation episode sensitivity for BioMonitor and Reveal\xa0LINQ were 78.0% and 79.0% respectively. Patient-averaged positive predictive values were 98.7% for BioMonitor and 99.7% for Reveal\xa0LINQ.\n\n## Evidence on clinical outcomes\n\nThe EAG said that atrial fibrillation was detected in only 5 people in the conventional follow-up arm of CRYSTAL‑AF (and none after 24\xa0months; see table\xa01). This means it is difficult to make any conclusions about the effect of using Reveal\xa0XT from the median time to atrial fibrillation detection data. Atrial fibrillation was detected in more people with longer follow up, and therefore the median time to detection also increased. There was a greater increase in the median time to atrial fibrillation detection with Reveal\xa0XT compared with conventional follow up across all time points. The EAG said that the low detection rate of atrial fibrillation in the conventional follow-up arm was the likely cause of this difference.\n\nThere were 18 observational studies that reported time from device insertion to atrial fibrillation detection. Average follow up ranged from 7\xa0months to 20\xa0months, and median time to first atrial fibrillation detection had a wide range, from 21\xa0days to 217\xa0days. When reported, interquartile ranges also showed high variability within studies.\n\nNo data were reported in CRYSTAL‑AF or the observational studies.\n\nNo data were reported in CRYSTAL‑AF or the observational studies.\n\nMost people diagnosed with atrial fibrillation using Reveal\xa0XT started having an oral anticoagulant (more than 90%) in the CRYSTAL‑AF study. The reasons people did not start on anticoagulants after being diagnosed with atrial fibrillation were not clear. The EAG noted that some people who were not diagnosed with atrial fibrillation in the trial were also started on anticoagulants. Reasons for this were not provided.\n\nSeven observational studies (Asaithambi et al. 2018, Carrazco et al. 2018, Christensen et al. 2014, Etgen et al. 2013, Li et al. 2018, Merce et al. 2013 and Seow et al. 2018) reported that uptake of anticoagulants for people with atrial fibrillation detected by Reveal\xa0XT or LINQ was high: between 83.3% and 100%.\n\nNo data were reported in CRYSTAL‑AF or the observational studies.\n\nNo incidence of Reveal\xa0XT failure was reported in CRYSTAL‑AF. The device had to be removed early because of infection or pocket erosion from 5 out of 208 (2.4%) people by 36\xa0months.\n\nThree non-comparative observational studies reported how many devices were removed during follow up. In Christensen et al. (2014), Reveal\xa0XT was removed prematurely in 5.7% people because of skin reactions and discomfort. A further 3.4% of people chose to have the device removed after more than 1\xa0year without atrial fibrillation being detected. In Asaithambi et al. (2018), 2.6% of people chose to have Reveal\xa0LINQ removed, and for 0.9% of people the devices migrated or fell out. In Ritter et al. (2013), study participants were offered removal of Reveal\xa0XT once atrial fibrillation was detected. But they did not report how many of the 30% of removals were because of this, or for other reasons such as discomfort.\n\nNo data were reported in CRYSTAL‑AF or the observational studies.\n\nNo data were reported in CRYSTAL‑AF or the observational studies.\n\nIn CRYSTAL‑AF, a non-significant trend of fewer recurrent events (stroke or TIA) in the Reveal\xa0XT arm was reported (see table\xa02). The study was not powered for this outcome. It is not clear if the recurrent stroke or TIA events occurred in people who were diagnosed with atrial fibrillation or not.\n\nMonth\n\nReveal XT (n=221): people having another stroke or TIA(n [%])\n\nConventional follow up (n=220): people having another stroke or TIA(n [%])\n\nHazard\xa0ratio(95% CI)\n\n\n\n(5.0)\n\n(8.2)\n\nNot reported\n\n\n\n(6.8)\n\n(8.6)\n\n(0.22 to 1.80)\n\n\n\n(9.1)\n\n(10.9)\n\n(0.30 to 1.97)\n\nAbbreviations: CI, confidence interval; TIA, transient ischaemic attack.\n\nOf the studies, 6 non-comparative observational studies reported variable incidences of secondary stroke or TIA in people with an implantable cardiac monitor: from 0% to\xa014.6%.\n\nNo data were reported in CRYSTAL‑AF or the observational studies.\n\nThe EAG said that the incidence of device-related adverse effects (such as pain and infection) was relatively low for people who had Reveal\xa0XT implanted in CRYSTAL‑AF. However, adverse events did lead to the device being removed in 2.4% of patients. The proportion of people with serious adverse events was slightly higher for Reveal\xa0XT (30.8%) than conventional follow up (27.9%). More people had non-serious adverse events in the Reveal\xa0XT arm (18.6%) than in the conventional follow-up arm (4.1%). No details of these events were reported, and the EAG said that it was unclear why there was a difference between the study arms. Reveal\xa0XT is larger than Reveal\xa0LINQ.\n\nFor 5 non-comparative observational studies, there were no complications from the procedure or insertion site reported at follow up (length of follow up was not specified). These were Merce et al. (2013), Reinke et al. (2018) and Ritter et al. (2013) for Reveal\xa0XT; Poli et al. (2016) for Reveal\xa0LINQ and XT; and Israel et al. (2017) for Reveal\xa0XT and BioMonitor.\n\nNo data were reported in CRYSTAL‑AF or the observational studies.\n\n## Evidence on patient-reported outcomes\n\nHealth-related quality of life data were collected in CRYSTAL‑AF using the EuroQol 5-Dimensions (EQ-5D) tool. Unpublished data were provided by the company as academic in confidence so they cannot be reported here.\n\nNo data were reported in CRYSTAL‑AF or the observational studies.\n\n## Evidence from non-cryptogenic stroke populations\n\nThe EAG provided a narrative summary of studies in non-cryptogenic stroke populations identified by manufacturers of the devices. These studies were not done in populations who had exclusively had a cryptogenic stroke or TIA although some were in a 'mixed population' (less than 50% of the study population had a cryptogenic stroke or TIA and subgroup analysis was not provided). All studies were either single-arm observational studies or assessed the diagnostic accuracy of the devices compared with Holter monitoring. The EAG highlighted that the performance of the devices depends on the patient population, atrial fibrillation incidence rate, and the type of atrial fibrillation. Therefore, the results from these studies do not necessarily represent the devices' performance in people with cryptogenic stroke.\n\nThe EAG did not do a full systematic literature search to validate the inclusion of the studies. This was because of time constraints and concerns about the applicability of results to the cryptogenic stroke population. The EAG said that the data may have study selection bias as well as clinical heterogeneity caused by the variation in the patient populations of each of the studies.\n\nThe company said the Detect\xa0AF study (Nölker et al. 2016) was potentially relevant for assessing Confirm\xa0Rx. The EAG noted that the device used in Detect\xa0AF was the Confirm model DM2102. This is an older and larger model of Confirm\xa0Rx. The EAG was unsure how the software in this earlier version compared with the current Confirm\xa0Rx.\n\nDetect\xa0AF was a prospective observational study. It assessed the diagnostic accuracy of the Confirm system in detecting atrial fibrillation compared with Holter monitoring (reference standard) with simultaneous use of the devices. In per-patient analysis, sensitivity of the Confirm system was 100%, positive predictive value was 64.0%, specificity was 85.7% and negative predictive value was 100%. Most of the episodes of atrial fibrillation detected by the Confirm system but not confirmed by the Holter monitor were because of irregular sinus rhythms. No adverse events associated with the device were reported.\n\nThe EAG discussed 5 single-arm prospective observational studies (in 8\xa0publications) provided by Biotronik. Three of these studies (which included data on diagnostic accuracy) were unpublished and were provided as academic or commercial in confidence so details cannot be reported here.\n\nReinsch et al. (2018) reported that BioMonitor\xa02 was successfully implanted in a catheterisation laboratory with a median time from first cut to final suture of 8\xa0minutes (interquartile range 7\xa0minutes to 10\xa0minutes). Ooi et al. (2017) reported that all insertions of the device were made on first attempt in a catheterisation laboratory with a median time of 9\xa0minutes (interquartile range 5\xa0minutes to 14\xa0minutes). Ooi et al. reported that 1\xa0pocket infection occurred when using the device. Reinsch et al. reported that no devices implanted in the study migrated, and 1 person needed the device removing because of device-related pocket infection. Another patient complained of slight discomfort.\n\nReinsch et al. reported results from patient satisfaction surveys. Of the respondents, 7% reported moderate to severe pain and 20% reported mild pain within 24\xa0hours of device insertion. One person reported a moderate impairment in daily life. Of the respondents, 63% said that the cosmetic result was 'very satisfying' and 30% said 'satisfying'.\n\nThe EAG discussed 5 studies highlighted by the company. Two compared the diagnostic accuracy of Reveal devices (per-patient analysis) with Holter monitoring for detecting atrial fibrillation (Hindricks et al. 2010 and Sanders et al. 2016). In Hindricks et al. (2010), Reveal\xa0XT was used (the XPECT trial). Another study (Puerefellner et al. 2014) used data from this trial and recalculated accuracy estimates when changes were made to the atrial fibrillation detection algorithm. This incorporated data on P\xa0waves when classifying patients, and this algorithm change was applied in Reveal\xa0LINQ. Sanders et al. (2016) used Reveal\xa0LINQ. A subsequent study (Puerefellner et al. 2018) was published using this dataset (and the XPECT data) to calculate the accuracy of a modified algorithm for detecting atrial fibrillation (using the TruRhythm algorithm that has now been incorporated in the device). Data on the diagnostic accuracy reported in these studies are shown in table\xa03.\n\nMeasure\n\nXPECT study\n\nHindricks et al. 2010\n\n(Reveal XT)\n\nXPECT dataset\n\nPuerefellner et al. 2014\n\n(Reveal XT with P-sense enhancement)\n\nLINQ usability study\n\nSanders et al. 2016\n\n(Reveal LINQ)\n\nLINQ usability dataset\n\nPuerefellner et al. 2018\n\n(Reveal LINQ with adaptive P-sense; TruRhythm)\n\nSensitivity (%)\n\n\n\n\n\n\n\n\n\nSpecificity (%)\n\n\n\n\n\n\n\n\n\nPositive predictive value (%)\n\n\n\n\n\n\n\n\n\nNegative predictive value (%)\n\n\n\n\n\n\n\n\n\nAccuracy (%)\n\n\n\n\n\n\n\n\n\nPositive predictive value, negative predictive value and accuracy for the XPECT dataset calculated by the EAG using data in Puerefellner et al.\xa0(2014).\n\nThe EAG said that the studies showed improved detection of atrial fibrillation by Reveal\xa0LINQ compared with Reveal\xa0XT. Changes made to the algorithm also improved detection. But the results should be interpreted with caution because these studies were not done in people who had had a cryptogenic stroke. However, the EAG said that these data suggest that Reveal\xa0LINQ is likely to be as effective as Reveal\xa0XT, if not better, at detecting atrial fibrillation. Therefore, the clinical data from CRYSTAL‑AF (which uses the Reveal\xa0XT) could be a conservative estimate of the clinical effectiveness of the device.\n\nMittal et al. (2015) reported adverse event data from 2 observational studies that used Reveal\xa0LINQ. An infection occurred in 1.5% of people, an adverse event in 4.0% and a serious adverse event in 1.1%.\n\nThe EAG identified 8 potentially relevant ongoing studies from searches of trial registries and electronic databases, in addition to company submissions. There are 3 ongoing randomised controlled trials assessing Reveal\xa0LINQ. Of these, 1 is in people with cryptogenic stroke. This is a Canadian randomised trial comparing the clinical and cost effectiveness of Reveal\xa0LINQ with external loop recording in 300 people who have had cryptogenic stroke. It was estimated to complete in December 2019 (PERDIEM; NCT02428140). One ongoing study identified is assessing Confirm\xa0Rx: the SMART registry (NCT03505801). This is a post-approval study planned for at least 2,000 patients with Confirm\xa0Rx across multiple indications, with a planned subgroup analysis for cryptogenic stroke. Completion was expected during 2019. At consultation on the draft guidance, a stakeholder submitted a recent conference abstract (Yokokawa et al. 2019). The abstract gave only limited methodological detail. In this study, people were randomised to have either Confirm\xa0Rx or Reveal LINQ implanted (n=80; 52 had cryptogenic stroke but no subgroup analysis was provided). The abstract reported that 28 of 51 atrial fibrillation events (55%) were detected accurately by Reveal\xa0LINQ and 131 of 301 atrial fibrillation events (44%) were accurately detected by Confirm Rx (p=0.13).\n\n# Cost effectiveness\n\n## Systematic review of cost-effectiveness evidence\n\nThe EAG did a systematic review to identify any published economic evaluations of implantable cardiac monitors to detect atrial fibrillation in people with cryptogenic stroke. There were 5 studies that met the EAG inclusion criteria. Of these, 2 assessed the cost effectiveness of Reveal\xa0XT compared with standard care monitoring (DeAngelis et al. 2016 and Diamantopoulos et al. 2016). Another study assessed BioMonitor 2‑AF (Maervoet et al. 2017; further details provided as unpublished report and model by the device manufacturer as commercial in confidence), and 2\xa0studies did not indicate which implantable cardiac monitor was being assessed (Quiroz et al. 2017 and Thijs et al. 2018). Only 1 study (Diamantopoulos et al. 2016) was based on an NHS payer perspective and was discussed in the diagnostics assessment report.\n\nThis study was a cost–utility analysis. It compared use of Reveal\xa0XT in people who have had a cryptogenic stroke or TIA with conventional follow\xa0up, as assessed in the CRYSTAL‑AF study. A Markov model structure was used with 3 main health states for atrial fibrillation status: free, detected and undetected. The deterministic base case produced an incremental cost-effectiveness ratio (ICER) of £17,175 per quality-adjusted life year (QALY) gained for Reveal\xa0XT compared with standard care (£2,587 higher costs, 0.151 additional QALYs). The probabilistic ICER was lower.\n\nThe EAG considered that results from this model were potentially unreliable because there was uncertainty about how parameters in the model had been estimated. The estimation of treatment effects by indirect comparison, atrial fibrillation incidence and detection rates used in the analysis were particularly unclear. The study authors used indirect comparisons to estimate hazard ratios for the benefit of anticoagulants on the occurrence of ischaemic stroke, bleeding events, intracranial haemorrhages, extracranial haemorrhages and mortality. The EAG tried to verify these figures but was unable to because there were insufficient details in the publication about how the indirect comparisons were done and how publications that informed the analysis were identified. The EAG also considered that estimation of some of the hazard ratios could be flawed. For example, the authors estimated a hazard ratio to adjust mortality in the model, but the source data used are based on standardised mortality ratios. Furthermore, people without atrial fibrillation detected were assumed to be offered aspirin, but the EAG's clinical experts said that clopidogrel would be used as an antiplatelet treatment.\n\nThe EAG developed a de novo economic model to assess the cost effectiveness of using implantable cardiac monitors (BioMonitor 2‑AF, Confirm\xa0Rx or Reveal\xa0LINQ) to assess for suspected paroxysmal atrial fibrillation in people who have had a cryptogenic stroke (including TIA).\n\nThe EAG developed a 2-stage economic model. The first stage (an Excel model developed by the EAG) modelled people having either monitoring for suspected paroxysmal atrial fibrillation after a cryptogenic stroke (including TIA) with the implantable cardiac monitors or conventional follow up. Everyone starts the model having antiplatelet therapy (clopidogrel) for stroke prevention. At every 3‑month cycle in the model, a proportion of people have atrial fibrillation. For people with an implantable cardiac monitor, all cases of atrial fibrillation are detected, and treatment is switched to anticoagulants (atrial fibrillation detected). For people with conventional follow up, a proportion of people with atrial fibrillation are detected (and switch to anticoagulants) but most are not (atrial fibrillation undetected) and remain on antiplatelet therapy.\n\nFor the subsequent long-term anticoagulation model, the EAG adapted a published economic model to model the long-term effect of people with detected atrial fibrillation (anticoagulant treatment) or undetected atrial fibrillation (remain on antiplatelet therapy with clopidogrel). This is the 'adapted direct oral anticoagulant (DOAC) model' (Sterne et al. 2017 and Welton et al. 2017). People enter the model after having atrial fibrillation in an 'atrial fibrillation well' state. After this, clinical events can occur. These are TIA, ischaemic stroke, intracranial haemorrhage, myocardial infarction, clinically relevant (extracranial) bleed or systemic embolism (multiple events can happen to one person over the course of the model). The risks of these events happening in the model were based on a population with a history of ischaemic stroke and paroxysmal atrial fibrillation. The model structure is the same for people with detected and undetected atrial fibrillation. However, the probability of the events happening depends on the treatment used (anticoagulants or antiplatelet therapy).\n\nThe population in the model was people who had had a cryptogenic stroke (including TIA), when there was suspected paroxysmal atrial fibrillation. These people had had at least 24\xa0hours of outpatient external ambulatory ECG monitoring that had not detected atrial fibrillation. Characteristics were based on the population in the CRYSTAL‑AF study, with a mean age of 61\xa0years and about 65% people assumed to be men.\n\nIn the model, the EAG used data from the control arm of CRYSTAL‑AF for the comparator. People in the study were assessed at scheduled visits (every 3\xa0months) and unscheduled visits if they were having symptoms of atrial fibrillation. Tests included ECGs and Holter monitoring (for 24\xa0hours, 48\xa0hours or 7\xa0days).\n\n## Model inputs\n\nDiagnostic yield data from CRYSTAL‑AF were used for the number of people with atrial fibrillation detected by an implantable cardiac monitor or by conventional follow up. No equivalent data were identified for BioMonitor 2‑AF or Confirm\xa0Rx (or the current Reveal\xa0LINQ version). Therefore, the EAG assumed equal efficacy for all devices. A published model (Sterne et al. 2017 and Welton et al. 2017; the 'adapted DOAC' model) was used to model longer-term clinical outcomes for people with atrial fibrillation that is detected (treatment with an anticoagulant) or not detected (treatment with an antiplatelet drug). Outcomes included were ischaemic stroke, myocardial infarction, TIA, systemic embolism, clinically relevant extracranial bleed, intracranial haemorrhage and all-cause mortality.\n\nAll costs in the model were valued in 2018, in UK pounds sterling. Device costs are shown in table\xa04.\n\nDevice\n\nUnit cost (£ excluding VAT)\n\nBioMonitor 2‑AF\n\n,030\n\nConfirm Rx\n\n,600\n\nReveal LINQ\n\n,800\n\nMedtronic also offers an optional triage service for use with Reveal\xa0LINQ (FOCUSON) that was included in scenario analyses. There were 2 cost options included: £187 per patient per year or £374 per patient per device. The EAG did not include the cost of reviewing alerts generated by the devices in the base case.\n\nIn the base case, the EAG estimated the cost of implanting the devices as £24.17. This was based on advice from the clinical experts about the staff involved (cardiologist and nurse) and time taken for the procedure (10\xa0minutes). The cost of removing the devices was assumed to be £238, based on NHS reference costs schedule 2017/18 (EY13Z – removal of electrocardiography loop recorder, outpatient setting, treatment function code 320). Costs associated with adverse events from implanting the devices were not included in the EAG's analysis.\n\nThe EAG based costs for the comparator on the conventional follow-up arm of CRYSTAL‑AF. Costs per cycle in the model were calculated based on the proportion of people having testing every 3\xa0months or no testing in the study. The unit cost of monitoring was £141, based on the NHS reference costs schedule 2017/18 (HRG code EY51Z – ECG monitoring or stress testing [outpatient procedures, service code 320]). The EAG assumed that people with an implantable cardiac monitor will have 1\xa0face-to-face follow up a month after the procedure and then will be remotely monitored. For people in the conventional follow-up arm who do not have atrial fibrillation detected, follow-up appointments are assumed to happen after 1, 3, 6 and 12\xa0months, based on clinical expert advice. If atrial fibrillation is detected, a follow-up appointment is assumed to discuss treatment. The cost of an initial follow up (£163.36) and subsequent follow up (£128.05) were taken from NHS reference costs.\n\nThe costs of DOACs and clopidogrel were taken from the BNF September 2018 to March 2019 edition. Costs of acute and chronic health events were taken from NHS reference costs or Luengo-Fernandez et al. (2013).\n\n## Health-related quality of life and QALY decrements\n\nThe EAG did a systematic review to identify relevant utility values to update the adapted DOAC model. There were 2 papers (Berg et al. 2010 and Luengo-Fernandez et al. 2013) with relevant utility values for ischaemic stroke, intracranial haemorrhage, myocardial infarction and TIA events. These were included in the model and were used to update the adapted DOAC model. The utility value used for people with atrial fibrillation in a 'well' health state (that is, when no clinical events such as stroke have occurred) was 0.78 (Berg et al. 2010). The duration of disutility for an acute event was assumed to be 3\xa0months (1 model cycle).\n\n## Base-case assumptions\n\nThe following assumptions (in addition to those described in previous sections) were applied in the base-case analysis:\n\nThe prevalence of atrial fibrillation in this population was equal to the detection rate in CRYSTAL‑AF.\n\nReveal\xa0LINQ was as good as Reveal\xa0XT (the device used in CRYSTAL‑AF) for detecting atrial fibrillation.\n\nBioMonitor 2‑AF and Confirm\xa0Rx were equivalent to Reveal\xa0XT or Reveal\xa0LINQ for detecting atrial fibrillation.\n\nThe detection of atrial fibrillation was capped at 3\xa0years for BioMonitor 2‑AF even though the manufacturer said the battery life is expected to be 4\xa0years. This was because atrial fibrillation detection data were only available for 3\xa0years of follow up.\n\nAtrial fibrillation detection was capped at 2\xa0years for Confirm\xa0Rx because this is the expected battery life of the device, and the clinical experts advised that devices are unlikely to be replaced once a battery expires.\n\nAfter 3\xa0years, detection rates of atrial fibrillation are the same in both the implantable cardiac monitors and conventional follow-up arms.\n\nOnce atrial fibrillation was detected, all patients accepted anticoagulation.\n\nDOACs were the only anticoagulation therapies offered (use of warfarin was investigated in a scenario analysis).\n\n## Base-case results\n\nDuring the first consultation on this guidance, errors were identified in the economic model. NICE commissioned a review of the model by the NICE Decision Support Unit (DSU) who validated the coding and corrected a further minor error. The updated cost-effectiveness results produced by the DSU were provided for the third committee meeting (see table\xa05 for deterministic results). Probabilistic results (shown in section\xa03.72) and deterministic results were similar.\n\nType of monitoring\n\nTotal costs (£)\n\nTotal QALYs\n\nIncremental costs (£)\n\nIncremental QALYs\n\nICER (£)\n\nConventional follow up\n\n,600\n\n\n\n–\n\n–\n\n–\n\nReveal LINQ\n\n,092\n\n\n\n,492\n\n\n\n,342\n\nBioMonitor 2‑AF\n\n,322\n\n\n\n\n\n\n\n,006\n\nConfirm Rx\n\n,866\n\n\n\n,267\n\n\n\n,879\n\nAbbreviations: ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life year.\n\nThe ICERs in table\xa05 were produced by separate comparisons of each of the 3\xa0implantable cardiac monitors with conventional follow up. The lower number of QALYs generated by Confirm\xa0Rx is because the battery is assumed to last 2\xa0years, rather than 3\xa0years. The EAG noted that if BioMonitor 2‑AF battery life was 4\xa0years, rather than 3\xa0years, as assumed in the model, the device might detect more cases of atrial fibrillation than are captured in the analyses.\n\nThe fully incremental analysis is shown in table\xa06. The EAG advised that the BioMonitor 2‑AF and Confirm\xa0Rx results should be viewed with caution because they are based on a strong assumption of equivalence with Reveal\xa0LINQ. The difference in costs between BioMonitor 2‑AF and Reveal\xa0LINQ is because of the difference in costs of the devices alone.\n\nType of monitoring\n\nTotal costs (£)\n\nTotal QALYs\n\nIncremental costs (£)\n\nIncremental QALYs\n\nICER (£)\n\nConventional follow up\n\n,600\n\n\n\n–\n\n–\n\n–\n\nReveal LINQ\n\n,092\n\n\n\n\n\n\n\nDominated\n\nBioMonitor 2‑AF\n\n,322\n\n\n\n\n\n\n\n,006\n\nConfirm Rx\n\n,866\n\n\n\n\n\n-0.05\n\nDominated\n\nAbbreviations: ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life year. Dominated means that using the device costs more but produced fewer, or the same number of, QALYs than the comparator.\n\n## Scenario analyses\n\nThe EAG did some scenario analysis to assess the effect of some of the assumptions made in the model. Selected results are shown in table\xa07.\n\nScenario\n\n\n\nReveal LINQ ICER\n\n(£ compared with conventional follow up)\n\nBioMonitor 2‑AF ICER\n\n(£ compared with conventional follow up)\n\nConfirm Rx ICER\n\n(£ compared with conventional follow up)\n\nBase case\n\n,342\n\n,006\n\n,879\n\nAddition of FOCUSON triage service provided by Medtronic for Reveal LINQ\n\nOption 1: £187 per patient per year\n\n,100\n\nNA\n\nNA\n\nAddition of FOCUSON triage service provided by Medtronic for Reveal LINQ\n\nOption 2: one-off fee of £374 per patient per device\n\n,934\n\nNA\n\nNA\n\nNo monitoring in conventional follow-up arm (monitoring costs and cases of AF detected in the conventional follow-up arm removed)\n\n,617\n\n,823\n\n,304\n\nAbbreviations: AF, atrial fibrillation; DOAC, direct oral anticoagulant; ICER, incremental cost-effectiveness ratio; NA, not applicable.\n\nThe DSU provided updated probabilistic sensitivity analysis for the third committee meeting. The ICERs in table\xa08 were produced by separate comparisons of each of the 3 implantable cardiac monitors with conventional follow up.\n\nType of monitoring\n\nTotal costs (£)\n\nTotal QALYs\n\nIncremental costs (£)\n\nIncremental QALYs\n\nICER (£)\n\nConventional follow up\n\n,600\n\n\n\n–\n\n–\n\n–\n\nReveal LINQ\n\n,093\n\n\n\n,493\n\n\n\n,350\n\nBioMonitor 2‑AF\n\n,323\n\n\n\n\n\n\n\n,014\n\nConfirm Rx\n\n,867\n\n\n\n,268\n\n\n\n,888\n\nAbbreviations: ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life year.\n\nFrom the cost-effectiveness acceptability curves (each device was compared independently with conventional follow up), at a maximum acceptable ICER of £20,000 per QALY, all 3 devices had an almost 100% probability of being cost effective.", 'Committee discussion': "# Clinical need\n\n## Technologies that improve paroxysmal atrial fibrillation detection after cryptogenic stroke or TIA could have substantial benefits for people\n\nThe patient expert told the committee how, when someone has a stroke or transient ischaemic attack (TIA) with no identifiable cause, they can live in fear of having another stroke. This is because they know that the cause of the stroke is not being treated. This can make them anxious and want to visit the GP often for reassurance. Paroxysmal atrial fibrillation is often a cause of cryptogenic stroke. But it's often not detected because it's not present when someone has their initial assessment. If atrial fibrillation is detected, the clinical experts highlighted the importance of offering anticoagulants, rather than antiplatelet therapy, to reduce the risk of a further stroke or TIA. The patient expert explained that people who have had a cryptogenic stroke tend to be younger than people who have had a stroke with a known cause. Therefore, they're more likely to be working and have dependants, such as elderly parents or children. They pointed out the benefits of preventing further strokes, including reducing post-stroke dementia and the psychological impact of sudden illness. The clinical experts said that current practice is to monitor for suspected atrial fibrillation for up to about 14\xa0days at most using Holter monitors if implantable cardiac monitors are not available. A patient expert said that at the moment, monitoring often misses atrial fibrillation in people who have had a stroke, who could benefit from treatment. The committee concluded that identifying the cause of a cryptogenic stroke is important to reduce risk of a further stroke or TIA. Technologies that can identify paroxysmal atrial fibrillation missed by current post-stroke follow-up testing could have substantial benefits for people who have had a cryptogenic stroke.\n\n## Implantable cardiac monitors can reassure people who have had a cryptogenic stroke or TIA, and their carers\n\nThe patient expert said that, if atrial fibrillation is suspected after a stroke or TIA, people can often be anxious that new symptoms may be related to the condition, and that they should report them to their doctor. A continuous electrocardiogram (ECG) monitor can reassure people that if they have symptoms, the monitor will detect any atrial fibrillation that caused them, and can be used to confirm or rule out the condition. Because the devices can remotely monitor people, they may need fewer follow-up appointments after a cryptogenic stroke. This could particularly benefit people living in remote areas far from a hospital. The patient expert said that after a stroke people are fatigued for a long time. Travelling to follow-up appointments can be tiring, costly and time-consuming. People may also need to go with a carer to help them and describe symptoms. The committee concluded that implantable cardiac monitors could have quality of life benefits beyond preventing another stroke.\n\n# Clinical effectiveness\n\n## The CRYSTAL-AF study population broadly represents people with cryptogenic stroke in the NHS\n\nThe only study identified by the external assessment group (EAG) that compared the effectiveness of using an implantable cardiac monitor with conventional follow up after a cryptogenic stroke was the CRYSTAL‑AF study. The clinical experts said that it's important that non-invasive ECG monitoring is done before an implantable cardiac monitor is considered. They also said that the length of monitoring in the NHS can vary. Holter monitors are typically used for 24\xa0hours to 7\xa0days. Not everyone in CRYSTAL‑AF had outpatient ECG monitoring before having an implantable cardiac monitor fitted. Those who did were monitored for a median of 23\xa0hours. The committee also considered that participants in CRYSTAL‑AF were younger than would be expected for people who have had a stroke (mean age about 61.5\xa0years). However, the clinical experts explained that people with cryptogenic stroke are usually younger than the overall stroke population. The committee concluded that the population in the CRYSTAL‑AF study broadly represented people with cryptogenic stroke who would have an implantable cardiac monitor fitted in the NHS.\n\n## People in the control arm of CRYSTAL-AF may have been tested more for atrial fibrillation than is usual in the NHS\n\nSome people in the control arm of the CRYSTAL‑AF study, who did not have a cardiac monitor implanted, were tested for atrial fibrillation every 3\xa0months using ECG, including Holter monitoring. The clinical experts said that in current practice, the amount of testing for atrial fibrillation varies if an implantable cardiac monitor is not used, but it is likely to be less than in CRYSTAL‑AF. They also said that people may only be tested again for atrial fibrillation if they have another stroke. The committee concluded that testing for atrial fibrillation in the control arm of CRYSTAL‑AF may be more than is done in the NHS, which may underestimate the increased yield of people with atrial fibrillation reported for the intervention arm.\n\n## Reveal\xa0XT increases atrial fibrillation detection, but the effect on further stroke or TIA reduction is uncertain\n\nIn the CRYSTAL‑AF study, Reveal\xa0XT detected more people with atrial fibrillation than conventional follow up (see table\xa01). There were also fewer strokes or TIAs in the Reveal\xa0XT arm of the study (see table\xa02). However, because of the length of follow up and sample size, the true effect of the device on reducing stroke or TIA incidence is uncertain; the 95% confidence interval for the hazard ratio at 12\xa0months was 0.22\xa0to\xa01.80. The committee concluded that there was good evidence that Reveal\xa0XT detected more people with atrial fibrillation than conventional follow up, and that this was likely to be seen in clinical practice. However, the extent of a subsequent reduction in stroke or TIA occurrence is uncertain.\n\n## CRYSTAL-AF data can be used to assess how well Reveal LINQ detects atrial fibrillation in people who have had a cryptogenic stroke, but not BioMonitor 2‑AF or Confirm\xa0Rx\n\nThe CRYSTAL‑AF study used Reveal\xa0XT, a predecessor model of Reveal\xa0LINQ. Changes have been made to the atrial fibrillation detection algorithm that is now used in Reveal\xa0LINQ. There was some evidence that suggested this had improved its ability to detect atrial fibrillation. The clinical experts said that the atrial fibrillation detection algorithms in other manufacturers' devices may use the same features of an ECG to detect potential atrial fibrillation. But how these features are used to determine if atrial fibrillation is likely to be present, or to classify an arrythmia as atrial fibrillation or another type of arrythmia, is likely to differ between devices. At consultation, the manufacturer of the BioMonitor submitted an unpublished technical validation report that compared the ability of the BioMonitor 2‑AF and Reveal\xa0LINQ to detect atrial fibrillation from a Holter monitor recording (see section\xa03.21). The EAG commented that this was not a clinical comparison of the devices, which might perform differently when implanted. The study was also not done in a cryptogenic stroke population, where the device may perform differently because of different patient characteristics. The committee noted that the study had a small population size and had not been published and so was not peer reviewed. Clinical experts commented that electrode positioning is different for Holter monitors and implantable cardiac monitors. So the ECG output from a Holter monitor is not the same as the signal that an implantable cardiac monitor receives. The results could therefore be considered to be artificial and not reflect clinical reality. The committee considered that this study did not show that the Reveal\xa0LINQ and BioMonitor devices were comparable in detecting atrial fibrillation in a cryptogenic stroke population. The committee concluded that it is feasible that data from Reveal\xa0XT are likely to apply to the updated version from the same manufacturer, Reveal\xa0LINQ. But there is too much uncertainty over whether the data can be used to show the performance of the BioMonitor 2‑AF or Confirm\xa0Rx to detect atrial fibrillation in people who have had a cryptogenic stroke. Therefore, the committee did not accept that evidence from the CRYSTAL‑AF study could be applied to these devices.\n\n# Cost effectiveness\n\n## It is not appropriate to use data from CRYSTAL-AF to model the performance of BioMonitor 2-AF or Confirm\xa0Rx\n\nThe EAG used diagnostic yield data (a measure of how many people with atrial fibrillation were diagnosed) from the CRYSTAL‑AF study in the economic model for all 3 devices. The committee considered data from this study to be appropriate to assess how well Reveal\xa0LINQ detected atrial fibrillation in people who have had a cryptogenic stroke. But it did not think it was appropriate to use it for BioMonitor 2‑AF or Confirm\xa0Rx (see section\xa04.6). In the absence of clinical or comparative data for these devices in people who have had a cryptogenic stroke, the committee concluded that it was not appropriate to consider the cost-effectiveness estimates for BioMonitor 2‑AF or Confirm\xa0Rx.\n\n## It is appropriate to use a linked evidence approach to estimate the impact of implantable cardiac monitors on stroke or TIA incidence\n\nBased on data from the CRYSTAL‑AF study, the extent of any reduction in further stroke or TIA as a result of using an implantable cardiac monitor is uncertain (see section\xa04.5). The EAG used diagnostic yield data from CRYSTAL‑AF to estimate the increase in cases of atrial fibrillation detected by implantable cardiac monitors (compared with conventional follow up). It then used an existing model (Sterne et al. 2017 and Welton et al. 2017) to estimate the effect of subsequent anticoagulant or antiplatelet treatment on the incidence of clinical events such as stroke. The committee considered that the absolute risk of stroke may differ between people with permanent or persistent atrial fibrillation and people with paroxysmal atrial fibrillation. The clinical experts said that people with paroxysmal atrial fibrillation do benefit from anticoagulant treatment. The EAG ran the model with the risks of events adjusted to reflect a secondary stroke population with paroxysmal atrial fibrillation. The committee concluded that there is uncertainty about the impact of using implantable cardiac monitors on the reduction of further strokes or TIAs. But it agreed that, in the absence of long-term data on this, the EAG's approach of linking evidence on the extent of atrial fibrillation detection, the impact of diagnosis on treatment choice, and the effect of treatment on the incidence of subsequent clinical events such as stroke and TIA in the economic model, was suitable for decision making.\n\n## Not including adverse events caused by implanting Reveal LINQ is unlikely to have a large impact on cost-effectiveness estimates\n\nThe EAG's economic model did not include the effect of any adverse events caused by implanting the devices. The EAG explained that the proportions of people who had non-serious adverse events was reported in CRYSTAL‑AF, but there were no details on what these events were. Therefore, the EAG could not include any costs or disutilities caused by these events in the model. The clinical and patient experts said that there are some minor issues caused by the devices, such as irritation and pain when they are fitted or removed, or if someone unintentionally exposes the device through the skin, but that these are not common and do not have severe consequences. The committee concluded that not including any adverse events caused by implanting the devices was unlikely to have had a large effect on cost-effectiveness estimates.\n\n## There may be uncaptured benefit in detecting non-atrial fibrillation arrythmia, but the impact of this on patient outcomes is uncertain\n\nThe model did not include detection of non-atrial fibrillation arrythmias. There was not much evidence on the number of these arrhythmias detected by the devices, and what evidence there was came from non-comparative observational studies. The clinical experts explained that most asymptomatic non-atrial fibrillation arrythmia detected by the implantable cardiac monitors would not lead to any change in care. The committee concluded that using the devices may increase detection of non-atrial fibrillation arrythmias, but that the extent of this increase, and the clinical significance of these arrythmias and consequent impact on patient outcomes, is highly uncertain.\n\n## The base case may overestimate how much monitoring for atrial fibrillation is done in current practice, which lowers the ICER\n\nThe EAG used the control arm of the CRYSTAL‑AF study to model current practice ('conventional follow up'). The committee had earlier concluded that this may include more monitoring for suspected atrial fibrillation than would be done in the NHS (see section\xa04.4). This may make the increased diagnostic yield of atrial fibrillation for Reveal\xa0LINQ in the model a conservative estimate. But it may also mean that the model overestimates the cost of monitoring for atrial fibrillation in current practice. The EAG did a scenario analysis in which no further monitoring for atrial fibrillation was done in current practice (that is, no people with atrial fibrillation were detected or cost of monitoring included). This increased the incremental cost-effectiveness ratio (ICER) for Reveal\xa0LINQ by about £1,300 per quality-adjusted life year (QALY) gained. The committee concluded that the EAG's scenario may be too extreme, in that some monitoring is likely to be done in the NHS for people with no implantable cardiac monitor fitted. However, the amount of assessment for atrial fibrillation in current practice is likely to have been overestimated in the base-case model, which lowered the base-case ICER by up to about £1,300 per QALY gained.\n\n## The number of false positive alerts from Reveal LINQ is uncertain, and including this in the economic model increases the base-case ICER\n\nThe base-case model did not include the cost of interpreting alerts produced by Reveal\xa0LINQ. The EAG explained that this was because of a lack of data on the number of alerts produced by the device. The clinical experts said that the device would produce false positive alerts. Anecdotal evidence differed on the impact of false positive alerts on workload. One clinical expert said that alerts from the devices can generate several hours of work per day for electrophysiologists to review, although this was based largely on alerts from people with syncope. However, another clinical expert said that it takes minimal time to review alerts generated for possible atrial fibrillation (less than 10\xa0seconds), and that the increase in workload for technicians would be minimal. The clinical experts highlighted that the number of alerts can vary widely between people and noted that cardiac physiologists need to triage the alerts. The EAG did 2 scenario analyses that included the costs of an optional triage service for alerts offered by Medtronic for Reveal\xa0LINQ. This increased the ICER by about £2,600 to £3,800 per QALY gained, depending on the cost option used. The clinical experts said that the costs used (£187 per patient per year or £374 per patient) are likely to be a realistic estimate and could be considered a reasonable proxy for the costs of triaging alerts in the NHS. The committee concluded that there is uncertainty about the likely number of false alerts that Reveal\xa0LINQ generates in people who have had a cryptogenic stroke if used in routine clinical practice, and the impact on services. Including costs for reviewing alerts in the economic model would increase the ICER for Reveal\xa0LINQ, although it is uncertain by how much.\n\n## The EAG's model, following DSU review and amendment, is suitable for decision making\n\nAt the first committee meeting, the committee was concerned by the difference between the deterministic and probabilistic base-case results provided by the EAG. There was a large difference in the incremental costs and QALYs generated for the devices (compared with conventional follow up) between these analyses. For the second committee meeting, the EAG provided updated analyses in which an error in the model code used to run the probabilistic sensitivity analysis was corrected. The updated base-case probabilistic sensitivity analysis results were now very similar to the deterministic results. At the first committee meeting, the committee was concerned that the model results may not be realistic (lacking face validity) because of the small number of total QALYs generated in the model. At the second committee meeting, the EAG explained that this was because QALYs in the model were only generated by people who had episodes of atrial fibrillation, which was 30% of the total population. No QALYs were considered for the remaining 70% because there would be no difference in the number of QALYs generated between people with implantable cardiac monitors fitted and conventional follow up (and therefore no impact on ICERs). The EAG further explained that the cohort modelled had a starting age of 62, had all had a stroke or TIA, and all had atrial fibrillation. Therefore, they did not consider that the number of QALYs generated was unrealistic. During the first consultation on this guidance, an error was identified in the model. On reviewing the model, the EAG identified another error. NICE commissioned a review of the model by NICE's Decision Support Unit (DSU). The DSU checked the model and corrected another small error. Updated model results were presented at the third committee meeting. The committee concluded that, considering the DSU's review of the model, the corrections made to the model and the explanations provided, the revised model was suitable for decision making.\n\n## The different parameters used in the EAG's and Diamantopoulos et al. models are unlikely to affect decision making\n\nThe updated cost-effectiveness estimate for the Reveal\xa0LINQ provided for the third meeting was now lower than the results of a previous economic model that also used data from CRYSTAL‑AF (Diamantopoulos et al. 2016; see sections\xa03.53 and\xa03.54). The EAG's updated base-case ICER was £10,342 compared with £17,175 per QALY gained for Diamantopoulos et al. and the incremental QALYs were similar (0.14 and 0.15). The EAG explained that the difference between the results of the models was driven by differences in how the impact of anticoagulant treatment was modelled. Because of differences in model structure, the outcomes included, and the mechanisms used to estimate outcomes, the EAG considered a direct comparison of the parameters used in each model to be difficult and potentially not very informative. The DSU's amended version of the EAG's model estimated that the number of strokes that would be avoided by using an implantable cardiac monitor was 52 per 1,000 people with cryptogenic stroke, compared with 40 per 1,000 people estimated by the Diamantopoulos et al. model. The committee recalled that the size of any reduction in further stroke or TIA caused by using the devices was uncertain (see section\xa04.5). The committee concluded that there was uncertainty about which was the most appropriate approach to modelling the impact of anticoagulant treatment. The acute and post-stroke utilities were lower in the Diamantopoulos et al. model, which would also have contributed to the difference in incremental QALYs between models. At consultation, several stakeholders commented that the underlying model used (reported in Sterne et al.) was developed for a primary stroke population. The EAG explained that they had adjusted parameters in the model (for example, risk of further stroke, TIA, systemic embolism, intracranial haemorrhage and bleeds) for a secondary stroke population. Stakeholders also highlighted that the impact of a secondary, rather than primary, stroke may have been underestimated in the model. For example, the costs of ongoing treatment and impact on someone's health-related quality of life. The committee concluded that there is uncertainty about the most appropriate parameters to use to model the longer-term effects of anticoagulant and antiplatelet treatment in this population, but that the different parameters used in the EAG's and Diamantopoulos et al. models are unlikely to affect decision making.\n\n## The most plausible ICER for Reveal LINQ is likely to be less than £20,000 per QALY gained\n\nThe committee only considered cost-effectiveness estimates for Reveal\xa0LINQ (see section\xa04.7). The probabilistic ICER for Reveal\xa0LINQ in the EAG's model was almost identical to the deterministic value. The deterministic base case for Reveal\xa0LINQ compared with conventional follow up was £10,342 per QALY gained. If assessment for atrial fibrillation in the conventional follow-up arm is removed from the EAG's base-case model, the ICER increases by about £1,300 per QALY gained. However, the assumption that no longer-term monitoring for atrial fibrillation is done in standard monitoring is unlikely (see section\xa04.11). In addition, costs of reviewing alerts produced by Reveal\xa0LINQ were not included in the base-case model. If the cost of a triage service was included, the EAG's base-case ICER increased by about £2,600 to £3,800 per QALY gained (see section\xa04.12). The committee concluded that there was uncertainty about the most plausible ICER for Reveal\xa0LINQ. Including its preferences in the EAG's model would increase the base-case ICER, but this was unlikely to increase to over £20,000 per QALY gained. The committee concluded that the most plausible ICER for Reveal\xa0LINQ is likely to be less than £20,000 per QALY gained.\n\n## Reveal LINQ is likely to be a cost-effective use of NHS resources\n\nThe committee agreed that Reveal\xa0LINQ was likely to be clinically effective because it identifies more people who have atrial fibrillation after a cryptogenic stroke or TIA than current practice. The committee recalled its conclusion that technologies that improve the detection of paroxysmal atrial fibrillation after cryptogenic stroke or TIA could have substantial benefits for patients. In addition, there is an unmet need for longer-term monitoring for atrial fibrillation after a cryptogenic stroke or TIA (see sections\xa04.1 and\xa04.2). The committee considered that the most plausible ICER for Reveal\xa0LINQ is likely to be less than £20,000 per QALY gained (see section\xa04.15). Therefore, the committee concluded that Reveal\xa0LINQ is likely to be a cost-effective use of NHS resources.\n\n## Reveal LINQ should only be used after non-invasive ECG monitoring has been done\n\nThe inclusion criteria for CRYSTAL‑AF included a requirement for a 12‑lead ECG and 24‑hour ECG monitoring for atrial fibrillation detection to establish the diagnosis of cryptogenic stroke (before use of an implantable cardiac monitor). The amount of atrial fibrillation detected in this study population was used for the cost-effectiveness estimates for Reveal\xa0LINQ in this assessment. During consultation, stakeholders highlighted that longer duration non-invasive monitors (that is, monitors that are not implanted) are increasingly available and questioned if this would impact the cost effectiveness of Reveal LINQ. The committee recalled that clinical experts had emphasised that Reveal LINQ would only be used after all available non-invasive monitoring had been done. Therefore, these non-invasive monitors were not comparators to implantable cardiac devices. However, longer duration non-invasive monitoring is likely to detect some cases of atrial fibrillation that shorter duration non-invasive monitoring would miss, and therefore there may be a lower yield of people with atrial fibrillation subsequently detected by implantable cardiac monitors. The EAG commented that longer duration non-invasive monitoring of up to a month was unlikely to have a large impact on the cost effectiveness of Reveal LINQ. They based their comment on exploratory model analysis that assumed that anyone with atrial fibrillation in the first month of CRYSTAL‑AF would not have had an implantable cardiac monitor (reducing the diagnostic yield for Reveal LINQ in the model). Clinical experts highlighted that it is important that non-invasive ECG monitoring is done first before Reveal\xa0LINQ is considered, and that the type and duration of non-invasive monitoring will vary by local availability across the NHS. The committee concluded that it's important that Reveal\xa0LINQ is only used if paroxysmal atrial fibrillation is still suspected after non-invasive ECG monitoring has been done.\n\n## Reveal LINQ should only be used if the device is discussed with patients and they, or a carer, are able to set up the MyCareLink Patient Monitor\n\nThe committee noted that clinicians should discuss implanting the device with patients and give advice about the MyCareLink Patient Monitor, which needs to be set up to transmit rhythm abnormalities recorded by Reveal\xa0LINQ. The committee noted that disabled people may need a carer to help set up the MyCareLink Patient Monitor to ensure data are transmitted.\n\n# Research considerations\n\n## Further evidence is needed to show the effectiveness of BioMonitor 2-AF and Confirm Rx to detect atrial fibrillation in people with cryptogenic stroke\n\nThe committee considered that there was no evidence plausibly showing that BioMonitor 2-AF and Confirm Rx (or previous versions) were as effective as Reveal devices at detecting atrial fibrillation in people with cryptogenic stroke. And the committee noted that it was difficult to get good comparative data on this. Only diagnostic yield data from a Reveal device were available to model cost effectiveness. A randomised controlled trial comparing Reveal LINQ with Confirm Rx was highlighted during consultation (Yokokawa et al. 2019; see section\xa03.51). Most of the people in the trial had had a cryptogenic stroke. But the study was only available as a conference abstract. Details of the methodology were limited, and it was not clear why the number of events detected in the Reveal LINQ and Confirm Rx arms were so different. Abbott Medical UK, which makes Confirm Rx, said it was not involved in the study and could not give any more information. The committee considered that it did not have enough information to be able to use the study to assess if Reveal LINQ and Confirm Rx had similar effectiveness. However, it concluded that the study did show that it was feasible to do a trial comparing the effectiveness of different implantable cardiac monitors to detect atrial fibrillation in a cryptogenic stroke population.", 'Recommendations for further research': 'Further research is recommended to assess the diagnostic yield of the BioMonitor\xa02‑AF and Confirm\xa0Rx (or later devices) for atrial fibrillation when used in people who have had a cryptogenic stroke. The committee noted that existing ongoing research may provide further data for these devices (see section\xa03.51 and section\xa04.19).'}
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https://www.nice.org.uk/guidance/dg41
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Evidence-based recommendations on implantable cardiac monitors to detect atrial fibrillation after cryptogenic stroke.
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b013d86396855a0cd28a14bc5743b910014f59b3
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nice
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Avelumab with axitinib for untreated advanced renal cell carcinoma
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Avelumab with axitinib for untreated advanced renal cell carcinoma
Evidence-based recommendations on avelumab (Bavencio) with axitinib (Inlyta) for untreated advanced renal cell carcinoma in adults.
# Recommendations
Avelumab with axitinib is recommended for use within the Cancer Drugs Fund as an option for untreated advanced renal cell carcinoma in adults. It is recommended only if the conditions in the managed access agreement for avelumab with axitinib are followed.
This recommendation is not intended to affect treatment with avelumab plus axitinib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Treatment for untreated advanced renal cell carcinoma includes sunitinib, pazopanib, tivozanib or cabozantinib.
Clinical trial evidence shows that, for people with untreated advanced renal cell carcinoma, avelumab plus axitinib increases how long people live without their disease getting worse compared with sunitinib. Early trial results suggest that avelumab plus axitinib also increases how long people with the disease live. But this is uncertain because the final trial results are not available yet. There are no trials comparing avelumab plus axitinib with tivozanib, pazopanib or cabozantinib directly. So, it is uncertain how it compares with these drugs.
Avelumab plus axitinib has the potential to be cost effective, but more evidence is needed:
Longer-term follow up of patients in JAVELIN Renal 101 would help to address the uncertainties about how long people live, and how long they live without their disease getting worse.
The economic model should reflect the treatment patients in the NHS would have after avelumab plus axitinib.Therefore, avelumab plus axitinib is recommended through the Cancer Drugs Fund while further data are collected, and the economic model is updated.# Information about avelumab with axitinib
# Marketing authorisation indication
Avelumab (Bavencio, Merck-Pfizer) with axitinib (Inlyta, Pfizer) 'is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma'.
# Dosage in the marketing authorisation
The dosage schedules are available in the avelumab summary of product characteristics and the axitinib summary of product characteristics.
# Price
Avelumab is available at a list price of £768.00 per 200-mg vial or £3,072.00 per 800-mg fixed dose (excluding VAT; companies' submission).
Axitinib is available in 4 strengths, which all come in packs of 56 tablets. The list prices are: £703.40 for 1-mg tablets, £2,110.20 for 3-mg tablets, £3,517.00 for 5-mg tablets and £4,923.80 for 7-mg tablets (excluding VAT; companies' submission).
There is a commercial arrangement for avelumab plus axitinib. This makes avelumab plus axitinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the companies' responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by 2 companies: Merck KGaA and Pfizer Ltd, a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that 1 issue was resolved during the technical engagement stage. It agreed that, in the comparison with tivozanib, survival estimates for avelumab plus axitinib in the model should be based on trial data rather than on network meta-analyses.
It recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, table 3, page 35), and took these into account in its decision making.
# Treatment pathway
## Comparators include pazopanib, sunitinib, tivozanib and cabozantinib
First-line treatment options in clinical practice for people with advanced renal cell carcinoma include pazopanib, sunitinib, tivozanib and, for people with disease classified as intermediate or poor risk, cabozantinib. Nivolumab with ipilimumab and pembrolizumab with axitinib cannot be comparators in this appraisal because they are not established clinical practice. Nivolumab with ipilimumab is recommended through the Cancer Drugs Fund (and so is not routinely commissioned) and pembrolizumab with axitinib is being appraised by NICE. Later-line treatments include axitinib alone, nivolumab, cabozantinib, lenvatinib with everolimus, and everolimus alone.
## Having avelumab plus axitinib affects which treatments people have later
The Cancer Drugs Fund clinical lead and the clinical experts explained that, if people were to have first-line treatment with avelumab (a checkpoint inhibitor) plus axitinib (a tyrosine kinase inhibitor), they would not be eligible in the NHS for nivolumab (another checkpoint inhibitor) or axitinib monotherapy later in the treatment pathway. The committee noted that any disease model should reflect this, but the current model does not. The clinical experts also explained that they would value being able to offer the most effective treatments at first line. The Cancer Drugs Fund clinical lead and the clinical experts stated that, if patients have avelumab plus axitinib first line, there would be interest from patients and clinicians in using current first-line treatments such as sunitinib in the second-line setting. The committee concluded that patients and clinicians should have the opportunity to choose between the most effective treatment options as early in the pathway as possible, and that the modelled treatment pathway should reflect both the costs and benefits of NHS care.
# Clinical trial evidence
## The key evidence comes from the JAVELIN Renal 101 trial
The companies presented evidence from JAVELIN Renal 101, a phase 3 randomised controlled trial of avelumab plus axitinib (442 patients) compared with sunitinib (444 patients) in advanced renal cell carcinoma. The original primary objective was to show the superiority of avelumab plus axitinib in prolonging progression-free survival in all patients in the trial. However, the investigators amended the protocol during the trial. The primary objective was changed to show superiority either on progression-free or overall survival in a subpopulation (that is, people with PD‑L1 positive tumours). The companies stated that this had changed because results from other trials suggested that avelumab plus axitinib may improve overall survival in the PD‑L1 subpopulation, and it improved effectiveness compared with the subpopulation whose tumours do not express PD‑L1. However, the European Medicines Agency ultimately granted the licence for the whole population. The clinical experts explained that NHS clinicians do not measure PD‑L1 in renal cell carcinoma. The committee was satisfied that it could take the results of the main population into account in its decision making.
## Avelumab plus axitinib is more effective than sunitinib for prolonging progression-free survival, but overall survival benefit is uncertain
The companies explained that the first interim analysis of JAVELIN Renal 101 showed a benefit for progression-free survival of avelumab plus axitinib over sunitinib, and that the companies continued the trial to evaluate overall survival. The companies submitted 2 data cuts from the trial: interim analysis 1 (June 2018) and interim analysis 2 (January 2019). The committee noted that avelumab plus axitinib was more effective in improving progression-free survival compared with sunitinib at the first interim analysis (hazard ratio 0.69, 95% confidence interval 0.56 to 0.84). The committee also noted that the results for overall survival from JAVELIN Renal 101 were immature (fewer than half of the 535 deaths needed for the planned final analysis had occurred at the January 2019 data cut) and the results showed a hazard ratio of 0.80 (95% CI 0.62 to 1.03). The clinical experts explained that people are likely to live longer if they take avelumab plus axitinib, which combines an immune-oncology drug (avelumab) and a tyrosine kinase inhibitor (axitinib), than if they take only a tyrosine kinase inhibitor (sunitinib). The committee concluded that avelumab plus axitinib prolongs progression-free survival compared with sunitinib. However, it added that the companies' immature data meant that uncertainty remained about whether avelumab plus axitinib prolongs overall survival compared with sunitinib and, if so, by how much
## There are no data to inform the long-term effects of avelumab plus axitinib
Given the absence of mature trial data for overall survival, the committee considered whether there were other data to inform effectiveness over time:
The clinical experts explained that there is no evidence to inform the long-term survival outcomes of either avelumab plus axitinib or any other checkpoint inhibitor in advanced renal cell carcinoma. They noted that, from their experience with checkpoint inhibitors, many patients do well in the longer term. The patient expert said that he was grateful to take part in an avelumab and axitinib trial. One clinical expert considered it plausible that 20% of patients would be alive at 5 years and 15% at 10 years.
The committee noted that there had been a previous avelumab plus axitinib trial (JAVELIN Renal 100). It included only 55 patients, but the committee thought that it could inform the treatment effect of avelumab plus axitinib over a longer time period.The committee agreed that any additional data would likely inform the longer-term overall survival effects of avelumab plus axitinib.
## The dosing in the marketing authorisation differs from that in JAVELIN Renal 101
The committee highlighted that a weight-based dose for avelumab was used in JAVELIN Renal 101, whereas the licence specifies a fixed dose. The companies explained that they derived the fixed dose using pharmacokinetic and pharmacodynamic data, and taking into account similar approaches used historically. The Cancer Drugs Fund clinical lead advised that this approach was taken with other drugs for this disease area. The committee was aware that it could appraise drugs only within their marketing authorisation. It accepted that the licensed fixed dose would have similar effectiveness to the weight-based dose, and concluded that it would use the licensed dose in making decisions.
## There is little evidence for avelumab plus axitinib in non-clear-cell renal cell carcinoma, as with other first-line treatments
The committee noted that most patients in JAVELIN Renal 101 had clear-cell disease, but in NHS practice some have non-clear-cell disease. The clinical experts stated that there is no evidence that the results in people with cancers characterised by clear-cell histology would be generalisable (or not) to people with disease characterised by non-clear-cell histology. Therefore, there might be an argument to limit avelumab plus axitinib to people with clear-cell disease only. However, the clinical experts noted, and the committee agreed, that the situation is similar with other first-line treatments for advanced renal cell carcinoma. The committee agreed that this was an area in need of further research. It suggested that data should be collated by histology in the Cancer Drugs Fund, to monitor whether there is a difference in effectiveness.
# Indirect treatment comparison
## An indirect comparison is needed to compare avelumab plus axitinib with comparators other than sunitinib
There are no head-to-head trials of avelumab plus axitinib compared with tivozanib, pazopanib or cabozantinib. The companies therefore indirectly compared avelumab plus axitinib with these comparators by network meta-analyses for progression-free and overall survival. The companies constructed networks for:
the whole population across the range of risk (and which included the treatments avelumab plus axitinib, sunitinib, tivozanib and pazopanib) and
the population with intermediate- or poor-risk disease (which included the treatments avelumab plus axitinib and cabozantinib).The committee agreed that, for the economic modelling, pazopanib had the same effectiveness as sunitinib, which the committee had accepted in NICE's technology appraisal guidance on tivozanib for treating advanced renal cell carcinoma and nivolumab with ipilimumab for untreated advanced renal cell carcinoma.
## Comparisons with sunitinib and pazopanib are the most relevant for decision making
There were several issues with using the network meta-analyses to compare avelumab plus axitinib with tivozanib:
To estimate overall survival, the companies used sunitinib and sorafenib as links in the network. The 2 trials comparing sunitinib with sorafenib (Eichelberg et al. 2015 and Tomita et al. 2017) had a randomised sequential design (that is, patients were randomised to have sunitinib followed by sorafenib, or sorafenib followed by sunitinib). The overall survival data were available in these trials only at the end of each treatment sequence. Therefore, these trials did not directly compare sorafenib with sunitinib for overall survival. The ERG noted that this invalidated the network.
The trial comparing tivozanib with sorafenib (Motzer et al. 2013) allowed crossover from sorafenib to tivozanib on disease progression (61% of patients who progressed on sorafenib crossed over to tivozanib).
A large proportion of the patients in all the trials included in the network had subsequent treatments after progression, which may not have reflected NHS practice, and which may have extended their lives.The ERG explained that a 'disconnected network' would be an alternative approach to estimate the effectiveness of avelumab plus axitinib compared with tivozanib. The committee noted that, in previous tivozanib technology appraisal guidance, it had concluded that tivozanib was 'at best' similar to sunitinib or pazopanib. This was based on tivozanib being less effective, but less expensive, than sunitinib. In comments received during the technical engagement stage for this appraisal, clinical experts noted that sunitinib and tivozanib are likely similarly effective, although a patient organisation argued that it was not appropriate to assume equal efficacy. The committee agreed that the network estimating overall survival comparing avelumab plus axitinib with tivozanib was not valid, so the effectiveness of tivozanib compared with other treatments is uncertain. However, the committee also heard from the Cancer Drugs Fund clinical lead that tivozanib was less commonly used than the other comparators in clinical practice. It therefore concluded that it would prioritise comparisons with sunitinib and pazopanib.
## The companies' network meta-analyses either relying on or not relying on proportional hazards both have high levels of uncertainty
The companies stated that some of the trial results in the networks appeared to violate the assumption of proportional hazards. They therefore did 2 sets of network meta-analyses. One set was a standard Bayesian network meta-analysis, which assumed proportional hazards. The output of this was a hazard ratio for avelumab plus axitinib compared with each comparator in the scope. In the other set, the companies did not assume proportional hazards. Instead, parametric curves were fitted to data from each treatment arm of each trial in the network to estimate time-varying treatment effects. This generated estimates of the probabilities of progression-free and overall survival at 1, 2 and 10 years for each treatment in the model. The companies chose the latter approach for their base case. The ERG was satisfied with the methods and rationale for both approaches. It noted that it was useful to see both approaches, as 1 generates a hazard ratio and the other a parametric curve over time. However, the ERG outlined that the concerns it had already highlighted with the network meta-analysis (see section 3.9) applied to both approaches. The committee concluded that methodological concerns and the immature data informing the model made these results uncertain.
# Assumptions in the economic model
## The model type is appropriate
The companies used a partitioned-survival economic model that included 3 health states: pre-progression, post-progression and death. Patients could have first-line treatment with avelumab plus axitinib, sunitinib, pazopanib or tivozanib. The population with intermediate and poor risk could have avelumab plus axitinib or cabozantinib. If disease progressed, patients could move on to several other subsequent treatments, depending on which treatment they had first line. The committee concluded that the model type was appropriate and consistent with the approach used in other appraisals for renal cell carcinoma.
## The committee would have preferred to see the effects of subsequent treatments explored further
In JAVELIN Renal 101, people in both treatment arms could have nivolumab after disease progression on first-line treatment. The committee noted that this differed from NHS practice in which only people having sunitinib would be eligible to have second-line nivolumab or axitinib in NHS practice. The committee appreciated that the results of JAVELIN Renal 101 reflected the effect of treatments offered second line and beyond (see section 3.1). The companies stated that this had biased the trial results against avelumab plus axitinib because a substantially higher proportion of patients had nivolumab in the sunitinib arm than in the avelumab plus axitinib arm. The companies also claimed that the proportion of patients in the trial having nivolumab after disease progression on sunitinib was higher than would be expected in NHS practice. To explore the effect of this, the companies adjusted the trial results using the rank preserving structural failure time method. The committee noted that the companies did not provide details of this method or the assumptions needed for it. Also, they did not justify their choice of this method over others. The committee was aware that, in the NHS, some patients would be expected to have nivolumab after sunitinib, whereas no patients would be expected to have nivolumab after avelumab plus axitinib. Therefore, the companies' adjustment was not appropriate. The committee concluded that it would have preferred to see the companies adjusting for any life-extending follow-on treatments offered in the trial that would not form part of a routine NHS treatment pathway, using an appropriate adjustment method.
## The committee would have preferred to see the costs of subsequent treatments explored further
The companies applied the costs of subsequent treatments using a one-off cost, which depended on the treatment offered first line. For avelumab plus axitinib, and for sunitinib, the treatment patients had in the model was estimated from the subsequent treatments given in the relevant treatment arm in JAVELIN Renal 101. All other first-line treatments in the model were assumed to be the same as sunitinib. The committee recognised that it was important to know all the treatments offered in the trial that are proven to extend life, but are not routinely commissioned in the NHS. However, the companies' model accounted only for the subsequent treatments taken by more than 10 people in either treatment arm of JAVELIN Renal 101. These treatments were cabozantinib, everolimus, axitinib, sunitinib, nivolumab, lenvatinib plus everolimus, and pazopanib. The companies confirmed that the trial had included some treatments that are not available in the NHS, such as durvalumab. As discussed (see section 3.12), a small proportion of patients in the model having avelumab plus axitinib went on to have other checkpoint inhibitors or axitinib after progression. The committee noted that although this likely had little effect on the cost-effectiveness estimates, given the small proportion of patients, it did not reflect clinical practice in England. The committee agreed that it would have liked to have seen base-case modelling that adjusted the trial data to reflect both the effects and costs of subsequent treatments offered in NHS practice.
# Overall survival extrapolations
## There are high levels of uncertainty when extrapolating overall survival
In the economic model, the companies used parametric distributions to extrapolate the data on overall survival from JAVELIN Renal 101. The committee noted several uncertainties with modelled overall survival:
The short-term data informing the model (median follow up was 12 months or less) meant that survival estimates varied widely depending on the choice of extrapolation curve. For example, in the companies' model at 5 years, the proportion of patients alive who had treatment with avelumab plus axitinib could be:
% using a Gompertz function
% using a log-normal function.
The companies fitted the parametric curves independently to the survival data of each comparator, but did not explicitly present the hazard plots, so the committee could not see the implied treatment effect over the time horizon of the model.
Using either a log-normal or a log-logistic function (as used in the companies' base case) or an exponential function (as preferred by the ERG) may have generated clinically implausible results for overall survival, with mortality rates for patients who had treatment with avelumab plus axitinib falling below those of the general population after 18 to 20 years.The committee recognised that using an exponential curve assumes that the treatment benefit remains constant over time. This is because the relative hazards stay constant, which may be more likely to reflect clinical experience with checkpoint inhibitors. However, the clinical experts explained that, in other cancers, for a small group of patients, their disease continues to have a lasting response to checkpoint inhibitors (and so the relative hazard may change over time). The committee noted this, but was also aware that observations in 1 type of cancer are not necessarily generalisable to another type of cancer. The committee concluded that all extrapolations were fundamentally uncertain because of the lack of data on long-term survival, and that only longer-term data on overall survival could address this. It also agreed that it would have preferred the companies to present the modelled treatment effect for overall survival over time explicitly.
## The latest data cut for overall survival and progression-free survival should be modelled
The companies based the cost-effectiveness estimates on the results from the June 2018 data cut, even though they had presented clinical results using the January 2019 data cut. The companies stated that this was because the first data cut was:
a complete data set
available at the time of economic modelling
reflecting the same time periods.The companies explained that the first interim analysis showed a progression-free survival benefit and the trial continued to evaluate overall survival. The committee concluded that, although the most mature data available for overall and progression-free survival would be useful, they would likely not reduce the uncertainty substantially (see section 3.14).
## It is not appropriate to include a stopping rule
In the economic model, the companies originally assumed that clinicians stop treatment with avelumab plus axitinib after 2 years of treatment, whether or not a patient's disease has progressed. After this, and despite stopping treatment, the companies assumed that:
two-thirds of patients would continue to have a lifetime treatment benefit
the other third would gradually assume the progression and mortality hazards of the comparator treatment over 2 years.The committee noted that the JAVELIN Renal 101 protocol and the marketing authorisation did not include stopping treatment. The Cancer Drugs Fund clinical lead confirmed that, if a stopping rule was accepted, retreatment with avelumab plus axitinib or a second-line checkpoint inhibitor would not be available for patients who had previous treatment with avelumab plus axitinib. The clinical experts stated that stopping treatment after 2 years might be reasonable for some patients. This is because clinical experience with other cancers shows that, for a small group of patients, their disease continues to have a lasting response to checkpoint inhibitors. However, the committee understood that this had not yet been shown in renal cell carcinoma and it was not appropriate to generalise from 1 cancer to another. It also recognised that currently there is no clear way of identifying these patients. The committee understood that if patients relapsed after stopping treatment, they would not be able to have the treatment again. The patient expert stated that he had had 4 years of treatment so far. He would be reluctant to abide by an arbitrary stopping rule for fear of losing benefit, and then not be able to have treatment again. The committee concluded that there was no evidence to support a stopping rule and that it should not be in the model. For its second meeting, the committee understood that the companies removed this assumption from their base case.
## It is not appropriate to include the approach chosen by the companies to address treatment waning
Related to the stopping rule, the companies assumed that two-thirds of patients who stopped treatment would have a treatment benefit over their lifetimes, and one-third would have waning of the treatment effect (that is, over 2 years, the effect of treatment would decrease to that of the comparator). The ERG presented scenarios exploring the effect of removing the treatment waning effect (that is, all patients maintained a full treatment effect in the absence of treatment). However, the committee was not clear how the ERG had implemented removing the treatment waning effect and the stopping rule (see section 3.15). The committee concluded that there was no evidence to support what proportion of patients would have a long-term treatment effect after stopping treatment. Therefore, the modelling should have accounted for a range of potential options, including the potential for no patients to have a long-term treatment effect after stopping treatment. At the second meeting, the committee was aware that the companies had removed the stopping rule, so the model now excluded treatment waning (that is, because treatment now continued in the model, there was no need to apply assumptions around what happens to the treatment effect after stopping treatment at a set time period, rather than for adverse events or progression). The committee agreed this was appropriate.
# Cost-effectiveness estimates
## Avelumab plus axitinib cannot be recommended for routine use
The cost-effectiveness results are commercial in confidence and cannot be reported here. The committee agreed that some of the original assumptions in the companies' base-case model were implausible. The committee went on to review the exploratory scenarios presented by the ERG, some (but not all) of which had used some of the committee's preferred assumptions:
no stopping rule
removed treatment waning effect as modelled
a range of overall survival extrapolations, including the exponential curve.The cumulative effect of the committee's preferred assumptions increased the companies' base case above what is considered to be a cost-effective use of NHS resources. The committee concluded that avelumab plus axitinib cannot be recommended for routine use.
# Cancer Drugs Fund
## The companies propose including avelumab plus axitinib in the Cancer Drugs Fund while more data are collected from JAVELIN Renal 101
Having concluded that avelumab plus axitinib could not be recommended for routine use, the committee then considered whether it could be recommended for treating advanced renal cell carcinoma within the Cancer Drugs Fund. It discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum). The committee noted that the key uncertainties were:
the immaturity of the overall survival data and the companies' approach to modelling overall survival over the long term
the lack of data on whether the treatment is effective for non-clear-cell disease and
the companies' methods for adjusting both the costs and benefits of subsequent treatments to reflect NHS practice.The committee agreed that the first 2 uncertainties could be resolved by collecting further data. It considered a proposal by the companies for including avelumab plus axitinib in the Cancer Drugs Fund as part of a managed access agreement. In this, the companies would collect further data from clinical trials, and would provide avelumab plus axitinib at a discounted price to the NHS for the duration of the managed access agreement. The committee agreed that avelumab plus axitinib showed plausible potential for cost effectiveness, but only if the companies address the committee's concerns about the modelling (see section 3.20) when there are mature data and the guidance is reviewed. The committee was satisfied that, until then, the proposed pricing arrangement compensates for the clinical uncertainty about survival while avelumab plus axitinib is in the Cancer Drugs Fund.
## Avelumab plus axitinib is recommended for use within the Cancer Drugs Fund
Based on the considerations in section 3.19, the committee considered that it could recommend avelumab plus axitinib for use in the Cancer Drugs Fund. The committee agreed that, at the end of the period in the Cancer Drugs Fund, when the guidance is reviewed, the updated model should include these preferred assumptions (unless new evidence indicates otherwise):
no stopping rule (see sections 3.16 and 3.17)
trial evidence and costs adjusted to reflect subsequent treatments used in NHS practice, including adjusting for life-extending treatments used in the trial not available in the NHS (see sections 3.12 and 3.13) and justifying the methods used to adjust for follow-on treatments (see section 3.12)
a range of overall survival extrapolations explored, including the exponential curve (see section 3.14)
the modelled overall survival treatment effect over comparators over time, explicitly presented (see section 3.14).
# Other factors
## Avelumab plus axitinib did not meet the criteria for end of life
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. It recognised that the companies did not submit evidence to support avelumab plus axitinib as an end-of-life therapy. It noted that the lower confidence interval boundary of median overall survival exceeded 24 months. The committee noted the comments from the companies in their submission that, in pivotal trials of the NICE-recommended first-line monotherapies for acute renal cell carcinoma (sunitinib, pazopanib, tivozanib and cabozantinib), median overall survival ranged from 21.8 to 30.3 months. As such, avelumab plus axitinib does not meet the criteria for consideration as a life-extending treatment at the end of life for patients with acute renal cell carcinoma with favourable- to poor-risk status. The committee concluded that avelumab plus axitinib does not meet the criteria for end of life.
# Innovation
## Benefits are likely captured in the quality-adjusted life year calculations
The clinical experts stated they considered avelumab plus axitinib to be innovative because it is the first combination of a checkpoint inhibitor plus a tyrosine kinase inhibitor licensed for use in patients with untreated advanced renal cell carcinoma. The committee considered that this does not make the treatment innovative. It also concluded that the associated benefits of treatment are likely captured in the quality-adjusted life year calculations.
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{'Recommendations': 'Avelumab with axitinib is recommended for use within the Cancer Drugs Fund as an option for untreated advanced renal cell carcinoma in adults. It is recommended only if the conditions in the managed access agreement for avelumab with axitinib are followed.\n\nThis recommendation is not intended to affect treatment with avelumab plus axitinib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nTreatment for untreated advanced renal cell carcinoma includes sunitinib, pazopanib, tivozanib or cabozantinib.\n\nClinical trial evidence shows that, for people with untreated advanced renal cell carcinoma, avelumab plus axitinib increases how long people live without their disease getting worse compared with sunitinib. Early trial results suggest that avelumab plus axitinib also increases how long people with the disease live. But this is uncertain because the final trial results are not available yet. There are no trials comparing avelumab plus axitinib with tivozanib, pazopanib or cabozantinib directly. So, it is uncertain how it compares with these drugs.\n\nAvelumab plus axitinib has the potential to be cost effective, but more evidence is needed:\n\nLonger-term follow up of patients in JAVELIN Renal\xa0101 would help to address the uncertainties about how long people live, and how long they live without their disease getting worse.\n\nThe economic model should reflect the treatment patients in the NHS would have after avelumab plus axitinib.Therefore, avelumab plus axitinib is recommended through the Cancer Drugs Fund while further data are collected, and the economic model is updated.', 'Information about avelumab with axitinib': "# Marketing authorisation indication\n\nAvelumab (Bavencio, Merck-Pfizer) with axitinib (Inlyta, Pfizer) 'is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedules are available in the avelumab summary of product characteristics and the axitinib summary of product characteristics.\n\n# Price\n\nAvelumab is available at a list price of £768.00 per 200-mg vial or £3,072.00 per 800-mg fixed dose (excluding VAT; companies' submission).\n\nAxitinib is available in 4\xa0strengths, which all come in packs of 56\xa0tablets. The list prices are: £703.40 for 1-mg tablets, £2,110.20 for 3-mg tablets, £3,517.00 for 5-mg tablets and £4,923.80 for 7-mg tablets (excluding VAT; companies' submission).\n\nThere is a commercial arrangement for avelumab plus axitinib. This makes avelumab plus axitinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the companies' responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by 2\xa0companies: Merck KGaA and Pfizer Ltd, a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that 1\xa0issue was resolved during the technical engagement stage. It agreed that, in the comparison with tivozanib, survival estimates for avelumab plus axitinib in the model should be based on trial data rather than on network meta-analyses.\n\nIt recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, table\xa03, page\xa035), and took these into account in its decision making.\n\n# Treatment pathway\n\n## Comparators include pazopanib, sunitinib, tivozanib and cabozantinib\n\nFirst-line treatment options in clinical practice for people with advanced renal cell carcinoma include pazopanib, sunitinib, tivozanib and, for people with disease classified as intermediate or poor risk, cabozantinib. Nivolumab with ipilimumab and pembrolizumab with axitinib cannot be comparators in this appraisal because they are not established clinical practice. Nivolumab with ipilimumab is recommended through the Cancer Drugs Fund (and so is not routinely commissioned) and pembrolizumab with axitinib is being appraised by NICE. Later-line treatments include axitinib alone, nivolumab, cabozantinib, lenvatinib with everolimus, and everolimus alone.\n\n## Having avelumab plus axitinib affects which treatments people have later\n\nThe Cancer Drugs Fund clinical lead and the clinical experts explained that, if people were to have first-line treatment with avelumab (a checkpoint inhibitor) plus axitinib (a tyrosine kinase inhibitor), they would not be eligible in the NHS for nivolumab (another checkpoint inhibitor) or axitinib monotherapy later in the treatment pathway. The committee noted that any disease model should reflect this, but the current model does not. The clinical experts also explained that they would value being able to offer the most effective treatments at first line. The Cancer Drugs Fund clinical lead and the clinical experts stated that, if patients have avelumab plus axitinib first line, there would be interest from patients and clinicians in using current first-line treatments such as sunitinib in the second-line setting. The committee concluded that patients and clinicians should have the opportunity to choose between the most effective treatment options as early in the pathway as possible, and that the modelled treatment pathway should reflect both the costs and benefits of NHS care.\n\n# Clinical trial evidence\n\n## The key evidence comes from the JAVELIN Renal\xa0101 trial\n\nThe companies presented evidence from JAVELIN Renal\xa0101, a phase\xa03 randomised controlled trial of avelumab plus axitinib (442\xa0patients) compared with sunitinib (444\xa0patients) in advanced renal cell carcinoma. The original primary objective was to show the superiority of avelumab plus axitinib in prolonging progression-free survival in all patients in the trial. However, the investigators amended the protocol during the trial. The primary objective was changed to show superiority either on progression-free or overall survival in a subpopulation (that is, people with PD‑L1 positive tumours). The companies stated that this had changed because results from other trials suggested that avelumab plus axitinib may improve overall survival in the PD‑L1 subpopulation, and it improved effectiveness compared with the subpopulation whose tumours do not express PD‑L1. However, the European Medicines Agency ultimately granted the licence for the whole population. The clinical experts explained that NHS clinicians do not measure PD‑L1 in renal cell carcinoma. The committee was satisfied that it could take the results of the main population into account in its decision making.\n\n## Avelumab plus axitinib is more effective than sunitinib for prolonging progression-free survival, but overall survival benefit is uncertain\n\nThe companies explained that the first interim analysis of JAVELIN Renal\xa0101 showed a benefit for progression-free survival of avelumab plus axitinib over sunitinib, and that the companies continued the trial to evaluate overall survival. The companies submitted 2\xa0data cuts from the trial: interim analysis\xa01 (June 2018) and interim analysis\xa02 (January 2019). The committee noted that avelumab plus axitinib was more effective in improving progression-free survival compared with sunitinib at the first interim analysis (hazard ratio [HR]\xa00.69, 95% confidence interval [CI] 0.56\xa0to\xa00.84). The committee also noted that the results for overall survival from JAVELIN Renal\xa0101 were immature (fewer than half of the 535\xa0deaths needed for the planned final analysis had occurred at the January 2019 data cut) and the results showed a hazard ratio of\xa00.80 (95%\xa0CI 0.62\xa0to\xa01.03). The clinical experts explained that people are likely to live longer if they take avelumab plus axitinib, which combines an immune-oncology drug (avelumab) and a tyrosine kinase inhibitor (axitinib), than if they take only a tyrosine kinase inhibitor (sunitinib). The committee concluded that avelumab plus axitinib prolongs progression-free survival compared with sunitinib. However, it added that the companies' immature data meant that uncertainty remained about whether avelumab plus axitinib prolongs overall survival compared with sunitinib and, if so, by how much\n\n## There are no data to inform the long-term effects of avelumab plus axitinib\n\nGiven the absence of mature trial data for overall survival, the committee considered whether there were other data to inform effectiveness over time:\n\nThe clinical experts explained that there is no evidence to inform the long-term survival outcomes of either avelumab plus axitinib or any other checkpoint inhibitor in advanced renal cell carcinoma. They noted that, from their experience with checkpoint inhibitors, many patients do well in the longer term. The patient expert said that he was grateful to take part in an avelumab and axitinib trial. One clinical expert considered it plausible that 20% of patients would be alive at 5\xa0years and 15% at 10\xa0years.\n\nThe committee noted that there had been a previous avelumab plus axitinib trial (JAVELIN Renal\xa0100). It included only 55\xa0patients, but the committee thought that it could inform the treatment effect of avelumab plus axitinib over a longer time period.The committee agreed that any additional data would likely inform the longer-term overall survival effects of avelumab plus axitinib.\n\n## The dosing in the marketing authorisation differs from that in JAVELIN Renal\xa0101\n\nThe committee highlighted that a weight-based dose for avelumab was used in JAVELIN Renal\xa0101, whereas the licence specifies a fixed dose. The companies explained that they derived the fixed dose using pharmacokinetic and pharmacodynamic data, and taking into account similar approaches used historically. The Cancer Drugs Fund clinical lead advised that this approach was taken with other drugs for this disease area. The committee was aware that it could appraise drugs only within their marketing authorisation. It accepted that the licensed fixed dose would have similar effectiveness to the weight-based dose, and concluded that it would use the licensed dose in making decisions.\n\n## There is little evidence for avelumab plus axitinib in non-clear-cell renal cell carcinoma, as with other first-line treatments\n\nThe committee noted that most patients in JAVELIN Renal\xa0101 had clear-cell disease, but in NHS practice some have non-clear-cell disease. The clinical experts stated that there is no evidence that the results in people with cancers characterised by clear-cell histology would be generalisable (or not) to people with disease characterised by non-clear-cell histology. Therefore, there might be an argument to limit avelumab plus axitinib to people with clear-cell disease only. However, the clinical experts noted, and the committee agreed, that the situation is similar with other first-line treatments for advanced renal cell carcinoma. The committee agreed that this was an area in need of further research. It suggested that data should be collated by histology in the Cancer Drugs Fund, to monitor whether there is a difference in effectiveness.\n\n# Indirect treatment comparison\n\n## An indirect comparison is needed to compare avelumab plus axitinib with comparators other than sunitinib\n\nThere are no head-to-head trials of avelumab plus axitinib compared with tivozanib, pazopanib or cabozantinib. The companies therefore indirectly compared avelumab plus axitinib with these comparators by network meta-analyses for progression-free and overall survival. The companies constructed networks for:\n\nthe whole population across the range of risk (and which included the treatments avelumab plus axitinib, sunitinib, tivozanib and pazopanib) and\n\nthe population with intermediate- or poor-risk disease (which included the treatments avelumab plus axitinib and cabozantinib).The committee agreed that, for the economic modelling, pazopanib had the same effectiveness as sunitinib, which the committee had accepted in NICE's technology appraisal guidance on tivozanib for treating advanced renal cell carcinoma and nivolumab with ipilimumab for untreated advanced renal cell carcinoma.\n\n## Comparisons with sunitinib and pazopanib are the most relevant for decision making\n\nThere were several issues with using the network meta-analyses to compare avelumab plus axitinib with tivozanib:\n\nTo estimate overall survival, the companies used sunitinib and sorafenib as links in the network. The 2\xa0trials comparing sunitinib with sorafenib (Eichelberg et al. 2015 and Tomita et al. 2017) had a randomised sequential design (that is, patients were randomised to have sunitinib followed by sorafenib, or sorafenib followed by sunitinib). The overall survival data were available in these trials only at the end of each treatment sequence. Therefore, these trials did not directly compare sorafenib with sunitinib for overall survival. The ERG noted that this invalidated the network.\n\nThe trial comparing tivozanib with sorafenib (Motzer et al. 2013) allowed crossover from sorafenib to tivozanib on disease progression (61% of patients who progressed on sorafenib crossed over to tivozanib).\n\nA large proportion of the patients in all the trials included in the network had subsequent treatments after progression, which may not have reflected NHS practice, and which may have extended their lives.The ERG explained that a 'disconnected network' would be an alternative approach to estimate the effectiveness of avelumab plus axitinib compared with tivozanib. The committee noted that, in previous tivozanib technology appraisal guidance, it had concluded that tivozanib was 'at best' similar to sunitinib or pazopanib. This was based on tivozanib being less effective, but less expensive, than sunitinib. In comments received during the technical engagement stage for this appraisal, clinical experts noted that sunitinib and tivozanib are likely similarly effective, although a patient organisation argued that it was not appropriate to assume equal efficacy. The committee agreed that the network estimating overall survival comparing avelumab plus axitinib with tivozanib was not valid, so the effectiveness of tivozanib compared with other treatments is uncertain. However, the committee also heard from the Cancer Drugs Fund clinical lead that tivozanib was less commonly used than the other comparators in clinical practice. It therefore concluded that it would prioritise comparisons with sunitinib and pazopanib.\n\n## The companies' network meta-analyses either relying on or not relying on proportional hazards both have high levels of uncertainty\n\nThe companies stated that some of the trial results in the networks appeared to violate the assumption of proportional hazards. They therefore did 2\xa0sets of network meta-analyses. One set was a standard Bayesian network meta-analysis, which assumed proportional hazards. The output of this was a hazard ratio for avelumab plus axitinib compared with each comparator in the scope. In the other set, the companies did not assume proportional hazards. Instead, parametric curves were fitted to data from each treatment arm of each trial in the network to estimate time-varying treatment effects. This generated estimates of the probabilities of progression-free and overall survival at\xa01,\xa02 and 10\xa0years for each treatment in the model. The companies chose the latter approach for their base case. The ERG was satisfied with the methods and rationale for both approaches. It noted that it was useful to see both approaches, as 1\xa0generates a hazard ratio and the other a parametric curve over time. However, the ERG outlined that the concerns it had already highlighted with the network meta-analysis (see section\xa03.9) applied to both approaches. The committee concluded that methodological concerns and the immature data informing the model made these results uncertain.\n\n# Assumptions in the economic model\n\n## The model type is appropriate\n\nThe companies used a partitioned-survival economic model that included 3\xa0health states: pre-progression, post-progression and death. Patients could have first-line treatment with avelumab plus axitinib, sunitinib, pazopanib or tivozanib. The population with intermediate and poor risk could have avelumab plus axitinib or cabozantinib. If disease progressed, patients could move on to several other subsequent treatments, depending on which treatment they had first line. The committee concluded that the model type was appropriate and consistent with the approach used in other appraisals for renal cell carcinoma.\n\n## The committee would have preferred to see the effects of subsequent treatments explored further\n\nIn JAVELIN Renal\xa0101, people in both treatment arms could have nivolumab after disease progression on first-line treatment. The committee noted that this differed from NHS practice in which only people having sunitinib would be eligible to have second-line nivolumab or axitinib in NHS practice. The committee appreciated that the results of JAVELIN Renal\xa0101 reflected the effect of treatments offered second line and beyond (see section\xa03.1). The companies stated that this had biased the trial results against avelumab plus axitinib because a substantially higher proportion of patients had nivolumab in the sunitinib arm than in the avelumab plus axitinib arm. The companies also claimed that the proportion of patients in the trial having nivolumab after disease progression on sunitinib was higher than would be expected in NHS practice. To explore the effect of this, the companies adjusted the trial results using the rank preserving structural failure time method. The committee noted that the companies did not provide details of this method or the assumptions needed for it. Also, they did not justify their choice of this method over others. The committee was aware that, in the NHS, some patients would be expected to have nivolumab after sunitinib, whereas no patients would be expected to have nivolumab after avelumab plus axitinib. Therefore, the companies' adjustment was not appropriate. The committee concluded that it would have preferred to see the companies adjusting for any life-extending follow-on treatments offered in the trial that would not form part of a routine NHS treatment pathway, using an appropriate adjustment method.\n\n## The committee would have preferred to see the costs of subsequent treatments explored further\n\nThe companies applied the costs of subsequent treatments using a one-off cost, which depended on the treatment offered first line. For avelumab plus axitinib, and for sunitinib, the treatment patients had in the model was estimated from the subsequent treatments given in the relevant treatment arm in JAVELIN Renal\xa0101. All other first-line treatments in the model were assumed to be the same as sunitinib. The committee recognised that it was important to know all the treatments offered in the trial that are proven to extend life, but are not routinely commissioned in the NHS. However, the companies' model accounted only for the subsequent treatments taken by more than 10\xa0people in either treatment arm of JAVELIN Renal\xa0101. These treatments were cabozantinib, everolimus, axitinib, sunitinib, nivolumab, lenvatinib plus everolimus, and pazopanib. The companies confirmed that the trial had included some treatments that are not available in the NHS, such as durvalumab. As discussed (see section\xa03.12), a small proportion of patients in the model having avelumab plus axitinib went on to have other checkpoint inhibitors or axitinib after progression. The committee noted that although this likely had little effect on the cost-effectiveness estimates, given the small proportion of patients, it did not reflect clinical practice in England. The committee agreed that it would have liked to have seen base-case modelling that adjusted the trial data to reflect both the effects and costs of subsequent treatments offered in NHS practice.\n\n# Overall survival extrapolations\n\n## There are high levels of uncertainty when extrapolating overall survival\n\nIn the economic model, the companies used parametric distributions to extrapolate the data on overall survival from JAVELIN Renal\xa0101. The committee noted several uncertainties with modelled overall survival:\n\nThe short-term data informing the model (median follow up was 12\xa0months or less) meant that survival estimates varied widely depending on the choice of extrapolation curve. For example, in the companies' model at 5\xa0years, the proportion of patients alive who had treatment with avelumab plus axitinib could be:\n\n\n\n% using a Gompertz function\n\n% using a log-normal function.\n\n\n\nThe companies fitted the parametric curves independently to the survival data of each comparator, but did not explicitly present the hazard plots, so the committee could not see the implied treatment effect over the time horizon of the model.\n\nUsing either a log-normal or a log-logistic function (as used in the companies' base case) or an exponential function (as preferred by the ERG) may have generated clinically implausible results for overall survival, with mortality rates for patients who had treatment with avelumab plus axitinib falling below those of the general population after 18\xa0to 20\xa0years.The committee recognised that using an exponential curve assumes that the treatment benefit remains constant over time. This is because the relative hazards stay constant, which may be more likely to reflect clinical experience with checkpoint inhibitors. However, the clinical experts explained that, in other cancers, for a small group of patients, their disease continues to have a lasting response to checkpoint inhibitors (and so the relative hazard may change over time). The committee noted this, but was also aware that observations in 1\xa0type of cancer are not necessarily generalisable to another type of cancer. The committee concluded that all extrapolations were fundamentally uncertain because of the lack of data on long-term survival, and that only longer-term data on overall survival could address this. It also agreed that it would have preferred the companies to present the modelled treatment effect for overall survival over time explicitly.\n\n## The latest data cut for overall survival and progression-free survival should be modelled\n\nThe companies based the cost-effectiveness estimates on the results from the June 2018 data cut, even though they had presented clinical results using the January 2019 data cut. The companies stated that this was because the first data cut was:\n\na complete data set\n\navailable at the time of economic modelling\n\nreflecting the same time periods.The companies explained that the first interim analysis showed a progression-free survival benefit and the trial continued to evaluate overall survival. The committee concluded that, although the most mature data available for overall and progression-free survival would be useful, they would likely not reduce the uncertainty substantially (see section\xa03.14).\n\n## It is not appropriate to include a stopping rule\n\nIn the economic model, the companies originally assumed that clinicians stop treatment with avelumab plus axitinib after 2\xa0years of treatment, whether or not a patient's disease has progressed. After this, and despite stopping treatment, the companies assumed that:\n\ntwo-thirds of patients would continue to have a lifetime treatment benefit\n\nthe other third would gradually assume the progression and mortality hazards of the comparator treatment over 2\xa0years.The committee noted that the JAVELIN Renal\xa0101 protocol and the marketing authorisation did not include stopping treatment. The Cancer Drugs Fund clinical lead confirmed that, if a stopping rule was accepted, retreatment with avelumab plus axitinib or a second-line checkpoint inhibitor would not be available for patients who had previous treatment with avelumab plus axitinib. The clinical experts stated that stopping treatment after 2\xa0years might be reasonable for some patients. This is because clinical experience with other cancers shows that, for a small group of patients, their disease continues to have a lasting response to checkpoint inhibitors. However, the committee understood that this had not yet been shown in renal cell carcinoma and it was not appropriate to generalise from 1\xa0cancer to another. It also recognised that currently there is no clear way of identifying these patients. The committee understood that if patients relapsed after stopping treatment, they would not be able to have the treatment again. The patient expert stated that he had had 4\xa0years of treatment so far. He would be reluctant to abide by an arbitrary stopping rule for fear of losing benefit, and then not be able to have treatment again. The committee concluded that there was no evidence to support a stopping rule and that it should not be in the model. For its second meeting, the committee understood that the companies removed this assumption from their base case.\n\n## It is not appropriate to include the approach chosen by the companies to address treatment waning\n\nRelated to the stopping rule, the companies assumed that two-thirds of patients who stopped treatment would have a treatment benefit over their lifetimes, and one-third would have waning of the treatment effect (that is, over 2\xa0years, the effect of treatment would decrease to that of the comparator). The ERG presented scenarios exploring the effect of removing the treatment waning effect (that is, all patients maintained a full treatment effect in the absence of treatment). However, the committee was not clear how the ERG had implemented removing the treatment waning effect and the stopping rule (see section\xa03.15). The committee concluded that there was no evidence to support what proportion of patients would have a long-term treatment effect after stopping treatment. Therefore, the modelling should have accounted for a range of potential options, including the potential for no patients to have a long-term treatment effect after stopping treatment. At the second meeting, the committee was aware that the companies had removed the stopping rule, so the model now excluded treatment waning (that is, because treatment now continued in the model, there was no need to apply assumptions around what happens to the treatment effect after stopping treatment at a set time period, rather than for adverse events or progression). The committee agreed this was appropriate.\n\n# Cost-effectiveness estimates\n\n## Avelumab plus axitinib cannot be recommended for routine use\n\nThe cost-effectiveness results are commercial in confidence and cannot be reported here. The committee agreed that some of the original assumptions in the companies' base-case model were implausible. The committee went on to review the exploratory scenarios presented by the ERG, some (but not all) of which had used some of the committee's preferred assumptions:\n\nno stopping rule\n\nremoved treatment waning effect as modelled\n\na range of overall survival extrapolations, including the exponential curve.The cumulative effect of the committee's preferred assumptions increased the companies' base case above what is considered to be a cost-effective use of NHS resources. The committee concluded that avelumab plus axitinib cannot be recommended for routine use.\n\n# Cancer Drugs Fund\n\n## The companies propose including avelumab plus axitinib in the Cancer Drugs Fund while more data are collected from JAVELIN Renal\xa0101\n\nHaving concluded that avelumab plus axitinib could not be recommended for routine use, the committee then considered whether it could be recommended for treating advanced renal cell carcinoma within the Cancer Drugs Fund. It discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum). The committee noted that the key uncertainties were:\n\nthe immaturity of the overall survival data and the companies' approach to modelling overall survival over the long term\n\nthe lack of data on whether the treatment is effective for non-clear-cell disease and\n\nthe companies' methods for adjusting both the costs and benefits of subsequent treatments to reflect NHS practice.The committee agreed that the first 2\xa0uncertainties could be resolved by collecting further data. It considered a proposal by the companies for including avelumab plus axitinib in the Cancer Drugs Fund as part of a managed access agreement. In this, the companies would collect further data from clinical trials, and would provide avelumab plus axitinib at a discounted price to the NHS for the duration of the managed access agreement. The committee agreed that avelumab plus axitinib showed plausible potential for cost effectiveness, but only if the companies address the committee's concerns about the modelling (see section\xa03.20) when there are mature data and the guidance is reviewed. The committee was satisfied that, until then, the proposed pricing arrangement compensates for the clinical uncertainty about survival while avelumab plus axitinib is in the Cancer Drugs Fund.\n\n## Avelumab plus axitinib is recommended for use within the Cancer Drugs Fund\n\nBased on the considerations in section\xa03.19, the committee considered that it could recommend avelumab plus axitinib for use in the Cancer Drugs Fund. The committee agreed that, at the end of the period in the Cancer Drugs Fund, when the guidance is reviewed, the updated model should include these preferred assumptions (unless new evidence indicates otherwise):\n\nno stopping rule (see sections\xa03.16 and 3.17)\n\ntrial evidence and costs adjusted to reflect subsequent treatments used in NHS practice, including adjusting for life-extending treatments used in the trial not available in the NHS (see sections\xa03.12 and 3.13) and justifying the methods used to adjust for follow-on treatments (see section\xa03.12)\n\na range of overall survival extrapolations explored, including the exponential curve (see section\xa03.14)\n\nthe modelled overall survival treatment effect over comparators over time, explicitly presented (see section\xa03.14).\n\n# Other factors\n\n## Avelumab plus axitinib did not meet the criteria for end of life\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. It recognised that the companies did not submit evidence to support avelumab plus axitinib as an end-of-life therapy. It noted that the lower confidence interval boundary of median overall survival exceeded 24\xa0months. The committee noted the comments from the companies in their submission that, in pivotal trials of the NICE-recommended first-line monotherapies for acute renal cell carcinoma (sunitinib, pazopanib, tivozanib and cabozantinib), median overall survival ranged from 21.8\xa0to 30.3\xa0months. As such, avelumab plus axitinib does not meet the criteria for consideration as a life-extending treatment at the end of life for patients with acute renal cell carcinoma with favourable- to poor-risk status. The committee concluded that avelumab plus axitinib does not meet the criteria for end of life.\n\n# Innovation\n\n## Benefits are likely captured in the quality-adjusted life year calculations\n\nThe clinical experts stated they considered avelumab plus axitinib to be innovative because it is the first combination of a checkpoint inhibitor plus a tyrosine kinase inhibitor licensed for use in patients with untreated advanced renal cell carcinoma. The committee considered that this does not make the treatment innovative. It also concluded that the associated benefits of treatment are likely captured in the quality-adjusted life year calculations."}
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https://www.nice.org.uk/guidance/ta645
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Evidence-based recommendations on avelumab (Bavencio) with axitinib (Inlyta) for untreated advanced renal cell carcinoma in adults.
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21fc3a8a0cdc2721e47be7eebc8d01bbd8efae18
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nice
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High-sensitivity troponin tests for the early rule out of NSTEMI
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High-sensitivity troponin tests for the early rule out of NSTEMI
Evidence-based recommendations on high-sensitivity troponin tests for the early rule out of NSTEMI (non-ST-segment elevation myocardial infarction).
# Recommendations
The following high-sensitivity troponin tests are recommended as options for the early rule out of non-ST-segment elevation myocardial infarction (NSTEMI) in people presenting to an emergency department with chest pain and suspected acute coronary syndrome:
Access High-Sensitivity Troponin I Assay
ADVIA Centaur High-Sensitivity Cardiac Troponin‑I Assay
Alinity High Sensitive Troponin‑I assay
ARCHITECT STAT High Sensitive Troponin‑I assay
Atellica IM High-Sensitivity Cardiac Troponin I Assay
Dimension Vista High-Sensitivity Cardiac Troponin I Assay
Dimension EXL High-Sensitivity Cardiac Troponin I Assay
Elecsys Troponin T-high sensitive assay
Elecsys Troponin T-high sensitive STAT assay
VIDAS High sensitive Troponin I assay
VITROS High Sensitivity Troponin I Assay.
The tests are recommended for use with different early rule-out test strategies alongside clinical judgement, including:
A single sample on presentation using a threshold at or near the limit of detection, which will vary depending on the assay being used. If this sample is positive it should not be used to rule in NSTEMI.
Multiple sample strategies, which typically include a sample at initial assessment followed by a second sample taken at 30 minutes to 3 hours (if clinically appropriate) and use of 99th percentile thresholds or thresholds at or near the limit of detection of the assay.Healthcare professionals should consider the likely time since the onset of symptoms when interpreting test results.
When NSTEMI is not ruled out using early rule-out test strategies, use NICE's guideline on recent-onset chest pain of suspected cardiac origin to help diagnose myocardial infarction, and consider using sex-specific thresholds at the 99th percentile (see section 4.7 and section 5.2).
Further research is recommended on the diagnostic performance of the TriageTrue High Sensitivity Troponin I test when using samples at point of care (see section 5.1).
Why the committee made these recommendations
When someone comes to a hospital emergency department with chest pain, tests are needed to work out if they're having a myocardial infarction (heart attack), and if so, what type it is and what treatment they need. Standard troponin tests take 10 to 12 hours, so people need to be admitted to hospital while they wait for the results.
High-sensitivity troponin tests can help to quickly rule out a type of heart attack called an NSTEMI. Doing these tests can mean people with normal troponin levels do not need to be admitted to hospital, and those with a confirmed NSTEMI can get earlier treatment.
Evidence shows that, of the high-sensitivity troponin tests, 9 are similarly effective in terms of diagnostic performance. Of these, 8 are also similarly cost effective compared with standard troponin tests in different early rule-out test strategies and so are recommended for use in the NHS.
There is only 1 diagnostic accuracy study for Elecsys STAT, and no diagnostic accuracy evidence for Alinity and Dimension EXL. But they use the same methods, principles and reagents as alternative versions of the tests that do have diagnostic accuracy evidence and were included in the economic model. The main difference is that they are run on different analysers. They are therefore also recommended.
Although the TriageTrue test has the potential to be cost effective, its diagnostic accuracy when used on whole blood is uncertain.# The diagnostic tests
# Clinical need and practice
Chest pain and suspected myocardial infarction were the cause of about 5% of all emergency hospital admissions in 2017 to 2018. However, myocardial infarction will have occurred in only about 20% of those admissions. Tests that can quickly tell whether a person is having a myocardial infarction or not could mean that unnecessary hospital admissions are avoided, reducing waiting time and anxiety for many people.
Cardiac troponins I and T are biological markers of cardiac muscle death (cardiomyocyte necrosis). They are released into the circulation, so rise when the cardiac muscle is damaged. They are used as markers of acute myocardial infarction along with clinical history taking and electrocardiography (ECG) monitoring. ST-segment elevation myocardial infarction (STEMI) can usually be diagnosed by ECG alone. So, the main diagnostic challenge is detecting or ruling out non-ST-segment elevation myocardial infarction (NSTEMI).
The optimum sensitivity of older (non-high-sensitivity) troponin tests (referred to here as standard troponin tests) for acute myocardial infarction is 10 to 12 hours after the onset of symptoms. For many people, this means hospital admission and observation while serial troponin testing is done. To overcome this, high-sensitivity troponin tests have been developed. These can detect lower levels of troponin in the blood earlier than standard troponin tests, so enable early rule out of NSTEMI after the onset of acute chest pain. This could lead to fewer people being admitted to hospital, earlier discharge for people with normal troponin levels and earlier intervention for those with a confirmed NSTEMI.
NICE's 2014 guidance on high-sensitivity troponin tests recommended the Elecsys troponin T-high sensitive test and ARCHITECT STAT High Sensitive Troponin‑I test as options for the early rule out of NSTEMI in people presenting to an emergency department with chest pain and suspected acute coronary syndrome. Since that guidance was published, NICE's guideline on recent-onset chest pain of suspected cardiac origin has been updated to include high-sensitivity troponin tests. But stakeholder feedback suggests that high-sensitivity troponin testing used with early rule-out strategies has not been routinely adopted in the NHS and, if it has, there is wide variation in how it is being done. This updated assessment is being done to ensure that guidance is based on evidence including new high-sensitivity tests developed and marketed since publication of the NICE guidance. It is also to provide more detailed recommendations on how to use high-sensitivity tests (for example, timing of testing and using sequential testing strategies) when possible.
# The interventions
All tests included in the assessment are CE marked and available to the NHS.
## Access High-Sensitivity Troponin I Assay (Beckman Coulter)
The Access test is designed to be used in a laboratory with the Beckman Coulter Access 2 and DxI/DxC analysers. The company says that the test's performance is the same regardless of analyser. It is a paramagnetic particle chemiluminescent immunoassay for in-vitro quantitative determination of troponin I in serum and plasma samples. Results are available in 17 minutes. Recommended 99th percentile cut-offs are:
ng/litre for the whole population
ng/litre for women
ng/litre for men.Each 99th percentile has a coefficient of variation (CV) of less than 10%. The test can detect troponin I in more than 97% of the reference population.
## ARCHITECT STAT High Sensitive Troponin‑I assay (Abbott Diagnostics)
The ARCHITECT test is designed to be used in a laboratory with the Abbott ARCHITECT i2000SR and i1000SR analysers. The test is a chemiluminescent microparticle immunoassay for in-vitro quantitative determination of troponin I in serum and plasma samples. Results are available in 18 minutes. The ARCHITECT test can detect troponin I in 96% of the reference population. Recommended 99th percentile cut-offs are:
ng/litre for the whole population with a CV of 4%
ng/litre for women (CV 5.3%)
ng/litre for men (CV 3.5%).
## Alinity High Sensitive Troponin‑I assay (Abbott Diagnostics)
The Alinity test is designed to be used in a laboratory with the Alinity i analyser. It is a chemiluminescent microparticle immunoassay for the quantitative determination of troponin I in plasma and serum samples. Results are available in 18 minutes. Recommended 99th percentile cut-offs are:
ng/litre for the whole population with a CV of 4.6%
ng/litre for women (CV 5.0%)
ng/litre for men (CV 4.5%).
## ADVIA Centaur High-Sensitivity Cardiac Troponin I Assay (Siemens Healthineers)
The ADVIA Centaur test is designed to be used in a laboratory with the Siemens ADVIA Centaur XP and ADVIA Centaur XPT analysers. It is a magnetic latex particle chemiluminescent immunoassay for the in-vitro quantitative determination of troponin I in serum and plasma samples. Test results are available in 18 minutes. Recommended 99th percentile cut-offs are:
ng/litre in lithium heparin and 46.47 ng/litre in serum for the whole population
ng/litre in lithium heparin and 39.59 ng/litre in serum for women
ng/litre in lithium heparin and 58.05 ng/litre in serum for men.Each 99th percentile has a CV of less than 10%. The test can detect troponin I in more than 50% of the reference population.
## Atellica IM High-Sensitivity Cardiac Troponin I Assay (Siemens Healthineers)
The Atellica test is designed to be used in a laboratory with the Siemens Atellica IM analyser. It is a magnetic latex particle chemiluminescent immunoassay for the in-vitro quantitative determination of troponin I in serum and plasma samples. Test results are available in 10 minutes. Recommended 99th percentile cut-offs are:
ng/litre in lithium heparin and 45.43 ng/litre in serum for the whole population
ng/litre in lithium heparin and 38.64 ng/litre in serum for women
ng/litre in lithium heparin and 53.53 ng/litre in serum for men.Each 99th percentile has a CV of less than 10%. The test can detect troponin I in more than 50% of the reference population.
## Dimension EXL High-Sensitivity Cardiac Troponin I Assay (Siemens Healthineers)
The Dimension EXL test is designed to be used in a laboratory with the Siemens Dimension EXL analyser. It is a magnetic latex particle chemiluminescent immunoassay for the in-vitro quantitative determination of troponin I in serum and plasma samples. Test results are available in 18 minutes. Recommended 99th percentile cut-offs are:
ng/litre in lithium heparin and 58.2 ng/litre in serum for the whole population
ng/litre in lithium heparin and 47.8 ng/litre in serum for women
ng/litre in lithium heparin and 71.8 ng/litre in serum for men.Each 99th percentile has a CV of less than 10%. The test can detect troponin I in more than 50% of the reference population.
## Dimension Vista High-Sensitivity Cardiac Troponin I Assay (Siemens Healthineers)
The Dimension Vista test is designed to be used in a laboratory with the Siemens Dimension Vista analysers. It is a magnetic latex particle chemiluminescent immunoassay, and is intended for the in-vitro quantitative determination of troponin I in serum and plasma samples. Test results are available in 10 minutes. Recommended 99th percentile cut-offs are:
ng/litre in lithium heparin and 57.9 ng/litre in serum for the whole population
ng/litre in lithium heparin and 51.1 ng/litre in serum for women
ng/litre in lithium heparin and 74.9 ng/litre in serum for men. Each 99th percentile has a CV of less than 10%. The test can detect troponin I in more than 50% of the reference population.
## Elecsys troponin T-high sensitive assay (Roche)
The Elecsys and Elecsys STAT tests are designed to be used in a laboratory on the Roche cobas e411, e601, and e602 analysers. The company says that performance is the same when used on these analysers. The test can also be run on the cobas e801 analyser, which is designed for very high throughput as both a standard and STAT test. The Elecsys test is a sandwich electrochemiluminescence immunoassay for in-vitro quantitative determination of troponin T in serum and plasma samples. Results are available in 18 minutes with the standard test and in 9 minutes with the STAT test. Both tests can detect troponin T in 57% of the reference population. Recommended 99th percentile cut-offs are:
ng/litre for the whole population with a CV of less than 10%
ng/litre for women
ng/litre for men.
## TriageTrue High Sensitivity Troponin I Test (Quidel Cardiovascular)
The TriageTrue test can be used at point of care or in a laboratory with the Triage MeterPro analyser. It is a fluorescence immunoassay for the in‑vitro quantitative determination of troponin I in EDTA anticoagulated whole blood and plasma samples. Test results are available in less than 20 minutes. Recommended 99th percentile cut-offs are:
ng/litre for the whole population with a CV of less than 10%
ng/litre for women
ng/litre for men.The test can detect troponin I in more than 50% of the reference population.
## VITROS High Sensitivity Troponin I Assay (Ortho Clinical Diagnostics)
The VITROS test is designed to be used in a laboratory on the following analysers: VITROS ECi/ECiQ/3600 Immunodiagnostic Systems and the VITROS 5600/XT 7600 Integrated System. It is an immunometric immunoassay for the in-vitro quantitative determination of troponin I in serum and plasma samples. Test results are available in 15 minutes. Recommended 99th percentile cut-offs are:
ng/litre in lithium heparin and serum for the whole population
ng/litre in lithium heparin and serum for women
ng/litre in lithium heparin and 12 ng/litre in serum for men.The test can detect troponin I in more than 50% of the reference population.
## VIDAS High sensitive Troponin I assay (bioMérieux)
The VIDAS test is designed to be used in a laboratory on the following analysers: VIDAS, MINI VIDAS and VIDAS 3. It is for the in-vitro quantitative determination of troponin I in serum and plasma (lithium heparin) samples. Test results are available in 20 minutes. Recommended 99th percentile cut-offs are:
ng/litre for the whole population
ng/litre for women
ng/litre for men.
# The comparator
The comparator was standard troponin testing over 10 to 12 hours from symptom onset used with early rule-out strategies.# Evidence
The diagnostics advisory committee considered evidence on high-sensitivity troponin tests for the early rule out of non-ST-segment elevation myocardial infarction (NSTEMI) from several sources. Full details of all the evidence are in the committee papers.
# Clinical effectiveness
The external assessment group (EAG) did a systematic review to identify evidence on the clinical effectiveness of high-sensitivity troponin tests for the early rule out of acute myocardial infarction, including NSTEMI, in people who come to hospital with chest pain. It also considered studies used to develop the original diagnostics guidance on early rule out of myocardial infarction using high-sensitivity troponin tests.
The EAG identified 37 studies that met the inclusion criteria. Test accuracy data were reported for the following high-sensitivity troponin tests: Elecsys (30 studies), ARCHITECT (9 studies), Atellica (2 studies), ADVIA Centaur (3 studies), Access (2 studies). One study each reported accuracy data for Dimension Vista, VITROS, VIDAS and TriageTrue.
Seven studies reported diagnostic accuracy data for more than 1 test. No studies were identified that matched the inclusion criteria for the review for Alinity or Dimension EXL tests. Two randomised controlled trials were included in the review: High-STEACS and HiSTORIC.
Of the 37 included studies, 22 were done in Europe (7 in the UK), 5 in Australia and New Zealand, 6 in the US, 3 in East Asia, and 1 was a worldwide study.
The randomised controlled trials were quality assessed using the revised Cochrane risk of bias tool for cluster randomised trials. Studies that evaluated a single high-sensitivity test were assessed using the QUADAS‑2 tool. Studies that provided data for 2 or more high-sensitivity tests were assessed using the QUADAS‑2C tool.
## Randomised controlled trials
Both trials used the ARCHITECT test.
The High-STEACS trial evaluated the implementation of an early rule-out strategy in 10 secondary and tertiary care hospitals in Scotland. It compared the rates at which conditions were reclassified after high-sensitivity troponin tests with the rates of reclassification after standard troponin testing. It also compared the subsequent incidence of myocardial infarction and cardiovascular death.
The HiSTORIC trial also evaluated the implementation of an early rule-out strategy in 7 acute hospitals in Scotland. The primary outcomes were length of stay and myocardial infarction or cardiac death after discharge at 30 days. The results are academic in confidence.
During the validation phase of High-STEACS (6 to 12 months), results of the high-sensitivity troponin I test were concealed from the attending clinician, and a standard cardiac troponin test was used to guide care. A high-sensitivity test was introduced after 6 months (early implementation) or 12 months (late implementation).
In patients whose condition was reclassified in the High-STEACS trial, there were no differences between high-sensitivity and standard troponin tests in the primary or any of the secondary efficacy and safety outcome measures (myocardial infarction, unplanned coronary revascularisation, all-cause death, death from cardiovascular causes, hospital admission for heart failure and ischaemic stroke). The median length of stay for patients without myocardial injury was 7 hours (interquartile range 3 to 24) in the validation phase and 4 hours (interquartile range 3 to 20) in the implementation phase. The authors of High-STEACS concluded that implementing an early rule-out strategy was not associated with any increase in myocardial infarction or cardiovascular death within 1 year of initial presentation.
## Diagnostic test accuracy
Summary estimates of sensitivity and specificity from testing a single sample, using a 99th percentile diagnostic threshold for the general population, were 90% (95% confidence interval 85 to 94) and 78% (95% CI 72 to 83) respectively, based on data from 22 studies. The summary estimates of sensitivity and specificity, using a single sample and a limit of detection threshold, were 99% (95% CI 97 to 99) and 36% (95% CI 28 to 45) respectively, based on data from 9 studies. The 8 studies that assessed the diagnostic performance of a limit of blank threshold in a single sample gave a similarly high summary estimate of sensitivity of 100% (95% CI 98 to 100), but a reduced specificity of 19% (95% CI 11 to 31). All estimates were similar when the analyses were restricted to studies that excluded people with ST-segment elevation myocardial infarction (STEMI).
Using multiple sample strategies appears to offer better specificity without substantial loss of sensitivity than using a single sample on presentation and a very low limit of detection or limit of blank threshold. The European Society of Cardiology's (ESC) 0/1‑hour rule-out pathway combines an initial sample and a very low limit of detection threshold (5 ng/litre) in patients reporting a minimum symptom duration of 3 hours. The strategy tests at presentation and 1 hour later for patients whose acute myocardial infarction is not ruled out by the initial test, that is, it uses an 'OR' combination. The threshold for repeat testing is an initial troponin concentration of less than 12 ng/litre with an absolute change in troponin concentration, from 0 to 1 hour, of less than 3 ng/litre. For NSTEMI, the sensitivity and specificity estimates for this strategy were 99% (95% CI 98 to 100) and 68% (95% CI 67 to 70), respectively. Estimates of diagnostic performance were similar for strategies using an 'AND' combination of initial high-sensitivity troponin level and absolute change in troponin level.
Summary estimates of sensitivity and specificity for a single sample using a diagnostic threshold of the 99th percentile for the general population were 75% (95% CI 65 to 82) and 94% (95% CI 94 to 96) respectively, based on data from 5 studies. These estimates were similar if the analysis was restricted to studies that excluded people with STEMI. The summary estimates of sensitivity and specificity, using a limit of detection threshold (2 ng/litre) in a single sample taken on presentation, were 100% (95% CI 99 to 100) and 21% (95% CI 16 to 26) respectively, based on data from 4 studies in NSTEMI.
For multiple sample strategies, the High-STEACS pathway was used as follows:
in the whole population, symptoms for 2 hours or more and a troponin concentration of less than 5 ng/litre at 0 hours, or
in women, 16 ng/litre or lower when measured 3 hours from presentation and an absolute change of less than 3 ng/litre at 0 to 3 hours, or
in men, 34 ng/litre or lower when measured 3 hours from presentation and an absolute change of less than 3 ng/litre at 0 to 3 hours.
Using the High-STEACS pathway in this way appeared to offer increased specificity without substantial loss of sensitivity compared with a single sample on presentation and a risk stratification threshold of less than 5 ng/litre. The sensitivity and specificity estimates for this strategy were 99% (95% CI 97 to 100) and 76% (95% CI 73 to 78) respectively, for NSTEMI. The ESC 0/1‑hour rule-out pathway reported a lower specificity than the High-STEACS pathway. It used an initial sample and a limit of detection threshold of less than 2 ng/litre, or repeat testing combining an initial troponin concentration of less than 5 ng/litre and an absolute change in troponin concentration, from 0 to 1 hour, of less than 2 ng/litre. Summary sensitivity and specificity estimates were 99% (95% CI 98 to 100) and 57% (95% CI 56 to 59) respectively for NSTEMI.
The 2 studies evaluating the Access test each assessed a different multiple sample strategy. One followed the ESC 0/1‑hour rule-out pathway (initial sample and a limit of detection threshold of less than 4 ng/litre, or repeat testing combining an initial concentration of less than 5 ng/litre and an absolute change in troponin concentration, from 0 to 1 hour, of less than 4 ng/litre), giving sensitivity and specificity estimates of 99% (95% CI 94 to 100) and 70% (95% CI 66 to 74) respectively for NSTEMI. The second study assessed a similar strategy, but with repeat testing at 2 hours. The sensitivity estimates were similar for the 2 strategies, but the specificity of the 2-hour repeat testing strategy was higher than that of the 1‑hour strategy.
The study evaluating the VIDAS test assessed a multiple sample strategy, with samples taken on presentation and at 2 hours using a threshold of less than 2 ng/litre at presentation, or less than 6 ng/litre at presentation and at 2 hours. The reported sensitivity and specificity estimates were 98% (95% CI 92 to 100) and 64% (95% CI 59 to 68) respectively for NSTEMI.
The study evaluating the VITROS test assessed the ESC 0/1‑hour rule-out pathway. This combined an initial sample and a limit of detection threshold of less than 1 ng/litre, or repeat testing combining an initial troponin concentration of less than 2 ng/litre and an absolute change in troponin concentration, from 0 to 1 hour, of less than 1 ng/litre. The reported sensitivity and specificity estimates were 100% (95% CI 95 to 100) and 60% (95% CI 55 to 64) respectively for NSTEMI.
The study evaluating the TriageTrue test assessed the ESC 0/1‑hour rule-out pathway. This combined an initial sample and a limit of detection threshold of less than 4 ng/litre, or repeat testing combining an initial troponin concentration of less than 5 ng/litre and an absolute change in troponin concentration, from 0 to 1 hour, of less than 3 ng/litre. The reported sensitivity of this strategy was 100% (95% CI 97 to 100) and the specificity was 66% (95% CI 62 to 70) for NSTEMI.
Three studies evaluated the ADVIA Centaur test. Using a rule-out threshold of 2 ng/litre in a single sample taken on presentation, the sensitivity and specificity estimates were 100% (95% CI 99 to 100) and 23% (95% CI 21 to 25) respectively for NSTEMI. Two multiple sample strategies were evaluated. One followed the ESC 0/1‑hour rule-out pathway. This combined an initial sample and a limit of detection threshold of less than 3 ng/litre, or repeat testing combining an initial concentration of less than 6 ng/litre and an absolute change in troponin concentration, from 0 to 1 hour, of less than 3 ng/litre. The sensitivity and specificity estimates for this strategy were 99% (95% CI 95 to 100) and 56% (95% CI 52 to 60) respectively for NSTEMI. The second study assessed a similar strategy, but with higher thresholds and repeat testing at 2 hours. The sensitivity and specificity estimates for this strategy were 100% (95% CI 95 to 100) and 67% (95% CI 61 to 72) respectively for NSTEMI.
Using a rule-out threshold of 2 ng/litre, in a single sample taken on presentation, the sensitivity and specificity estimates for the Atellica test were 100% (95% CI 98 to 100) and 26% (95% CI 24 to 28) respectively for NSTEMI. Sensitivity and specificity estimates for the High-STEACS pathway (symptoms for at least 2 hours and an initial troponin concentration of less than 5 ng/litre, or a troponin concentration of 34 ng/litre or less in women, or 53 ng/litre or less in men at 3 hours and an absolute change in concentration from 0 to 3 hours, of less than 3 ng/litre) were 98% (95% CI 95 to 100) and 74% (95% CI 72 to 76) respectively for NSTEMI.
The study of the Dimension Vista test assessed a strategy using measurements done at baseline using a troponin concentration threshold of less than 5 ng/litre and an absolute change of less than 2 ng/litre within 1 hour. The sensitivity of the strategy was 100% (95% CI 97 to 100) and specificity was 66% (95% CI 62 to 69) for NSTEMI.
## Diagnostic accuracy in relevant subgroups
The EAG identified some data on the subgroups described in the scope for this guidance. In a study using the Elecsys test and a 99th percentile threshold on a single sample at presentation, a higher sensitivity for any acute myocardial infarction was estimated in people over 70 than for people aged 70 or under (97% and 88% respectively). The estimate of sensitivity for people over 70 was also higher than the corresponding summary estimates from all 22 studies that used the 99th percentile diagnostic threshold. There was a similar pattern for people with a high pre-test probability (determined by clinical judgement of cardiovascular risk factors, type of chest pain, physical findings and electrocardiography abnormalities) compared with those with a low to moderate pre-test probability. The same was found for people without pre-existing cardiovascular disease compared with those with pre-existing cardiovascular disease.
Only the High-STEACS trial reported using sex-specific thresholds. Data from this study appeared to show that testing using a single sample taken on presentation is markedly more sensitive if sex-specific 99th percentile cut-offs are used, compared with a standard troponin test with a uniform threshold. This is particularly true in women, for whom the 99th percentile is lower. This study also used sex-specific thresholds as part of a multiple test strategy: the High-STEACS pathway. It is unclear whether using sex-specific thresholds in this strategy offers any advantage over using a single general population threshold. This is because no equivalent strategy, using a single universal threshold, was evaluated. Other studies reported data on men and women using a single general population threshold in each group. Results from a study on the Elecsys test showed very similar accuracy estimates for the subgroups, although a study on the Dimension Vista reported a lower sensitivity and specificity in men than in women.
Two studies on the Elecsys test and 2 on the ARCHITECT test reported data on how diagnostic performance varies with renal function. All studies show a decrease in specificity as renal function decreases.
## Comparative diagnostic accuracy for more than 1 test
Seven studies reported accuracy data for more than 1 test.
The APACE study provided data on the ESC 0/1‑hour pathway using the Elecsys, ARCHITECT and ADVIA Centaur tests. It also provided data on the ESC 0/1‑hour pathway using the Access, VITROS and TriageTrue tests, but these results came from different patient subgroups and were reported in different publications. Data showed that the ESC 0/1‑hour pathway performed consistently across all 6 high-sensitivity troponin tests evaluated with sensitivity estimates of 98% or higher.
Three other studies, ADAPT, ROMI-3, and TRUST, compared the Elecsys and ARCHITECT tests. Although the sensitivity estimates for the Elecsys test, using the 99th percentile and a single sample at presentation, were higher than those for the ARCHITECT test, both had sensitivity estimates of less than 97%. When the limit of detection threshold was used with a single sample at presentation, sensitivity estimates were comparable for the Elecsys test and the ARCHITECT test, and were always 99% or higher.
The High-STEACS trial provided data on the rule-out performance of 3 strategies (ESC 0/1‑hour, ESC 0/3-hour and High-STEACS 0/3-hour) using the ARCHITECT and Atellica tests. It is unclear whether both tests were evaluated in the same subgroup of people in the study. Data showed that the sensitivity of the ESC 0/1‑hour pathway was lower using the Atellica test (94% ) than using the ARCHITECT test (100% ). The sensitivity and specificity estimates for the High-STEACS 0/3-hour rule-out pathway were similar using either test (both had sensitivity estimates of 98% or more). The ESC 0/3-hour rule-out pathway in this study consisted of:
symptoms for 6 hours or more and a troponin concentration of 16 ng/litre or less in women or 34 ng/litre or less in men at 0 hours, or
a troponin concentration of 16 ng/litre or less in women or 34 ng/litre or less in men at 3 hours, or
an absolute change of less than 50% of the 99th percentile at 0 to 3 hours.The sensitivity and specificity estimates for the ESC 0/3-hour rule-out pathway were both less than 97% using either test.
The HIGH-US study compared 2 Siemens tests (Atellica and ADVIA Centaur), using 3 low thresholds and a single sample at presentation. The results showed sensitivity estimates were 99% or more for both tests for all thresholds.
The BEST study compared 2 single sample at presentation strategies using the ADVIA Centaur test (threshold of 3 ng/litre) and Elecsys test (limit of detection threshold). Data were reported in separate publications with different numbers of people. The sensitivity estimates were 99% for both tests, but the Elecsys test had a higher specificity (47% ) than the ADVIA Centaur test (33% ).
# Cost effectiveness
The EAG did a search to identify evidence on the cost effectiveness of high-sensitivity troponin tests for the early rule out of acute myocardial infarction, including NSTEMI. The EAG also developed a de novo economic model to assess the cost effectiveness of the different testing strategies.
## Review of economic evidence
Studies were eligible if they reported a full economic analysis of the cost effectiveness of either high-sensitivity troponin testing or standard troponin testing. They also had to include survival or quality-adjusted life years (QALYs) as an outcome measure.
Five studies identified in the original assessment report and 1 new study were included in the systematic review. Results varied in the 5 studies from the original report, and the EAG concluded that there was uncertainty about the cost effectiveness of diagnostic strategies using high-sensitivity troponin testing. The EAG noted that the key drivers of cost effectiveness in the included studies were the accuracy of high-sensitivity troponin tests, and the efficiency of decision making once test results were available.
The most recent study (Ambavane et al. 2017) reported that a 1‑hour strategy using high-sensitivity troponin testing had higher sensitivity (87% compared with 69%) but lower specificity (96% compared with 97%) than standard care. The reference standard used to calculate diagnostic accuracy was determination of final diagnosis based on a comprehensive review of medical records. Total costs were less for the 1‑hour strategy compared with standard care (£2,480 compared with £4,561). This was mainly because of a shorter length of stay in the emergency department.
## Economic analysis
The EAG developed a de novo economic model to explore the cost effectiveness of high-sensitivity troponin tests for the early rule out of acute myocardial infarction, including NSTEMI, in people with acute chest pain (used up to 4 hours from the onset of chest pain or at presentation). The model compared high-sensitivity tests with standard troponin T or I testing, or both, on admission and at 10 to 12 hours after the onset of symptoms. The population in the model was people presenting to the emergency department with suspected non-ST-segment elevation acute coronary syndrome, who have no major comorbidities needing hospitalisation (for example, heart failure or arrhythmia) and in whom STEMI has been ruled out.
Only high-sensitivity troponin tests with a sensitivity of 97% or above were used in the economic model, based on expert opinion of the minimum sensitivity acceptable in clinical practice. The strategies evaluated are described in table 1.
Strategy number
Test
Strategy
Elecsys
th percentile threshold (under 14 ng/litre at 0 hours AND 3 hours)
Elecsys
Limit of detection under 5 ng/litre at 0 hours
Elecsys
ESC 0/1‑hour pathway: symptoms over 3 hours AND under 5 ng/litre at 0 hours OR under 12 ng/litre at 0 hours AND an absolute change of less than 3 ng/litre at 0 to 1 hour
Elecsys
Under 8 ng/litre at 0 hours AND an absolute change of less than 3 ng/litre at 0 to 0.5 hours
Elecsys
Under 12 ng/litre at 0 hours AND an absolute change of less than 3 ng/litre at 0 to 1 hour
Dimension Vista
Under 5 ng/litre at 0 hours AND an absolute change of less than 2 ng/litre at 0 to 1 hours
ARCHITECT
Under 12 ng/litre at 0 hours AND an absolute change of less than 3 ng/litre at 0 to 1 hour
ARCHITECT
ESC 0/1‑hour pathway: symptoms over 3 hours AND under 2 ng/litre at 0 hoursOR under 5 ng/litre at 0 hours AND an absolute change of less than 2 ng/litre at 0 to 1 hours
ARCHITECT
High-STEACS pathway: symptoms for 2 hours or more AND under 5 ng/litre at 0 hoursOR 16 ng/litre or more (women) and 34 ng/litre or more (men) at 3 hours AND an absolute change of less than 3 ng/litre
ARCHITECT
Under 4 ng/litre at 0 hours
ADVIA Centaur
Under 2 ng/litre at 0 hours
ADVIA Centaur
Under 3 ng/litre at 0 hours OR under 8 ng/litre at 0 hours AND an absolute change of less than 7 ng/litre at 0 to 2 hours
ADVIA Centaur
ESC 0/1‑hour pathway: symptoms over 3 hours AND under 3 ng/litre at 0 hours OR under 6 ng/litre at 0 hours AND an absolute change of less than 3 ng/litre at 0 to 1 hour
ADVIA Centaur
Under 5 ng/litre at 0 hours
Atellica
Under 2 ng/litre at 0 hours
Atellica
High-STEACS pathway: symptoms for 2 hours or more AND under 5 ng/litre at 0 hours OR 34 ng/litre or less (women) and 53 ng/litre or less (men) at 3 hours AND an absolute change of less than 3 ng/litre
Access
ESC 0/1‑hour pathway: symptoms over 3 hours AND under 4 ng/litre at 0 hoursOR under 5 ng/litre and an absolute change of less than 4 ng/litre at 0 to 1 hour
Access
Symptoms over 3 hours AND under 4 ng/litre at 0 hoursOR under 5 ng/litre and an absolute change of less than 5 ng/litre at 0 to 2 hours
VITROS
ESC 0/1‑hour pathway: symptoms over 3 hours AND under 1 ng/litre at 0 hoursOR under 2 ng/litre at 0 hours AND an absolute change of under 1 ng/litre at 0 to 1 hour
VIDAS
Under 2 ng/litre at 0 hours
OR under 6 ng/litre at 0 AND 2 hours
TriageTrue
ESC 0/1‑hour pathway: symptoms over 3 hours AND under 4 ng/litre at 0 hoursOR under 5 ng/litre at 0 hours AND an absolute change of less than 3 ng/litre at 0 to 1 hour
## Model structure
The model structure from the original diagnostics assessment report was used. This model structure was adapted from the health technology assessment report from Goodacre et al. (2013). It consists of a decision tree and a state-transition model. The decision tree was used to model the 30‑day outcomes after presentation, based on test results and the accompanying treatment decision. The following health states were included:
no acute coronary syndrome and no unstable angina (no ACS, no UA)
unstable angina (UA)
post-acute myocardial infarction, treated and untreated (post-AMI)
post-acute myocardial infarction with reinfarction (post-AMI with reinfarction)
death.
People presenting at the emergency department with suspected non-ST elevation acute coronary syndrome were tested and results were classified as either true positive, false positive, false negative or true negative. These people entered health states as listed (people could also die after treatment or be discharged):
People with true positive test results were correctly treated for acute myocardial infarction and were allocated to 'non-fatal AMI (treated)'.
People with false positive test results were considered to have no acute myocardial infarction, but did not meet early rule-out criteria. They were subdivided between 'no ACS, no UA' and 'UA'. It was assumed that people with false positive test results would remain in the hospital longer but would not be treated for acute myocardial infarction.
People with true negative test results were considered not to be treated for acute myocardial infarction and were subdivided between 'no ACS, no UA' and 'UA'.
People with false negative test results were assumed to have untreated acute myocardial infarction resulting in increased reinfarction and mortality probabilities for 1 year and were allocated to 'non-fatal AMI (untreated)'.
The long-term consequences in terms of costs and QALYs were estimated using a state-transition cohort model with a lifetime time horizon (60 years) and a cycle time of 1 year (except for the first cycle which was adjusted to 335.25 days to ensure that the decision tree period and the first cycle summed to 1 year). Discount rates of 3.5% and a half-cycle correction were applied for both costs and effects.
Estimates for the model input parameters were retrieved from the literature and from consulting experts. Accuracy estimates were derived from the systematic review component of the assessment. The proportion of people testing positive or negative was based on the estimated accuracy of the testing strategies considered (table 2) and the estimated prevalence of NSTEMI in the UK (12.2%).
Number
Test
Strategy
Sensitivity (SE)
Specificity (SE)
Standard troponin
At presentation and after 10 to 12 hours
Elecsys
th percentile at 0 hours AND 3 hours
Elecsys
Limit of detection at 0 hours
Elecsys
ESC 0/1‑hour pathway
Elecsys
Less than 8 ng/litre at 0 hours AND change of less than 3 ng/litre at 0 to 0.5 hours
Elecsys
Less than 12 ng/litre at 0 hours AND change of less than 3 ng/litre at 0 to 1 hour
Dimension Vista
Less than 5 ng/litre at 0 hours AND change less than 2 ng/litre at 0 to 1 hour
ARCHITECT
Limit of detection at 0 hours
ARCHITECT
ESC 0/1‑hour pathway
ARCHITECT
High-STEACS pathway
ARCHITECT
Less than 4 ng/litre at 0 hours
ADVIA Centaur
Less than 2 ng/litre at 0 hours
ADVIA Centaur
Less than 3 ng/litre at 0 hours OR less than 8 ng/litre at 0 hours AND change of less than 7 ng/litre at 0 to 2 hours
ADVIA Centaur
ESC 0/1‑hour pathway
ADVIA Centaur
Less than 5 ng/litre at 0 hours
Atellica
Less than 2 ng/litre at 0 hours
Atellica
High-STEACS pathway
Access
ESC 0/1‑hour pathway
Access
Symptoms at more than 3 hours AND less than 4 ng/litre at 0 hour OR less than 5 ng/litre and change of less than 5 ng/litre at 0 to 2 hours
VITROS
ESC 0/1‑hour pathway
VIDAS
Less than 2 ng/litre at 0 hour OR less than 6 ng/litre at 0 AND 2 hours
TriageTrue
ESC 0/1‑hour pathway
ESC, European Society of Cardiology; SE, standard error; ng/litre is nanograms troponin per litre of blood.
Test-specific resource use consisted of the number of tests done and the duration of hospital stay in hours before discharge or acute myocardial infarction treatment. For test strategies that involved a subsequent test conditional on the outcome of the first test, the rule-out rate for the presentation sample was used to calculate the number of subsequent tests. The resource use included a delay from the time at which sampling could be done to the time at which results became available (2 hours) and delay between arrival at hospital and troponin assessment starting (1 hour).
Health state costs were taken from a retrospective cohort study done in the UK (Danese et al. 2016). Acute myocardial infarction treatment costs were based on NHS reference costs and hospital stay costs were based on data from the Personal Social Services Research Unit.
In the base case, test costs were assumed to be identical for all tests (£2.50) except for the point-of-care test (£25.00, based on information provided by Quidel). A scenario analysis was done using test-specific costs and assuming that costs relating to the analyser and staff time were identical for all strategies.
Age-dependent utility scores from the UK general population were calculated for people in the 'no ACS, no UA' health state. These age-dependent utility scores were combined with age-dependent disutility values for acute myocardial infarction, to calculate utility values for the 'post-AMI' health states (with or without reinfarction). Utility values for the 'UA' health state were calculated based on the 'post-MI' utility values and assuming a utility increment of 0.010.
The following assumptions were applied in the base-case analysis:
Standard troponin testing (at presentation and after 10 to 12 hours) has perfect accuracy.
Compared with acute myocardial infarctions occurring during the decision tree period, all acute myocardial infarctions (either first or reinfarction) occurring in the state-transition model are diagnosed correctly, so are treated.
Unstable angina is always correctly diagnosed, so is treated.
The reinfarction probability for the 'post-AMI with reinfarction' health state is equal to the reinfarction probability for the 'post-AMI' health state.
The increased post-acute myocardial infarction reinfarction and mortality probabilities for untreated acute myocardial infarction were assumed to last 1 year. After this a relative risk of 1.0 was applied (for untreated compared with treated acute myocardial infarction).
There is no additional benefit of starting treatment early, so treatment effect for high-sensitivity strategies is equal to treatment effect for standard troponin strategies.
All 30‑day deaths (after presentation at the emergency department) are due to fatal acute myocardial infarction events and will receive the associated costs.
For the base case, it was assumed that people who tested negative on standard troponin tests and positive on high-sensitivity troponin tests would have a life expectancy and quality of life equal to people with true negative test results, but this assumption is debatable. A meta-analysis by Liplinski et al. (2015) showed that people with a negative standard troponin test and positive high-sensitivity troponin test have an increased risk of reinfarction and mortality compared with those who test negative on both standard troponin and high-sensitivity troponin tests. Although this risk was not as high as in people with both positive standard troponin and positive high-sensitivity troponin tests, it could still be considered prognostically important. A secondary analysis was done in which the risk of acute myocardial infarction and mortality was adjusted for people with false positive results.
In the base case, standard troponin testing was the most effective and the most expensive strategy. But other testing strategies with a sensitivity of 100% (subject to uncertainty) were almost equally as effective, resulting in the same QALY gain up to 4 decimal places. Compared with standard troponin testing, high-sensitivity troponin testing resulted in probabilistic incremental cost-effectiveness ratios (ICERs) ranging between £34,307 and £36,842,603 savings per QALY lost.
In the secondary analysis, standard troponin was the cheapest and the least effective testing strategy. Compared with standard troponin testing, high-sensitivity troponin testing resulted in probabilistic ICERs ranging between £4,043 and £6,148 per QALY gained.
For all scenario analyses of the secondary analysis, results were similar to those from the secondary analysis base case. Standard troponin remained the cheapest and the least effective testing strategy (deterministic analysis). In all scenario analyses of the secondary analysis, high-sensitivity troponin testing compared with standard troponin testing resulted in ICERs less than £10,000 per QALY gained.
One-way sensitivity analyses were done including all parameters that were changed in the probabilistic sensitivity analysis. In the secondary analysis, the parameters that had a notable effect on the estimated cost-effectiveness estimates were:
‑day mortality for untreated acute myocardial infarction
mortality 1 year after treated and untreated acute myocardial infarction
discount rate used for outcomes
relative mortality for people who had a true positive result compared with those who had a false positive result.At extreme values (based on 95% confidence intervals) of these inputs, standard troponin testing remains cheaper and less effective than the high-sensitivity troponin tests.# Committee discussion
# Quick, accurate tests may reduce anxiety for patients and carers
The committee heard from a patient expert who highlighted the stresses and fears that patients and their families experience when attending the emergency department with chest pain. Reducing waiting times is important for patients. Technologies that reduce the time taken from sample to clinical decision, while providing good diagnostic accuracy, may help reduce patient anxiety. Patients may be reassured that they are having the most appropriate treatment with tests that provide an accurate result.
# Flexibility on tests and strategies helps hospitals
NICE has previously recommended high-sensitivity troponin for early rule out of acute myocardial infarction, so most emergency departments are already set up for high-sensitivity troponin testing. Many have implemented early rule-out strategies as routine practice. The committee considered that there were practical issues around early rule-out strategies that incorporate serial testing but that these could be resolved in practice. It also considered that, if more tests and different testing strategies were found to be cost effective and were recommended, this would help with procurement and give hospitals more flexibility to implement a strategy that works for them.
# Clinical effectiveness
## The comparative accuracy of the different tests is uncertain
There were concerns about the level of clinical evidence available for some of the tests. Most diagnostic accuracy results related to the Elecsys (30 studies) and ARCHITECT (9 studies) tests. Other tests had less evidence available but were mostly still acceptable. The committee noted that there was also limited evidence comparing the diagnostic performance of 1 test with another. This meant that although there may be differences in performance between the tests, it is difficult to estimate these differences with any certainty.
## The sensitivity of single-sample early rule-out strategies varies depending on which threshold is used
Results from the diagnostic accuracy studies showed that strategies that test a single sample on presentation using a threshold at or close to the limit of detection gave high sensitivity but low specificity. However, the committee commented that single sample strategies can be useful to rule out non-ST-segment elevation myocardial infarction (NSTEMI) early in emergency departments and, for this purpose, specificity is not a priority. There were concerns about the consistency of different analysers to provide accurate results at these low thresholds. However, clinical experts commented that samples with results close to these low thresholds would be from people considered very low risk and would have a good prognosis regardless of treatment. In contrast, results from diagnostic accuracy studies showed that a single test strategy using the 99th percentile threshold had sensitivity estimates too low to be safely used in clinical practice.
## Multiple sample early rule-out strategies have better specificity than single-sample strategies
Results from the diagnostic accuracy studies showed that multiple sample early rule-out strategies, that is, those that included a second rule-out step, had better specificity than single-sample strategies using a very low threshold. Multiple sample strategies also maintained high levels of sensitivity. However, clinical experts commented that it was difficult to make direct comparisons of the different test strategies based on specificity because the number of true negatives would be affected by the prevalence of NSTEMI in each of the different study populations.
## High-sensitivity troponin tests should be used alongside clinical judgement
Clinical experts noted that the clinical context in which decisions on discharging or admitting someone to hospital is important, and that decisions should never be based solely on the results of a high-sensitivity troponin test. For example, a person with a negative high-sensitivity troponin test result should not be discharged without further investigations if they look visibly unwell or if the sample was collected too soon after the suspected cardiac event, a practice that could result in a false negative result.
## Using sex-specific 99th percentile thresholds could reduce inequality in women's treatment
Clinical experts explained that there was consistent evidence from reference range studies that the 99th percentile threshold differs between men and women. For the Elecsys and ARCHITECT tests, the 99th percentile upper reference limit for women is much lower than the general (mixed) population 99th percentile. The High-STEACS trial was the only strategy included in the cost-effectiveness modelling to use sex-specific 99th percentile thresholds in an early rule-out strategy. But it did not provide a direct comparison with a general population 99th percentile threshold. The committee therefore considered that the evidence on using sex-specific 99th percentile thresholds in early rule-out strategies was unclear. Clinical experts noted that sex-specific 99th percentile thresholds were sometimes used in clinical practice to help diagnose NSTEMI, but that there was no evidence that using them affected clinical outcomes. They noted that the ongoing CODE-MI study aims to evaluate the effect of using the sex-specific 99th percentile threshold for women for high-sensitivity cardiac troponin. This will be compared with the general (mixed) population 99th percentile threshold, for the diagnosis, treatment and outcomes of women presenting to the emergency department with cardiac chest pain. The committee noted that there was a wider equality issue because women with acute myocardial infarction are generally under-diagnosed and under-treated compared with men. The committee considered that using sex-specific 99th percentile thresholds to help diagnose NSTEMI could be a step towards reducing this health inequality. It concluded that, when NSTEMI is not ruled out using early rule-out test strategies, NICE's guideline on recent-onset chest pain of suspected cardiac origin may be used to help diagnose myocardial infarction, and the use of sex-specific thresholds at the 99th percentile should be considered (see section 5.2).
## Randomised controlled trial evidence shows early rule-out strategies do not negatively affect health
The committee considered evidence from 2 randomised controlled trials, High-STEACS and HiSTORIC. It noted that the authors of High-STEACS concluded that the implementation of an early rule-out strategy was not associated with any increase in myocardial infarction or cardiovascular death within 1 year of initial presentation. The HiSTORIC trial was submitted to NICE as academic-in-confidence evidence. The committee concluded that evidence from the randomised controlled trials, which reported end clinical outcomes, strongly supported using high-sensitivity troponin tests with early rule-out strategies in clinical practice.
## The TriageTrue point-of-care test is innovative but its diagnostic accuracy is uncertain
The committee noted that the TriageTrue point-of-care test had a turnaround time of around 20 minutes and had the potential to be an important development in the field. The rapid time to test results could have benefits because of a reduced length of time spent waiting for a result in the emergency department (see section 4.1). Only 1 study was available on the TriageTrue test. In this study troponin levels were tested in stored plasma samples rather than the whole blood samples used in clinical practice. The committee noted that the evidence did not reflect how the test would be used in clinical practice at the point of care. It concluded that further evidence on TriageTrue's diagnostic performance when used on whole blood at the point of care is needed before the test can be recommended for use in clinical practice.
## The Alinity, Dimension EXL and Elecsys STAT tests are likely to have the same performance as alternative versions of tests
The Alinity and Dimension EXL tests were not included in the economic model because there were no direct diagnostic accuracy data for them in the systematic review. However, the committee noted that these tests were based on the same methods and principles, and used the same reagents as other tests that were included in the modelling. The committee heard that the Alinity test was a newer version of the ARCHITECT test and that the Dimension EXL test was a different version of the Vista test, but the tests were all run on different analysers. It noted further that the Elecsys STAT test was the same in terms of technical specification and performance as the Elecsys troponin T-high sensitive test, and is run on the same analysers. The committee concluded that the diagnostic accuracy of these different versions of the tests should be comparable. It also concluded that it was the responsibility of individual laboratories to assess the equivalency of these tests in practice, and to validate their diagnostic performance against their current system. This would be achieved in part by participating in external quality assessment schemes.
# Cost effectiveness
## Only including early rule-out strategies with a minimum sensitivity of 97% in the economic analysis is acceptable
Only early rule-out strategies with a sensitivity of 97% or more were used in the cost-effectiveness modelling, based on expert opinion about the minimum sensitivity acceptable in clinical practice. The committee noted that this approach could mean that some potentially cost-effective strategies were excluded from the economic modelling. But overall it agreed that it was an acceptable approach that was necessary to keep the number of test strategies in the economic model manageable and ensure that those considered were likely to be safe in practice.
## The prognostic benefits associated with a false positive high-sensitivity troponin test should be incorporated into decision making
The secondary analysis incorporated prognostic benefits associated with false positive high-sensitivity troponin test results. Clinical experts noted that it is now widely accepted that people with a negative standard troponin test and a positive high-sensitivity troponin test (classified as false positives in the analysis) have an increased risk of reinfarction and mortality compared with people who have a negative result from both tests. The committee concluded that the secondary analysis was most appropriate for decision making.
## All early rule-out test strategies in the model are cost effective compared with standard troponin testing at 0 hours and 12 hours
Compared with standard troponin testing, high-sensitivity troponin test strategies resulted in incremental cost-effectiveness ratios (ICERs) of less than £7,000 per quality-adjusted life year (QALY) gained. These ICERs are below £20,000 per QALY gained, which NICE would typically consider to be cost effective. The committee noted that there were only small differences in costs and QALYs between the different test strategies included in the economic model, and recalled its previous conclusion that it was not possible to indirectly compare the tests and early rule-out strategies. The committee concluded that it was not possible to differentiate between the different test strategies, and that all early rule-out strategies had the potential to be recommended for clinical practice, provided that each test used with them had enough diagnostic accuracy data.
## The results of the economic model are robust to changes in the input parameter values
The model results were robust to changes in the input parameter values, for example, the number of admissions based on the specificity of the test strategy and the prevalence of NSTEMI. Early rule-out strategies with lower specificities would likely result in fewer people being discharged from hospital, but this does not have a substantial effect on the cost-effectiveness results. In addition, clinical experts noted that people having standard troponin testing and who get a negative test result would probably have a hospital length of stay of 24 hours rather than the 14 hours assumed in the economic model. So the benefits of using early rule-out strategies may have been underestimated. The external assessment group (EAG) commented that changing this assumption would be unlikely to affect the model results.
## Recommending a range of different high-sensitivity troponin tests gives greater flexibility to NHS trusts
Some of the tests had lower levels of clinical evidence than others. But the diagnostic performance and costs of all the tests used in the modelling were comparable (except for the test cost for TriageTrue). There was no strong evidence to differentiate one test over another (see section 4.3), and when used in the early rule-out strategies all were cost effective compared with the standard troponin test (see section 4.13). The committee noted that recommending a range of tests would benefit hospitals by enabling them to operate within existing equipment contracts or investments in a particular platform. It concluded that recommending a range of high-sensitivity troponin tests gives greater flexibility to NHS trusts and enables them to work with any local restrictions or equipment contracts.
## Recommending a range of early rule-out strategies means hospitals can use one that works for their emergency department
The original NICE diagnostics guidance on troponin tests for myocardial infarction recommended strategies that test at 0 hours and 3 hours, report absolute values and use an upper reference limit at the 99th percentile. The committee noted that much more evidence is now available on different early rule-out strategies. The committee considered the different strategies included in the model:
single-sample strategies using a threshold at or near to the limit of detection
multiple sample strategies in which all patients would be tested at baseline and again at 1 to 3 hours after the initial test
multiple sample strategies in which people only had a second test (1 hour to 3 hours after the initial test) if the first test result could not be used to rule out acute myocardial infarction.The multiple sample strategies incorporated different thresholds, including those at or close to the limit of detection, the general (mixed) population 99th percentile, and sex-specific 99th percentiles. The committee recalled that all single-sample strategies and multiple sample strategies included in the model were highly sensitive, that is, they had a low false negative rate (see sections 4.4 and 4.5). It considered that strategies in which people could be safely discharged after the first test could be beneficial because fewer people would have to remain in the emergency department for a second test. The committee noted further that all strategies were cost effective compared with a standard troponin test strategy (see section 4.13). The committee concluded that recommending a range of early rule-out strategies would enable hospitals to use strategies that worked with the set up of their emergency department.
## Further diagnostic accuracy evidence is needed before the TriageTrue test can be recommended for routine clinical use
The TriageTrue point-of-care test, when used in the European Society of Cardiology 0/1‑hour pathway, was cost effective compared with a standard troponin test strategy, with an ICER of less than £5,000 per QALY gained. The committee considered that the potential benefits associated with the rapid turnaround times of point-of-care tests (see section 4.9) may not have been fully captured in the economic model. But the committee was concerned about the evidence used to provide the diagnostic accuracy inputs in the model, so concluded that further research was needed on the TriageTrue test before it could be recommended for routine clinical use.
# Research considerations
## Further research to understand the 99th percentile in population subgroups would be useful
Some evidence supported using sex-specific 99th percentile thresholds in clinical practice in men and women but overall their value in early rule-out is unclear (see section 4.7). The clinical experts said that there are much less data on the 99th percentile in other subgroups, such as older or younger people, people with or without renal disease and black, Asian and minority ethnic groups. The committee considered that it would be helpful to have a better understanding of differences in the 99th percentile between these subgroups.# Recommendations for further research
Further research is recommended on the diagnostic performance of the TriageTrue high-sensitivity troponin test using samples at point of care.
Further research is recommended on how using sex-specific 99th percentile thresholds affects treatment decisions and clinical outcomes for men and women.
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{'Recommendations': "The following high-sensitivity troponin tests are recommended as options for the early rule out of non-ST-segment elevation myocardial infarction (NSTEMI) in people presenting to an emergency department with chest pain and suspected acute coronary syndrome:\n\nAccess High-Sensitivity Troponin\xa0I Assay\n\nADVIA Centaur High-Sensitivity Cardiac Troponin‑I Assay\n\nAlinity High Sensitive Troponin‑I assay\n\nARCHITECT STAT High Sensitive Troponin‑I assay\n\nAtellica IM High-Sensitivity Cardiac Troponin\xa0I Assay\n\nDimension Vista High-Sensitivity Cardiac Troponin\xa0I Assay\n\nDimension EXL High-Sensitivity Cardiac Troponin\xa0I Assay\n\nElecsys Troponin T-high sensitive assay\n\nElecsys Troponin T-high sensitive STAT assay\n\nVIDAS High sensitive Troponin\xa0I assay\n\nVITROS High Sensitivity Troponin\xa0I Assay.\n\nThe tests are recommended for use with different early rule-out test strategies alongside clinical judgement, including:\n\nA single sample on presentation using a threshold at or near the limit of detection, which will vary depending on the assay being used. If this sample is positive it should not be used to rule in NSTEMI.\n\nMultiple sample strategies, which typically include a sample at initial assessment followed by a second sample taken at 30\xa0minutes to 3\xa0hours (if clinically appropriate) and use of 99th percentile thresholds or thresholds at or near the limit of detection of the assay.Healthcare professionals should consider the likely time since the onset of symptoms when interpreting test results.\n\nWhen NSTEMI is not ruled out using early rule-out test strategies, use NICE's guideline on recent-onset chest pain of suspected cardiac origin to help diagnose myocardial infarction, and consider using sex-specific thresholds at the 99th percentile (see section 4.7 and section 5.2).\n\nFurther research is recommended on the diagnostic performance of the TriageTrue High Sensitivity Troponin\xa0I test when using samples at point of care (see section 5.1).\n\nWhy the committee made these recommendations\n\nWhen someone comes to a hospital emergency department with chest pain, tests are needed to work out if they're having a myocardial infarction (heart attack), and if so, what type it is and what treatment they need. Standard troponin tests take 10 to 12\xa0hours, so people need to be admitted to hospital while they wait for the results.\n\nHigh-sensitivity troponin tests can help to quickly rule out a type of heart attack called an NSTEMI. Doing these tests can mean people with normal troponin levels do not need to be admitted to hospital, and those with a confirmed NSTEMI can get earlier treatment.\n\nEvidence shows that, of the high-sensitivity troponin tests, 9 are similarly effective in terms of diagnostic performance. Of these, 8 are also similarly cost effective compared with standard troponin tests in different early rule-out test strategies and so are recommended for use in the NHS.\n\nThere is only 1 diagnostic accuracy study for Elecsys STAT, and no diagnostic accuracy evidence for Alinity and Dimension EXL. But they use the same methods, principles and reagents as alternative versions of the tests that do have diagnostic accuracy evidence and were included in the economic model. The main difference is that they are run on different analysers. They are therefore also recommended.\n\nAlthough the TriageTrue test has the potential to be cost effective, its diagnostic accuracy when used on whole blood is uncertain.", 'The diagnostic tests': "# Clinical need and practice\n\nChest pain and suspected myocardial infarction were the cause of about 5% of all emergency hospital admissions in 2017 to 2018. However, myocardial infarction will have occurred in only about 20% of those admissions. Tests that can quickly tell whether a person is having a myocardial infarction or not could mean that unnecessary hospital admissions are avoided, reducing waiting time and anxiety for many people.\n\nCardiac troponins I and T are biological markers of cardiac muscle death (cardiomyocyte necrosis). They are released into the circulation, so rise when the cardiac muscle is damaged. They are used as markers of acute myocardial infarction along with clinical history taking and electrocardiography (ECG) monitoring. ST-segment elevation myocardial infarction (STEMI) can usually be diagnosed by ECG alone. So, the main diagnostic challenge is detecting or ruling out non-ST-segment elevation myocardial infarction (NSTEMI).\n\nThe optimum sensitivity of older (non-high-sensitivity) troponin tests (referred to here as standard troponin tests) for acute myocardial infarction is 10 to 12\xa0hours after the onset of symptoms. For many people, this means hospital admission and observation while serial troponin testing is done. To overcome this, high-sensitivity troponin tests have been developed. These can detect lower levels of troponin in the blood earlier than standard troponin tests, so enable early rule out of NSTEMI after the onset of acute chest pain. This could lead to fewer people being admitted to hospital, earlier discharge for people with normal troponin levels and earlier intervention for those with a confirmed NSTEMI.\n\nNICE's 2014 guidance on high-sensitivity troponin tests recommended the Elecsys troponin\xa0T-high sensitive test and ARCHITECT STAT High Sensitive Troponin‑I test as options for the early rule out of NSTEMI in people presenting to an emergency department with chest pain and suspected acute coronary syndrome. Since that guidance was published, NICE's guideline on recent-onset chest pain of suspected cardiac origin has been updated to include high-sensitivity troponin tests. But stakeholder feedback suggests that high-sensitivity troponin testing used with early rule-out strategies has not been routinely adopted in the NHS and, if it has, there is wide variation in how it is being done. This updated assessment is being done to ensure that guidance is based on evidence including new high-sensitivity tests developed and marketed since publication of the NICE guidance. It is also to provide more detailed recommendations on how to use high-sensitivity tests (for example, timing of testing and using sequential testing strategies) when possible.\n\n# The interventions\n\nAll tests included in the assessment are CE marked and available to the NHS.\n\n## Access High-Sensitivity Troponin\xa0I Assay (Beckman Coulter)\n\nThe Access test is designed to be used in a laboratory with the Beckman Coulter Access 2 and DxI/DxC analysers. The company says that the test's performance is the same regardless of analyser. It is a paramagnetic particle chemiluminescent immunoassay for in-vitro quantitative determination of troponin\xa0I in serum and plasma samples. Results are available in 17\xa0minutes. Recommended 99th percentile cut-offs are:\n\nng/litre for the whole population\n\nng/litre for women\n\nng/litre for men.Each 99th percentile has a coefficient of variation (CV) of less than 10%. The test can detect troponin\xa0I in more than 97% of the reference population.\n\n## ARCHITECT STAT High Sensitive Troponin‑I assay (Abbott Diagnostics)\n\nThe ARCHITECT test is designed to be used in a laboratory with the Abbott ARCHITECT i2000SR and i1000SR analysers. The test is a chemiluminescent microparticle immunoassay for in-vitro quantitative determination of troponin\xa0I in serum and plasma samples. Results are available in 18\xa0minutes. The ARCHITECT test can detect troponin\xa0I in 96% of the reference population. Recommended 99th percentile cut-offs are:\n\nng/litre for the whole population with a CV of 4%\n\nng/litre for women (CV 5.3%)\n\nng/litre for men (CV 3.5%).\n\n## Alinity High Sensitive Troponin‑I assay (Abbott Diagnostics)\n\nThe Alinity test is designed to be used in a laboratory with the Alinity\xa0i analyser. It is a chemiluminescent microparticle immunoassay for the quantitative determination of troponin\xa0I in plasma and serum samples. Results are available in 18\xa0minutes. Recommended 99th percentile cut-offs are:\n\nng/litre for the whole population with a CV of 4.6%\n\nng/litre for women (CV 5.0%)\n\nng/litre for men (CV 4.5%).\n\n## ADVIA Centaur High-Sensitivity Cardiac Troponin\xa0I Assay (Siemens Healthineers)\n\nThe ADVIA Centaur test is designed to be used in a laboratory with the Siemens ADVIA Centaur XP and ADVIA Centaur XPT analysers. It is a magnetic latex particle chemiluminescent immunoassay for the in-vitro quantitative determination of troponin\xa0I in serum and plasma samples. Test results are available in 18\xa0minutes. Recommended 99th percentile cut-offs are:\n\nng/litre in lithium heparin and 46.47\xa0ng/litre in serum for the whole population\n\nng/litre in lithium heparin and 39.59\xa0ng/litre in serum for women\n\nng/litre in lithium heparin and 58.05\xa0ng/litre in serum for men.Each 99th percentile has a CV of less than 10%. The test can detect troponin\xa0I in more than 50% of the reference population.\n\n## Atellica IM High-Sensitivity Cardiac Troponin\xa0I Assay (Siemens Healthineers)\n\nThe Atellica test is designed to be used in a laboratory with the Siemens Atellica IM analyser. It is a magnetic latex particle chemiluminescent immunoassay for the in-vitro quantitative determination of troponin\xa0I in serum and plasma samples. Test results are available in 10\xa0minutes. Recommended 99th percentile cut-offs are:\n\nng/litre in lithium heparin and 45.43\xa0ng/litre in serum for the whole population\n\nng/litre in lithium heparin and 38.64\xa0ng/litre in serum for women\n\nng/litre in lithium heparin and 53.53\xa0ng/litre in serum for men.Each 99th percentile has a CV of less than 10%. The test can detect troponin\xa0I in more than 50% of the reference population.\n\n## Dimension EXL High-Sensitivity Cardiac Troponin\xa0I Assay (Siemens Healthineers)\n\nThe Dimension EXL test is designed to be used in a laboratory with the Siemens Dimension EXL analyser. It is a magnetic latex particle chemiluminescent immunoassay for the in-vitro quantitative determination of troponin\xa0I in serum and plasma samples. Test results are available in 18\xa0minutes. Recommended 99th percentile cut-offs are:\n\nng/litre in lithium heparin and 58.2\xa0ng/litre in serum for the whole population\n\nng/litre in lithium heparin and 47.8\xa0ng/litre in serum for women\n\nng/litre in lithium heparin and 71.8\xa0ng/litre in serum for men.Each 99th percentile has a CV of less than 10%. The test can detect troponin\xa0I in more than 50% of the reference population.\n\n## Dimension Vista High-Sensitivity Cardiac Troponin\xa0I Assay (Siemens Healthineers)\n\nThe Dimension Vista test is designed to be used in a laboratory with the Siemens Dimension Vista analysers. It is a magnetic latex particle chemiluminescent immunoassay, and is intended for the in-vitro quantitative determination of troponin\xa0I in serum and plasma samples. Test results are available in 10\xa0minutes. Recommended 99th percentile cut-offs are:\n\nng/litre in lithium heparin and 57.9\xa0ng/litre in serum for the whole population\n\nng/litre in lithium heparin and 51.1\xa0ng/litre in serum for women\n\nng/litre in lithium heparin and 74.9\xa0ng/litre in serum for men. Each 99th percentile has a CV of less than 10%. The test can detect troponin\xa0I in more than 50% of the reference population.\n\n## Elecsys troponin T-high sensitive assay (Roche)\n\nThe Elecsys and Elecsys STAT tests are designed to be used in a laboratory on the Roche cobas e411, e601, and e602 analysers. The company says that performance is the same when used on these analysers. The test can also be run on the cobas e801 analyser, which is designed for very high throughput as both a standard and STAT test. The Elecsys test is a sandwich electrochemiluminescence immunoassay for in-vitro quantitative determination of troponin T in serum and plasma samples. Results are available in 18\xa0minutes with the standard test and in 9\xa0minutes with the STAT test. Both tests can detect troponin T in 57% of the reference population. Recommended 99th percentile cut-offs are:\n\nng/litre for the whole population with a CV of less than 10%\n\nng/litre for women\n\nng/litre for men.\n\n## TriageTrue High Sensitivity Troponin\xa0I Test (Quidel Cardiovascular)\n\nThe TriageTrue test can be used at point of care or in a laboratory with the Triage MeterPro analyser. It is a fluorescence immunoassay for the in‑vitro quantitative determination of troponin\xa0I in EDTA anticoagulated whole blood and plasma samples. Test results are available in less than 20\xa0minutes. Recommended 99th percentile cut-offs are:\n\nng/litre for the whole population with a CV of less than 10%\n\nng/litre for women\n\nng/litre for men.The test can detect troponin\xa0I in more than 50% of the reference population.\n\n## VITROS High Sensitivity Troponin\xa0I Assay (Ortho Clinical Diagnostics)\n\nThe VITROS test is designed to be used in a laboratory on the following analysers: VITROS ECi/ECiQ/3600 Immunodiagnostic Systems and the VITROS 5600/XT 7600 Integrated System. It is an immunometric immunoassay for the in-vitro quantitative determination of troponin\xa0I in serum and plasma samples. Test results are available in 15\xa0minutes. Recommended 99th percentile cut-offs are:\n\nng/litre in lithium heparin and serum for the whole population\n\nng/litre in lithium heparin and serum for women\n\nng/litre in lithium heparin and 12\xa0ng/litre in serum for men.The test can detect troponin\xa0I in more than 50% of the reference population.\n\n## VIDAS High sensitive Troponin\xa0I assay (bioMérieux)\n\nThe VIDAS test is designed to be used in a laboratory on the following analysers: VIDAS, MINI VIDAS and VIDAS\xa03. It is for the in-vitro quantitative determination of troponin\xa0I in serum and plasma (lithium heparin) samples. Test results are available in 20\xa0minutes. Recommended 99th percentile cut-offs are:\n\nng/litre for the whole population\n\nng/litre for women\n\nng/litre for men.\n\n# The comparator\n\nThe comparator was standard troponin testing over 10 to 12\xa0hours from symptom onset used with early rule-out strategies.", 'Evidence': "The diagnostics advisory committee considered evidence on high-sensitivity troponin tests for the early rule out of non-ST-segment elevation myocardial infarction (NSTEMI) from several sources. Full details of all the evidence are in the committee papers.\n\n# Clinical effectiveness\n\nThe external assessment group (EAG) did a systematic review to identify evidence on the clinical effectiveness of high-sensitivity troponin tests for the early rule out of acute myocardial infarction, including NSTEMI, in people who come to hospital with chest pain. It also considered studies used to develop the original diagnostics guidance on early rule out of myocardial infarction using high-sensitivity troponin tests.\n\nThe EAG identified 37 studies that met the inclusion criteria. Test accuracy data were reported for the following high-sensitivity troponin tests: Elecsys (30 studies), ARCHITECT (9 studies), Atellica (2 studies), ADVIA Centaur (3 studies), Access (2 studies). One study each reported accuracy data for Dimension Vista, VITROS, VIDAS and TriageTrue.\n\nSeven studies reported diagnostic accuracy data for more than 1 test. No studies were identified that matched the inclusion criteria for the review for Alinity or Dimension EXL tests. Two randomised controlled trials were included in the review: High-STEACS and HiSTORIC.\n\nOf the 37 included studies, 22 were done in Europe (7 in the UK), 5 in Australia and New Zealand, 6 in the US, 3 in East Asia, and 1 was a worldwide study.\n\nThe randomised controlled trials were quality assessed using the revised Cochrane risk of bias tool for cluster randomised trials. Studies that evaluated a single high-sensitivity test were assessed using the QUADAS‑2 tool. Studies that provided data for 2 or more high-sensitivity tests were assessed using the QUADAS‑2C tool.\n\n## Randomised controlled trials\n\nBoth trials used the ARCHITECT test.\n\nThe High-STEACS trial evaluated the implementation of an early rule-out strategy in 10 secondary and tertiary care hospitals in Scotland. It compared the rates at which conditions were reclassified after high-sensitivity troponin tests with the rates of reclassification after standard troponin testing. It also compared the subsequent incidence of myocardial infarction and cardiovascular death.\n\nThe HiSTORIC trial also evaluated the implementation of an early rule-out strategy in 7 acute hospitals in Scotland. The primary outcomes were length of stay and myocardial infarction or cardiac death after discharge at 30\xa0days. The results are academic in confidence.\n\nDuring the validation phase of High-STEACS (6 to 12\xa0months), results of the high-sensitivity troponin\xa0I test were concealed from the attending clinician, and a standard cardiac troponin test was used to guide care. A high-sensitivity test was introduced after 6\xa0months (early implementation) or 12\xa0months (late implementation).\n\nIn patients whose condition was reclassified in the High-STEACS trial, there were no differences between high-sensitivity and standard troponin tests in the primary or any of the secondary efficacy and safety outcome measures (myocardial infarction, unplanned coronary revascularisation, all-cause death, death from cardiovascular causes, hospital admission for heart failure and ischaemic stroke). The median length of stay for patients without myocardial injury was 7\xa0hours (interquartile range 3 to 24) in the validation phase and 4\xa0hours (interquartile range 3 to 20) in the implementation phase. The authors of High-STEACS concluded that implementing an early rule-out strategy was not associated with any increase in myocardial infarction or cardiovascular death within 1\xa0year of initial presentation.\n\n## Diagnostic test accuracy\n\nSummary estimates of sensitivity and specificity from testing a single sample, using a 99th percentile diagnostic threshold for the general population, were 90% (95% confidence interval [CI] 85 to 94) and 78% (95% CI 72 to 83) respectively, based on data from 22 studies. The summary estimates of sensitivity and specificity, using a single sample and a limit of detection threshold, were 99% (95% CI 97 to 99) and 36% (95% CI 28 to 45) respectively, based on data from 9\xa0studies. The 8 studies that assessed the diagnostic performance of a limit of blank threshold in a single sample gave a similarly high summary estimate of sensitivity of 100% (95% CI 98 to 100), but a reduced specificity of 19% (95% CI 11 to 31). All estimates were similar when the analyses were restricted to studies that excluded people with ST-segment elevation myocardial infarction (STEMI).\n\nUsing multiple sample strategies appears to offer better specificity without substantial loss of sensitivity than using a single sample on presentation and a very low limit of detection or limit of blank threshold. The European Society of Cardiology's (ESC) 0/1‑hour rule-out pathway combines an initial sample and a very low limit of detection threshold (5\xa0ng/litre) in patients reporting a minimum symptom duration of 3\xa0hours. The strategy tests at presentation and 1\xa0hour later for patients whose acute myocardial infarction is not ruled out by the initial test, that is, it uses an 'OR' combination. The threshold for repeat testing is an initial troponin concentration of less than 12\xa0ng/litre with an absolute change in troponin concentration, from 0 to 1\xa0hour, of less than 3\xa0ng/litre. For NSTEMI, the sensitivity and specificity estimates for this strategy were 99% (95% CI 98 to 100) and 68% (95% CI 67 to 70), respectively. Estimates of diagnostic performance were similar for strategies using an 'AND' combination of initial high-sensitivity troponin level and absolute change in troponin level.\n\nSummary estimates of sensitivity and specificity for a single sample using a diagnostic threshold of the 99th percentile for the general population were 75% (95% CI 65 to 82) and 94% (95% CI 94 to 96) respectively, based on data from 5 studies. These estimates were similar if the analysis was restricted to studies that excluded people with STEMI. The summary estimates of sensitivity and specificity, using a limit of detection threshold (2\xa0ng/litre) in a single sample taken on presentation, were 100% (95% CI 99 to 100) and 21% (95% CI 16 to 26) respectively, based on data from 4 studies in NSTEMI.\n\nFor multiple sample strategies, the High-STEACS pathway was used as follows:\n\nin the whole population, symptoms for 2\xa0hours or more and a troponin concentration of less than 5\xa0ng/litre at 0\xa0hours, or\n\nin women, 16\xa0ng/litre or lower when measured 3\xa0hours from presentation and an absolute change of less than 3\xa0ng/litre at 0 to 3\xa0hours, or\n\nin men, 34\xa0ng/litre or lower when measured 3\xa0hours from presentation and an absolute change of less than 3\xa0ng/litre at 0 to 3\xa0hours.\n\nUsing the High-STEACS pathway in this way appeared to offer increased specificity without substantial loss of sensitivity compared with a single sample on presentation and a risk stratification threshold of less than 5\xa0ng/litre. The sensitivity and specificity estimates for this strategy were 99% (95% CI 97 to 100) and 76% (95% CI 73 to 78) respectively, for NSTEMI. The ESC 0/1‑hour rule-out pathway reported a lower specificity than the High-STEACS pathway. It used an initial sample and a limit of detection threshold of less than 2\xa0ng/litre, or repeat testing combining an initial troponin concentration of less than 5\xa0ng/litre and an absolute change in troponin concentration, from 0 to 1\xa0hour, of less than 2\xa0ng/litre. Summary sensitivity and specificity estimates were 99% (95%\xa0CI 98 to 100) and 57% (95% CI 56 to 59) respectively for NSTEMI.\n\nThe 2 studies evaluating the Access test each assessed a different multiple sample strategy. One followed the ESC 0/1‑hour rule-out pathway (initial sample and a limit of detection threshold of less than 4\xa0ng/litre, or repeat testing combining an initial concentration of less than 5\xa0ng/litre and an absolute change in troponin concentration, from 0 to 1\xa0hour, of less than 4\xa0ng/litre), giving sensitivity and specificity estimates of 99% (95% CI 94 to 100) and 70% (95% CI 66 to 74) respectively for NSTEMI. The second study assessed a similar strategy, but with repeat testing at 2\xa0hours. The sensitivity estimates were similar for the 2 strategies, but the specificity of the 2-hour repeat testing strategy was higher than that of the 1‑hour strategy.\n\nThe study evaluating the VIDAS test assessed a multiple sample strategy, with samples taken on presentation and at 2\xa0hours using a threshold of less than 2\xa0ng/litre at presentation, or less than 6\xa0ng/litre at presentation and at 2\xa0hours. The reported sensitivity and specificity estimates were 98% (95% CI 92 to 100) and 64% (95% CI 59 to 68) respectively for NSTEMI.\n\nThe study evaluating the VITROS test assessed the ESC 0/1‑hour rule-out pathway. This combined an initial sample and a limit of detection threshold of less than 1\xa0ng/litre, or repeat testing combining an initial troponin concentration of less than 2\xa0ng/litre and an absolute change in troponin concentration, from 0 to 1\xa0hour, of less than 1\xa0ng/litre. The reported sensitivity and specificity estimates were 100% (95% CI 95 to 100) and 60% (95% CI 55 to 64) respectively for NSTEMI.\n\nThe study evaluating the TriageTrue test assessed the ESC 0/1‑hour rule-out pathway. This combined an initial sample and a limit of detection threshold of less than 4\xa0ng/litre, or repeat testing combining an initial troponin concentration of less than 5\xa0ng/litre and an absolute change in troponin concentration, from 0 to 1\xa0hour, of less than 3\xa0ng/litre. The reported sensitivity of this strategy was 100% (95% CI 97 to 100) and the specificity was 66% (95% CI 62 to 70) for NSTEMI.\n\nThree studies evaluated the ADVIA Centaur test. Using a rule-out threshold of 2\xa0ng/litre in a single sample taken on presentation, the sensitivity and specificity estimates were 100% (95% CI 99 to 100) and 23% (95% CI 21 to 25) respectively for NSTEMI. Two multiple sample strategies were evaluated. One followed the ESC 0/1‑hour rule-out pathway. This combined an initial sample and a limit of detection threshold of less than 3\xa0ng/litre, or repeat testing combining an initial concentration of less than 6\xa0ng/litre and an absolute change in troponin concentration, from 0 to 1\xa0hour, of less than 3\xa0ng/litre. The sensitivity and specificity estimates for this strategy were 99% (95% CI 95 to 100) and 56% (95% CI 52 to 60) respectively for NSTEMI. The second study assessed a similar strategy, but with higher thresholds and repeat testing at 2\xa0hours. The sensitivity and specificity estimates for this strategy were 100% (95% CI 95 to 100) and 67% (95% CI 61 to 72) respectively for NSTEMI.\n\nUsing a rule-out threshold of 2\xa0ng/litre, in a single sample taken on presentation, the sensitivity and specificity estimates for the Atellica test were 100% (95% CI 98 to 100) and 26% (95% CI 24 to 28) respectively for NSTEMI. Sensitivity and specificity estimates for the High-STEACS pathway (symptoms for at least 2\xa0hours and an initial troponin concentration of less than 5\xa0ng/litre, or a troponin concentration of 34\xa0ng/litre or less in women, or 53\xa0ng/litre or less in men at 3\xa0hours and an absolute change in concentration from 0 to 3\xa0hours, of less than 3\xa0ng/litre) were 98% (95% CI 95 to 100) and 74% (95% CI 72 to 76) respectively for NSTEMI.\n\nThe study of the Dimension Vista test assessed a strategy using measurements done at baseline using a troponin concentration threshold of less than 5\xa0ng/litre and an absolute change of less than 2\xa0ng/litre within 1\xa0hour. The sensitivity of the strategy was 100% (95% CI 97 to 100) and specificity was 66% (95% CI 62 to 69) for NSTEMI.\n\n## Diagnostic accuracy in relevant subgroups\n\nThe EAG identified some data on the subgroups described in the scope for this guidance. In a study using the Elecsys test and a 99th percentile threshold on a single sample at presentation, a higher sensitivity for any acute myocardial infarction was estimated in people over 70 than for people aged 70 or under (97% [95% CI 92 to 99] and 88% [95% CI\xa078 to 94] respectively). The estimate of sensitivity for people over 70 was also higher than the corresponding summary estimates from all 22\xa0studies that used the 99th percentile diagnostic threshold. There was a similar pattern for people with a high pre-test probability (determined by clinical judgement of cardiovascular risk factors, type of chest pain, physical findings and electrocardiography [ECG] abnormalities) compared with those with a low to moderate pre-test probability. The same was found for people without pre-existing cardiovascular disease compared with those with pre-existing cardiovascular disease.\n\nOnly the High-STEACS trial reported using sex-specific thresholds. Data from this study appeared to show that testing using a single sample taken on presentation is markedly more sensitive if sex-specific 99th percentile cut-offs are used, compared with a standard troponin test with a uniform threshold. This is particularly true in women, for whom the 99th percentile is lower. This study also used sex-specific thresholds as part of a multiple test strategy: the High-STEACS pathway. It is unclear whether using sex-specific thresholds in this strategy offers any advantage over using a single general population threshold. This is because no equivalent strategy, using a single universal threshold, was evaluated. Other studies reported data on men and women using a single general population threshold in each group. Results from a study on the Elecsys test showed very similar accuracy estimates for the subgroups, although a study on the Dimension Vista reported a lower sensitivity and specificity in men than in women.\n\nTwo studies on the Elecsys test and 2 on the ARCHITECT test reported data on how diagnostic performance varies with renal function. All studies show a decrease in specificity as renal function decreases.\n\n## Comparative diagnostic accuracy for more than 1 test\n\nSeven studies reported accuracy data for more than 1 test.\n\nThe APACE study provided data on the ESC 0/1‑hour pathway using the Elecsys, ARCHITECT and ADVIA Centaur tests. It also provided data on the ESC 0/1‑hour pathway using the Access, VITROS and TriageTrue tests, but these results came from different patient subgroups and were reported in different publications. Data showed that the ESC 0/1‑hour pathway performed consistently across all 6 high-sensitivity troponin tests evaluated with sensitivity estimates of 98% or higher.\n\nThree other studies, ADAPT, ROMI-3, and TRUST, compared the Elecsys and ARCHITECT tests. Although the sensitivity estimates for the Elecsys test, using the 99th percentile and a single sample at presentation, were higher than those for the ARCHITECT test, both had sensitivity estimates of less than 97%. When the limit of detection threshold was used with a single sample at presentation, sensitivity estimates were comparable for the Elecsys test and the ARCHITECT test, and were always 99% or higher.\n\nThe High-STEACS trial provided data on the rule-out performance of 3 strategies (ESC 0/1‑hour, ESC 0/3-hour and High-STEACS 0/3-hour) using the ARCHITECT and Atellica tests. It is unclear whether both tests were evaluated in the same subgroup of people in the study. Data showed that the sensitivity of the ESC 0/1‑hour pathway was lower using the Atellica test (94% [95% CI 79 to 99]) than using the ARCHITECT test (100% [95% CI 91 to 100]). The sensitivity and specificity estimates for the High-STEACS 0/3-hour rule-out pathway were similar using either test (both had sensitivity estimates of 98% or more). The ESC 0/3-hour rule-out pathway in this study consisted of:\n\nsymptoms for 6\xa0hours or more and a troponin concentration of 16\xa0ng/litre or less in women or 34\xa0ng/litre or less in men at 0\xa0hours, or\n\na troponin concentration of 16\xa0ng/litre or less in women or 34\xa0ng/litre or less in men at 3\xa0hours, or\n\nan absolute change of less than 50% of the 99th percentile at 0\xa0to\xa03\xa0hours.The sensitivity and specificity estimates for the ESC 0/3-hour rule-out pathway were both less than 97% using either test.\n\nThe HIGH-US study compared 2 Siemens tests (Atellica and ADVIA Centaur), using 3 low thresholds and a single sample at presentation. The results showed sensitivity estimates were 99% or more for both tests for all thresholds.\n\nThe BEST study compared 2 single sample at presentation strategies using the ADVIA Centaur test (threshold of 3\xa0ng/litre) and Elecsys test (limit of detection [5\xa0ng/litre] threshold). Data were reported in separate publications with different numbers of people. The sensitivity estimates were 99% for both tests, but the Elecsys test had a higher specificity (47% [95% CI 43 to 51]) than the ADVIA Centaur test (33% [95% CI 30 to 36]).\n\n# Cost effectiveness\n\nThe EAG did a search to identify evidence on the cost effectiveness of high-sensitivity troponin tests for the early rule out of acute myocardial infarction, including NSTEMI. The EAG also developed a de novo economic model to assess the cost effectiveness of the different testing strategies.\n\n## Review of economic evidence\n\nStudies were eligible if they reported a full economic analysis of the cost effectiveness of either high-sensitivity troponin testing or standard troponin testing. They also had to include survival or quality-adjusted life years (QALYs) as an outcome measure.\n\nFive studies identified in the original assessment report and 1 new study were included in the systematic review. Results varied in the 5 studies from the original report, and the EAG concluded that there was uncertainty about the cost effectiveness of diagnostic strategies using high-sensitivity troponin testing. The EAG noted that the key drivers of cost effectiveness in the included studies were the accuracy of high-sensitivity troponin tests, and the efficiency of decision making once test results were available.\n\nThe most recent study (Ambavane et al. 2017) reported that a 1‑hour strategy using high-sensitivity troponin testing had higher sensitivity (87% compared with 69%) but lower specificity (96% compared with 97%) than standard care. The reference standard used to calculate diagnostic accuracy was determination of final diagnosis based on a comprehensive review of medical records. Total costs were less for the 1‑hour strategy compared with standard care (£2,480 compared with £4,561). This was mainly because of a shorter length of stay in the emergency department.\n\n## Economic analysis\n\nThe EAG developed a de novo economic model to explore the cost effectiveness of high-sensitivity troponin tests for the early rule out of acute myocardial infarction, including NSTEMI, in people with acute chest pain (used up to 4\xa0hours from the onset of chest pain or at presentation). The model compared high-sensitivity tests with standard troponin T or I testing, or both, on admission and at 10 to 12\xa0hours after the onset of symptoms. The population in the model was people presenting to the emergency department with suspected non-ST-segment elevation acute coronary syndrome, who have no major comorbidities needing hospitalisation (for example, heart failure or arrhythmia) and in whom STEMI has been ruled out.\n\nOnly high-sensitivity troponin tests with a sensitivity of 97% or above were used in the economic model, based on expert opinion of the minimum sensitivity acceptable in clinical practice. The strategies evaluated are described in table 1.\n\nStrategy number\n\nTest\n\nStrategy\n\n\n\nElecsys\n\nth percentile threshold (under 14\xa0ng/litre at 0\xa0hours AND 3\xa0hours)\n\n\n\nElecsys\n\nLimit of detection under 5\xa0ng/litre at 0\xa0hours\n\n\n\nElecsys\n\nESC 0/1‑hour pathway: symptoms over 3\xa0hours AND under 5\xa0ng/litre at 0\xa0hours OR under 12\xa0ng/litre at 0\xa0hours AND an absolute change of less than 3\xa0ng/litre at 0 to 1\xa0hour\n\n\n\nElecsys\n\nUnder 8\xa0ng/litre at 0\xa0hours AND an absolute change of less than 3\xa0ng/litre at 0 to 0.5\xa0hours\n\n\n\nElecsys\n\nUnder 12\xa0ng/litre at 0\xa0hours AND an absolute change of less than 3\xa0ng/litre at 0 to 1\xa0hour\n\n\n\nDimension Vista\n\nUnder 5\xa0ng/litre at 0\xa0hours AND an absolute change of less than 2\xa0ng/litre at 0 to 1\xa0hours\n\n\n\nARCHITECT\n\nUnder 12\xa0ng/litre at 0\xa0hours AND an absolute change of less than 3\xa0ng/litre at 0 to 1\xa0hour\n\n\n\nARCHITECT\n\nESC 0/1‑hour pathway: symptoms over 3\xa0hours AND under 2\xa0ng/litre at 0\xa0hoursOR under 5\xa0ng/litre at 0\xa0hours AND an absolute change of less than 2\xa0ng/litre at 0 to 1\xa0hours\n\n\n\nARCHITECT\n\nHigh-STEACS pathway: symptoms for 2\xa0hours or more AND under 5\xa0ng/litre at 0\xa0hoursOR 16\xa0ng/litre or more (women) and 34\xa0ng/litre or more (men) at 3\xa0hours AND an absolute change of less than 3\xa0ng/litre\n\n\n\nARCHITECT\n\nUnder 4\xa0ng/litre at 0\xa0hours\n\n\n\nADVIA Centaur\n\nUnder 2\xa0ng/litre at 0\xa0hours\n\n\n\nADVIA Centaur\n\nUnder 3\xa0ng/litre at 0\xa0hours OR under 8\xa0ng/litre at 0\xa0hours AND an absolute change of less than 7\xa0ng/litre at 0 to 2\xa0hours\n\n\n\nADVIA Centaur\n\nESC 0/1‑hour pathway: symptoms over 3\xa0hours AND under 3\xa0ng/litre at 0\xa0hours OR under 6\xa0ng/litre at 0\xa0hours AND an absolute change of less than 3\xa0ng/litre at 0 to 1\xa0hour\n\n\n\nADVIA Centaur\n\nUnder 5\xa0ng/litre at 0\xa0hours\n\n\n\nAtellica\n\nUnder 2\xa0ng/litre at 0\xa0hours\n\n\n\nAtellica\n\nHigh-STEACS pathway: symptoms for 2\xa0hours or more AND under 5\xa0ng/litre at 0\xa0hours OR 34\xa0ng/litre or less (women) and 53\xa0ng/litre or less (men) at 3\xa0hours AND an absolute change of less than 3\xa0ng/litre\n\n\n\nAccess\n\nESC 0/1‑hour pathway: symptoms over 3\xa0hours AND under 4\xa0ng/litre at 0\xa0hoursOR under 5\xa0ng/litre and an absolute change of less than 4\xa0ng/litre at 0 to 1\xa0hour\n\n\n\nAccess\n\nSymptoms over 3\xa0hours AND under 4\xa0ng/litre at 0\xa0hoursOR under 5\xa0ng/litre and an absolute change of less than 5\xa0ng/litre at 0 to 2\xa0hours\n\n\n\nVITROS\n\nESC 0/1‑hour pathway: symptoms over 3\xa0hours AND under 1\xa0ng/litre at 0\xa0hoursOR under 2\xa0ng/litre at 0\xa0hours AND an absolute change of under 1\xa0ng/litre at 0 to 1\xa0hour\n\n\n\nVIDAS\n\nUnder 2\xa0ng/litre at 0\xa0hours\n\nOR under 6\xa0ng/litre at 0 AND 2\xa0hours\n\n\n\nTriageTrue\n\nESC 0/1‑hour pathway: symptoms over 3\xa0hours AND under 4\xa0ng/litre at 0\xa0hoursOR under 5\xa0ng/litre at 0\xa0hours AND an absolute change of less than 3\xa0ng/litre at 0 to 1\xa0hour\n\n## Model structure\n\nThe model structure from the original diagnostics assessment report was used. This model structure was adapted from the health technology assessment report from Goodacre et al. (2013). It consists of a decision tree and a state-transition model. The decision tree was used to model the 30‑day outcomes after presentation, based on test results and the accompanying treatment decision. The following health states were included:\n\nno acute coronary syndrome and no unstable angina (no ACS, no UA)\n\nunstable angina (UA)\n\npost-acute myocardial infarction, treated and untreated (post-AMI)\n\npost-acute myocardial infarction with reinfarction (post-AMI with reinfarction)\n\ndeath.\n\nPeople presenting at the emergency department with suspected non-ST elevation acute coronary syndrome were tested and results were classified as either true positive, false positive, false negative or true negative. These people entered health states as listed (people could also die after treatment or be discharged):\n\nPeople with true positive test results were correctly treated for acute myocardial infarction and were allocated to 'non-fatal AMI (treated)'.\n\nPeople with false positive test results were considered to have no acute myocardial infarction, but did not meet early rule-out criteria. They were subdivided between 'no ACS, no UA' and 'UA'. It was assumed that people with false positive test results would remain in the hospital longer but would not be treated for acute myocardial infarction.\n\nPeople with true negative test results were considered not to be treated for acute myocardial infarction and were subdivided between 'no ACS, no UA' and 'UA'.\n\nPeople with false negative test results were assumed to have untreated acute myocardial infarction resulting in increased reinfarction and mortality probabilities for 1\xa0year and were allocated to 'non-fatal AMI (untreated)'.\n\nThe long-term consequences in terms of costs and QALYs were estimated using a state-transition cohort model with a lifetime time horizon (60\xa0years) and a cycle time of 1\xa0year (except for the first cycle which was adjusted to 335.25\xa0days to ensure that the decision tree period and the first cycle summed to 1\xa0year). Discount rates of 3.5% and a half-cycle correction were applied for both costs and effects.\n\nEstimates for the model input parameters were retrieved from the literature and from consulting experts. Accuracy estimates were derived from the systematic review component of the assessment. The proportion of people testing positive or negative was based on the estimated accuracy of the testing strategies considered (table\xa02) and the estimated prevalence of NSTEMI in the UK (12.2%).\n\nNumber\n\nTest\n\nStrategy\n\nSensitivity (SE)\n\nSpecificity (SE)\n\n\n\nStandard troponin\n\nAt presentation and after 10 to 12\xa0hours\n\n(-)\n\n(-)\n\n\n\nElecsys\n\nth percentile at 0\xa0hours AND 3\xa0hours\n\n(0.03)\n\n(0.08)\n\n\n\nElecsys\n\nLimit of detection at 0\xa0hours\n\n(0.01)\n\n(0.05)\n\n\n\nElecsys\n\nESC 0/1‑hour pathway\n\n(0.01)\n\n(0.01)\n\n\n\nElecsys\n\nLess than 8\xa0ng/litre at 0\xa0hours AND change of less than 3\xa0ng/litre at 0 to 0.5\xa0hours\n\n(0.02)\n\n(0.02)\n\n\n\nElecsys\n\nLess than 12\xa0ng/litre at 0\xa0hours AND change of less than 3\xa0ng/litre at 0 to 1\xa0hour\n\n(0.01)\n\n(0.01)\n\n\n\nDimension Vista\n\nLess than 5\xa0ng/litre at 0\xa0hours AND change less than 2\xa0ng/litre at 0 to 1\xa0hour\n\n(0.02)\n\n(0.02)\n\n\n\nARCHITECT\n\nLimit of detection at 0\xa0hours\n\n(0.00)\n\n(0.03)\n\n\n\nARCHITECT\n\nESC 0/1‑hour pathway\n\n(0.00)\n\n(0.01)\n\n\n\nARCHITECT\n\nHigh-STEACS pathway\n\n(0.01)\n\n(0.01)\n\n\n\nARCHITECT\n\nLess than 4\xa0ng/litre at 0\xa0hours\n\n(0.01)\n\n(0.01)\n\n\n\nADVIA Centaur\n\nLess than 2\xa0ng/litre at 0\xa0hours\n\n(0.00)\n\n(0.01)\n\n\n\nADVIA Centaur\n\nLess than 3\xa0ng/litre at 0\xa0hours OR less than 8\xa0ng/litre at 0\xa0hours AND change of less than 7\xa0ng/litre at 0 to 2\xa0hours\n\n(0.01)\n\n(0.03)\n\n\n\nADVIA Centaur\n\nESC 0/1‑hour pathway\n\n(0.01)\n\n(0.02)\n\n\n\nADVIA Centaur\n\nLess than 5\xa0ng/litre at 0\xa0hours\n\n(0.01)\n\n(0.01)\n\n\n\nAtellica\n\nLess than 2\xa0ng/litre at 0\xa0hours\n\n(0.01)\n\n(0.01)\n\n\n\nAtellica\n\nHigh-STEACS pathway\n\n(0.01)\n\n(0.01)\n\n\n\nAccess\n\nESC 0/1‑hour pathway\n\n(0.02)\n\n(0.02)\n\n\n\nAccess\n\nSymptoms at more than 3\xa0hours AND less than 4\xa0ng/litre at 0\xa0hour OR less than 5\xa0ng/litre and change of less than 5\xa0ng/litre at 0 to 2\xa0hours\n\n(0.02)\n\n(0.01)\n\n\n\nVITROS\n\nESC 0/1‑hour pathway\n\n(0.01)\n\n(0.02)\n\n\n\nVIDAS\n\nLess than 2\xa0ng/litre at 0\xa0hour OR less than 6\xa0ng/litre at 0 AND 2\xa0hours\n\n(0.02)\n\n(0.02)\n\n\n\nTriageTrue\n\nESC 0/1‑hour pathway\n\n(0.01)\n\n(0.02)\n\nESC, European Society of Cardiology; SE, standard error; ng/litre is nanograms troponin per litre of blood.\n\nTest-specific resource use consisted of the number of tests done and the duration of hospital stay in hours before discharge or acute myocardial infarction treatment. For test strategies that involved a subsequent test conditional on the outcome of the first test, the rule-out rate for the presentation sample was used to calculate the number of subsequent tests. The resource use included a delay from the time at which sampling could be done to the time at which results became available (2\xa0hours) and delay between arrival at hospital and troponin assessment starting (1\xa0hour).\n\nHealth state costs were taken from a retrospective cohort study done in the UK (Danese et al. 2016). Acute myocardial infarction treatment costs were based on NHS reference costs and hospital stay costs were based on data from the Personal Social Services Research Unit.\n\nIn the base case, test costs were assumed to be identical for all tests (£2.50) except for the point-of-care test (£25.00, based on information provided by Quidel). A scenario analysis was done using test-specific costs and assuming that costs relating to the analyser and staff time were identical for all strategies.\n\nAge-dependent utility scores from the UK general population were calculated for people in the 'no ACS, no UA' health state. These age-dependent utility scores were combined with age-dependent disutility values for acute myocardial infarction, to calculate utility values for the 'post-AMI' health states (with or without reinfarction). Utility values for the 'UA' health state were calculated based on the 'post-MI' utility values and assuming a utility increment of 0.010.\n\nThe following assumptions were applied in the base-case analysis:\n\nStandard troponin testing (at presentation and after 10 to 12\xa0hours) has perfect accuracy.\n\nCompared with acute myocardial infarctions occurring during the decision tree period, all acute myocardial infarctions (either first or reinfarction) occurring in the state-transition model are diagnosed correctly, so are treated.\n\nUnstable angina is always correctly diagnosed, so is treated.\n\nThe reinfarction probability for the 'post-AMI with reinfarction' health state is equal to the reinfarction probability for the 'post-AMI' health state.\n\nThe increased post-acute myocardial infarction reinfarction and mortality probabilities for untreated acute myocardial infarction were assumed to last 1\xa0year. After this a relative risk of 1.0 was applied (for untreated compared with treated acute myocardial infarction).\n\nThere is no additional benefit of starting treatment early, so treatment effect for high-sensitivity strategies is equal to treatment effect for standard troponin strategies.\n\nAll 30‑day deaths (after presentation at the emergency department) are due to fatal acute myocardial infarction events and will receive the associated costs.\n\nFor the base case, it was assumed that people who tested negative on standard troponin tests and positive on high-sensitivity troponin tests would have a life expectancy and quality of life equal to people with true negative test results, but this assumption is debatable. A meta-analysis by Liplinski et al. (2015) showed that people with a negative standard troponin test and positive high-sensitivity troponin test have an increased risk of reinfarction and mortality compared with those who test negative on both standard troponin and high-sensitivity troponin tests. Although this risk was not as high as in people with both positive standard troponin and positive high-sensitivity troponin tests, it could still be considered prognostically important. A secondary analysis was done in which the risk of acute myocardial infarction and mortality was adjusted for people with false positive results.\n\nIn the base case, standard troponin testing was the most effective and the most expensive strategy. But other testing strategies with a sensitivity of 100% (subject to uncertainty) were almost equally as effective, resulting in the same QALY gain up to 4 decimal places. Compared with standard troponin testing, high-sensitivity troponin testing resulted in probabilistic incremental cost-effectiveness ratios (ICERs) ranging between £34,307 and £36,842,603 savings per QALY lost.\n\nIn the secondary analysis, standard troponin was the cheapest and the least effective testing strategy. Compared with standard troponin testing, high-sensitivity troponin testing resulted in probabilistic ICERs ranging between £4,043 and £6,148 per QALY gained.\n\nFor all scenario analyses of the secondary analysis, results were similar to those from the secondary analysis base case. Standard troponin remained the cheapest and the least effective testing strategy (deterministic analysis). In all scenario analyses of the secondary analysis, high-sensitivity troponin testing compared with standard troponin testing resulted in ICERs less than £10,000 per QALY gained.\n\nOne-way sensitivity analyses were done including all parameters that were changed in the probabilistic sensitivity analysis. In the secondary analysis, the parameters that had a notable effect on the estimated cost-effectiveness estimates were:\n\n‑day mortality for untreated acute myocardial infarction\n\nmortality 1\xa0year after treated and untreated acute myocardial infarction\n\ndiscount rate used for outcomes\n\nrelative mortality for people who had a true positive result compared with those who had a false positive result.At extreme values (based on 95% confidence intervals) of these inputs, standard troponin testing remains cheaper and less effective than the high-sensitivity troponin tests.", 'Committee discussion': "# Quick, accurate tests may reduce anxiety for patients and carers\n\nThe committee heard from a patient expert who highlighted the stresses and fears that patients and their families experience when attending the emergency department with chest pain. Reducing waiting times is important for patients. Technologies that reduce the time taken from sample to clinical decision, while providing good diagnostic accuracy, may help reduce patient anxiety. Patients may be reassured that they are having the most appropriate treatment with tests that provide an accurate result.\n\n# Flexibility on tests and strategies helps hospitals\n\nNICE has previously recommended high-sensitivity troponin for early rule out of acute myocardial infarction, so most emergency departments are already set up for high-sensitivity troponin testing. Many have implemented early rule-out strategies as routine practice. The committee considered that there were practical issues around early rule-out strategies that incorporate serial testing but that these could be resolved in practice. It also considered that, if more tests and different testing strategies were found to be cost effective and were recommended, this would help with procurement and give hospitals more flexibility to implement a strategy that works for them.\n\n# Clinical effectiveness\n\n## The comparative accuracy of the different tests is uncertain\n\nThere were concerns about the level of clinical evidence available for some of the tests. Most diagnostic accuracy results related to the Elecsys (30 studies) and ARCHITECT (9 studies) tests. Other tests had less evidence available but were mostly still acceptable. The committee noted that there was also limited evidence comparing the diagnostic performance of 1 test with another. This meant that although there may be differences in performance between the tests, it is difficult to estimate these differences with any certainty.\n\n## The sensitivity of single-sample early rule-out strategies varies depending on which threshold is used\n\nResults from the diagnostic accuracy studies showed that strategies that test a single sample on presentation using a threshold at or close to the limit of detection gave high sensitivity but low specificity. However, the committee commented that single sample strategies can be useful to rule out non-ST-segment elevation myocardial infarction (NSTEMI) early in emergency departments and, for this purpose, specificity is not a priority. There were concerns about the consistency of different analysers to provide accurate results at these low thresholds. However, clinical experts commented that samples with results close to these low thresholds would be from people considered very low risk and would have a good prognosis regardless of treatment. In contrast, results from diagnostic accuracy studies showed that a single test strategy using the 99th percentile threshold had sensitivity estimates too low to be safely used in clinical practice.\n\n## Multiple sample early rule-out strategies have better specificity than single-sample strategies\n\nResults from the diagnostic accuracy studies showed that multiple sample early rule-out strategies, that is, those that included a second rule-out step, had better specificity than single-sample strategies using a very low threshold. Multiple sample strategies also maintained high levels of sensitivity. However, clinical experts commented that it was difficult to make direct comparisons of the different test strategies based on specificity because the number of true negatives would be affected by the prevalence of NSTEMI in each of the different study populations.\n\n## High-sensitivity troponin tests should be used alongside clinical judgement\n\nClinical experts noted that the clinical context in which decisions on discharging or admitting someone to hospital is important, and that decisions should never be based solely on the results of a high-sensitivity troponin test. For example, a person with a negative high-sensitivity troponin test result should not be discharged without further investigations if they look visibly unwell or if the sample was collected too soon after the suspected cardiac event, a practice that could result in a false negative result.\n\n## Using sex-specific 99th percentile thresholds could reduce inequality in women's treatment\n\nClinical experts explained that there was consistent evidence from reference range studies that the 99th percentile threshold differs between men and women. For the Elecsys and ARCHITECT tests, the 99th percentile upper reference limit for women is much lower than the general (mixed) population 99th percentile. The High-STEACS trial was the only strategy included in the cost-effectiveness modelling to use sex-specific 99th percentile thresholds in an early rule-out strategy. But it did not provide a direct comparison with a general population 99th percentile threshold. The committee therefore considered that the evidence on using sex-specific 99th percentile thresholds in early rule-out strategies was unclear. Clinical experts noted that sex-specific 99th percentile thresholds were sometimes used in clinical practice to help diagnose NSTEMI, but that there was no evidence that using them affected clinical outcomes. They noted that the ongoing CODE-MI study aims to evaluate the effect of using the sex-specific 99th percentile threshold for women for high-sensitivity cardiac troponin. This will be compared with the general (mixed) population 99th percentile threshold, for the diagnosis, treatment and outcomes of women presenting to the emergency department with cardiac chest pain. The committee noted that there was a wider equality issue because women with acute myocardial infarction are generally under-diagnosed and under-treated compared with men. The committee considered that using sex-specific 99th percentile thresholds to help diagnose NSTEMI could be a step towards reducing this health inequality. It concluded that, when NSTEMI is not ruled out using early rule-out test strategies, NICE's guideline on recent-onset chest pain of suspected cardiac origin may be used to help diagnose myocardial infarction, and the use of sex-specific thresholds at the 99th percentile should be considered (see section 5.2).\n\n## Randomised controlled trial evidence shows early rule-out strategies do not negatively affect health\n\nThe committee considered evidence from 2 randomised controlled trials, High-STEACS and HiSTORIC. It noted that the authors of High-STEACS concluded that the implementation of an early rule-out strategy was not associated with any increase in myocardial infarction or cardiovascular death within 1\xa0year of initial presentation. The HiSTORIC trial was submitted to NICE as academic-in-confidence evidence. The committee concluded that evidence from the randomised controlled trials, which reported end clinical outcomes, strongly supported using high-sensitivity troponin tests with early rule-out strategies in clinical practice.\n\n## The TriageTrue point-of-care test is innovative but its diagnostic accuracy is uncertain\n\nThe committee noted that the TriageTrue point-of-care test had a turnaround time of around 20\xa0minutes and had the potential to be an important development in the field. The rapid time to test results could have benefits because of a reduced length of time spent waiting for a result in the emergency department (see section 4.1). Only 1 study was available on the TriageTrue test. In this study troponin levels were tested in stored plasma samples rather than the whole blood samples used in clinical practice. The committee noted that the evidence did not reflect how the test would be used in clinical practice at the point of care. It concluded that further evidence on TriageTrue's diagnostic performance when used on whole blood at the point of care is needed before the test can be recommended for use in clinical practice.\n\n## The Alinity, Dimension EXL and Elecsys STAT tests are likely to have the same performance as alternative versions of tests\n\nThe Alinity and Dimension EXL tests were not included in the economic model because there were no direct diagnostic accuracy data for them in the systematic review. However, the committee noted that these tests were based on the same methods and principles, and used the same reagents as other tests that were included in the modelling. The committee heard that the Alinity test was a newer version of the ARCHITECT test and that the Dimension EXL test was a different version of the Vista test, but the tests were all run on different analysers. It noted further that the Elecsys STAT test was the same in terms of technical specification and performance as the Elecsys troponin T-high sensitive test, and is run on the same analysers. The committee concluded that the diagnostic accuracy of these different versions of the tests should be comparable. It also concluded that it was the responsibility of individual laboratories to assess the equivalency of these tests in practice, and to validate their diagnostic performance against their current system. This would be achieved in part by participating in external quality assessment schemes.\n\n# Cost effectiveness\n\n## Only including early rule-out strategies with a minimum sensitivity of 97% in the economic analysis is acceptable\n\nOnly early rule-out strategies with a sensitivity of 97% or more were used in the cost-effectiveness modelling, based on expert opinion about the minimum sensitivity acceptable in clinical practice. The committee noted that this approach could mean that some potentially cost-effective strategies were excluded from the economic modelling. But overall it agreed that it was an acceptable approach that was necessary to keep the number of test strategies in the economic model manageable and ensure that those considered were likely to be safe in practice.\n\n## The prognostic benefits associated with a false positive high-sensitivity troponin test should be incorporated into decision making\n\nThe secondary analysis incorporated prognostic benefits associated with false positive high-sensitivity troponin test results. Clinical experts noted that it is now widely accepted that people with a negative standard troponin test and a positive high-sensitivity troponin test (classified as false positives in the analysis) have an increased risk of reinfarction and mortality compared with people who have a negative result from both tests. The committee concluded that the secondary analysis was most appropriate for decision making.\n\n## All early rule-out test strategies in the model are cost effective compared with standard troponin testing at 0\xa0hours and 12\xa0hours\n\nCompared with standard troponin testing, high-sensitivity troponin test strategies resulted in incremental cost-effectiveness ratios (ICERs) of less than £7,000 per quality-adjusted life year (QALY) gained. These ICERs are below £20,000 per QALY gained, which NICE would typically consider to be cost effective. The committee noted that there were only small differences in costs and QALYs between the different test strategies included in the economic model, and recalled its previous conclusion that it was not possible to indirectly compare the tests and early rule-out strategies. The committee concluded that it was not possible to differentiate between the different test strategies, and that all early rule-out strategies had the potential to be recommended for clinical practice, provided that each test used with them had enough diagnostic accuracy data.\n\n## The results of the economic model are robust to changes in the input parameter values\n\nThe model results were robust to changes in the input parameter values, for example, the number of admissions based on the specificity of the test strategy and the prevalence of NSTEMI. Early rule-out strategies with lower specificities would likely result in fewer people being discharged from hospital, but this does not have a substantial effect on the cost-effectiveness results. In addition, clinical experts noted that people having standard troponin testing and who get a negative test result would probably have a hospital length of stay of 24\xa0hours rather than the 14\xa0hours assumed in the economic model. So the benefits of using early rule-out strategies may have been underestimated. The external assessment group (EAG) commented that changing this assumption would be unlikely to affect the model results.\n\n## Recommending a range of different high-sensitivity troponin tests gives greater flexibility to NHS trusts\n\nSome of the tests had lower levels of clinical evidence than others. But the diagnostic performance and costs of all the tests used in the modelling were comparable (except for the test cost for TriageTrue). There was no strong evidence to differentiate one test over another (see section 4.3), and when used in the early rule-out strategies all were cost effective compared with the standard troponin test (see section 4.13). The committee noted that recommending a range of tests would benefit hospitals by enabling them to operate within existing equipment contracts or investments in a particular platform. It concluded that recommending a range of high-sensitivity troponin tests gives greater flexibility to NHS trusts and enables them to work with any local restrictions or equipment contracts.\n\n## Recommending a range of early rule-out strategies means hospitals can use one that works for their emergency department\n\nThe original NICE diagnostics guidance on troponin tests for myocardial infarction recommended strategies that test at 0\xa0hours and 3\xa0hours, report absolute values and use an upper reference limit at the 99th percentile. The committee noted that much more evidence is now available on different early rule-out strategies. The committee considered the different strategies included in the model:\n\nsingle-sample strategies using a threshold at or near to the limit of detection\n\nmultiple sample strategies in which all patients would be tested at baseline and again at 1 to 3\xa0hours after the initial test\n\nmultiple sample strategies in which people only had a second test (1\xa0hour to 3\xa0hours after the initial test) if the first test result could not be used to rule out acute myocardial infarction.The multiple sample strategies incorporated different thresholds, including those at or close to the limit of detection, the general (mixed) population 99th percentile, and sex-specific 99th percentiles. The committee recalled that all single-sample strategies and multiple sample strategies included in the model were highly sensitive, that is, they had a low false negative rate (see sections 4.4 and 4.5). It considered that strategies in which people could be safely discharged after the first test could be beneficial because fewer people would have to remain in the emergency department for a second test. The committee noted further that all strategies were cost effective compared with a standard troponin test strategy (see section 4.13). The committee concluded that recommending a range of early rule-out strategies would enable hospitals to use strategies that worked with the set up of their emergency department.\n\n## Further diagnostic accuracy evidence is needed before the TriageTrue test can be recommended for routine clinical use\n\nThe TriageTrue point-of-care test, when used in the European Society of Cardiology 0/1‑hour pathway, was cost effective compared with a standard troponin test strategy, with an ICER of less than £5,000 per QALY gained. The committee considered that the potential benefits associated with the rapid turnaround times of point-of-care tests (see section 4.9) may not have been fully captured in the economic model. But the committee was concerned about the evidence used to provide the diagnostic accuracy inputs in the model, so concluded that further research was needed on the TriageTrue test before it could be recommended for routine clinical use.\n\n# Research considerations\n\n## Further research to understand the 99th percentile in population subgroups would be useful\n\nSome evidence supported using sex-specific 99th percentile thresholds in clinical practice in men and women but overall their value in early rule-out is unclear (see section 4.7). The clinical experts said that there are much less data on the 99th percentile in other subgroups, such as older or younger people, people with or without renal disease and black, Asian and minority ethnic groups. The committee considered that it would be helpful to have a better understanding of differences in the 99th percentile between these subgroups.", 'Recommendations for further research': 'Further research is recommended on the diagnostic performance of the TriageTrue high-sensitivity troponin test using samples at point of care.\n\nFurther research is recommended on how using sex-specific 99th percentile thresholds affects treatment decisions and clinical outcomes for men and women.'}
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https://www.nice.org.uk/guidance/dg40
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Evidence-based recommendations on high-sensitivity troponin tests for the early rule out of NSTEMI (non-ST-segment elevation myocardial infarction).
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c43ee4adee7f4d5f7f844d8996b700eb2ffde1b7
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nice
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Anaphylaxis: assessment and referral after emergency treatment
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Anaphylaxis: assessment and referral after emergency treatment
This guideline covers assessment and referral for anaphylaxis. It aims to improve the quality of care for people with suspected anaphylaxis by detailing the assessments that are needed and recommending referral to specialist allergy services.
# Introduction
Anaphylaxis is a severe, life-threatening, generalised or systemic hypersensitivity reaction. It is characterised by rapidly developing, life-threatening problems involving: the airway (pharyngeal or laryngeal oedema) and/or breathing (bronchospasm with tachypnoea) and/or circulation (hypotension and/or tachycardia). According to Resuscitation Council UK's guideline on emergency treatment of anaphylactic reactions, in most cases, there are associated skin and mucosal changes.
In emergency departments a person who presents with the signs and symptoms listed above may be classified as having a 'severe allergic' reaction rather than an 'anaphylactic' reaction. Throughout this guideline, anyone who presents with such signs and symptoms is classed as experiencing a 'suspected anaphylactic reaction', and should be diagnosed as having 'suspected anaphylaxis'.
People who have had a mild or moderate allergic reaction are at risk of, and may subsequently present with, suspected anaphylaxis. Certain groups may be at higher risk, either because of an existing comorbidity (for example asthma) or because they are more likely to be exposed to the same allergen again (for example people with venom allergies or reactions to specific food triggers). These groups were not included within the scope of this guideline, which is specific to those who have received emergency treatment for suspected anaphylaxis.
Anaphylaxis may be an allergic response that is immunologically mediated, or a non-immunologically mediated response, or idiopathic. Certain foods, insect venoms, some drugs and latex are common precipitants of immunoglobulin E (IgE)-mediated allergic anaphylaxis. Many drugs can also act through non‑allergic mechanisms. A significant proportion of anaphylaxis is classified as idiopathic, in which there are significant clinical effects but no readily identifiable cause. The relative likelihood of the reaction being allergic, non‑allergic or idiopathic varies considerably with age.
Food is a particularly common trigger in children, while medicinal products are much more common triggers in older people. In the UK it is estimated that 500,000 people have had a venom-induced anaphylactic reaction and 220,000 people up to the age of 44 have had a nut-induced anaphylactic reaction.
There is no overall figure for the frequency of anaphylaxis from all causes in the UK. Because anaphylaxis presents mainly in accident and emergency departments and outpatient settings, few estimates of prevalence are available from NHS sources. Anaphylaxis may not be recorded, or may be misdiagnosed as something else, for example, asthma. It may also be recorded by cause, such as food allergy, rather than as an anaphylactic reaction.
Available UK estimates suggest that approximately 1 in 1333 of the population of England has experienced anaphylaxis at some point in their lives. There are approximately 20 deaths from anaphylaxis reported each year in the UK, with around half the deaths being iatrogenic, although this may be an underestimate.
After an acute anaphylactic reaction, it is believed that many people do not receive optimal management of their condition. One reason for this is healthcare professionals' lack of understanding when making a diagnosis, for example failing to differentiate anaphylaxis from less severe histamine-releasing reactions or from other conditions that mimic some or all of its clinical features. Another reason is a lack of understanding of when or where to refer patients. This can affect the likelihood of the person receiving a definitive diagnosis, which can lead to anxiety, inappropriate management and recurrent reactions. It can also lead to avoidable costs for the NHS and increase the need for acute care.# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.
# List of all recommendations
Document the acute clinical features of the suspected anaphylactic reaction (rapidly developing, life-threatening problems involving the airway and/or breathing and/or circulation and, in most cases, associated skin and mucosal changes).
Record the time of onset of the reaction.
Record the circumstances immediately before the onset of symptoms to help to identify the possible trigger.
After a suspected anaphylactic reaction in adults or young people aged 16 years or older, take timed blood samples for mast cell tryptase testing as follows:
a sample as soon as possible after emergency treatment has started
a second sample ideally within 1 to 2 hours (but no later than 4 hours) from the onset of symptoms.
After a suspected anaphylactic reaction in children younger than 16 years, consider taking blood samples for mast cell tryptase testing as follows if the cause is thought to be venom-related, drug-related or idiopathic:
a sample as soon as possible after emergency treatment has started
a second sample ideally within 1 to 2 hours (but no later than 4 hours) from the onset of symptoms.
Inform the person (or, as appropriate, their parent and/or carer) that a blood sample may be required at follow-up with the specialist allergy service to measure baseline mast cell tryptase.
Adults and young people aged 16 years or older who have had emergency treatment for suspected anaphylaxis should be observed for 6 to 12 hours from the onset of symptoms, depending on their response to emergency treatment. In people with reactions that are controlled promptly and easily, a shorter observation period may be considered provided that they receive appropriate post‑reaction care prior to discharge.
Children younger than 16 years who have had emergency treatment for suspected anaphylaxis should be admitted to hospital under the care of a paediatric medical team.
After emergency treatment for suspected anaphylaxis, offer people a referral to a specialist allergy service (age-appropriate where possible) consisting of healthcare professionals with the skills and competencies necessary to accurately investigate, diagnose, monitor and provide ongoing management of, and patient education about, suspected anaphylaxis.
After emergency treatment for suspected anaphylaxis, offer people (or, as appropriate, their parent and/or carer) an appropriate adrenaline injector as an interim measure before the specialist allergy service appointment.
Before discharge a healthcare professional with the appropriate skills and competencies should offer people (or, as appropriate, their parent and/or carer) the following:
information about anaphylaxis, including the signs and symptoms of an anaphylactic reaction
information about the risk of a biphasic reaction
information on what to do if an anaphylactic reaction occurs (use the adrenaline injector and call emergency services)
a brand-specific demonstration of the correct use of the adrenaline injector and when to use it, including advice that the person should lie down after using the adrenaline injector (or sit up if they are struggling to breathe) and should not stand up or change position suddenly, even if they feel better
a prescription for 2 further adrenaline injectors, with advice to carry the injectors with them at all times
advice about how to avoid the suspected trigger (if known)
information about the need for referral to a specialist allergy service and the referral process
information about patient support groups.
Each hospital trust providing emergency treatment for suspected anaphylaxis should have separate referral pathways for suspected anaphylaxis in adults (and young people) and children.
# Terms used in this guideline
## Anaphylaxis
Anaphylaxis is a severe, life-threatening, generalised or systemic hypersensitivity reaction. It is characterised by rapidly developing, life-threatening problems involving: the airway (pharyngeal or laryngeal oedema) and/or breathing (bronchospasm with tachypnoea) and/or circulation (hypotension and/or tachycardia). In most cases, there are associated skin and mucosal changes.
## Biphasic anaphylaxis
After complete recovery of anaphylaxis, a recurrence of symptoms within 72 hours with no further exposure to the allergen. It is managed in the same way as anaphylaxis.
## Idiopathic anaphylaxis
Denotes a form of anaphylaxis where no identifiable stimulus can be found. All known causes of anaphylaxis must be excluded before this diagnosis can be reached.
## Suspected anaphylaxis
The diagnosis, prior to assessment by a specialist allergist, for people who present with symptoms of anaphylaxis.
In emergency departments a person who presents with the signs and symptoms of anaphylaxis may be classified as having a 'severe allergic' reaction rather than an 'anaphylactic' reaction. Throughout this guideline, anyone who presents with such signs and symptoms is classed as experiencing a 'suspected anaphylactic reaction', and should be diagnosed as having 'suspected anaphylaxis'.
Please see the NICE glossary for an explanation of terms not described above.# Recommendations for research
The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future.
# Mediators of anaphylactic reactions
Aside from mast cell tryptase, which other chemical inflammatory mediators offer potential as indicators of anaphylaxis?
## Why this is important
Although mast cell tryptase is widely used to support the diagnosis of anaphylaxis, it is not universally suitable. Mast cell tryptase is not always elevated in children, when food is the allergen, or when the main severe feature is respiratory.
It is recommended that a cross-sectional study be carried out into the diagnostic accuracy of other potential chemical inflammatory mediators. The study should be conducted in both adults and children who have had a suspected anaphylactic reaction. The sensitivity and specificity of the proposed mediator should be compared against mast cell tryptase, using clinical assessment in conjunction with immuno-allergic study as the reference standard for both. The diagnostic accuracy of any mediator should be carried out for a range of potential allergens.
# The frequency and effects of biphasic reactions
What are the frequency, timing, severity and predictors of biphasic reactions in people who have received emergency treatment for anaphylaxis?
## Why this is important
Limited evidence was found on the frequency, timing severity and predictors of biphasic reactions and the resulting effect of these on morbidity and mortality.
It is recommended that a UK-based prospective cohort study be conducted that follows patients up after emergency treatment for anaphylaxis.
The study should follow people up for 7 days after discharge from the emergency department. The aim is to collect data on the predictors (for example, the person's response to the initial treatment), the time to any reaction, the severity of any biphasic reaction and the effect of the biphasic reaction on morbidity and mortality.
# Length of observation period following emergency treatment for anaphylaxis
For how long should a person who has received emergency treatment for anaphylaxis be observed?
## Why this is important
No studies were found that compared different observational periods or the effect of these on relevant patient outcomes.
It is recommended that a cluster randomised controlled trial is conducted for people who have received emergency treatment for anaphylaxis.
The interventions for the trial should be differing time periods of observation, within the secondary care setting, ranging from 1 hour to 24 hours after symptom resolution of the index reaction. Patients should then be followed up for 7 days following the end of the observational period to determine if a biphasic reaction has occurred and the effects of any reaction. The aim is to determine whether differing periods of observation have a detrimental effect on morbidity and mortality and to gather information about resource use.
# Prevalence of anaphylactic reactions and related outcomes
What is the annual incidence of anaphylaxis and its related outcomes within the UK?
## Why this is important
Limited evidence exists on the annual incidence of anaphylactic reactions and their associated outcomes within the UK.
It is recommended that a prospective observational study be conducted that records the annual incidence of anaphylactic reactions within the UK.
The overall number of anaphylactic reactions that occur in adults and children should be recorded and these should be classified into those that are first-time reactions, recurrent reactions or biphasic reactions. A clear, pre-defined, definition of what constitutes an anaphylactic reaction should be used, in order to avoid the misclassification of milder reactions. Data should also be collected on any emergency treatment that was delivered (by a clinician, use of an adrenaline injector) and the associated outcomes (morbidity, mortality, adverse events). Data should also be collected on any previous treatment received, such as that from a specialist allergy service or the provision of adrenaline injectors.
# Effect of specialist services on health-related quality of life
For people who have experienced suspected anaphylaxis, what is the effect on health-related quality of life of (a) referral to specialist allergy services and (b) provision of adrenaline injectors, when compared with emergency treatment alone?
## Why this is important
The GDG believed that referral to specialist services and/or the provision of adrenaline injectors was likely to provide day-to-day HRQoL benefit for people who have experienced suspected anaphylaxis, as a result of decreased anxiety and ongoing support. However, the health economic model relied on GDG opinion alone to quantify this benefit. Future economic analyses would be greatly improved by a reliable demonstration of this effect and an estimate of its magnitude. It is recommended that data are collected using validated measure(s) of HRQoL, including EQ-5D.
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{'Introduction ': "Anaphylaxis is a severe, life-threatening, generalised or systemic hypersensitivity reaction. It is characterised by rapidly developing, life-threatening problems involving: the airway (pharyngeal or laryngeal oedema) and/or breathing (bronchospasm with tachypnoea) and/or circulation (hypotension and/or tachycardia). According to Resuscitation Council UK's guideline on emergency treatment of anaphylactic reactions, in most cases, there are associated skin and mucosal changes.\n\nIn emergency departments a person who presents with the signs and symptoms listed above may be classified as having a 'severe allergic' reaction rather than an 'anaphylactic' reaction. Throughout this guideline, anyone who presents with such signs and symptoms is classed as experiencing a 'suspected anaphylactic reaction', and should be diagnosed as having 'suspected anaphylaxis'.\n\nPeople who have had a mild or moderate allergic reaction are at risk of, and may subsequently present with, suspected anaphylaxis. Certain groups may be at higher risk, either because of an existing comorbidity (for example asthma) or because they are more likely to be exposed to the same allergen again (for example people with venom allergies or reactions to specific food triggers). These groups were not included within the scope of this guideline, which is specific to those who have received emergency treatment for suspected anaphylaxis.\n\nAnaphylaxis may be an allergic response that is immunologically mediated, or a non-immunologically mediated response, or idiopathic. Certain foods, insect venoms, some drugs and latex are common precipitants of immunoglobulin E (IgE)-mediated allergic anaphylaxis. Many drugs can also act through non‑allergic mechanisms. A significant proportion of anaphylaxis is classified as idiopathic, in which there are significant clinical effects but no readily identifiable cause. The relative likelihood of the reaction being allergic, non‑allergic or idiopathic varies considerably with age.\n\nFood is a particularly common trigger in children, while medicinal products are much more common triggers in older people. In the UK it is estimated that 500,000 people have had a venom-induced anaphylactic reaction and 220,000 people up to the age of 44 have had a nut-induced anaphylactic reaction.\n\nThere is no overall figure for the frequency of anaphylaxis from all causes in the UK. Because anaphylaxis presents mainly in accident and emergency departments and outpatient settings, few estimates of prevalence are available from NHS sources. Anaphylaxis may not be recorded, or may be misdiagnosed as something else, for example, asthma. It may also be recorded by cause, such as food allergy, rather than as an anaphylactic reaction.\n\nAvailable UK estimates suggest that approximately 1 in 1333 of the population of England has experienced anaphylaxis at some point in their lives. There are approximately 20 deaths from anaphylaxis reported each year in the UK, with around half the deaths being iatrogenic, although this may be an underestimate.\n\nAfter an acute anaphylactic reaction, it is believed that many people do not receive optimal management of their condition. One reason for this is healthcare professionals' lack of understanding when making a diagnosis, for example failing to differentiate anaphylaxis from less severe histamine-releasing reactions or from other conditions that mimic some or all of its clinical features. Another reason is a lack of understanding of when or where to refer patients. This can affect the likelihood of the person receiving a definitive diagnosis, which can lead to anxiety, inappropriate management and recurrent reactions. It can also lead to avoidable costs for the NHS and increase the need for acute care.", 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThe following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.\n\n# List of all recommendations\n\nDocument the acute clinical features of the suspected anaphylactic reaction (rapidly developing, life-threatening problems involving the airway [pharyngeal or laryngeal oedema] and/or breathing [bronchospasm with tachypnoea] and/or circulation [hypotension and/or tachycardia] and, in most cases, associated skin and mucosal changes).\n\nRecord the time of onset of the reaction.\n\nRecord the circumstances immediately before the onset of symptoms to help to identify the possible trigger.\n\nAfter a suspected anaphylactic reaction in adults or young people aged 16\xa0years or older, take timed blood samples for mast cell tryptase testing as follows:\n\na sample as soon as possible after emergency treatment has started\n\na second sample ideally within 1 to 2 hours (but no later than 4\xa0hours) from the onset of symptoms.\n\nAfter a suspected anaphylactic reaction in children younger than 16\xa0years, consider taking blood samples for mast cell tryptase testing as follows if the cause is thought to be venom-related, drug-related or idiopathic:\n\na sample as soon as possible after emergency treatment has started\n\na second sample ideally within 1 to 2 hours (but no later than 4\xa0hours) from the onset of symptoms.\n\nInform the person (or, as appropriate, their parent and/or carer) that a blood sample may be required at follow-up with the specialist allergy service to measure baseline mast cell tryptase.\n\nAdults and young people aged 16\xa0years or older who have had emergency treatment for suspected anaphylaxis should be observed for 6 to 12 hours from the onset of symptoms, depending on their response to emergency treatment. In people with reactions that are controlled promptly and easily, a shorter observation period may be considered provided that they receive appropriate post‑reaction care prior to discharge.\n\nChildren younger than 16\xa0years who have had emergency treatment for suspected anaphylaxis should be admitted to hospital under the care of a paediatric medical team.\n\nAfter emergency treatment for suspected anaphylaxis, offer people a referral to a specialist allergy service (age-appropriate where possible) consisting of healthcare professionals with the skills and competencies necessary to accurately investigate, diagnose, monitor and provide ongoing management of, and patient education about, suspected anaphylaxis.\n\nAfter emergency treatment for suspected anaphylaxis, offer people (or, as appropriate, their parent and/or carer) an appropriate adrenaline injector as an interim measure before the specialist allergy service appointment.\n\nBefore discharge a healthcare professional with the appropriate skills and competencies should offer people (or, as appropriate, their parent and/or carer) the following:\n\ninformation about anaphylaxis, including the signs and symptoms of an anaphylactic reaction\n\ninformation about the risk of a biphasic reaction\n\ninformation on what to do if an anaphylactic reaction occurs (use the adrenaline injector and call emergency services)\n\na brand-specific demonstration of the correct use of the adrenaline injector and when to use it, including advice that the person should lie down after using the adrenaline injector (or sit up if they are struggling to breathe) and should not stand up or change position suddenly, even if they feel better\n\na prescription for 2 further adrenaline injectors, with advice to carry the injectors with them at all times\n\nadvice about how to avoid the suspected trigger (if known)\n\ninformation about the need for referral to a specialist allergy service and the referral process\n\ninformation about patient support groups.\n\nEach hospital trust providing emergency treatment for suspected anaphylaxis should have separate referral pathways for suspected anaphylaxis in adults (and young people) and children.\n\n# Terms used in this guideline\n\n## Anaphylaxis\n\nAnaphylaxis is a severe, life-threatening, generalised or systemic hypersensitivity reaction. It is characterised by rapidly developing, life-threatening problems involving: the airway (pharyngeal or laryngeal oedema) and/or breathing (bronchospasm with tachypnoea) and/or circulation (hypotension and/or tachycardia). In most cases, there are associated skin and mucosal changes.\n\n## Biphasic anaphylaxis\n\nAfter complete recovery of anaphylaxis, a recurrence of symptoms within 72\xa0hours with no further exposure to the allergen. It is managed in the same way as anaphylaxis.\n\n## Idiopathic anaphylaxis\n\nDenotes a form of anaphylaxis where no identifiable stimulus can be found. All known causes of anaphylaxis must be excluded before this diagnosis can be reached.\n\n## Suspected anaphylaxis\n\nThe diagnosis, prior to assessment by a specialist allergist, for people who present with symptoms of anaphylaxis.\n\nIn emergency departments a person who presents with the signs and symptoms of anaphylaxis may be classified as having a 'severe allergic' reaction rather than an 'anaphylactic' reaction. Throughout this guideline, anyone who presents with such signs and symptoms is classed as experiencing a 'suspected anaphylactic reaction', and should be diagnosed as having 'suspected anaphylaxis'.\n\nPlease see the NICE glossary for an explanation of terms not described above.", 'Recommendations for research': "The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future.\n\n# Mediators of anaphylactic reactions\n\nAside from mast cell tryptase, which other chemical inflammatory mediators offer potential as indicators of anaphylaxis?\n\n## Why this is important\n\nAlthough mast cell tryptase is widely used to support the diagnosis of anaphylaxis, it is not universally suitable. Mast cell tryptase is not always elevated in children, when food is the allergen, or when the main severe feature is respiratory.\n\nIt is recommended that a cross-sectional study be carried out into the diagnostic accuracy of other potential chemical inflammatory mediators. The study should be conducted in both adults and children who have had a suspected anaphylactic reaction. The sensitivity and specificity of the proposed mediator should be compared against mast cell tryptase, using clinical assessment in conjunction with immuno-allergic study as the reference standard for both. The diagnostic accuracy of any mediator should be carried out for a range of potential allergens.\n\n# The frequency and effects of biphasic reactions\n\nWhat are the frequency, timing, severity and predictors of biphasic reactions in people who have received emergency treatment for anaphylaxis?\n\n## Why this is important\n\nLimited evidence was found on the frequency, timing severity and predictors of biphasic reactions and the resulting effect of these on morbidity and mortality.\n\nIt is recommended that a UK-based prospective cohort study be conducted that follows patients up after emergency treatment for anaphylaxis.\n\nThe study should follow people up for 7 days after discharge from the emergency department. The aim is to collect data on the predictors (for example, the person's response to the initial treatment), the time to any reaction, the severity of any biphasic reaction and the effect of the biphasic reaction on morbidity and mortality.\n\n# Length of observation period following emergency treatment for anaphylaxis\n\nFor how long should a person who has received emergency treatment for anaphylaxis be observed?\n\n## Why this is important\n\nNo studies were found that compared different observational periods or the effect of these on relevant patient outcomes.\n\nIt is recommended that a cluster randomised controlled trial is conducted for people who have received emergency treatment for anaphylaxis.\n\nThe interventions for the trial should be differing time periods of observation, within the secondary care setting, ranging from 1 hour to 24 hours after symptom resolution of the index reaction. Patients should then be followed up for 7 days following the end of the observational period to determine if a biphasic reaction has occurred and the effects of any reaction. The aim is to determine whether differing periods of observation have a detrimental effect on morbidity and mortality and to gather information about resource use.\n\n# Prevalence of anaphylactic reactions and related outcomes\n\nWhat is the annual incidence of anaphylaxis and its related outcomes within the UK?\n\n## Why this is important\n\nLimited evidence exists on the annual incidence of anaphylactic reactions and their associated outcomes within the UK.\n\nIt is recommended that a prospective observational study be conducted that records the annual incidence of anaphylactic reactions within the UK.\n\nThe overall number of anaphylactic reactions that occur in adults and children should be recorded and these should be classified into those that are first-time reactions, recurrent reactions or biphasic reactions. A clear, pre-defined, definition of what constitutes an anaphylactic reaction should be used, in order to avoid the misclassification of milder reactions. Data should also be collected on any emergency treatment that was delivered (by a clinician, use of an adrenaline injector) and the associated outcomes (morbidity, mortality, adverse events). Data should also be collected on any previous treatment received, such as that from a specialist allergy service or the provision of adrenaline injectors.\n\n# Effect of specialist services on health-related quality of life\n\nFor people who have experienced suspected anaphylaxis, what is the effect on health-related quality of life of (a) referral to specialist allergy services and (b) provision of adrenaline injectors, when compared with emergency treatment alone?\n\n## Why this is important\n\nThe GDG believed that referral to specialist services and/or the provision of adrenaline injectors was likely to provide day-to-day HRQoL benefit for people who have experienced suspected anaphylaxis, as a result of decreased anxiety and ongoing support. However, the health economic model relied on GDG opinion alone to quantify this benefit. Future economic analyses would be greatly improved by a reliable demonstration of this effect and an estimate of its magnitude. It is recommended that data are collected using validated measure(s) of HRQoL, including EQ-5D."}
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https://www.nice.org.uk/guidance/cg134
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This guideline covers assessment and referral for anaphylaxis. It aims to improve the quality of care for people with suspected anaphylaxis by detailing the assessments that are needed and recommending referral to specialist allergy services.
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f8f12f17384b662caeabacab098b10ea8167d09b
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nice
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Surgical site infections: prevention and treatment
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Surgical site infections: prevention and treatment
This guideline covers preventing and treating surgical site infections in adults, young people and children who are having a surgical procedure involving a cut through the skin. It focuses on methods used before, during and after surgery to minimise the risk of infection.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Information for patients and carers
Offer patients and carers clear, consistent information and advice throughout all stages of their care. This should include the risks of surgical site infections, what is being done to reduce them and how they are managed. For more guidance on providing information to adults and discussing their preferences with them, see the NICE guideline on patient experience in adult NHS services.
Offer patients and carers information and advice on how to care for their wound after discharge.
Offer patients and carers information and advice about how to recognise a surgical site infection and who to contact if they are concerned. Use an integrated care pathway for healthcare-associated infections to help communicate this information to both patients and all those involved in their care after discharge.
Always inform patients after their operation if they have been given antibiotics.
# Preoperative phase
## Preoperative showering
Advise patients to shower or have a bath (or help patients to shower, bath or bed bath) using soap, either the day before, or on the day of, surgery.
## Nasal decolonisation
Consider nasal mupirocin in combination with a chlorhexidine body wash before procedures in which Staphylococcus aureus is a likely cause of a surgical site infection. This should be locally determined and take into account:
the type of procedure
individual patient risk factors
the increased risk of side effects in preterm infants (see recommendation 1.3.8)
the potential impact of infection.
Maintain surveillance on antimicrobial resistance associated with the use of mupirocin. For information on antimicrobial stewardship programmes, see the NICE guideline on antimicrobial stewardship: systems and processes for effective antimicrobial medicine use.
To find out why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on nasal decolonisation .
Full details of the evidence and the committee's discussion are in evidence review A: nasal decontamination in the prevention of surgical site infection.
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## Hair removal
Do not use hair removal routinely to reduce the risk of surgical site infection.
If hair has to be removed, use electric clippers with a single-use head on the day of surgery. Do not use razors for hair removal, because they increase the risk of surgical site infection.
## Patient theatre wear
Give patients specific theatre wear that is appropriate for the procedure and clinical setting, and that provides easy access to the operative site and areas for placing devices, such as intravenous cannulas. Take into account the patient's comfort and dignity.
## Staff theatre wear
All staff should wear specific non-sterile theatre wear in all areas where operations are undertaken.
## Staff leaving the operating area
Staff wearing non-sterile theatre wear should keep their movements in and out of the operating area to a minimum.
## Mechanical bowel preparation
Do not use mechanical bowel preparation routinely to reduce the risk of surgical site infection.
## Hand jewellery, artificial nails and nail polish
The operating team should remove hand jewellery before operations.
The operating team should remove artificial nails and nail polish before operations.
## Antibiotic prophylaxis
Give antibiotic prophylaxis to patients before:
clean surgery involving the placement of a prosthesis or implant
clean-contaminated surgery
contaminated surgery. For advice on antibiotic prophylaxis before caesarean section, see the section on surgical techniques for caesarean section: timing of antibiotic administration in NICE's guideline on caesarean section. For information on antimicrobial stewardship programmes see the NICE guideline on antimicrobial stewardship: systems and processes for effective antimicrobial medicine use.
Do not use antibiotic prophylaxis routinely for clean non-prosthetic uncomplicated surgery.
Use the local antibiotic formulary and always take into account the potential adverse effects when choosing specific antibiotics for prophylaxis.
Consider giving a single dose of antibiotic prophylaxis intravenously on starting anaesthesia. However, give prophylaxis earlier for operations in which a tourniquet is used.
Before giving antibiotic prophylaxis, take into account the timing and pharmacokinetics (for example, the serum half-life) and necessary infusion time of the antibiotic. Give a repeat dose of antibiotic prophylaxis when the operation is longer than the half-life of the antibiotic given.
Give antibiotic treatment (in addition to prophylaxis) to patients having surgery on a dirty or infected wound.
Inform patients before the operation, whenever possible, if they will need antibiotic prophylaxis, and afterwards if they have been given antibiotics during their operation.
# Intraoperative phase
## Hand decontamination
The operating team should wash their hands prior to the first operation on the list using an aqueous antiseptic surgical solution, with a single-use brush or pick for the nails, and ensure that hands and nails are visibly clean.
Before subsequent operations, hands should be washed using either an alcoholic hand rub or an antiseptic surgical solution. If hands are soiled then they should be washed again with an antiseptic surgical solution.
## Incise drapes
Do not use non-iodophor-impregnated incise drapes routinely for surgery as they may increase the risk of surgical site infection.
If an incise drape is required, use an iodophor-impregnated drape unless the patient has an iodine allergy.
## Sterile gowns
The operating team should wear sterile gowns in the operating theatre during the operation.
## Gloves
Consider wearing 2 pairs of sterile gloves when there is a high risk of glove perforation and the consequences of contamination may be serious.
## Antiseptic skin preparation
Prepare the skin at the surgical site immediately before incision using an antiseptic preparation.
Be aware of the risks of using skin antiseptics in babies, in particular the risk of severe chemical injuries with the use of chlorhexidine (both alcohol-based and aqueous solutions) in preterm babies.
When deciding which antiseptic skin preparation to use, options may include those in table 1.
When
Choice of antiseptic skin preparation
First choice unless contraindicated or the surgical site is next to a mucous membrane
Alcohol-based solution of chlorhexidine
At the time of publication (April 2019), 0.5% chlorhexidine in 70% alcohol solution (Hydrex; Prevase) was licensed for 'preoperative skin disinfection prior to minor surgical procedures' and 2.0% chlorhexidine in 70% alcohol applicators (ChloraPrep) was licensed for 'disinfection of the skin prior to invasive medical procedures'. Some formulations of chlorhexidine in alcohol were off label for this use. See NICE's information on prescribing medicines.
Alternative if the surgical site is next to a mucous membrane
Aqueous solution of chlorhexidine
At the time of publication (April 2019), 4.0% aqueous chlorhexidine (Hibiscrub) was licensed for 'preoperative and postoperative skin antisepsis for patients undergoing elective surgery'; however, relevant instructions were limited to use as a body wash to be used before the person enters the operating theatre. Other formulations of aqueous chlorhexidine were off label for this use. See NICE's information on prescribing medicines.
Alternative if chlorhexidine is contraindicated
Alcohol-based solution of povidone-iodine
At the time of publication (April 2019), 10% povidone-iodine alcoholic solution (Videne alcoholic tincture) was licensed for 'topical application'. 10% povidone-iodine (Betadine Alcoholic solution) was licensed for 'antiseptic skin cleanser for major and minor surgical procedures'. Other formulations of povidone-iodine alcoholic solution were off label for this use. See NICE's information on prescribing medicines.
If both an alcohol-based solution and chlorhexidine are unsuitable
Aqueous solution of povidone-iodine
At the time of publication (April 2019), 7.5% povidone-iodine surgical scrub solution (Videne) was licensed for disinfecting the site of incision prior to elective surgery' and 7.5% povidone-iodine (Betadine surgical scrub) was licensed for 'preoperative preparation of patients' skin'. 10% iodine antiseptic solution (Videne) was licensed for 'disinfection of intact external skin or as a mucosal antiseptic' and 10% povidone-iodine solution (Standardised Betadine antiseptic solution) was licensed for 'preoperative and postoperative antiseptic skin cleanser for major and minor surgical procedures'. Other formulations of povidone-iodine aqueous solution were off label for this use. See NICE's information on prescribing medicines.
If diathermy is to be carried out:
use evaporation to dry antiseptic skin preparations and
avoid pooling of alcohol-based preparations.
To find out why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on antiseptic skin preparation .
Full details of the evidence and the committee's discussion are in evidence review B: skin antiseptics in the prevention of surgical site infection.
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## Diathermy
Do not use diathermy for surgical incision to reduce the risk of surgical site infection.
## Maintaining patient homeostasis
Maintain patient temperature in line with NICE's guideline on hypothermia: prevention and management in adults having surgery.
Maintain optimal oxygenation during surgery. In particular, give patients sufficient oxygen during major surgery and in the recovery period to ensure that a haemoglobin saturation of more than 95% is maintained.
Maintain adequate perfusion during surgery. See additional recommendations on intravenous fluids and cardiac monitoring for adults in NICE's guideline on perioperative care in adults.
Do not give insulin routinely to patients who do not have diabetes to optimise blood glucose postoperatively as a means of reducing the risk of surgical site infection. See the additional recommendation on blood glucose control for adults in NICE's guideline on perioperative care in adults.
## Wound irrigation and intracavity lavage
Do not use wound irrigation to reduce the risk of surgical site infection.
Do not use intracavity lavage to reduce the risk of surgical site infection.
## Antiseptics and antibiotics before wound closure
Only apply an antiseptic or antibiotic to the wound before closure as part of a clinical research trial.
Consider using gentamicin-collagen implants in cardiac surgery.
To find out why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on antiseptics and antibiotics before wound closure .
Full details of the evidence and the committee's discussion are in evidence review C: intraoperative antiseptics and antibiotics before wound closure.
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## Closure methods
When using sutures, consider using antimicrobial triclosan-coated sutures, especially for paediatric surgery, to reduce the risk of surgical site infection.
Consider using sutures rather than staples to close the skin after caesarean section to reduce the risk of superficial wound dehiscence.
To find out why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on closure methods .
Full details of the evidence and the committee's discussion are in evidence review D: closure materials and techniques in the prevention of surgical site infection.
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## Wound dressings
Cover surgical incisions with an appropriate interactive dressing at the end of the operation.
# Postoperative phase
## Changing dressings
Use an aseptic non-touch technique for changing or removing surgical wound dressings.
## Postoperative cleansing
Use sterile saline for wound cleansing up to 48 hours after surgery.
Advise patients that they may shower safely 48 hours after surgery.
Use tap water for wound cleansing after 48 hours if the surgical wound has separated or has been surgically opened to drain pus.
## Topical antimicrobial agents for wound healing by primary intention
Do not use topical antimicrobial agents for surgical wounds that are healing by primary intention to reduce the risk of surgical site infection.
## Dressings for wound healing by secondary intention
Do not use Eusol and gauze, or moist cotton gauze or mercuric antiseptic solutions to manage surgical wounds that are healing by secondary intention.
Use an appropriate interactive dressing to manage surgical wounds that are healing by secondary intention.
Ask a tissue viability nurse (or another healthcare professional with tissue viability expertise) for advice on appropriate dressings for the management of surgical wounds that are healing by secondary intention.
## Antibiotic treatment of surgical site infection and treatment failure
When surgical site infection is suspected by the presence of cellulitis, either by a new infection or an infection caused by treatment failure, give the patient an antibiotic that covers the likely causative organisms. Consider local resistance patterns and the results of microbiological tests in choosing an antibiotic. For information on antimicrobial stewardship programmes see the NICE guideline on antimicrobial stewardship: systems and processes for effective antimicrobial medicine use.
## Debridement
Do not use Eusol and gauze, or dextranomer or enzymatic treatments for debridement in the management of surgical site infection.
## Specialist wound care services
Use a structured approach to care to improve overall management of surgical wounds. This should include preoperative assessments to identify people with potential wound healing problems. Enhanced education of healthcare workers, patients and carers, and sharing of clinical expertise is needed to support this.
# Terms used in this guideline
## Decolonisation
The process of eradicating or reducing asymptomatic carriage of methicillin-resistant S. aureus (MRSA). This used to be referred to as decontamination.
## Healing by primary intention
Occurs when a wound has been sutured after an operation and heals to leave a minimal, cosmetically acceptable scar.
## Healing by secondary intention
Occurs when a wound is deliberately left open at the end of an operation because of excessive bacterial contamination, particularly by anaerobes or when there is a risk of devitalised tissue, which leads to infection and delayed healing. It may be sutured within a few days (delayed primary closure), or much later when the wound is clean and granulating (secondary closure), or left to complete healing naturally without suturing.
## Interactive dressing
Dressings designed to promote the wound healing process through the creation and maintenance of a local, warm, moist environment underneath the chosen dressing, when left in place for a period indicated through a continuous assessment process.
## Surgical site (wound) infection
A surgical wound with local signs and symptoms of infection, for example, heat, redness, pain and swelling, and (in more serious cases) with systemic signs of fever or a raised white blood cell count. Infection in the surgical wound may prevent healing, causing the wound edges to separate, or it may cause an abscess to form in the deeper tissues.
Definitions of the severity of surgical site infections vary and this should be taken into account when comparing reported rates of surgical site infection.
## Surgical wound classification
Clean: an incision in which no inflammation is encountered in a surgical procedure, without a break in sterile technique, and during which the respiratory, alimentary or genitourinary tracts are not entered.
Clean-contaminated: an incision through which the respiratory, alimentary, or genitourinary tract is entered under controlled conditions but with no contamination encountered.
Contaminated: an incision undertaken during an operation in which there is a major break in sterile technique or gross spillage from the gastrointestinal tract, or an incision in which acute, non-purulent inflammation is encountered. Open traumatic wounds that are more than 12 to 24 hours old also fall into this category.
Dirty or infected: an incision undertaken during an operation in which the viscera are perforated or when acute inflammation with pus is encountered (for example, emergency surgery for faecal peritonitis), and for traumatic wounds if treatment is delayed, there is faecal contamination, or devitalised tissue is present# Recommendations for research
The 2008 guideline committee made the following recommendations for research marked . The guideline committee's full set of research recommendations is detailed in the 2008 full guideline.
As part of the 2019 update, the guideline committee updated research recommendations on nasal decolonisation and wound closure methods, and made new research recommendations on antiseptic skin preparation and antiseptics and antibiotics before wound closure. These are marked .
# Key recommendations for research
## Nasal decolonisation: effectiveness
What is the clinical effectiveness of preoperative nasal decolonisation using mupirocin in combination with a chlorhexidine body wash in the whole population?
## Nasal decolonisation: antimicrobial resistance
Is the use of chlorhexidine body wash associated with increased antimicrobial resistance?
For a short explanation of why the committee made the recommendation for research, see the rationale on nasal decolonisation .
Full details of the evidence and the committee's discussion are in evidence review A: nasal decontamination in the prevention of surgical site infection.
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## Antiseptic skin preparation
What is the clinical and cost effectiveness of chlorhexidine in alcohol at different concentrations in the prevention of surgical site infection when applied to the skin before incision?
For a short explanation of why the committee made the recommendation for research, see the rationale on antiseptic skin preparation .
Full details of the evidence and the committee's discussion are in evidence review B: skin antiseptics in the prevention of surgical site infection.
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## Antiseptics and antibiotics before wound closure
Is the application of antiseptics and antibiotics in the operative field before wound closure, clinically and cost effective in reducing surgical site infection rates?
For a short explanation of why the committee made the recommendation for research, see the rationale on antiseptics and antibiotics before wound closure .
Full details of the evidence and the committee's discussion are in evidence review C: intraoperative antiseptics and antibiotics before wound closure.
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## Closure methods
Which patient groups, contamination groups and which layers gain the most benefit from the use of triclosan-coated or triclosan-impregnated sutures?
For a short explanation of why the committee made the recommendation for research, see the rationale on closure methods .
Full details of the evidence and the committee's discussion are in evidence review D: closure materials and techniques in the prevention of surgical site infection.
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# Other recommendations for research
## Nasal decolonisation: effectiveness
What is the contribution to clinical effectiveness of the timing of nasal decolonisation and body wash for the prevention of surgical site infection?
What is the effectiveness of decolonisation using alternative interventions in combination with nasal decolonisation in the prevention of surgical site infections when chlorhexidine is contraindicated?
## Antiseptic skin preparation
What is the clinical and cost effectiveness of a double application of antiseptic to the skin at the surgical site compared with a single application?
What is the clinical and cost effectiveness of different modes of applying skin antiseptic before incision in the prevention of surgical site infection?
## Closure methods
Does the use of barbed sutures for wound closure reduce the incidence of surgical site infection?
Which closure method or technique is the most effective for reducing surgical site infections in patients undergoing emergency surgery? # Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.
# Nasal decolonisation
Recommendations 1.2.2 to 1.2.3
## Why the committee made the recommendations
Evidence was identified on the use of mupirocin alone and mupirocin in combination with a chlorhexidine body wash. Mupirocin alone was effective in reducing Staphylococcus aureus infections caught in hospital in people who were identified as carriers of S. aureus. However, mupirocin alone did not reduce surgical site infections across all people undergoing surgery.
The evidence also showed that people identified as carriers of S. aureus who used nasal mupirocin in combination with a chlorhexidine body wash before surgery had fewer surgical site infections caused by S. aureus (including deep infections, methicillin-sensitive infections and infections caught in hospital) than those who did not have the intervention. However, the evidence was very limited and only covered S. aureus carriers.
Economic studies favoured the use of mupirocin alone. However, the studies were not UK-based and could not be applied to NHS practice (for example, because of the high cost of treating surgical site infections in US studies). An economic model based on UK data demonstrated that, compared with no treatment, using mupirocin with a chlorhexidine body wash before all operations was an efficient use of resources in most specialist surgeries. However, there was less certainty of cost effectiveness for surgery with a low risk of surgical site infections caused by S. aureus.
Because of the limited evidence, the committee were unable to make strong recommendations on nasal decolonisation before surgery and agreed that it should not be offered to all people having surgery. The committee applied their clinical understanding and experience of current best practice, and recommended that nasal mupirocin with chlorhexidine body wash should be considered before procedures that have an increased risk of surgical site infection caused by S. aureus, for which there would be the most benefit.
The recommendation does not define the surgical procedures in which S. aureus is a likely cause of a surgical site infection. The committee agreed that although cardiac and orthopaedic surgery can be considered high risk, decisions should be made locally through discussions between surgical and infection control teams, and should also take into account patient risk factors, such as whether the person is an S. aureus carrier and the potential impact of infection on the person, including the cost of managing the infection. The recommendation does not give an optimal timing for nasal decolonisation because of a lack of evidence. But the committee were aware that mupirocin with chlorhexidine can be given from 2 days before surgery to 3 days after surgery.
The committee also took into consideration the potential side effects of mupirocin (such as a burning sensation and local reactions) and the cautions identified for the use of chlorhexidine solution in people with existing skin conditions and in preterm newborn babies. The committee noted that the Medicines and Healthcare products Regulatory Agency (MHRA) has published MHRA advice on the use of chlorhexidine for skin disinfection in premature babies.
There was also a lack of evidence on antimicrobial resistance associated with the use of mupirocin and chlorhexidine body wash. The committee agreed that it would be helpful to encourage service providers to maintain surveillance on antimicrobial resistance associated with the use of mupirocin. This would allow any increase in resistance to be captured.
The committee developed a research recommendation on the effectiveness of nasal mupirocin with chlorhexidine body wash across all surgical procedures to help determine whether this should be extended to all people having surgery. Antimicrobial resistance associated with the use of chlorhexidine body wash was also identified by the committee as an important area for a research recommendation.
## How the recommendations might affect practice
There is considerable variability in practice. In some services decolonisation is always offered before certain types of surgery, for example, before orthopaedic surgery. In other services decolonisation is offered only to people who are identified as methicillin-resistant S. aureus (MRSA) or methicillin-sensitive S. aureus (MSSA) carriers.
The new recommendation reflects best practice and allows services the flexibility to consider decolonisation for people who are likely to benefit the most. The recommendation may reduce surgical site infections in people undergoing surgical procedures for which the consequences of an infection are severe, such as cardiac surgery. The evidence suggests that any additional costs incurred in providing decontamination are likely to be more than recouped by savings associated with a lower incidence of surgical site infections. However, the committee acknowledged that there may be training implications for those implementing the recommendation.
Maintenance of surveillance systems assessing antimicrobial resistance associated with the use of mupirocin will reinforce good practice.
Full details of the evidence and the committee's discussion are in evidence review A: nasal decontamination in the prevention of surgical site infection.
Return to recommendations
# Antiseptic skin preparation
Recommendations 1.3.7 to 1.3.10
## Why the committee made the recommendations
Based on their knowledge and experience, the committee agreed that an antiseptic should be used for skin preparation before surgery. Overall, the evidence showed that chlorhexidine in alcohol was associated with the lowest incidence of surgical site infections, whereas aqueous povidone-iodine was associated with the highest incidence. An economic analysis also showed that chlorhexidine in alcohol is likely to be cost effective. Based on the evidence, the committee agreed that an alcohol-based solution of chlorhexidine should usually be the first choice when deciding which antiseptic preparation to use. However, the quality of the studies was not good enough for the committee to make a strong recommendation for the choice of antiseptic preparation.
The committee discussed that alcohol-based solutions should not be applied to mucous membranes because of the risk of burns. For surgical procedures next to mucous membranes, they agreed to recommend an aqueous solution of chlorhexidine as an option for skin preparation. Because of the limited evidence, the committee were unable to make a strong recommendation.
There was little evidence to support the use of povidone-iodine, but based on their clinical experience the committee agreed that it should be an option when chlorhexidine is contraindicated, for example, in people with hypersensitivity to chlorhexidine.
There was no evidence on the use of skin antiseptics in babies. However, the committee were aware of risks, such as burns, associated with their use in this population, and wished to highlight this. The committee noted that the MHRA has published MHRA advice on the use of chlorhexidine for skin disinfection in premature babies.
The committee also discussed that some operative procedures may require diathermy. This means that precautions must be taken when using alcohol-based antiseptic solutions because they are flammable and can result in burns. Along with using evaporation to dry antiseptic skin preparations and avoiding pooling, the committee also agreed that soaked materials, drapes or gowns should be removed before diathermy, excessive quantities of alcohol antiseptics should not be used and no excess product should be present before applying an occlusive dressing.
The committee agreed that further research is needed to establish the effectiveness of different concentrations of chlorhexidine in reducing the risk of surgical site infections. Therefore the committee made a research recommendation to examine this further.
## How the recommendations might affect practice
Antiseptic skin preparation before skin incision is standard practice although the type of antiseptic used varies depending on the type of surgery.
The recommendations follow current trends in practice and should reduce variation.
Full details of the evidence and the committee's discussion are in evidence review B: skin antiseptics in the prevention of surgical site infection.
Return to recommendations
# Antiseptics and antibiotics before wound closure
Recommendations 1.3.18 and 1.3.19
## Why the committee made the recommendations
Limited evidence was identified on the intraoperative use of topical wound antiseptics before wound closure. Although this evidence suggested that topical povidone-iodine was effective in reducing surgical site infections, the studies were dated. This evidence also suggested that topical antiseptics, such as iodine in alcohol solution, are not effective in reducing surgical site infections.
The evidence on topical antibiotics before wound closure was varied, but also included several older studies. Some studies showed that antibiotics, such as ampicillin powder and cephaloridine, reduced the number of surgical site infections. However, the evidence for other antibiotics, such as vancomycin, which is widely used worldwide and commonly used in cardiac, orthopaedic and spine surgery, suggested no reduction in surgical site infections.
The committee agreed that the evidence was not current or clear enough to make a recommendation on the use of topical antiseptics and antibiotics before wound closure. The committee also took into account concerns about antimicrobial resistance and the potential for multidrug resistance, and agreed that without new conclusive evidence, use of intraoperative topical antibiotic and antiseptics should be stopped. They agreed that this is an important area for further research and recommended that they should be considered only in the context of further research to help limit unnecessary use and determine their clinical effectiveness. They also developed a research recommendation to determine the clinical and cost effectiveness of applying antiseptics and antibiotics before wound closure.
There was some economic evidence that antibiotic-loaded bone cement was cost effective when compared with plain cement. However, the committee were not confident that the evidence was applicable to current NHS practice. In addition, the clinical evidence suggested that antibiotic-loaded bone cement did not reduce the number of surgical site infections. The committee agreed that the evidence was too limited to make a recommendation for this intervention.
Evidence was also identified on the use of gentamicin implants before skin closure during different surgical procedures. In particular, the evidence suggested that gentamicin-collagen implants reduced the incidence of surgical site infections in people at 1 month and 2 months after cardiac surgery. Although the evidence was limited, cardiac surgery is associated with a high risk of surgical site infection, which is expensive to manage. Therefore, the committee agreed that gentamicin-collagen implants should be an option to reduce the risk of infection.
## How the recommendations might affect practice
In practice, the use of topical antiseptics and antibiotics before wound closure varies. Limiting their use to clinical trials is likely to reduce their misuse in practice and encourage research in this area.
Although gentamicin-collagen implants are used in cardiac surgery, not all services currently use them. The new recommendation may help to reduce variation and standardise practice. Any additional costs are likely to be balanced by savings from a reduction in the number of surgical site infections.
Full details of the evidence and the committee's discussion are in evidence review C: intraoperative antiseptics and antibiotics before wound closure.
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# Closure methods
Recommendations 1.3.20 and 1.3.21
## Why the committee made the recommendations
Overall, the evidence suggested that staples increase the incidence of wound dehiscence when compared with sutures for wound closure across different types of surgery. However, when the studies were analysed according to the type of surgery, many of the studies showing this difference were found to be on wound closure after caesarean section. The committee agreed that there was not enough evidence to recommend sutures over staples in all surgery, and decided to focus the recommendation on caesarean section. The committee agreed that this was important in improving recovery for women having caesarean sections, and that it should be reflected in the recommendations. However, the committee noted that the evidence did not capture all populations, for example obese women. Therefore, the recommendation was made to consider sutures rather than staples.
The committee discussed the evidence for antimicrobial triclosan-coated sutures and agreed that the evidence overall favoured triclosan-coated sutures over standard sutures for reducing surgical site infection. However, they noted that the studies covered many different types of surgery and were of variable quality, meaning that it was difficult to be confident of the benefit. Further analysis by the type of surgery showed a clear benefit of using triclosan-coated sutures only in paediatric surgery. The committee therefore agreed that they should be considered as an option for wound closure in all types of surgery, and that their use in paediatric surgery should be emphasised in particular. The committee also developed a research recommendation to better clarify which patients should have triclosan-coated sutures and which surgical layers they should be used for.
## How the recommendations might affect practice
The recommendations are unlikely to have a major effect on current practice. Current practice in wound closure varies, so the new recommendations may help to reduce variation and standardise practice.
Using sutures rather than staples for wound closure in caesarean section may lead to a reduction in the number of women experiencing wound dehiscence following surgery, which may reduce the costs of treatment. However, the committee acknowledged that there may be training implications for those implementing the recommendation.
Use of antimicrobial triclosan-coated sutures may increase, which may have cost implications because they are more expensive than standard sutures. However, it is likely that the increased cost will be outweighed by savings from a reduction in the number of surgical site infections, which are costly to treat.
Full details of the evidence and the committee's discussion are in evidence review D: closure materials and techniques in the prevention of surgical site infection.
Return to recommendations# Context
Surgical site infection is a type of healthcare-associated infection in which a wound infection occurs after an invasive (surgical) procedure. Other types of healthcare-associated infections that mainly affect surgical patients are postoperative respiratory and urinary tract infections, bacteraemias (including methicillin-resistant Staphylococcus aureus infections and intravascular cannula infections) and antibiotic-related diarrhoeas (particularly Clostridium difficile enteritis). Surgical site infections have been shown to compose up to 20% of all healthcare-associated infections. At least 5% of patients undergoing a surgical procedure develop a surgical site infection.
A surgical site infection may range from a spontaneously limited wound discharge within 7 to 10 days of an operation to a life-threatening postoperative complication, such as a sternal infection after open heart surgery. Most surgical site infections are caused by contamination of an incision with microorganisms from the patient's own body during surgery. Infection caused by microorganisms from an outside source following surgery is less common. Most surgical site infections are preventable. Measures can be taken in the pre-, intra- and postoperative phases of care to reduce the risk of infection.
Surgical site infections can have a significant effect on quality of life for the patient. They are associated with considerable morbidity and extended hospital stay. In addition, surgical site infections result in a considerable financial burden to healthcare providers. Advances in surgery and anaesthesia have resulted in patients who are at greater risk of surgical site infections being considered for surgery. In addition, increased numbers of infections are now being seen in primary care because patients are allowed home earlier following day case and fast-track surgery.
The guideline makes recommendations for prevention and management of surgical site infections based on rigorous evaluation of the best available published evidence.
The guideline will assume that prescribers will use a drug's summary of product characteristics to inform their decisions for individual patients. In addition, published identified characteristics of appropriate interactive dressings and antimicrobial products should be considered before use, and local formularies and guidelines based on local microbial resistance patterns should be used to inform choice of antibiotics.
In 2017, the NICE surveillance team reviewed the guideline and identified new evidence on nasal decolonisation, skin antiseptics, the use of antiseptics and antibiotics before wound closure, and closure methods. This evidence has been reviewed and the recommendations in these areas updated.# Finding more information and resources
You can see everything NICE says on surgical site infections in our NICE Pathway on prevention and control of healthcare-associated infections.
To find out what NICE has said on topics related to this guideline, see our web page on healthcare-associated infections.
For full details of the evidence and the guideline committee's discussions, see the evidence reviews. You can also find information about how the guideline was developed, including details of the committee.
NICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting NICE guidelines into practice see resources to help you put guidance into practice.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Information for patients and carers\n\nOffer patients and carers clear, consistent information and advice throughout all stages of their care. This should include the risks of surgical site infections, what is being done to reduce them and how they are managed. For more guidance on providing information to adults and discussing their preferences with them, see the NICE guideline on patient experience in adult NHS services. \n\nOffer patients and carers information and advice on how to care for their wound after discharge. \n\nOffer patients and carers information and advice about how to recognise a surgical site infection and who to contact if they are concerned. Use an integrated care pathway for healthcare-associated infections to help communicate this information to both patients and all those involved in their care after discharge. \n\nAlways inform patients after their operation if they have been given antibiotics. \n\n# Preoperative phase\n\n## Preoperative showering\n\nAdvise patients to shower or have a bath (or help patients to shower, bath or bed bath) using soap, either the day before, or on the day of, surgery. \n\n## Nasal decolonisation\n\nConsider nasal mupirocin in combination with a chlorhexidine body wash before procedures in which Staphylococcus aureus is a likely cause of a surgical site infection. This should be locally determined and take into account:\n\nthe type of procedure\n\nindividual patient risk factors\n\nthe increased risk of side effects in preterm infants (see recommendation 1.3.8)\n\nthe potential impact of infection. \n\nMaintain surveillance on antimicrobial resistance associated with the use of mupirocin. For information on antimicrobial stewardship programmes, see the NICE guideline on antimicrobial stewardship: systems and processes for effective antimicrobial medicine use. \n\nTo find out why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on nasal decolonisation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: nasal decontamination in the prevention of surgical site infection.\n\nLoading. Please wait.\n\n## Hair removal\n\nDo not use hair removal routinely to reduce the risk of surgical site infection. \n\nIf hair has to be removed, use electric clippers with a single-use head on the day of surgery. Do not use razors for hair removal, because they increase the risk of surgical site infection. \n\n## Patient theatre wear\n\nGive patients specific theatre wear that is appropriate for the procedure and clinical setting, and that provides easy access to the operative site and areas for placing devices, such as intravenous cannulas. Take into account the patient's comfort and dignity. \n\n## Staff theatre wear\n\nAll staff should wear specific non-sterile theatre wear in all areas where operations are undertaken. \n\n## Staff leaving the operating area\n\nStaff wearing non-sterile theatre wear should keep their movements in and out of the operating area to a minimum. \n\n## Mechanical bowel preparation\n\nDo not use mechanical bowel preparation routinely to reduce the risk of surgical site infection. \n\n## Hand jewellery, artificial nails and nail polish\n\nThe operating team should remove hand jewellery before operations. \n\nThe operating team should remove artificial nails and nail polish before operations. \n\n## Antibiotic prophylaxis\n\nGive antibiotic prophylaxis to patients before:\n\nclean surgery involving the placement of a prosthesis or implant\n\nclean-contaminated surgery\n\ncontaminated surgery. For advice on antibiotic prophylaxis before caesarean section, see the section on surgical techniques for caesarean section: timing of antibiotic administration in NICE's guideline on caesarean section. For information on antimicrobial stewardship programmes see the NICE guideline on antimicrobial stewardship: systems and processes for effective antimicrobial medicine use.\n\nDo not use antibiotic prophylaxis routinely for clean non-prosthetic uncomplicated surgery. \n\nUse the local antibiotic formulary and always take into account the potential adverse effects when choosing specific antibiotics for prophylaxis. \n\nConsider giving a single dose of antibiotic prophylaxis intravenously on starting anaesthesia. However, give prophylaxis earlier for operations in which a tourniquet is used. \n\nBefore giving antibiotic prophylaxis, take into account the timing and pharmacokinetics (for example, the serum half-life) and necessary infusion time of the antibiotic. Give a repeat dose of antibiotic prophylaxis when the operation is longer than the half-life of the antibiotic given. \n\nGive antibiotic treatment (in addition to prophylaxis) to patients having surgery on a dirty or infected wound. \n\nInform patients before the operation, whenever possible, if they will need antibiotic prophylaxis, and afterwards if they have been given antibiotics during their operation. \n\n# Intraoperative phase\n\n## Hand decontamination\n\nThe operating team should wash their hands prior to the first operation on the list using an aqueous antiseptic surgical solution, with a single-use brush or pick for the nails, and ensure that hands and nails are visibly clean. \n\nBefore subsequent operations, hands should be washed using either an alcoholic hand rub or an antiseptic surgical solution. If hands are soiled then they should be washed again with an antiseptic surgical solution. \n\n## Incise drapes\n\nDo not use non-iodophor-impregnated incise drapes routinely for surgery as they may increase the risk of surgical site infection. \n\nIf an incise drape is required, use an iodophor-impregnated drape unless the patient has an iodine allergy. \n\n## Sterile gowns\n\nThe operating team should wear sterile gowns in the operating theatre during the operation. \n\n## Gloves\n\nConsider wearing 2 pairs of sterile gloves when there is a high risk of glove perforation and the consequences of contamination may be serious. \n\n## Antiseptic skin preparation\n\nPrepare the skin at the surgical site immediately before incision using an antiseptic preparation. \n\nBe aware of the risks of using skin antiseptics in babies, in particular the risk of severe chemical injuries with the use of chlorhexidine (both alcohol-based and aqueous solutions) in preterm babies. \n\nWhen deciding which antiseptic skin preparation to use, options may include those in table\xa01. \n\n\n\nWhen\n\nChoice of antiseptic skin preparation\n\nFirst choice unless contraindicated or the surgical site is next to a mucous membrane\n\nAlcohol-based solution of chlorhexidine\n\nAt the time of publication (April 2019), 0.5% chlorhexidine in 70% alcohol solution (Hydrex; Prevase) was licensed for 'preoperative skin disinfection prior to minor surgical procedures' and 2.0% chlorhexidine in 70% alcohol applicators (ChloraPrep) was licensed for 'disinfection of the skin prior to invasive medical procedures'. Some formulations of chlorhexidine in alcohol were off label for this use. See NICE's information on prescribing medicines.\n\nAlternative if the surgical site is next to a mucous membrane\n\nAqueous solution of chlorhexidine\n\nAt the time of publication (April 2019), 4.0% aqueous chlorhexidine (Hibiscrub) was licensed for 'preoperative and postoperative skin antisepsis for patients undergoing elective surgery'; however, relevant instructions were limited to use as a body wash to be used before the person enters the operating theatre. Other formulations of aqueous chlorhexidine were off label for this use. See NICE's information on prescribing medicines.\n\nAlternative if chlorhexidine is contraindicated\n\nAlcohol-based solution of povidone-iodine\n\nAt the time of publication (April 2019), 10% povidone-iodine alcoholic solution (Videne alcoholic tincture) was licensed for 'topical application'. 10% povidone-iodine (Betadine Alcoholic solution) was licensed for 'antiseptic skin cleanser for major and minor surgical procedures'. Other formulations of povidone-iodine alcoholic solution were off label for this use. See NICE's information on prescribing medicines.\n\nIf both an alcohol-based solution and chlorhexidine are unsuitable\n\nAqueous solution of povidone-iodine\n\nAt the time of publication (April 2019), 7.5% povidone-iodine surgical scrub solution (Videne) was licensed for disinfecting the site of incision prior to elective surgery' and 7.5% povidone-iodine (Betadine surgical scrub) was licensed for 'preoperative preparation of patients' skin'. 10% iodine antiseptic solution (Videne) was licensed for 'disinfection of intact external skin or as a mucosal antiseptic' and 10% povidone-iodine solution (Standardised Betadine antiseptic solution) was licensed for 'preoperative and postoperative antiseptic skin cleanser for major and minor surgical procedures'. Other formulations of povidone-iodine aqueous solution were off label for this use. See NICE's information on prescribing medicines.\n\nIf diathermy is to be carried out:\n\nuse evaporation to dry antiseptic skin preparations and\n\navoid pooling of alcohol-based preparations. \n\nTo find out why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on antiseptic skin preparation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B: skin antiseptics in the prevention of surgical site infection.\n\nLoading. Please wait.\n\n## Diathermy\n\nDo not use diathermy for surgical incision to reduce the risk of surgical site infection. \n\n## Maintaining patient homeostasis\n\nMaintain patient temperature in line with NICE's guideline on hypothermia: prevention and management in adults having surgery. \n\nMaintain optimal oxygenation during surgery. In particular, give patients sufficient oxygen during major surgery and in the recovery period to ensure that a haemoglobin saturation of more than 95% is maintained. \n\nMaintain adequate perfusion during surgery. See additional recommendations on intravenous fluids and cardiac monitoring for adults in NICE's guideline on perioperative care in adults. [2008, amended 2020]\n\nDo not give insulin routinely to patients who do not have diabetes to optimise blood glucose postoperatively as a means of reducing the risk of surgical site infection. See the additional recommendation on blood glucose control for adults in NICE's guideline on perioperative care in adults. [2008, amended 2020]\n\n## Wound irrigation and intracavity lavage\n\nDo not use wound irrigation to reduce the risk of surgical site infection. \n\nDo not use intracavity lavage to reduce the risk of surgical site infection. \n\n## Antiseptics and antibiotics before wound closure\n\nOnly apply an antiseptic or antibiotic to the wound before closure as part of a clinical research trial. \n\nConsider using gentamicin-collagen implants in cardiac surgery. \n\nTo find out why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on antiseptics and antibiotics before wound closure\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: intraoperative antiseptics and antibiotics before wound closure.\n\nLoading. Please wait.\n\n## Closure methods\n\nWhen using sutures, consider using antimicrobial triclosan-coated sutures, especially for paediatric surgery, to reduce the risk of surgical site infection. \n\nConsider using sutures rather than staples to close the skin after caesarean section to reduce the risk of superficial wound dehiscence.\n\nTo find out why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on closure methods\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: closure materials and techniques in the prevention of surgical site infection.\n\nLoading. Please wait.\n\n## Wound dressings\n\nCover surgical incisions with an appropriate interactive dressing at the end of the operation. \n\n# Postoperative phase\n\n## Changing dressings\n\nUse an aseptic non-touch technique for changing or removing surgical wound dressings. \n\n## Postoperative cleansing\n\nUse sterile saline for wound cleansing up to 48\xa0hours after surgery. \n\nAdvise patients that they may shower safely 48\xa0hours after surgery. \n\nUse tap water for wound cleansing after 48\xa0hours if the surgical wound has separated or has been surgically opened to drain pus. \n\n## Topical antimicrobial agents for wound healing by primary intention\n\nDo not use topical antimicrobial agents for surgical wounds that are healing by primary intention to reduce the risk of surgical site infection. \n\n## Dressings for wound healing by secondary intention\n\nDo not use Eusol and gauze, or moist cotton gauze or mercuric antiseptic solutions to manage surgical wounds that are healing by secondary intention. \n\nUse an appropriate interactive dressing to manage surgical wounds that are healing by secondary intention. \n\nAsk a tissue viability nurse (or another healthcare professional with tissue viability expertise) for advice on appropriate dressings for the management of surgical wounds that are healing by secondary intention. \n\n## Antibiotic treatment of surgical site infection and treatment failure\n\nWhen surgical site infection is suspected by the presence of cellulitis, either by a new infection or an infection caused by treatment failure, give the patient an antibiotic that covers the likely causative organisms. Consider local resistance patterns and the results of microbiological tests in choosing an antibiotic. For information on antimicrobial stewardship programmes see the NICE guideline on antimicrobial stewardship: systems and processes for effective antimicrobial medicine use. \n\n## Debridement\n\nDo not use Eusol and gauze, or dextranomer or enzymatic treatments for debridement in the management of surgical site infection. \n\n## Specialist wound care services\n\nUse a structured approach to care to improve overall management of surgical wounds. This should include preoperative assessments to identify people with potential wound healing problems. Enhanced education of healthcare workers, patients and carers, and sharing of clinical expertise is needed to support this. \n\n# Terms used in this guideline\n\n## Decolonisation\n\nThe process of eradicating or reducing asymptomatic carriage of methicillin-resistant S. aureus (MRSA). This used to be referred to as decontamination.\n\n## Healing by primary intention\n\nOccurs when a wound has been sutured after an operation and heals to leave a minimal, cosmetically acceptable scar.\n\n## Healing by secondary intention\n\nOccurs when a wound is deliberately left open at the end of an operation because of excessive bacterial contamination, particularly by anaerobes or when there is a risk of devitalised tissue, which leads to infection and delayed healing. It may be sutured within a few days (delayed primary closure), or much later when the wound is clean and granulating (secondary closure), or left to complete healing naturally without suturing.\n\n## Interactive dressing\n\nDressings designed to promote the wound healing process through the creation and maintenance of a local, warm, moist environment underneath the chosen dressing, when left in place for a period indicated through a continuous assessment process.\n\n## Surgical site (wound) infection\n\nA surgical wound with local signs and symptoms of infection, for example, heat, redness, pain and swelling, and (in more serious cases) with systemic signs of fever or a raised white blood cell count. Infection in the surgical wound may prevent healing, causing the wound edges to separate, or it may cause an abscess to form in the deeper tissues.\n\nDefinitions of the severity of surgical site infections vary and this should be taken into account when comparing reported rates of surgical site infection.\n\n## Surgical wound classification\n\nClean: an incision in which no inflammation is encountered in a surgical procedure, without a break in sterile technique, and during which the respiratory, alimentary or genitourinary tracts are not entered.\n\nClean-contaminated: an incision through which the respiratory, alimentary, or genitourinary tract is entered under controlled conditions but with no contamination encountered.\n\nContaminated: an incision undertaken during an operation in which there is a major break in sterile technique or gross spillage from the gastrointestinal tract, or an incision in which acute, non-purulent inflammation is encountered. Open traumatic wounds that are more than 12 to 24 hours old also fall into this category.\n\nDirty or infected: an incision undertaken during an operation in which the viscera are perforated or when acute inflammation with pus is encountered (for example, emergency surgery for faecal peritonitis), and for traumatic wounds if treatment is delayed, there is faecal contamination, or devitalised tissue is present", 'Recommendations for research': "The 2008 guideline committee made the following recommendations for research marked . The guideline committee's full set of research recommendations is detailed in the 2008 full guideline.\n\nAs part of the 2019 update, the guideline committee updated research recommendations on nasal decolonisation and wound closure methods, and made new research recommendations on antiseptic skin preparation and antiseptics and antibiotics before wound closure. These are marked .\n\n# Key recommendations for research\n\n## Nasal decolonisation: effectiveness\n\nWhat is the clinical effectiveness of preoperative nasal decolonisation using mupirocin in combination with a chlorhexidine body wash in the whole population? \n\n## Nasal decolonisation: antimicrobial resistance\n\nIs the use of chlorhexidine body wash associated with increased antimicrobial resistance? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on nasal decolonisation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: nasal decontamination in the prevention of surgical site infection.\n\nLoading. Please wait.\n\n## Antiseptic skin preparation\n\nWhat is the clinical and cost effectiveness of chlorhexidine in alcohol at different concentrations in the prevention of surgical site infection when applied to the skin before incision? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on antiseptic skin preparation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B: skin antiseptics in the prevention of surgical site infection.\n\nLoading. Please wait.\n\n## Antiseptics and antibiotics before wound closure\n\nIs the application of antiseptics and antibiotics in the operative field before wound closure, clinically and cost effective in reducing surgical site infection rates? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on antiseptics and antibiotics before wound closure\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: intraoperative antiseptics and antibiotics before wound closure.\n\nLoading. Please wait.\n\n## Closure methods\n\nWhich patient groups, contamination groups and which layers gain the most benefit from the use of triclosan-coated or triclosan-impregnated sutures? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on closure methods\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: closure materials and techniques in the prevention of surgical site infection.\n\nLoading. Please wait.\n\n# Other recommendations for research\n\n## Nasal decolonisation: effectiveness\n\nWhat is the contribution to clinical effectiveness of the timing of nasal decolonisation and body wash for the prevention of surgical site infection? \n\nWhat is the effectiveness of decolonisation using alternative interventions in combination with nasal decolonisation in the prevention of surgical site infections when chlorhexidine is contraindicated? \n\n## Antiseptic skin preparation\n\nWhat is the clinical and cost effectiveness of a double application of antiseptic to the skin at the surgical site compared with a single application? \n\nWhat is the clinical and cost effectiveness of different modes of applying skin antiseptic before incision in the prevention of surgical site infection? \n\n## Closure methods\n\nDoes the use of barbed sutures for wound closure reduce the incidence of surgical site infection? \n\nWhich closure method or technique is the most effective for reducing surgical site infections in patients undergoing emergency surgery? ", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.\n\n# Nasal decolonisation\n\nRecommendations 1.2.2 to 1.2.3\n\n## Why the committee made the recommendations\n\nEvidence was identified on the use of mupirocin alone and mupirocin in combination with a chlorhexidine body wash. Mupirocin alone was effective in reducing Staphylococcus aureus infections caught in hospital in people who were identified as carriers of S.\xa0aureus. However, mupirocin alone did not reduce surgical site infections across all people undergoing surgery.\n\nThe evidence also showed that people identified as carriers of S.\xa0aureus who used nasal mupirocin in combination with a chlorhexidine body wash before surgery had fewer surgical site infections caused by S.\xa0aureus (including deep infections, methicillin-sensitive infections and infections caught in hospital) than those who did not have the intervention. However, the evidence was very limited and only covered S.\xa0aureus carriers.\n\nEconomic studies favoured the use of mupirocin alone. However, the studies were not UK-based and could not be applied to NHS practice (for example, because of the high cost of treating surgical site infections in US studies). An economic model based on UK data demonstrated that, compared with no treatment, using mupirocin with a chlorhexidine body wash before all operations was an efficient use of resources in most specialist surgeries. However, there was less certainty of cost effectiveness for surgery with a low risk of surgical site infections caused by S.\xa0aureus.\n\nBecause of the limited evidence, the committee were unable to make strong recommendations on nasal decolonisation before surgery and agreed that it should not be offered to all people having surgery. The committee applied their clinical understanding and experience of current best practice, and recommended that nasal mupirocin with chlorhexidine body wash should be considered before procedures that have an increased risk of surgical site infection caused by S.\xa0aureus, for which there would be the most benefit.\n\nThe recommendation does not define the surgical procedures in which S.\xa0aureus is a likely cause of a surgical site infection. The committee agreed that although cardiac and orthopaedic surgery can be considered high risk, decisions should be made locally through discussions between surgical and infection control teams, and should also take into account patient risk factors, such as whether the person is an S.\xa0aureus carrier and the potential impact of infection on the person, including the cost of managing the infection. The recommendation does not give an optimal timing for nasal decolonisation because of a lack of evidence. But the committee were aware that mupirocin with chlorhexidine can be given from 2\xa0days before surgery to 3\xa0days after surgery.\n\nThe committee also took into consideration the potential side effects of mupirocin (such as a burning sensation and local reactions) and the cautions identified for the use of chlorhexidine solution in people with existing skin conditions and in preterm newborn babies. The committee noted that the Medicines and Healthcare products Regulatory Agency (MHRA) has published MHRA advice on the use of chlorhexidine for skin disinfection in premature babies.\n\nThere was also a lack of evidence on antimicrobial resistance associated with the use of mupirocin and chlorhexidine body wash. The committee agreed that it would be helpful to encourage service providers to maintain surveillance on antimicrobial resistance associated with the use of mupirocin. This would allow any increase in resistance to be captured.\n\nThe committee developed a research recommendation on the effectiveness of nasal mupirocin with chlorhexidine body wash across all surgical procedures to help determine whether this should be extended to all people having surgery. Antimicrobial resistance associated with the use of chlorhexidine body wash was also identified by the committee as an important area for a research recommendation.\n\n## How the recommendations might affect practice\n\nThere is considerable variability in practice. In some services decolonisation is always offered before certain types of surgery, for example, before orthopaedic surgery. In other services decolonisation is offered only to people who are identified as methicillin-resistant S.\xa0aureus (MRSA) or methicillin-sensitive S.\xa0aureus (MSSA) carriers.\n\nThe new recommendation reflects best practice and allows services the flexibility to consider decolonisation for people who are likely to benefit the most. The recommendation may reduce surgical site infections in people undergoing surgical procedures for which the consequences of an infection are severe, such as cardiac surgery. The evidence suggests that any additional costs incurred in providing decontamination are likely to be more than recouped by savings associated with a lower incidence of surgical site infections. However, the committee acknowledged that there may be training implications for those implementing the recommendation.\n\nMaintenance of surveillance systems assessing antimicrobial resistance associated with the use of mupirocin will reinforce good practice.\n\nFull details of the evidence and the committee's discussion are in evidence review A: nasal decontamination in the prevention of surgical site infection.\n\nReturn to recommendations\n\n# Antiseptic skin preparation\n\nRecommendations 1.3.7 to 1.3.10\n\n## Why the committee made the recommendations\n\nBased on their knowledge and experience, the committee agreed that an antiseptic should be used for skin preparation before surgery. Overall, the evidence showed that chlorhexidine in alcohol was associated with the lowest incidence of surgical site infections, whereas aqueous povidone-iodine was associated with the highest incidence. An economic analysis also showed that chlorhexidine in alcohol is likely to be cost effective. Based on the evidence, the committee agreed that an alcohol-based solution of chlorhexidine should usually be the first choice when deciding which antiseptic preparation to use. However, the quality of the studies was not good enough for the committee to make a strong recommendation for the choice of antiseptic preparation.\n\nThe committee discussed that alcohol-based solutions should not be applied to mucous membranes because of the risk of burns. For surgical procedures next to mucous membranes, they agreed to recommend an aqueous solution of chlorhexidine as an option for skin preparation. Because of the limited evidence, the committee were unable to make a strong recommendation.\n\nThere was little evidence to support the use of povidone-iodine, but based on their clinical experience the committee agreed that it should be an option when chlorhexidine is contraindicated, for example, in people with hypersensitivity to chlorhexidine.\n\nThere was no evidence on the use of skin antiseptics in babies. However, the committee were aware of risks, such as burns, associated with their use in this population, and wished to highlight this. The committee noted that the MHRA has published MHRA advice on the use of chlorhexidine for skin disinfection in premature babies.\n\nThe committee also discussed that some operative procedures may require diathermy. This means that precautions must be taken when using alcohol-based antiseptic solutions because they are flammable and can result in burns. Along with using evaporation to dry antiseptic skin preparations and avoiding pooling, the committee also agreed that soaked materials, drapes or gowns should be removed before diathermy, excessive quantities of alcohol antiseptics should not be used and no excess product should be present before applying an occlusive dressing.\n\nThe committee agreed that further research is needed to establish the effectiveness of different concentrations of chlorhexidine in reducing the risk of surgical site infections. Therefore the committee made a research recommendation to examine this further.\n\n## How the recommendations might affect practice\n\nAntiseptic skin preparation before skin incision is standard practice although the type of antiseptic used varies depending on the type of surgery.\n\nThe recommendations follow current trends in practice and should reduce variation.\n\nFull details of the evidence and the committee's discussion are in evidence review B: skin antiseptics in the prevention of surgical site infection.\n\nReturn to recommendations\n\n# Antiseptics and antibiotics before wound closure\n\nRecommendations 1.3.18 and 1.3.19\n\n## Why the committee made the recommendations\n\nLimited evidence was identified on the intraoperative use of topical wound antiseptics before wound closure. Although this evidence suggested that topical povidone-iodine was effective in reducing surgical site infections, the studies were dated. This evidence also suggested that topical antiseptics, such as iodine in alcohol solution, are not effective in reducing surgical site infections.\n\nThe evidence on topical antibiotics before wound closure was varied, but also included several older studies. Some studies showed that antibiotics, such as ampicillin powder and cephaloridine, reduced the number of surgical site infections. However, the evidence for other antibiotics, such as vancomycin, which is widely used worldwide and commonly used in cardiac, orthopaedic and spine surgery, suggested no reduction in surgical site infections.\n\nThe committee agreed that the evidence was not current or clear enough to make a recommendation on the use of topical antiseptics and antibiotics before wound closure. The committee also took into account concerns about antimicrobial resistance and the potential for multidrug resistance, and agreed that without new conclusive evidence, use of intraoperative topical antibiotic and antiseptics should be stopped. They agreed that this is an important area for further research and recommended that they should be considered only in the context of further research to help limit unnecessary use and determine their clinical effectiveness. They also developed a research recommendation to determine the clinical and cost effectiveness of applying antiseptics and antibiotics before wound closure.\n\nThere was some economic evidence that antibiotic-loaded bone cement was cost effective when compared with plain cement. However, the committee were not confident that the evidence was applicable to current NHS practice. In addition, the clinical evidence suggested that antibiotic-loaded bone cement did not reduce the number of surgical site infections. The committee agreed that the evidence was too limited to make a recommendation for this intervention.\n\nEvidence was also identified on the use of gentamicin implants before skin closure during different surgical procedures. In particular, the evidence suggested that gentamicin-collagen implants reduced the incidence of surgical site infections in people at 1\xa0month and 2\xa0months after cardiac surgery. Although the evidence was limited, cardiac surgery is associated with a high risk of surgical site infection, which is expensive to manage. Therefore, the committee agreed that gentamicin-collagen implants should be an option to reduce the risk of infection.\n\n## How the recommendations might affect practice\n\nIn practice, the use of topical antiseptics and antibiotics before wound closure varies. Limiting their use to clinical trials is likely to reduce their misuse in practice and encourage research in this area.\n\nAlthough gentamicin-collagen implants are used in cardiac surgery, not all services currently use them. The new recommendation may help to reduce variation and standardise practice. Any additional costs are likely to be balanced by savings from a reduction in the number of surgical site infections.\n\nFull details of the evidence and the committee's discussion are in evidence review C: intraoperative antiseptics and antibiotics before wound closure.\n\nReturn to recommendations\n\n# Closure methods\n\nRecommendations 1.3.20 and 1.3.21\n\n## Why the committee made the recommendations\n\nOverall, the evidence suggested that staples increase the incidence of wound dehiscence when compared with sutures for wound closure across different types of surgery. However, when the studies were analysed according to the type of surgery, many of the studies showing this difference were found to be on wound closure after caesarean section. The committee agreed that there was not enough evidence to recommend sutures over staples in all surgery, and decided to focus the recommendation on caesarean section. The committee agreed that this was important in improving recovery for women having caesarean sections, and that it should be reflected in the recommendations. However, the committee noted that the evidence did not capture all populations, for example obese women. Therefore, the recommendation was made to consider sutures rather than staples.\n\nThe committee discussed the evidence for antimicrobial triclosan-coated sutures and agreed that the evidence overall favoured triclosan-coated sutures over standard sutures for reducing surgical site infection. However, they noted that the studies covered many different types of surgery and were of variable quality, meaning that it was difficult to be confident of the benefit. Further analysis by the type of surgery showed a clear benefit of using triclosan-coated sutures only in paediatric surgery. The committee therefore agreed that they should be considered as an option for wound closure in all types of surgery, and that their use in paediatric surgery should be emphasised in particular. The committee also developed a research recommendation to better clarify which patients should have triclosan-coated sutures and which surgical layers they should be used for.\n\n## How the recommendations might affect practice\n\nThe recommendations are unlikely to have a major effect on current practice. Current practice in wound closure varies, so the new recommendations may help to reduce variation and standardise practice.\n\nUsing sutures rather than staples for wound closure in caesarean section may lead to a reduction in the number of women experiencing wound dehiscence following surgery, which may reduce the costs of treatment. However, the committee acknowledged that there may be training implications for those implementing the recommendation.\n\nUse of antimicrobial triclosan-coated sutures may increase, which may have cost implications because they are more expensive than standard sutures. However, it is likely that the increased cost will be outweighed by savings from a reduction in the number of surgical site infections, which are costly to treat.\n\nFull details of the evidence and the committee's discussion are in evidence review D: closure materials and techniques in the prevention of surgical site infection.\n\nReturn to recommendations", 'Context': "Surgical site infection is a type of healthcare-associated infection in which a wound infection occurs after an invasive (surgical) procedure. Other types of healthcare-associated infections that mainly affect surgical patients are postoperative respiratory and urinary tract infections, bacteraemias (including methicillin-resistant Staphylococcus aureus infections and intravascular cannula infections) and antibiotic-related diarrhoeas (particularly Clostridium difficile enteritis). Surgical site infections have been shown to compose up to 20% of all healthcare-associated infections. At least 5% of patients undergoing a surgical procedure develop a surgical site infection.\n\nA surgical site infection may range from a spontaneously limited wound discharge within 7\xa0to 10\xa0days of an operation to a life-threatening postoperative complication, such as a sternal infection after open heart surgery. Most surgical site infections are caused by contamination of an incision with microorganisms from the patient's own body during surgery. Infection caused by microorganisms from an outside source following surgery is less common. Most surgical site infections are preventable. Measures can be taken in the pre-, intra- and postoperative phases of care to reduce the risk of infection.\n\nSurgical site infections can have a significant effect on quality of life for the patient. They are associated with considerable morbidity and extended hospital stay. In addition, surgical site infections result in a considerable financial burden to healthcare providers. Advances in surgery and anaesthesia have resulted in patients who are at greater risk of surgical site infections being considered for surgery. In addition, increased numbers of infections are now being seen in primary care because patients are allowed home earlier following day case and fast-track surgery.\n\nThe guideline makes recommendations for prevention and management of surgical site infections based on rigorous evaluation of the best available published evidence.\n\nThe guideline will assume that prescribers will use a drug's summary of product characteristics to inform their decisions for individual patients. In addition, published identified characteristics of appropriate interactive dressings and antimicrobial products should be considered before use, and local formularies and guidelines based on local microbial resistance patterns should be used to inform choice of antibiotics.\n\nIn 2017, the NICE surveillance team reviewed the guideline and identified new evidence on nasal decolonisation, skin antiseptics, the use of antiseptics and antibiotics before wound closure, and closure methods. This evidence has been reviewed and the recommendations in these areas updated.", 'Finding more information and resources': "You can see everything NICE says on surgical site infections in our NICE Pathway on prevention and control of healthcare-associated infections.\n\nTo find out what NICE has said on topics related to this guideline, see our web page on healthcare-associated infections.\n\nFor full details of the evidence and the guideline committee's discussions, see the evidence reviews. You can also find information about how the guideline was developed, including details of the committee.\n\nNICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting NICE guidelines into practice see resources to help you put guidance into practice."}
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https://www.nice.org.uk/guidance/ng125
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This guideline covers preventing and treating surgical site infections in adults, young people and children who are having a surgical procedure involving a cut through the skin. It focuses on methods used before, during and after surgery to minimise the risk of infection.
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0ff4c69cbe94f16a9405263fc4266125a3de209a
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nice
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Perioperative care in adults
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Perioperative care in adults
This guideline covers care for adults (aged 18 and over) having elective or emergency surgery, including dental surgery. It covers all phases of perioperative care, from the time people are booked for surgery until they are discharged afterward. The guideline includes recommendations on preparing for surgery, keeping people safe during surgery and pain relief during recovery.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Information and support for people having surgery
## Providing a point of contact
When booking surgery, give people a point of contact within the perioperative care team who can be approached for information and support before and after their surgery.
For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on information and support for people having surgery .
Full details of the evidence and the committee's discussion are in evidence review A: information and support needs.
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## Communicating and giving information
Follow the recommendations in the NICE guidelines on patient experience in adult NHS services and shared decision making, particularly relating to:
involvement of family members and carers
communication
information
shared decision making.
For people with a learning disability, follow the recommendations on communicating and making information accessible in the NICE guideline on care and support of people growing older with learning disabilities.
# Enhanced recovery programmes
Offer an enhanced recovery programme to people having elective major or complex surgery.
Use an enhanced recovery programme that includes preoperative, intraoperative and postoperative components.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on enhanced recovery programmes .
Full details of the evidence and the committee's discussion are in evidence review B: enhanced recovery programmes.
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# Preoperative care
## Assessing the risks of surgery
Use a validated risk stratification tool to supplement clinical assessment when planning surgery, including dental surgery. Discuss the person's risks and surgical options with them to allow for informed shared decision making.
Discuss lifestyle modifications with people having surgery, for example stopping smoking and reducing alcohol consumption. Follow the relevant NICE guidance on lifestyle and wellbeing.
## Preoperative optimisation clinics for older people
Be aware that there was not enough clear evidence to show whether the benefits of preoperative optimisation clinics for older people outweigh the costs. Therefore, the committee made a recommendation for research.
## Managing iron-deficiency anaemia
For people with iron-deficiency anaemia having surgery, follow the recommendations on intravenous and oral iron in the NICE guideline on blood transfusion.
Consider an alternate-day oral iron regimen for people who have side effects from taking oral iron every day.
Be aware that there was no evidence comparing different starting times for iron supplementation, so the committee made a recommendation for research.
Follow the recommendations in the NICE guideline on medicines adherence to encourage adherence to oral iron regimens.
## Reducing the risk of venous thromboembolism
Follow the recommendations on assessing and reducing the risk of venous thromboembolism for people having surgery in the NICE guideline on venous thromboembolism in over 16s.
## Anticoagulation for people taking a vitamin K antagonist who need bridging therapy
Be aware that there was no evidence comparing low molecular weight heparin with unfractionated heparin used as perioperative anticoagulant bridging therapy for people taking a vitamin K antagonist. The committee therefore made a recommendation for research.
## Nutritional assessment
Offer preoperative nutritional screening to people having intermediate surgery or major or complex surgery.
Follow the recommendations in the NICE guideline on nutrition support for adults on:
screening for malnutrition
indications for nutrition support
what to give.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on preoperative care .
Full details of the evidence and the committee's discussion are in:
evidence review C: preoperative risk stratification tools
evidence review D: preoperative optimisation clinics for older adults
evidence review E: preoperative management of anaemia
evidence review F: management of anticoagulant medication
evidence review G: nutritional screening in preoperative assessment.
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# Intraoperative care
## Managing fluids
Tell people having surgery, including dental surgery, that:
they may drink clear fluids until 2 hours before their operation
drinking clear fluids before the operation can help reduce headaches, nausea and vomiting afterwards
clear fluids are water, fruit juice without pulp, coffee or tea without milk and ice lollies.
Consider carbohydrate drinks before surgery for people having abdominal major or complex surgery.
Consider using intravenous crystalloid for intraoperative fluid maintenance.
Follow the recommendations in the NICE guideline on intravenous fluid therapy in adults in hospital on resuscitation and routine maintenance.
## Cardiac output monitoring
Consider cardiac output monitoring for people having major or complex surgery or high-risk surgery.
## Blood glucose control
For people with type 1 diabetes, follow the recommendations on care of adults with type 1 diabetes in hospital in the NICE guideline on type 1 diabetes in adults.
Do not use glucose-lowering medicines to achieve tight blood glucose control (4 to 6 mmol/litre) for people having surgery who have type 2 diabetes or do not have diabetes.
## Surgical safety checklists
Ensure that the World Health Organization (WHO) surgical safety checklist is completed for each surgical procedure, including dental procedures.
Consider adding steps to the WHO surgical safety checklist to eliminate preventable events reported locally or nationally, such as those in NHS Improvement's national patient safety alerts and surgical 'never events'. Follow the WHO surgical safety checklist implementation manual when adding steps to the checklist.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on intraoperative care .
Full details of the evidence and the committee's discussion are in:
evidence review H: preoperative fasting
evidence review I: intravenous fluid management strategy
evidence review J: non-invasive cardiac output monitoring
evidence review K: blood glucose control management
evidence review L: management systems to promote safety in operating theatres.
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# Postoperative care
Provide postoperative care in a specialist recovery area (a high-dependency unit, a post-anaesthesia care unit or an intensive care unit) for people with a high risk of complications or mortality.
For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on postoperative care .
Full details of the evidence and the committee's discussion are in evidence review M: postoperative recovery in specialist areas.
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# Managing pain
## Planning pain management
Discuss the options for postoperative pain management with people before they have surgery, including dental surgery. Take into account:
clinical features including comorbidities, age, frailty, renal and liver function, allergies, current medicines and cognitive function
whether the surgery is immediate, urgent, expedited or elective. Include in the discussion:
the likely impact of the procedure on the person's pain
the person's preferences and expectations
their pain history
the potential benefits and risks, including long-term risks, of different types of pain relief
plans for discharge.
## Selecting analgesia
Offer a multimodal approach in which analgesics from different classes are combined to manage postoperative pain. Take into account the factors listed in recommendation 1.6.1.
If controlled drugs are used, follow the recommendations on prescribing controlled drugs in the NICE guideline on controlled drugs.
Consider prescribing pre-emptive analgesia for use when local anaesthesia wears off.
Offer oral paracetamol before and after surgery, including dental surgery, irrespective of pain severity.
Do not offer intravenous paracetamol unless the person cannot take oral medicine.
Offer oral ibuprofen to manage immediate postoperative pain of all severities (including pain after dental surgery) unless the person has had surgery for hip fracture (see the recommendations on analgesia in the NICE guideline on hip fracture).
Do not offer an intravenous NSAID to manage immediate postoperative pain (including pain after dental surgery) unless the person cannot take oral medicine.
If offering an intravenous NSAID to manage immediate postoperative pain, choose a traditional NSAID rather than a COX‑2 (cyclo-oxygenase‑2) inhibitor.
Offer an oral opioid only if immediate postoperative pain is expected to be moderate to severe. When giving an oral opioid:
give the opioid as soon as the person can eat and drink after surgery
adjust the dose to help the person achieve functional recovery (such as coughing and mobilising) as soon as possible.
For people who cannot take oral opioids, offer a choice of PCA (patient-controlled analgesia) or a continuous epidural to relieve pain after surgery. Take into account the benefits of a continuous epidural for people who:
are having major or complex open‑torso surgery or
are expected to have severe pain or
have cognitive impairment.
Consider a single dose (0.25 mg/kg to 1 mg/kg) of intravenous ketamine given either during or immediately after surgery to supplement other types of pain relief if:
the person's pain is expected to be moderate to severe and an intravenous opioid alone does not provide adequate pain relief or
the person has opioid sensitivity. In August 2020, this was an off‑label use of intravenous ketamine. See NICE's information on prescribing medicines.
Be aware that, although there was evidence showing that the use of gabapentin to supplement other types of pain relief can be beneficial, the evidence about when to give gabapentin, and how much to give, was inconclusive. The committee therefore made a recommendation for research.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on managing pain .
Full details of the evidence and the committee's discussion are in:
evidence review A: information and support needs
evidence review N1: managing acute postoperative pain
evidence review N2: managing acute postoperative pain (appendices).
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# Terms used in this guideline
## Cardiac output monitoring
Interventions to monitor parameters such as stroke volume, cardiac output or central venous pressure to evaluate volume status and guide decisions on fluid replacement therapy.
## High-risk surgery
Surgery with a risk of mortality greater than 5%.
## Immediate postoperative pain
Pain during the first 24 hours after surgery.
## Intermediate surgery
Examples include primary repair of inguinal hernia, excising varicose veins in the leg, tonsillectomy or adenotonsillectomy, and knee arthroscopy.
## Major or complex surgery
Examples include total abdominal hysterectomy, endoscopic resection of prostate, lumbar discectomy, thyroidectomy, total joint replacement, lung operations, colonic resection and radical neck dissection.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Key recommendations for research
## Preoperative optimisation clinics for older people
What is the clinical and cost effectiveness of preoperative optimisation clinics for older people?
For a short explanation of why the committee made this recommendation for research, see the rationale on preoperative care .
Full details of the evidence and the committee's discussion are in evidence review D: preoperative optimisation clinics for older adults.
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## Oral iron supplementation
For people with iron-deficiency anaemia, how long before surgery should oral iron supplementation be started, and what is the clinical and cost effectiveness of daily oral iron compared with oral iron given on alternate days?
For a short explanation of why the committee made this recommendation for research, see the rationale on preoperative care .
Full details of the evidence and the committee's discussion are in evidence review E: preoperative management of anaemia.
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## Managing anticoagulation treatment for people taking a vitamin K antagonist who need bridging therapy
What is the most clinical and cost-effective strategy, as identified by a consensus survey, for the perioperative management of anticoagulation treatment in people taking a vitamin K antagonist with a target international normalised ratio (INR) of more than 3 who need bridging therapy?
For a short explanation of why the committee made this recommendation for research, see the rationale on preoperative care .
Full details of the evidence and the committee's discussion are in evidence review F: management of anticoagulant medication.
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## Enhanced recovery programmes
What is the clinical and cost effectiveness of enhanced recovery programmes for adults having major emergency surgery?
For a short explanation of why the committee made this recommendation for research, see the rationale on enhanced recovery programmes .
Full details of the evidence and the committee's discussion are in evidence review B: enhanced recovery programmes.
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## Specialist recovery areas
Which patients, other than those known to have a high risk of complications or mortality, would benefit from postoperative care in a specialist recovery area (a high-dependency unit, a post-anaesthesia care unit or an intensive care unit)?
For a short explanation of why the committee made this recommendation for research, see the rationale on postoperative care .
Full details of the evidence and the committee's discussion are in evidence review M: postoperative recovery in specialist areas.
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# Other recommendations for research
## Preoperative carbohydrate drinks
What is the optimal timing of administration of carbohydrate drinks as part of a preoperative fasting strategy?
For a short explanation of why the committee made this recommendation for research, see the rationale on intraoperative care .
Full details of the evidence and the committee's discussion are in evidence review H: preoperative fasting.
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## Single-dose gabapentin
What is the most clinically and cost-effective timing and dose of a single administration of gabapentin to relieve pain in people undergoing surgery whose pain is expected to be moderate to severe?
For a short explanation of why the committee made this recommendation for research, see the rationale on managing pain .
Full details of the evidence and the committee's discussion are in evidence review N2: managing acute postoperative pain (appendices).
Loading. Please wait.# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice.
# Information and support for people having surgery
Recommendation 1.1.1
## Why the committee made the recommendation
Evidence from studies using patient focus groups and face-to-face interviews showed that people place a high value on having information that is consistent and available when they need it. Patients in these studies stressed the importance of knowing who to contact if they have concerns or queries, particularly after discharge. The studies also illustrated how people's information needs change before, during and after surgery, with some postoperative patients reporting difficulty recalling information given to them before surgery. The committee agreed that their experience reflects the evidence. They also noted that people who feel well informed about their surgery and recovery are less anxious than those who do not.
The committee concurred that their recommendation, together with the recommendations in the NICE guidelines on patient experience in adult NHS services and care and support of people growing older with learning disabilities cover the information and support needed by adults during perioperative care.
## How the recommendation might affect practice
In larger hospitals the point of contact could be a specific team member such as a clinical nurse specialist. In smaller units the point of contact may need to be a team of people. The point of contact may change as people's needs change throughout the stages of perioperative care. In current practice the amount, availability and sources of information for people having surgery all vary. This recommendation is not expected to lead to major changes in practice.
Return to recommendations
# Enhanced recovery programmes
Recommendations 1.2.1 and 1.2.2
## Why the committee made the recommendations
There was a large body of evidence showing that hospital stays are shorter, postoperative complications less frequent and overall costs lower when people having elective major or complex surgery follow an enhanced recovery programme (ERP).
The committee agreed that, for optimum effectiveness, an ERP should span the preoperative, intraoperative and postoperative stages, so recommended that components covering all 3 stages be included. They acknowledged that the specific components of an ERP depend on the type of surgery so did not make recommendations detailing the particulars of these components.
There is no evidence on the effectiveness of ERPs in emergency surgery, but the committee thought they might be beneficial and made a recommendation for research on enhanced recovery programmes.
## How the recommendations might affect practice
According to the Perioperative Quality Improvement Programme (PQIP) 2017/2018 annual report, 61% of patients enrolled in the PQIP were following an ERP. The report noted that the use of ERPs varies across specialties and hospitals. To implement this recommendation, specialties and hospitals that do not currently provide an ERP covering all 3 stages of perioperative care for patients having major or complex elective surgery will need to restructure their surgical care. This might have an initial resource impact, although some features of an ERP, such as early mobilisation and early intake of food and fluids, are current practice in many hospitals. Introducing an ERP can be expected to reduce the length of hospital stays and the incidence of complications, thereby reducing overall costs.
Return to recommendations
# Preoperative care
Recommendations 1.3.1 to 1.3.11
## Why the committee made the recommendations
Validated preoperative risk stratification tools are freely available and can be completed rapidly. Although no risk stratification tool is 100% accurate, the evidence showed that validated tools are sufficiently accurate to be a useful supplement to clinical assessment.
The committee noted that a validated risk stratification tool can also help to frame discussions about risk with the person having surgery. This includes changes the person can make to reduce their risk, such as stopping smoking. The committee agreed that the risk of postoperative morbidity is an important concern for people when they are making decisions about surgery.
Preoperative optimisation clinics for older people are designed to reduce complications and deaths associated with surgery by proactively addressing risk factors identified during the preoperative assessment. These clinics are not available in all areas and are expensive to establish. Although a small number of studies suggested a possible improvement in surgical outcomes, the evidence was inconclusive. The committee decided that, because of the high cost and lack of clear evidence, they could not make a recommendation on these clinics. However, they agreed that this is an important area and made a recommendation for research on preoperative optimisation clinics for older people.
Oral iron supplements are usually taken daily but some people have unpleasant side effects from daily iron. The committee thought that, for these people, switching to an alternate-day regimen should be considered as a means of reducing side effects and encouraging adherence. They noted that an alternate-day regimen does not address problems with tolerability or absorption, and the potential benefits need to be balanced against the risk that an alternate-day regimen might be more complicated for people taking multiple daily medicines. There was no evidence on the comparative effectiveness of daily and alternate-day oral iron regimens.
In all of the studies, iron supplementation had been started about 3 weeks before surgery. In current practice, this varies. There were no studies that compared different starting times, so the committee were unable to determine the best time to start iron therapy before surgery.
The committee made a recommendation for research on oral iron supplementation.
People who take a vitamin K antagonist are at high risk of venous thromboembolism or stroke and therefore, it is usual practice to provide bridging anticoagulation during surgery with either subcutaneous low molecular weight heparin (LMWH) or intravenous unfractionated heparin (UFH). No clinical evidence was identified comparing LMWH with UFH in this high-risk group of patients. The committee noted that people who take a vitamin K antagonist with a target international normalised ratio (INR) of more than 3 and who need bridging therapy are a small proportion of the population taking vitamin K antagonists, and that many of these people have mechanical heart valves. Because of the lack of evidence, the committee made a recommendation for research on managing anticoagulation treatment for people taking a vitamin K antagonist who need bridging therapy.
No evidence on nutritional assessment was available. The committee noted that nutritional deficiency contributes to reduced physiological resilience, which is associated with increased complications and perioperative mortality. Because of this, they agreed that preoperative nutritional screening is useful for people having intermediate, major or complex surgery.
## How the recommendations might affect practice
Preoperative risk stratification tools are commonly used in current practice and the recommendation is not expected to change practice.
The option to consider switching from a daily to an alternate-day regimen might increase adherence to oral iron therapy in people who have unpleasant side effects from daily iron. This has the potential to reduce the need for blood transfusions and improve surgical outcomes for this group of people.
Preoperative nutritional assessment for intermediate, major or complex surgery is current practice and the recommendation is not expected to lead to changes in practice.
Return to recommendations
# Intraoperative care
Recommendations 1.4.1 to 1.4.9
## Why the committee made the recommendations
Some evidence showed that drinking water until 2 hours before surgery reduces postoperative headaches, nausea and vomiting. The committee noted that many patients are not aware of this and that there is a widespread belief that fluids should be avoided before surgery. They agreed that there was sufficient evidence to recommend drinking clear fluids before surgery, and that the benefits should be explained to patients.
There was not enough evidence to justify the routine use of preoperative carbohydrate drinks for most types of surgery. A small amount of evidence suggested reductions in postoperative thirst and headache in people given a carbohydrate drink before surgery. However, the evidence did not show any substantial benefits in terms of patient satisfaction or the occurrence of other side effects.
The committee noted that people having major abdominal surgery may need longer postoperative fasting periods and therefore might benefit more than others from preoperative carbohydrate drinks. Some evidence also suggested that length of hospital stay after major abdominal surgery is reduced in people given a preoperative carbohydrate drink. For these reasons, the committee agreed that carbohydrate drinks could be considered for people having this type of surgery.
There was no evidence on the best time to give preoperative carbohydrate drinks or clear fluids, so the committee made a recommendation for research on preoperative carbohydrate drinks.
A small amount of evidence suggested a possible reduction in mortality when intravenous crystalloid, rather than colloid, is used for intraoperative fluid management. However, there was also evidence showing that crystalloids resulted in a clinically important increase in nausea and vomiting. The committee were aware that crystalloid use has become more common after reports of increased risks of acute kidney injury, coagulopathy and mortality with colloid. They also noted that crystalloid is less expensive than colloid. They concluded that crystalloid should be considered for intraoperative fluid maintenance.
Older evidence suggested that cardiac output monitoring reduces some complications. However, the relevance of this evidence to current practice was unclear because of subsequent improvements in perioperative care such as better preoperative risk assessment and advancements in surgical techniques. More recent evidence also supported the use of cardiac output monitoring to reduce complications, but this evidence was from 1 small study. The committee agreed that cardiac output monitoring should be considered on a case-by-case basis.
There was no evidence that tight blood glucose control in hospital improves outcomes for people with type 2 diabetes or those without diabetes. In addition, there was evidence suggesting that tight blood glucose control increases episodes of hypoglycaemia. The committee therefore concluded that tight blood glucose control is not necessary for people in these 2 groups.
Evidence showed that using the World Health Organization (WHO) surgical safety checklist (SSC) reduces complications and mortality. Although the SSC is mandatory in NHS practice, the committee were aware from their experience that completion of the checklist varies. They reasoned that the occurrence of preventable 'never events' could be associated with this variation in completion of the SSC. They therefore decided to make a recommendation to highlight the importance of completing the SSC.
In the committee's view, reducing 'never events' should be a primary focus of surgical safety checklists. They agreed that adding steps to the SSC could help to achieve this and should be considered whenever relevant events are reported.
## How the recommendations might affect practice
Current clinical practice on allowing oral fluids before surgery varies, with some services offering carbohydrate drinks before surgery, some allowing clear fluids until 2 to 4 hours before surgery, and others advising people to fast from midnight before surgery. The committee noted that more centres are moving away from traditional preoperative fasting regimens and using the more liberal regimen of clear fluids up to 2 hours before surgery. This recommendation is expected to increase the number of services adopting more liberal regimens.
The use of intravenous crystalloid for intraoperative fluid maintenance reflects current practice and is not expected to result in a change in practice.
The recommendation on cardiac output monitoring reflects current practice and is not expected to lead to major changes in practice.
Blood glucose control varies in current practice, although there has been a shift away from tight control because of concerns about hypoglycaemic events. The recommendation is expected to change practice in services that still use tight blood glucose control for people with type 2 diabetes or without diabetes. It may also prevent operations being cancelled unnecessarily on the basis of blood glucose levels.
The recommendations are expected to reinforce use of the SSC in current practice. Modifying the SSC to address risks highlighted in national patient safety alerts and 'never events' reports, is expected to reduce the number of preventable 'never events' that occur.
Return to recommendations
# Postoperative care
Recommendation 1.5.1
## Why the committee made the recommendation
The committee agreed that people with a high risk of complications or mortality should have postoperative care in a non-ward-based specialist recovery area to improve outcomes such as quality of life and to reduce the incidence of adverse events. However, they noted that there is a large group of people in whom the need for postoperative care in a specialist recovery area is less clear, and made a recommendation for research on specialist recovery areas.
## How the recommendation might affect practice
The recommendation is expected to lead to a need for increased capacity and staff in hospitals performing major or complex surgery, or surgery in patients with a high risk of complications or mortality. The resource impact for the NHS is likely to be significant because of the high cost of care in specialist recovery areas and the large number of patients likely to need this care. However, there may also be savings achieved by reducing the occurrence of postoperative adverse events and the need to manage these.
Return to recommendations
# Managing pain
Recommendations 1.6.1 to 1.6.13
## Why the committee made the recommendations
Based on their experience, the committee agreed that people having surgery should be informed of the options for pain management and be actively involved in choosing their own pain management whenever possible.
The committee agreed, based on their experience, that multimodal analgesia provides more effective pain relief and reduces the need for opioids and the occurrence of opioid-related complications. They also agreed that prescribing pre‑emptive analgesia should be considered to ensure that pain is managed when local anaesthesia wears off.
Some evidence suggested that paracetamol used alongside opioid analgesia reduces the amount of opioid needed to manage pain. The committee therefore agreed that paracetamol is beneficial in reducing opioid consumption. There was no evidence showing a significant difference in effectiveness between oral and intravenous paracetamol. Intravenous paracetamol is much more expensive so the committee did not recommend it for people who can take oral medicines.
The evidence showed that NSAIDs provide effective additional pain relief, reducing the amount of other types of analgesia needed. Traditional NSAIDs are more cost effective than COX‑2 (cyclo‑oxygenase‑2) inhibitors, and oral ibuprofen is the most cost-effective traditional NSAID. There was no evidence showing a significant difference in effectiveness between NSAIDs or routes of administration. Intravenous NSAIDs are more expensive so the committee did not recommend them for people who can take oral medicines.
There was no evidence showing a significant difference in effectiveness between oral and intravenous opioids. Intravenous opioids are more expensive so the committee did not recommend them for people who can take oral medicines.
For people who cannot take an oral opioid, the committee agreed that a choice of PCA (patient-controlled analgesia) or epidural should be offered because there was no evidence favouring either mode of administration for most people having surgery. An exception is the group having major or complex open-torso surgery, who may benefit from the early pain relief provided by a continuous epidural. The committee pointed out that factors such as patient preference and ability to use a PCA pump effectively should be taken into account when choosing between PCA and continuous epidural. The committee looked at the possible benefits of spinal administration and agreed that there was insufficient evidence to support a recommendation.
There was evidence showing that adding intravenous ketamine to an intravenous opioid can reduce both pain and opioid consumption. The committee noted that ketamine has an additive analgesic effect. They agreed, based on their experience, that intravenous ketamine is helpful if an intravenous opioid alone does not provide adequate pain relief, or if the person is opioid sensitive (abnormal pain sensitivity). Based on the evidence and their experience, the committee agreed that a single dose of 0.25 mg/kg to 1 mg/kg should be considered in these situations.
Evidence showed that a single dose of gabapentin can lessen postoperative pain and reduce the amount of opioid needed. However, the studies used a range of doses and administered the gabapentin at different times, so the optimal dose and timing of administration remain uncertain. The committee therefore made a recommendation for research on single-dose gabapentin.
## How the recommendations might affect practice
The committee noted that pain management is usually planned during a preoperative assessment. Although preoperative assessments are standard in current practice, actively involving the person in decisions about their pain management may lead to a small increase in staff time required.
A multimodal approach is current practice and the recommendation is not expected to change this.
The recommendations can be expected to result in cost savings by reducing the use of intravenous paracetamol. They are also expected to lead to dose reductions in opioid analgesia, resulting in fewer side effects from opioid consumption.
Concerns about cardiac and renal complications have limited the use of NSAIDs in people having surgery. These recommendations can be expected to change practice by increasing the use of short courses of traditional oral NSAIDs for people having surgery.
Intravenous opioid administration is often used in current practice because it is perceived to be more convenient and offer better pain relief. The recommendations are expected to lead to a change in this practice, with a reduction in intravenous opioid administration and a concomitant increase in the use of oral opioids.
PCA and continuous epidurals are used routinely in current practice, although there are variations in their use across services.
Because these recommendations are for the perioperative period only, an opiate withdrawal plan is not necessary, but one would need to be considered if opioids were used in the longer term.
This recommendation is not expected to lead to major changes in practice.
The use of intravenous ketamine in postoperative pain management has increased in recent years. Although ketamine is more expensive than other analgesics, the recommendation is not expected to have a significant impact because it is restricted to a single dose and only one-third of people having surgery are expected to experience moderate to severe pain.
Return to recommendations# Context
Approximately 11 million people have surgery each year in the NHS. Over half are having elective (non-emergency) procedures. Although the standard of care during surgery is high, preventable complications and deaths still occur. Most of these are in high-risk patients, who make up 15% of all patients having surgery.
Perioperative care is a broad field covering an array of elective and emergency procedures across a varied population. This guideline focuses on aspects of perioperative care where practice varies. It brings together the available evidence and provides recommendations to standardise practice and improve surgical outcomes. It also highlights areas where research is needed to inform future guidance.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Information and support for people having surgery\n\n## Providing a point of contact\n\nWhen booking surgery, give people a point of contact within the perioperative care team who can be approached for information and support before and after their surgery.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on information and support for people having surgery\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: information and support needs.\n\nLoading. Please wait.\n\n## Communicating and giving information\n\nFollow the recommendations in the NICE guidelines on patient experience in adult NHS services and shared decision making, particularly relating to:\n\ninvolvement of family members and carers\n\ncommunication\n\ninformation\n\nshared decision making.\n\nFor people with a learning disability, follow the recommendations on communicating and making information accessible in the NICE guideline on care and support of people growing older with learning disabilities.\n\n# Enhanced recovery programmes\n\nOffer an enhanced recovery programme to people having elective major or complex surgery.\n\nUse an enhanced recovery programme that includes preoperative, intraoperative and postoperative components.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on enhanced recovery programmes\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: enhanced recovery programmes.\n\nLoading. Please wait.\n\n# Preoperative care\n\n## Assessing the risks of surgery\n\nUse a validated risk stratification tool to supplement clinical assessment when planning surgery, including dental surgery. Discuss the person's risks and surgical options with them to allow for informed shared decision making.\n\nDiscuss lifestyle modifications with people having surgery, for example stopping smoking and reducing alcohol consumption. Follow the relevant NICE guidance on lifestyle and wellbeing.\n\n## Preoperative optimisation clinics for older people\n\nBe aware that there was not enough clear evidence to show whether the benefits of preoperative optimisation clinics for older people outweigh the costs. Therefore, the committee made a recommendation for research.\n\n## Managing iron-deficiency anaemia\n\nFor people with iron-deficiency anaemia having surgery, follow the recommendations on intravenous and oral iron in the NICE guideline on blood transfusion.\n\nConsider an alternate-day oral iron regimen for people who have side effects from taking oral iron every day.\n\nBe aware that there was no evidence comparing different starting times for iron supplementation, so the committee made a recommendation for research.\n\nFollow the recommendations in the NICE guideline on medicines adherence to encourage adherence to oral iron regimens.\n\n## Reducing the risk of venous thromboembolism\n\nFollow the recommendations on assessing and reducing the risk of venous thromboembolism for people having surgery in the NICE guideline on venous thromboembolism in over\xa016s.\n\n## Anticoagulation for people taking a vitamin\xa0K antagonist who need bridging therapy\n\nBe aware that there was no evidence comparing low molecular weight heparin with unfractionated heparin used as perioperative anticoagulant bridging therapy for people taking a vitamin\xa0K antagonist. The committee therefore made a recommendation for research.\n\n## Nutritional assessment\n\nOffer preoperative nutritional screening to people having intermediate surgery or major or complex surgery.\n\nFollow the recommendations in the NICE guideline on nutrition support for adults on:\n\nscreening for malnutrition\n\nindications for nutrition support\n\nwhat to give.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on preoperative care\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review C: preoperative risk stratification tools\n\nevidence review D: preoperative optimisation clinics for older adults\n\nevidence review E: preoperative management of anaemia\n\nevidence review F: management of anticoagulant medication\n\nevidence review G: nutritional screening in preoperative assessment.\n\nLoading. Please wait.\n\n# Intraoperative care\n\n## Managing fluids\n\nTell people having surgery, including dental surgery, that:\n\nthey may drink clear fluids until 2\xa0hours before their operation\n\ndrinking clear fluids before the operation can help reduce headaches, nausea and vomiting afterwards\n\nclear fluids are water, fruit juice without pulp, coffee or tea without milk and ice lollies.\n\nConsider carbohydrate drinks before surgery for people having abdominal major or complex surgery.\n\nConsider using intravenous crystalloid for intraoperative fluid maintenance.\n\nFollow the recommendations in the NICE guideline on intravenous fluid therapy in adults in hospital on resuscitation and routine maintenance.\n\n## Cardiac output monitoring\n\nConsider cardiac output monitoring for people having major or complex surgery or high-risk surgery.\n\n## Blood glucose control\n\nFor people with type\xa01 diabetes, follow the recommendations on care of adults with type\xa01 diabetes in hospital in the NICE guideline on type\xa01 diabetes in adults.\n\nDo not use glucose-lowering medicines to achieve tight blood glucose control (4\xa0to\xa06\xa0mmol/litre) for people having surgery who have type\xa02 diabetes or do not have diabetes.\n\n## Surgical safety checklists\n\nEnsure that the World Health Organization (WHO) surgical safety checklist is completed for each surgical procedure, including dental procedures.\n\nConsider adding steps to the WHO surgical safety checklist to eliminate preventable events reported locally or nationally, such as those in NHS Improvement's national patient safety alerts and surgical 'never events'. Follow the WHO surgical safety checklist implementation manual when adding steps to the checklist.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on intraoperative care\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review H: preoperative fasting\n\nevidence review I: intravenous fluid management strategy\n\nevidence review J: non-invasive cardiac output monitoring\n\nevidence review K: blood glucose control management\n\nevidence review L: management systems to promote safety in operating theatres.\n\nLoading. Please wait.\n\n# Postoperative care\n\nProvide postoperative care in a specialist recovery area (a high-dependency unit, a post-anaesthesia care unit or an intensive care unit) for people with a high risk of complications or mortality.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on postoperative care\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0M: postoperative recovery in specialist areas.\n\nLoading. Please wait.\n\n# Managing pain\n\n## Planning pain management\n\nDiscuss the options for postoperative pain management with people before they have surgery, including dental surgery. Take into account:\n\nclinical features including comorbidities, age, frailty, renal and liver function, allergies, current medicines and cognitive function\n\nwhether the surgery is immediate, urgent, expedited or elective. Include in the discussion:\n\nthe likely impact of the procedure on the person's pain\n\nthe person's preferences and expectations\n\ntheir pain history\n\nthe potential benefits and risks, including long-term risks, of different types of pain relief\n\nplans for discharge.\n\n## Selecting analgesia\n\nOffer a multimodal approach in which analgesics from different classes are combined to manage postoperative pain. Take into account the factors listed in recommendation\xa01.6.1.\n\nIf controlled drugs are used, follow the recommendations on prescribing controlled drugs in the NICE guideline on controlled drugs.\n\nConsider prescribing pre-emptive analgesia for use when local anaesthesia wears off.\n\nOffer oral paracetamol before and after surgery, including dental surgery, irrespective of pain severity.\n\nDo not offer intravenous paracetamol unless the person cannot take oral medicine.\n\nOffer oral ibuprofen to manage immediate postoperative pain of all severities (including pain after dental surgery) unless the person has had surgery for hip fracture (see the recommendations on analgesia in the NICE guideline on hip fracture).\n\nDo not offer an intravenous NSAID to manage immediate postoperative pain (including pain after dental surgery) unless the person cannot take oral medicine.\n\nIf offering an intravenous NSAID to manage immediate postoperative pain, choose a traditional NSAID rather than a COX‑2 (cyclo-oxygenase‑2) inhibitor.\n\nOffer an oral opioid only if immediate postoperative pain is expected to be moderate to severe. When giving an oral opioid:\n\ngive the opioid as soon as the person can eat and drink after surgery\n\nadjust the dose to help the person achieve functional recovery (such as coughing and mobilising) as soon as possible.\n\nFor people who cannot take oral opioids, offer a choice of PCA (patient-controlled analgesia) or a continuous epidural to relieve pain after surgery. Take into account the benefits of a continuous epidural for people who:\n\nare having major or complex open‑torso surgery or\n\nare expected to have severe pain or\n\nhave cognitive impairment.\n\nConsider a single dose (0.25\xa0mg/kg to 1\xa0mg/kg) of intravenous ketamine given either during or immediately after surgery to supplement other types of pain relief if:\n\nthe person's pain is expected to be moderate to severe and an intravenous opioid alone does not provide adequate pain relief or\n\nthe person has opioid sensitivity. In August 2020, this was an off‑label use of intravenous ketamine. See NICE's information on prescribing medicines.\n\nBe aware that, although there was evidence showing that the use of gabapentin to supplement other types of pain relief can be beneficial, the evidence about when to give gabapentin, and how much to give, was inconclusive. The committee therefore made a recommendation for research.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on managing pain\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0A: information and support needs\n\nevidence review N1: managing acute postoperative pain\n\nevidence review N2: managing acute postoperative pain (appendices).\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\n## Cardiac output monitoring\n\nInterventions to monitor parameters such as stroke volume, cardiac output or central venous pressure to evaluate volume status and guide decisions on fluid replacement therapy.\n\n## High-risk surgery\n\nSurgery with a risk of mortality greater than\xa05%.\n\n## Immediate postoperative pain\n\nPain during the first 24\xa0hours after surgery.\n\n## Intermediate surgery\n\nExamples include primary repair of inguinal hernia, excising varicose veins in the leg, tonsillectomy or adenotonsillectomy, and knee arthroscopy.\n\n## Major or complex surgery\n\nExamples include total abdominal hysterectomy, endoscopic resection of prostate, lumbar discectomy, thyroidectomy, total joint replacement, lung operations, colonic resection and radical neck dissection.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Preoperative optimisation clinics for older people\n\nWhat is the clinical and cost effectiveness of preoperative optimisation clinics for older people?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale on preoperative care\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: preoperative optimisation clinics for older adults.\n\nLoading. Please wait.\n\n## Oral iron supplementation\n\nFor people with iron-deficiency anaemia, how long before surgery should oral iron supplementation be started, and what is the clinical and cost effectiveness of daily oral iron compared with oral iron given on alternate days?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale on preoperative care\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: preoperative management of anaemia.\n\nLoading. Please wait.\n\n## Managing anticoagulation treatment for people taking a vitamin\xa0K antagonist who need bridging therapy\n\nWhat is the most clinical and cost-effective strategy, as identified by a consensus survey, for the perioperative management of anticoagulation treatment in people taking a vitamin\xa0K antagonist with a target international normalised ratio (INR) of more than\xa03 who need bridging therapy?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale on preoperative care\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: management of anticoagulant medication.\n\nLoading. Please wait.\n\n## Enhanced recovery programmes\n\nWhat is the clinical and cost effectiveness of enhanced recovery programmes for adults having major emergency surgery?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale on enhanced recovery programmes\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: enhanced recovery programmes.\n\nLoading. Please wait.\n\n## Specialist recovery areas\n\nWhich patients, other than those known to have a high risk of complications or mortality, would benefit from postoperative care in a specialist recovery area (a high-dependency unit, a post-anaesthesia care unit or an intensive care unit)?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale on postoperative care\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0M: postoperative recovery in specialist areas.\n\nLoading. Please wait.\n\n# Other recommendations for research\n\n## Preoperative carbohydrate drinks\n\nWhat is the optimal timing of administration of carbohydrate drinks as part of a preoperative fasting strategy?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale on intraoperative care\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: preoperative fasting.\n\nLoading. Please wait.\n\n## Single-dose gabapentin\n\nWhat is the most clinically and cost-effective timing and dose of a single administration of gabapentin to relieve pain in people undergoing surgery whose pain is expected to be moderate to severe?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale on managing pain\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0N2: managing acute postoperative pain (appendices).\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice.\n\n# Information and support for people having surgery\n\nRecommendation\xa01.1.1\n\n## Why the committee made the recommendation\n\nEvidence from studies using patient focus groups and face-to-face interviews showed that people place a high value on having information that is consistent and available when they need it. Patients in these studies stressed the importance of knowing who to contact if they have concerns or queries, particularly after discharge. The studies also illustrated how people's information needs change before, during and after surgery, with some postoperative patients reporting difficulty recalling information given to them before surgery. The committee agreed that their experience reflects the evidence. They also noted that people who feel well informed about their surgery and recovery are less anxious than those who do not.\n\nThe committee concurred that their recommendation, together with the recommendations in the NICE guidelines on patient experience in adult NHS services and care and support of people growing older with learning disabilities cover the information and support needed by adults during perioperative care.\n\n## How the recommendation might affect practice\n\nIn larger hospitals the point of contact could be a specific team member such as a clinical nurse specialist. In smaller units the point of contact may need to be a team of people. The point of contact may change as people's needs change throughout the stages of perioperative care. In current practice the amount, availability and sources of information for people having surgery all vary. This recommendation is not expected to lead to major changes in practice.\n\nReturn to recommendations\n\n# Enhanced recovery programmes\n\nRecommendations 1.2.1 and 1.2.2\n\n## Why the committee made the recommendations\n\nThere was a large body of evidence showing that hospital stays are shorter, postoperative complications less frequent and overall costs lower when people having elective major or complex surgery follow an enhanced recovery programme (ERP).\n\nThe committee agreed that, for optimum effectiveness, an ERP should span the preoperative, intraoperative and postoperative stages, so recommended that components covering all 3\xa0stages be included. They acknowledged that the specific components of an ERP depend on the type of surgery so did not make recommendations detailing the particulars of these components.\n\nThere is no evidence on the effectiveness of ERPs in emergency surgery, but the committee thought they might be beneficial and made a recommendation for research on enhanced recovery programmes.\n\n## How the recommendations might affect practice\n\nAccording to the Perioperative Quality Improvement Programme (PQIP) 2017/2018 annual report, 61% of patients enrolled in the PQIP were following an ERP. The report noted that the use of ERPs varies across specialties and hospitals. To implement this recommendation, specialties and hospitals that do not currently provide an ERP covering all 3\xa0stages of perioperative care for patients having major or complex elective surgery will need to restructure their surgical care. This might have an initial resource impact, although some features of an ERP, such as early mobilisation and early intake of food and fluids, are current practice in many hospitals. Introducing an ERP can be expected to reduce the length of hospital stays and the incidence of complications, thereby reducing overall costs.\n\nReturn to recommendations\n\n# Preoperative care\n\nRecommendations 1.3.1 to 1.3.11\n\n## Why the committee made the recommendations\n\nValidated preoperative risk stratification tools are freely available and can be completed rapidly. Although no risk stratification tool is 100% accurate, the evidence showed that validated tools are sufficiently accurate to be a useful supplement to clinical assessment.\n\nThe committee noted that a validated risk stratification tool can also help to frame discussions about risk with the person having surgery. This includes changes the person can make to reduce their risk, such as stopping smoking. The committee agreed that the risk of postoperative morbidity is an important concern for people when they are making decisions about surgery.\n\nPreoperative optimisation clinics for older people are designed to reduce complications and deaths associated with surgery by proactively addressing risk factors identified during the preoperative assessment. These clinics are not available in all areas and are expensive to establish. Although a small number of studies suggested a possible improvement in surgical outcomes, the evidence was inconclusive. The committee decided that, because of the high cost and lack of clear evidence, they could not make a recommendation on these clinics. However, they agreed that this is an important area and made a recommendation for research on preoperative optimisation clinics for older people.\n\nOral iron supplements are usually taken daily but some people have unpleasant side effects from daily iron. The committee thought that, for these people, switching to an alternate-day regimen should be considered as a means of reducing side effects and encouraging adherence. They noted that an alternate-day regimen does not address problems with tolerability or absorption, and the potential benefits need to be balanced against the risk that an alternate-day regimen might be more complicated for people taking multiple daily medicines. There was no evidence on the comparative effectiveness of daily and alternate-day oral iron regimens.\n\nIn all of the studies, iron supplementation had been started about 3\xa0weeks before surgery. In current practice, this varies. There were no studies that compared different starting times, so the committee were unable to determine the best time to start iron therapy before surgery.\n\nThe committee made a recommendation for research on oral iron supplementation.\n\nPeople who take a vitamin\xa0K antagonist are at high risk of venous thromboembolism or stroke and therefore, it is usual practice to provide bridging anticoagulation during surgery with either subcutaneous low molecular weight heparin (LMWH) or intravenous unfractionated heparin (UFH). No clinical evidence was identified comparing LMWH with UFH in this high-risk group of patients. The committee noted that people who take a vitamin\xa0K antagonist with a target international normalised ratio (INR) of more than\xa03 and who need bridging therapy are a small proportion of the population taking vitamin\xa0K antagonists, and that many of these people have mechanical heart valves. Because of the lack of evidence, the committee made a recommendation for research on managing anticoagulation treatment for people taking a vitamin\xa0K antagonist who need bridging therapy.\n\nNo evidence on nutritional assessment was available. The committee noted that nutritional deficiency contributes to reduced physiological resilience, which is associated with increased complications and perioperative mortality. Because of this, they agreed that preoperative nutritional screening is useful for people having intermediate, major or complex surgery.\n\n## How the recommendations might affect practice\n\nPreoperative risk stratification tools are commonly used in current practice and the recommendation is not expected to change practice.\n\nThe option to consider switching from a daily to an alternate-day regimen might increase adherence to oral iron therapy in people who have unpleasant side effects from daily iron. This has the potential to reduce the need for blood transfusions and improve surgical outcomes for this group of people.\n\nPreoperative nutritional assessment for intermediate, major or complex surgery is current practice and the recommendation is not expected to lead to changes in practice.\n\nReturn to recommendations\n\n# Intraoperative care\n\nRecommendations 1.4.1 to 1.4.9\n\n## Why the committee made the recommendations\n\nSome evidence showed that drinking water until 2\xa0hours before surgery reduces postoperative headaches, nausea and vomiting. The committee noted that many patients are not aware of this and that there is a widespread belief that fluids should be avoided before surgery. They agreed that there was sufficient evidence to recommend drinking clear fluids before surgery, and that the benefits should be explained to patients.\n\nThere was not enough evidence to justify the routine use of preoperative carbohydrate drinks for most types of surgery. A small amount of evidence suggested reductions in postoperative thirst and headache in people given a carbohydrate drink before surgery. However, the evidence did not show any substantial benefits in terms of patient satisfaction or the occurrence of other side effects.\n\nThe committee noted that people having major abdominal surgery may need longer postoperative fasting periods and therefore might benefit more than others from preoperative carbohydrate drinks. Some evidence also suggested that length of hospital stay after major abdominal surgery is reduced in people given a preoperative carbohydrate drink. For these reasons, the committee agreed that carbohydrate drinks could be considered for people having this type of surgery.\n\nThere was no evidence on the best time to give preoperative carbohydrate drinks or clear fluids, so the committee made a recommendation for research on preoperative carbohydrate drinks.\n\nA small amount of evidence suggested a possible reduction in mortality when intravenous crystalloid, rather than colloid, is used for intraoperative fluid management. However, there was also evidence showing that crystalloids resulted in a clinically important increase in nausea and vomiting. The committee were aware that crystalloid use has become more common after reports of increased risks of acute kidney injury, coagulopathy and mortality with colloid. They also noted that crystalloid is less expensive than colloid. They concluded that crystalloid should be considered for intraoperative fluid maintenance.\n\nOlder evidence suggested that cardiac output monitoring reduces some complications. However, the relevance of this evidence to current practice was unclear because of subsequent improvements in perioperative care such as better preoperative risk assessment and advancements in surgical techniques. More recent evidence also supported the use of cardiac output monitoring to reduce complications, but this evidence was from 1\xa0small study. The committee agreed that cardiac output monitoring should be considered on a case-by-case basis.\n\nThere was no evidence that tight blood glucose control in hospital improves outcomes for people with type\xa02 diabetes or those without diabetes. In addition, there was evidence suggesting that tight blood glucose control increases episodes of hypoglycaemia. The committee therefore concluded that tight blood glucose control is not necessary for people in these 2\xa0groups.\n\nEvidence showed that using the World Health Organization (WHO) surgical safety checklist (SSC) reduces complications and mortality. Although the SSC is mandatory in NHS practice, the committee were aware from their experience that completion of the checklist varies. They reasoned that the occurrence of preventable 'never events' could be associated with this variation in completion of the SSC. They therefore decided to make a recommendation to highlight the importance of completing the SSC.\n\nIn the committee's view, reducing 'never events' should be a primary focus of surgical safety checklists. They agreed that adding steps to the SSC could help to achieve this and should be considered whenever relevant events are reported.\n\n## How the recommendations might affect practice\n\nCurrent clinical practice on allowing oral fluids before surgery varies, with some services offering carbohydrate drinks before surgery, some allowing clear fluids until 2\xa0to\xa04\xa0hours before surgery, and others advising people to fast from midnight before surgery. The committee noted that more centres are moving away from traditional preoperative fasting regimens and using the more liberal regimen of clear fluids up to 2\xa0hours before surgery. This recommendation is expected to increase the number of services adopting more liberal regimens.\n\nThe use of intravenous crystalloid for intraoperative fluid maintenance reflects current practice and is not expected to result in a change in practice.\n\nThe recommendation on cardiac output monitoring reflects current practice and is not expected to lead to major changes in practice.\n\nBlood glucose control varies in current practice, although there has been a shift away from tight control because of concerns about hypoglycaemic events. The recommendation is expected to change practice in services that still use tight blood glucose control for people with type\xa02 diabetes or without diabetes. It may also prevent operations being cancelled unnecessarily on the basis of blood glucose levels.\n\nThe recommendations are expected to reinforce use of the SSC in current practice. Modifying the SSC to address risks highlighted in national patient safety alerts and 'never events' reports, is expected to reduce the number of preventable 'never events' that occur.\n\nReturn to recommendations\n\n# Postoperative care\n\nRecommendation\xa01.5.1\n\n## Why the committee made the recommendation\n\nThe committee agreed that people with a high risk of complications or mortality should have postoperative care in a non-ward-based specialist recovery area to improve outcomes such as quality of life and to reduce the incidence of adverse events. However, they noted that there is a large group of people in whom the need for postoperative care in a specialist recovery area is less clear, and made a recommendation for research on specialist recovery areas.\n\n## How the recommendation might affect practice\n\nThe recommendation is expected to lead to a need for increased capacity and staff in hospitals performing major or complex surgery, or surgery in patients with a high risk of complications or mortality. The resource impact for the NHS is likely to be significant because of the high cost of care in specialist recovery areas and the large number of patients likely to need this care. However, there may also be savings achieved by reducing the occurrence of postoperative adverse events and the need to manage these.\n\nReturn to recommendations\n\n# Managing pain\n\nRecommendations 1.6.1 to 1.6.13\n\n## Why the committee made the recommendations\n\nBased on their experience, the committee agreed that people having surgery should be informed of the options for pain management and be actively involved in choosing their own pain management whenever possible.\n\nThe committee agreed, based on their experience, that multimodal analgesia provides more effective pain relief and reduces the need for opioids and the occurrence of opioid-related complications. They also agreed that prescribing pre‑emptive analgesia should be considered to ensure that pain is managed when local anaesthesia wears off.\n\nSome evidence suggested that paracetamol used alongside opioid analgesia reduces the amount of opioid needed to manage pain. The committee therefore agreed that paracetamol is beneficial in reducing opioid consumption. There was no evidence showing a significant difference in effectiveness between oral and intravenous paracetamol. Intravenous paracetamol is much more expensive so the committee did not recommend it for people who can take oral medicines.\n\nThe evidence showed that NSAIDs provide effective additional pain relief, reducing the amount of other types of analgesia needed. Traditional NSAIDs are more cost effective than COX‑2 (cyclo‑oxygenase‑2) inhibitors, and oral ibuprofen is the most cost-effective traditional NSAID. There was no evidence showing a significant difference in effectiveness between NSAIDs or routes of administration. Intravenous NSAIDs are more expensive so the committee did not recommend them for people who can take oral medicines.\n\nThere was no evidence showing a significant difference in effectiveness between oral and intravenous opioids. Intravenous opioids are more expensive so the committee did not recommend them for people who can take oral medicines.\n\nFor people who cannot take an oral opioid, the committee agreed that a choice of PCA (patient-controlled analgesia) or epidural should be offered because there was no evidence favouring either mode of administration for most people having surgery. An exception is the group having major or complex open-torso surgery, who may benefit from the early pain relief provided by a continuous epidural. The committee pointed out that factors such as patient preference and ability to use a PCA pump effectively should be taken into account when choosing between PCA and continuous epidural. The committee looked at the possible benefits of spinal administration and agreed that there was insufficient evidence to support a recommendation.\n\nThere was evidence showing that adding intravenous ketamine to an intravenous opioid can reduce both pain and opioid consumption. The committee noted that ketamine has an additive analgesic effect. They agreed, based on their experience, that intravenous ketamine is helpful if an intravenous opioid alone does not provide adequate pain relief, or if the person is opioid sensitive (abnormal pain sensitivity). Based on the evidence and their experience, the committee agreed that a single dose of 0.25\xa0mg/kg to 1\xa0mg/kg should be considered in these situations.\n\nEvidence showed that a single dose of gabapentin can lessen postoperative pain and reduce the amount of opioid needed. However, the studies used a range of doses and administered the gabapentin at different times, so the optimal dose and timing of administration remain uncertain. The committee therefore made a recommendation for research on single-dose gabapentin.\n\n## How the recommendations might affect practice\n\nThe committee noted that pain management is usually planned during a preoperative assessment. Although preoperative assessments are standard in current practice, actively involving the person in decisions about their pain management may lead to a small increase in staff time required.\n\nA multimodal approach is current practice and the recommendation is not expected to change this.\n\nThe recommendations can be expected to result in cost savings by reducing the use of intravenous paracetamol. They are also expected to lead to dose reductions in opioid analgesia, resulting in fewer side effects from opioid consumption.\n\nConcerns about cardiac and renal complications have limited the use of NSAIDs in people having surgery. These recommendations can be expected to change practice by increasing the use of short courses of traditional oral NSAIDs for people having surgery.\n\nIntravenous opioid administration is often used in current practice because it is perceived to be more convenient and offer better pain relief. The recommendations are expected to lead to a change in this practice, with a reduction in intravenous opioid administration and a concomitant increase in the use of oral opioids.\n\nPCA and continuous epidurals are used routinely in current practice, although there are variations in their use across services.\n\nBecause these recommendations are for the perioperative period only, an opiate withdrawal plan is not necessary, but one would need to be considered if opioids were used in the longer term.\n\nThis recommendation is not expected to lead to major changes in practice.\n\nThe use of intravenous ketamine in postoperative pain management has increased in recent years. Although ketamine is more expensive than other analgesics, the recommendation is not expected to have a significant impact because it is restricted to a single dose and only one-third of people having surgery are expected to experience moderate to severe pain.\n\nReturn to recommendations", 'Context': 'Approximately 11\xa0million people have surgery each year in the NHS. Over half are having elective (non-emergency) procedures. Although the standard of care during surgery is high, preventable complications and deaths still occur. Most of these are in high-risk patients, who make up 15% of all patients having surgery.\n\nPerioperative care is a broad field covering an array of elective and emergency procedures across a varied population. This guideline focuses on aspects of perioperative care where practice varies. It brings together the available evidence and provides recommendations to standardise practice and improve surgical outcomes. It also highlights areas where research is needed to inform future guidance.'}
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https://www.nice.org.uk/guidance/ng180
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This guideline covers care for adults (aged 18 and over) having elective or emergency surgery, including dental surgery. It covers all phases of perioperative care, from the time people are booked for surgery until they are discharged afterward. The guideline includes recommendations on preparing for surgery, keeping people safe during surgery and pain relief during recovery.
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be32d98c2c16de825ce76b55f12954288ea27542
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nice
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Rehabilitation for adults with complex psychosis
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Rehabilitation for adults with complex psychosis
This guideline covers mental health rehabilitation for adults with complex psychosis. It aims to ensure people can have rehabilitation when they need it and promotes a positive approach to long-term recovery. It includes recommendations on organising rehabilitation services, assessment and care planning, delivering programmes and interventions, and meeting people’s physical healthcare needs.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
In this guideline, 'complex psychosis' refers to a primary diagnosis of a psychotic illness (this includes schizophrenia, bipolar affective disorder, psychotic depression, delusional disorders and schizoaffective disorder) with severe and treatment-resistant symptoms of psychosis and functional impairment.
People with complex psychosis usually also have 1 or more of the following:
cognitive impairments associated with their psychosis
coexisting mental health conditions (including substance misuse)
pre-existing neurodevelopmental disorders, such as autism spectrum disorder or attention deficit hyperactivity disorder
physical health problems, such as diabetes, cardiovascular disease or pulmonary conditions.
Together, these complex problems severely affect the person's social and everyday functioning, and mean they need a period of rehabilitation to enable their recovery and ensure they achieve their optimum level of independence.
The guideline does not cover people who have a primary diagnosis of a non-psychotic illness. However, rehabilitation practitioners can also provide advice to services outside the rehabilitation pathway on appropriate treatment and support, including specialist placements and tailored support packages, for people with other primary mental health diagnoses or neurodevelopmental conditions, such as personality disorders or autism spectrum disorder.
# Who should be offered rehabilitation?
Offer rehabilitation to people with complex psychosis:
as soon as it is identified that they have treatment-resistant symptoms of psychosis and impairments affecting their social and everyday functioning
wherever they are living, including in inpatient or community settings. In particular, this should include people who:
have experienced recurrent admissions or extended stays in acute inpatient or psychiatric units, either locally or out of area
live in 24‑hour staffed accommodation whose placement is breaking down.
For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on who should be offered rehabilitation .
Full details of the evidence and the committee's discussion are in evidence review A: identifying people who would benefit most and evidence review D: effectiveness of rehabilitation services.
Other supporting information can be found in evidence review F: components of an effective rehabilitation pathway, evidence review J: rehabilitation approaches, care, support and treatment and evidence review Q: factors associated with successful transition.
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# Overarching principles of rehabilitation
Rehabilitation services for people with complex psychosis should:
be embedded in a local comprehensive mental healthcare service
provide a recovery-orientated approach that has a shared ethos and agreed goals, a sense of hope and optimism, and aims to reduce stigma
deliver individualised, person-centred care through collaboration and shared decision making with service users and their carers involved
be offered in the least restrictive environment and aim to help people progress from more intensive support to greater independence through the rehabilitation pathway
recognise that not everyone returns to the same level of independence they had before their illness and may require supported accommodation (such as residential care, supported housing or floating outreach) in the long term.
For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on overarching principles of rehabilitation .
Full details of the evidence and the committee's discussion are in evidence review J: rehabilitation approaches, care, support and treatment.
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# Organising the rehabilitation pathway
All local mental healthcare systems should include a defined rehabilitation pathway as part of their comprehensive service.
Use the local joint strategic needs assessment to inform the commissioning of specific service components (see recommendation 1.3.4) that make up the rehabilitation pathway, to match the needs of the local population.
Conduct a local rehabilitation service needs assessment. This should include the number of people with complex psychosis who:
are currently placed out of area for rehabilitation
have recurrent admissions or extended stays (for example, longer than 60 days) in acute inpatient units and psychiatric intensive care units, either locally or out of area
live in highly supported (24‑hour staffed) accommodation
are receiving care from forensic services but will need to continue their rehabilitation locally when risks or behaviours that challenge have been sufficiently addressed (for example, fire setting, physical or sexual aggression)
are receiving care from early intervention for psychosis services and developing problems that are likely to require mental health rehabilitation services now or in the near future
are physically frail and may need specialist support in their accommodation
are young adults moving from children and young people's mental health services to adult mental health services.
The rehabilitation pathway should include the following components, as informed by the needs assessment:
rehabilitation in the community, providing clinical care from a community mental health rehabilitation team to people living in supported accommodation (residential care, supported housing and floating outreach) and
rehabilitation in inpatient settings, such as high-dependency rehabilitation units and/or community rehabilitation units.
Health and social care commissioners should work together with health services, local authorities, housing providers and other partners (third sector and independent sector providers, service users and their families and carers) to ensure that rehabilitation is provided as locally as possible for all those identified in the local rehabilitation service needs assessment.
Consider jointly commissioning the most specialised services (including highly specialist rehabilitation units and longer-term high-dependency rehabilitation units) across areas to provide these services at a regional level for people with particularly complex needs.
Ensure that the rehabilitation pathway is designed to provide flexibility, smooth transitions and support over the longer term, that enables people to:
join and leave the rehabilitation pathway at different points
move between parts of the pathway that provide higher or lower levels of support according to their changing needs
spend different periods of time at different stages of the pathway according to need
have access to more than 1 period of rehabilitation to progress successfully in their recovery and be swiftly referred back to the pathway if their needs increase and they would benefit from further rehabilitation.
## The lead commissioner
Health and social care commissioners should jointly designate a lead commissioner to oversee the commissioning of the specific services that make up the defined rehabilitation pathway for people with complex psychosis.
The lead commissioner should:
have in‑depth knowledge and experience of commissioning services for people with psychosis and other severe mental health conditions
have knowledge of local rehabilitation services and partnerships
be familiar with best practice in rehabilitation.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on organising the rehabilitation pathway and the lead commissioner .
Full details of the evidence and the committee's discussion are in evidence review A: identifying people who would benefit most and evidence review P: supported accommodation (recommendation 1.3.2 and 1.3.4); evidence review F: components of an effective rehabilitation pathway (recommendations 1.3.1, 1.3.3, 1.3.5, 1.3.6 and 1.3.7); and evidence review G: integrated rehabilitation care pathways involving multiple providers (recommendations 1.3.8 and 1.3.9).
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## Joint working
The lead commissioner should work together with service providers to deliver an integrated rehabilitation pathway, by ensuring that:
regular communication is supported between senior service managers and senior clinicians across providers of different services within the pathway
budgets and other resources are shared between local authorities and health services, so that local and regional rehabilitation services meet the local population's needs
funding mechanisms support collaboration between service providers and do not create unhelpful or perverse funding incentives that undermine people's progression through the rehabilitation pathway
clinical records and care plans are shared between providers
service level agreements are developed so that relevant services and agencies can work together in a timely and flexible way, including for transitions between services (see recommendation 1.3.7)
services within the pathway are staffed by appropriately skilled staff
the remit for each of the services making up the pathway (see recommendation 1.3.1) is clearly specified, including the population they cover.
The lead commissioner and service providers should ensure that transitions in people's care between the rehabilitation service and other mental health teams or primary care are:
guided by criteria that are clearly defined in local policy
supported by a group of local rehabilitation practitioners, with whom clinicians can discuss potential referrals and re-referrals and receive advice on appropriate treatment and support
supported by close collaboration, including comprehensive handovers or an individually tailored period of co‑working between services
agreed with the person and their family or carers (as appropriate) and the clinicians involved in the person's care, at least 3 months before the transition (unless a referral is urgent).
The lead commissioner and service providers should ensure that people have opportunities to visit potential supported accommodation before moving in to help them make an informed choice about the service.
The lead commissioner should think about ways to improve the sharing of information and IT systems between health and social care staff, particularly in relation to people placed out of area.
For more information on managing transitions, see the NICE guideline on transition between inpatient mental health settings and community or care home settings.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on joint working .
Full details of the evidence and the committee's discussion are in evidence review G: integrated rehabilitation care pathways involving multiple providers (recommendation 1.3.10); evidence review Q: factors associated with successful transition (recommendations 1.3.11 and 1.3.12); evidence review B: barriers in accessing rehabilitation services (recommendation 1.3.13); and evidence review R: supporting transitions (recommendations 1.3.14).
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## Working with other healthcare providers
The lead commissioner should oversee the agreement of local protocols and service level agreements with primary and secondary physical healthcare providers, for people having inpatient or community rehabilitation. These protocols should:
promote access to national physical health screening programmes, health promotion, monitoring and interventions (see the section on physical healthcare)
ensure there is a system to monitor and report people's access to physical healthcare and outcomes that takes into account the increased physical health risks for specific subgroups, for example the higher prevalence of metabolic syndrome and diabetes in people from black, Asian and minority ethnic groups
ensure that any physical health conditions are assessed and treated (see the section on physical healthcare)
ensure practitioners in primary care, secondary physical care and rehabilitation services work collaboratively and flexibly, drawing together the necessary expertise and capacity to manage physical health conditions
ensure that the processes of the Mental Capacity Act (including Court of Protection decisions) do not delay care and treatment.
The lead commissioner should agree local protocols with specialist substance misuse services for people having inpatient or community rehabilitation who have substance misuse problems. These should:
define local arrangements and the content of care to ensure people can get support from local substance misuse services
include in‑reach arrangements for people in inpatient rehabilitation services
monitor and review access to substance misuse services and outcomes.
The lead commissioner should agree a local protocol with the community mental health service to enable clozapine to be started or restarted in the community. This protocol should:
be drawn up by, or in consultation with, the community mental health services pharmacist
include all relevant safety checks
include informing the person's GP.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on working with other healthcare providers .
Full details of the evidence and the committee's discussion are in evidence review C: prevalence of comorbidity (recommendation 1.3.15); evidence review O: substance misuse (recommendation 1.3.16); and evidence review H: adjustments to standard treatment (recommendation 1.3.17).
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# Improving access to rehabilitation
The lead commissioner and service providers should provide information about the local rehabilitation pathway and how it is accessed to health and social care practitioners, people who may benefit from rehabilitation and their families and carers.
The lead commissioner should work together with service providers to ensure that everyone with complex psychosis has access to rehabilitation services regardless of age, gender, ethnicity and other characteristics protected by the Equality Act 2010, and should actively monitor and report on access at least every 6 months.
If any differences are found in rates of access for specific groups of people (for example, women or ethnic groups) compared with anticipated rates, these should be addressed, for example through:
providing bespoke services for specific groups, such as women-only services
providing outreach into other services that work with under-served groups, or home visiting
providing tailored information and advocacy.
Service providers should support people to access legal advice about their immigration status if required.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on improving access to rehabilitation .
Full details of the evidence and the committee's discussion are in evidence review B: barriers in accessing rehabilitation services.
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# Delivering services within the rehabilitation pathway
## Multidisciplinary teams
Inpatient and community rehabilitation services for people with complex psychosis should be staffed by multidisciplinary teams comprising a range of professionals with skills and competence in mental health rehabilitation, including:
rehabilitation psychiatrists
practitioner psychologists
nurses
-ccupational therapists
social workers
approved mental health professionals
support workers (including peer support workers)
specialist mental health pharmacists.
The multidisciplinary team should have access to physical exercise coaches, vocational trainers, welfare rights specialists, dietitians or nutritionists, podiatrists, speech and language therapists and physiotherapists.
## Size of accommodation
Commissioners and providers of inpatient rehabilitation services and supported accommodation should be aware of the benefits to people of providing rehabilitation in smaller facilities, for example for promoting self-management, autonomy and social integration.
## Service quality improvement
Consider using tools to support quality improvement such as the Quality Indicator for Rehabilitative Care (QuIRC) for inpatient rehabilitation units, and the QuIRC-Supported Accommodation (QuIRC‑SA) for supported accommodation.
Consider joining a peer accreditation or quality improvement forum.
## Rehabilitation in the community
For people with complex psychosis who are living in supported accommodation, specialist clinical care should be provided by a multidisciplinary community mental health rehabilitation team whose work is integrated within an overall framework for the delivery of community mental health services. This team should:
coordinate the person's care and hold overall clinical responsibility for the person's mental health while they are living in the community
provide a designated care coordinator for each person but operate with a shared team caseload approach; this involves discussing people's care together at regular team meetings to pool and agree ideas about care and treatment
make the majority of contacts with the person in their home or community settings rather than where the team is based
work closely with staff at the person's supported accommodation to tailor people's care plans to their needs (see recommendation 1.7.7) and make clear which staff are responsible for providing different parts of the person's treatment and support as part of their rehabilitation
support and oversee the person's progression through the rehabilitation pathway by:
increasing the intensity of treatment and support during periods of relapse
providing ongoing contact and support during any periods of acute inpatient care
enabling the person's discharge home at the earliest opportunity
adjusting care plans to enable the person to gain the skills and confidence to manage in more independent accommodation
liaise with the person's GP about their physical healthcare
liaise with the relevant service when the person is ready to be discharged from the team to ensure a smooth transition.
Senior clinicians in the community mental health rehabilitation team should work with commissioners and supported accommodation providers to:
hold an overview of the local mental health supported accommodation services, including current vacancies and the quality of care provided
ensure that the rehabilitation pathway continues to develop in line with changes in the needs of the local population.
Community mental health rehabilitation teams should include as part of their team the staff who are designated care managers for people placed out of area.
To avoid unnecessary delays, staff should understand when and how to assess people's mental capacity in relation to decisions about moving to supported accommodation. Staff must follow the necessary steps set out in the Mental Capacity Act to enable this move. Also see the NICE guideline on decision making and mental capacity.
Supported accommodation services should:
provide support appropriate to the person's mental and physical health needs
promote stability and avoid unnecessary moves
be in a familiar place close to the person's social and cultural networks, if this is clinically appropriate
include support with tasks such as managing money and everyday living while encouraging independence and participation in society
give the person the option (if they are eligible) to have a personal budget or direct payment so they can choose and control their social care and support (for more information on personal budgets and direct payments, see the NICE guideline on people's experience in adult social care services)
give the person a safe place that feels like their own
recognise and safeguard individual vulnerability, risk, loneliness and exploitation.
## Rehabilitation in inpatient settings
Inpatient rehabilitation services should have an expected maximum length of stay (which should be used as a guide rather than an absolute) to reduce the chance of people becoming 'institutionalised'.
Service providers should advise people about the impact of being in inpatient rehabilitation services for an extended period of time on their welfare benefits and the tenure of any existing housing tenancy.
## Out-of-area placements
Out-of-area placements should be limited to people with particularly complex needs. This could include:
people with psychosis and brain injury, or psychosis and autism spectrum disorder, who need treatment in a highly specialist rehabilitation unit or
people who have a clear clinical or legal requirement to receive treatment outside their home area.
Out-of-area placements should only be provided after a local placement funding panel (including a rehabilitation practitioner, a senior service manager and local commissioner) has confirmed that the person's care cannot be provided locally.
A designated care manager (or 'out-of-area placement review officer') based within the community mental health rehabilitation team, should review the person's placement after the first 3 months and then every 6 months, to ensure it still meets their needs. This should include:
reviewing the person's progress with them and the multidisciplinary team at their placement
agreeing the necessary steps to help the person progress in their recovery so they can transfer to an appropriate placement in their local area at the earliest opportunity (also see the recommendations on maintaining links with the community in the hospital discharge section of the NICE guideline on transition between inpatient mental health settings and community or care home settings).
When people are placed in out-of-area rehabilitation services, provide an explanation in writing to the person (and their family or carers, as appropriate):
why they have been placed out of area
the steps that will be taken so they can return to their local area
how their family or carers will be helped to keep in contact
the advocacy support available to help them.
For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on delivering services within the rehabilitation pathway .
Full details of the evidence and the committee's discussion are in evidence review E: comparative effectiveness of different types of rehabilitation services (recommendations 1.5.1, 1.5.2, 1.5.6 to 1.5.8 and 1.5.13 to 1.5.16); evidence review F: components of an effective rehabilitation pathway (recommendations 1.5.3 to 1.5.5, 1.5.11); evidence review P: supported accommodation (recommendations 1.5.10 and 1.5.12); and evidence review R: supporting transitions (recommendation 1.5.9).
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# Recovery-orientated rehabilitation services
Staff in rehabilitation services should aim to foster people's autonomy, help them take an active part in treatment decisions and support self‑management.
Staff should build on people's strengths and encourage hope and optimism by:
helping people choose and work towards personal goals, based on their skills, aspirations and motivations
developing and maintaining continuity of individual therapeutic relationships wherever possible
helping them find meaningful occupations (including work, leisure or education) and build support networks using voluntary, health, social care and mainstream resources
helping people to gain skills to manage both their everyday activities and their mental health, including moving towards self-management of medication (see the recommendations on helping people to manage their own medicines)
providing opportunities for sharing experiences with peers
encouraging positive risk-taking
developing people's self-esteem and confidence
validating people's achievements and celebrating their progress
recognising that people vary in their experiences and progress at different rates
improving people's understanding of their experiences and the treatment and support that may help them – for example, through accessible written information, face-to-face discussions and group work.
## Supporting people to make decisions
Ensure staff in rehabilitation services follow recommendations on communication needs in the section on co-production and enabling people to make decisions in NICE's guideline on people's experience in adult social care services.
Staff must meet people's communication needs as set out in the NHS Accessible Information Standard.
Ensure staff in rehabilitation services follow recommendations in the NICE guideline on decision making and mental capacity.
Provide support to people, if they need it, to express their views, preferences and aspirations about their care and support in line with recommendations in the NICE guideline on people's experience in adult social care services.
Local authorities must, in line with the Care Act 2014, provide independent advocacy to enable people to participate in:
care and support needs assessment and
care planning and
the implementation process and review where they would otherwise have substantial difficulty in doing so.
## Universal staff competencies
These recommendations apply to all staff working in the services described in recommendation 1.3.4.
Ensure that staff training emphasises recovery principles so that all rehabilitation staff work with a recovery-orientated approach.
Staff should establish and maintain non-judgemental, collaborative relationships with people with complex psychosis.
Provide support for staff to acknowledge and manage any feelings of pessimism about people's potential for recovery. Support could include helping staff to share experiences and frustrations with each other, for example through supervision, reflective practice and peer support groups.
Ensure that staff attend appropriate diversity training and have the skills and competence to deliver non-discriminatory practice. They should understand that people may experience stigma resulting from their mental health condition, which could add to the stigma that people in a minority group (for example people from black, Asian and minority ethnic groups) may already experience.
Ensure that all staff are trained and skilled in supporting structured group activities and promoting daily living skills.
Ensure that staff have skills and competence in risk assessment and management to an appropriate level for the service they work in. For example, staff in high-dependency units should be able to work with people who have a history of, or currently present with, serious risks to themselves or others.
Rehabilitation services should ensure that their healthcare staff are competent to recognise and care for people with psychosis and coexisting substance misuse.
## Maintaining and supporting social networks
Discuss with the person whether, and how, they want their family or carers to be involved in their care. Discuss this at regular intervals to take account of any changes in circumstances.
Ensure that staff receive training in the skills needed to negotiate and work with families and carers, and also in managing issues relating to information sharing and confidentiality.
Respect the rights and needs of carers alongside the person's right to confidentiality. Review the person's consent to share information with family members, carers and other services during their rehabilitation. Follow recommendations on involving families and carers in NICE's guideline on service user experience in adult mental health services.
Give families and carers information about support services in their area that can address their emotional, practical and other needs (this is particularly important if the person is accessing rehabilitation services for the first time).
For advice for adult carers about how to get a formal assessment of their own needs, follow recommendations in the NICE guideline on supporting adult carers.
Enable the person to maintain links with their home community by:
supporting them to maintain relationships with family and friends, for example, by finding ways to help with transport
helping them to stay in touch with social and recreational contacts
helping them to keep links with employment, education and their local community. This is particularly important if people are in an out-of-area placement.
For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on recovery-orientated rehabilitation services .
Full details of the evidence and the committee's discussion are in evidence review J: rehabilitation approaches, care, support and treatment (recommendations 1.6.1, 1.6.2 and 1.6.8); evidence review I: collaborative care planning (recommendations 1.6.3 to 1.6.7 and 1.6.15 to 1.6.20); evidence review B: barriers in accessing rehabilitation services (recommendations 1.6.9 to 1.6.11); evidence review K: activities of daily living (recommendation 1.6.12); evidence review A: identifying people who would benefit most (recommendation 1.6.13); and evidence review O: substance misuse (recommendation 1.6.14).
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# Person-centred care planning through assessment and formulation
## Assessment
December 2022:
The MHRA has issued new safety advice on risks associated with valproate for anyone under 55.
Offer people a comprehensive biopsychosocial needs assessment by a multidisciplinary team within 4 weeks of entering the rehabilitation service.
Include the following as part of the comprehensive assessment:
systematic assessment of primary and coexisting mental health problems
psychiatric history, including past admissions and treatments, responses to treatment, adverse effects from medicines, and medication adherence
medicines reconciliation by a specialist mental health pharmacist (see the section on medicines reconciliation in NICE's guideline on medicines optimisation)
vulnerabilities, including self-neglect, exploitation and abuse, and the person's risk of harm to themselves (including suicide) and others
physical health and wellbeing through a physical health check (see recommendation 1.7.3)
developmental history from birth, including milestones; relationships with peers; and problems at school (identifying any problems with social or cognitive functioning, motor development and skills or coexisting neurodevelopmental conditions)
-ccupational and educational history, including educational attainment and reason for leaving any employment
social history, including accommodation history (noting the highest level of independence); culture, ethnicity and spirituality; leisure activities; and finances
smoking, alcohol and illicit substance use
psychological and psychosocial history, including relationships, life history, experiences of abuse and trauma, coping strategies, strengths, resiliency, and previous psychological or psychosocial interventions
current social network, including any caring responsibilities
current skills in activities of daily living
current cognitive function, including any communication needs
the person's capacity to give informed consent for their treatment in line with the Mental Capacity Act 2005.
The initial physical health check in the comprehensive assessment by the rehabilitation service should include:
body mass index
waist circumference
full blood count
pulse and blood pressure
glycosylated haemoglobin (HbA1c), blood lipid profile, liver function tests, renal function tests and thyroid function
prolactin levels (for people on medicines that raise prolactin levels).
renal function tests and calcium levels (for people on lithium)
drug levels where appropriate, for example mood stabilising or anti-epileptic medicines, lithium and clozapine; do not offer valproate to women of childbearing potential, unless other options are unsuitable and the pregnancy prevention programme is in place (follow the Medicines and Healthcare Products Regulatory Agency safety advice on valproate use by women and girls)
electrocardiogram (ECG)
smoking, alcohol and illicit substance use
nutritional status, diet and level of physical activity
continence and constipation (particularly if the person is on clozapine)
any movement disorders
sexual health
vision, hearing and podiatry
-ral inspection of general dental health
any difficulties with swallowing.
Be aware that people with complex psychosis are more likely to have multiple comorbidities, both mental and physical.
Be aware that people with complex psychosis have a higher prevalence of the following mental health conditions (which may contribute to complexity in rehabilitation):
anxiety (see the NICE guideline on generalised anxiety disorder and panic disorder in adults)
attention deficit hyperactivity disorder (see the NICE guideline on attention deficit hyperactivity disorder)
autism spectrum disorder (see the NICE guidelines on autism spectrum disorder in under 19s: recognition, referral and diagnosis, autism spectrum disorder in under 19s: support and management and autism spectrum disorder in adults)
borderline personality disorder (see the NICE guidelines on borderline personality disorder and antisocial personality disorder)
cognitive impairments (including acquired brain disorders)
depression (see the NICE guideline on depression in adults)
speech, language and communication disorders.
Be aware that people with complex psychosis have a higher prevalence of the following physical health conditions (which may contribute to higher mortality in this population):
cardiovascular disease
chronic obstructive pulmonary disease (COPD)
dental problems and poor oral health
diabetes
metabolic syndrome
-besity
-steoporosis
substance misuse.See the section on care and treatment for physical health conditions for links to other relevant NICE guidance.
## Care planning and review
Use the results of the comprehensive assessment to make a team formulation to inform treatment and care planning. The care plan should:
be developed collaboratively with the person
cover the areas of need identified during assessment (see recommendation 1.7.2), including both mental and physical health (for physical healthcare planning, see the section on responsibilities of different healthcare providers)
include the person's personal recovery goals
clarify actions and responsibilities for staff, the person themselves and their family or carers (where relevant).
Consider using accessible formatting to support the person in jointly developing their care plan, regardless of whether or not they have identified communication and information needs.
Review people's progress and care plans with them at multidisciplinary care review meetings at least:
every month in the inpatient rehabilitation service
every 6 months in the community.
Incorporate both staff-rated and service user-rated measurements of the person's progress into their care plan reviews, so that their support can be adjusted if needed.
Update care plans according to changes in the person's needs after these meetings and between meetings as needed. At every meeting or review, consider and plan with the person their transition to the next step in the rehabilitation pathway.
Ensure that care plans are shared with the person and everyone involved in the person's care (for example, clinicians, supported accommodation staff, and the person's family or carers, if the person agrees) at:
each review
each transition point in the rehabilitation pathway
at discharge from the service. For more on care plans and assessment before discharge, see recommendations 1.5.20 and 1.5.21 in the NICE guideline on transition between inpatient mental health settings and community or care home settings.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on person-centred care planning through assessment and formulation .
Full details of the evidence and the committee's discussion are in evidence review C: prevalence of comorbidity (recommendations 1.7.1 to 1.7.6) and evidence review I: collaborative care planning (recommendations 1.7.7 to 1.7.12).
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# Rehabilitation programmes and interventions
## Daily living skills
Rehabilitation services should develop a culture that promotes activities to improve daily living skills as highly as other interventions (for example, medicines).
Provide activities to help people with complex psychosis develop and maintain daily living skills such as self-care, laundry, shopping, budgeting, using public transport, cooking and communicating (including using digital technology).
Support people to engage in activities to develop or improve their daily living skills by:
making a plan with each person that focuses on their needs and regularly reviews their goals
providing activities they enjoy and that motivate them
enabling them to practise their skills in risk-managed real life, such as kitchens and laundry rooms, wherever possible.
## Interpersonal and social skills
Offer structured group activities (social, leisure or occupational) aimed at improving interpersonal skills. These could be peer-led or peer-supported and should be offered:
daily in inpatient rehabilitation services
at least weekly in community settings.
Offer regular opportunities to discuss the choice of group activities, for example by inviting everyone in the inpatient unit or supported accommodation service to a 'community meeting'.
Offer regular one-to-one sessions with a named member of staff to help the person plan and review their activity programme. The person could be:
the primary nurse in inpatient rehabilitation or
the person's care coordinator or keyworker in community rehabilitation services.
## Engagement in community activities, including leisure, education and work
Programmes to engage people in community activities should:
be flexible and make reasonable adjustments to accommodate the person's illness and fluctuating needs
be individualised
develop structure and purpose in the person's day
aim to increase their sense of identity, belonging and social inclusion in the community
involve peer support
recognise people's skills and strengths.
Offer people the chance to be involved in a range of activities that they enjoy, tailored to their level of ability and wellness.
Offer people a range of educational and skill development opportunities, for example, recovery colleges and mainstream adult education settings, which build confidence and may lead to qualifications if the person wishes.
For people who would like to work towards mainstream employment, consider referring them to supported employment that uses the Individual Placement and Support approach.
Take into account and advise people about the impact of supported employment on their welfare benefits.
For people who are not ready to return to paid employment, consider alternatives such as transitional employment schemes and volunteering.
Consider providing a cognitive remediation intervention alongside vocational rehabilitation services.
Develop partnerships, for example with voluntary organisations and local employment advice schemes, to increase opportunities for support to prepare people for work or education.
## Substance misuse
Ask people about their substance use (alcohol and illicit substances) when they enter the rehabilitation service.
Assess people's readiness to address their substance misuse, for example, through motivational interviewing.
Rehabilitation services should work with specialist substance misuse services to support people in line with NICE guidelines on:
coexisting severe mental illness (psychosis) and substance misuse: assessment and management in healthcare settings
coexisting severe mental illness and substance misuse: community health and social care services
alcohol-use disorders: diagnosis, assessment and management of harmful drinking (high-risk drinking) and alcohol dependence.
Rehabilitation services should offer support and substance misuse interventions that aim to:
support harm reduction
change behaviour
help people develop coping strategies
improve engagement with substance misuse services
prevent relapse.
Substance misuse services should provide reasonable adjustments to help people use specialist substance misuse services, for example, by providing in‑reach services to people in the inpatient rehabilitation service.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on rehabilitation programmes and interventions .
Full details of the evidence and the committee's discussion are in evidence review K: activities of daily living (recommendations 1.8.1 to 1.8.3); evidence review L: interpersonal functioning (recommendations 1.8.4 to 1.8.6); evidence review M: engagement in community activities and evidence review J: rehabilitation approaches, care, support and treatment (recommendations 1.8.7 to 1.8.14); and evidence review O: substance misuse (recommendations 1.8.15 to 1.8.19).
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# Adjustments to mental health treatments in rehabilitation
For standard pharmacological and non-pharmacological treatments, follow recommendations in these sections of the NICE guideline on psychosis and schizophrenia in adults:
choice of antipsychotic medication (section 1.3.5)
how to use antipsychotic medication (section 1.3.6)
how to deliver psychological interventions (section 1.3.7)
subsequent acute episodes of psychosis or schizophrenia and referral in crisis (section 1.4). Also see the NICE guideline on bipolar disorder, in particular section 1.10 on how to use medication.
Discuss all mental health treatment options with people in line with the recommendations in NICE's guideline on shared decision making.
Routinely monitor for and treat other coexisting mental health conditions, including depression, obsessive-compulsive disorder, anxiety, substance misuse, and risk of suicide (for guidance on these conditions, see NICE's web page on mental health and behavioural conditions).
For people diagnosed with a coexisting autism spectrum disorder, follow recommendations in the NICE guideline on autism spectrum disorder in adults.
Follow the recommendations on medicines-related communication systems when people move from one care setting to another in the NICE guideline on medicines optimisation.
## Psychological therapies
Continue to offer people with complex psychosis individual cognitive behavioural therapy (CBT) and family intervention as recommended by the NICE guideline on psychosis and schizophrenia in adults. Follow the recommendations on delivery and monitoring in the section of that guideline on psychological interventions.
Consider additional psychological interventions, especially for people who are not ready to engage in CBT. Use psychological assessment and formulation to identify the most appropriate therapeutic intervention, guided by the person's preferences. Interventions could include:
those focusing on learned behaviours and how context influences behaviour
mindfulness approaches where people can be supported to focus on and attend to present experiences
approaches that include a focus on wider systems such as families or ward environments and their impact on the person.
Consider training all rehabilitation staff in psychologically informed approaches such as motivational interviewing, positive behaviour support, behavioural activation, trauma-informed care, and simple techniques for supporting people who are having troubling thoughts and feelings.
## Pharmacological treatments
December 2022:
The MHRA has issued new safety advice on risks associated with valproate for anyone under 55.
For people with complex psychosis whose symptoms have not responded adequately to an optimised dose of clozapine alone, consider augmenting clozapine with the following, depending on target symptoms:
an antipsychotic, for example aripiprazole for schizophrenia and related psychoses and/or
a mood stabiliser for psychosis with significant affective symptoms and/or
an antidepressant if there are significant depressive symptoms in addition to the psychotic condition. Be aware of potential drug interactions and note that not all combinations of treatments may be in accordance with UK marketing authorisations. Any off-licence prescribing should be communicated in writing with the person's GP. Seek specialist advice if needed, for example from another psychiatrist specialising in treatment-resistant symptoms or a specialist mental health pharmacist. Do not offer valproate to women of childbearing potential, unless other options are unsuitable and the pregnancy prevention programme is in place. Follow the MHRA safety advice on valproate use by women and girls.
Optimise the dosage (as tolerated) of medicines used to manage complex psychosis (see recommendations 1.9.1 and 1.9.9) according to the BNF and therapeutic plasma levels in the first instance.
Only use multiple medicines, or doses above BNF or summary of product characteristics limits, to treat complex psychosis:
if this is agreed and documented by the multidisciplinary team and the person (and their family, carer or advocate, as appropriate)
as a limited therapeutic trial, returning to conventional dosages or monotherapy after 3 months, unless the clinical benefits of higher doses or combined therapy clearly outweigh the risks
if the medicines are being used to treat specific symptoms that are disabling or distressing
after taking into account drug interactions and side effects, for example be cautious when adding an antidepressant to clozapine for someone who has experienced symptoms of mania
if systems and processes are in place for monitoring the person's response to treatment and side effects (monitoring may include physical examination, ECG and appropriate haematological tests).
Regularly review medicines used to manage complex psychosis and monitor effectiveness, adverse effects and drug interactions, including monitoring for constipation for those taking clozapine. Follow recommendations in the NICE guidelines on medicines optimisation and multimorbidity.
If pharmacological treatment is not effective, consider stopping the medicine:
following a thorough review of treatment
after agreeing and documenting the decision at a meeting with a multidisciplinary team and the person (and their family, carer or advocate, as appropriate)
with caution, particularly if the person has been on the medicine for many years
by reducing the dose slowly and closely monitoring the person for symptoms of relapse.
Monitor drug levels to check adherence and guide dosing:
At least annually and as needed for clozapine and mood stabilising anti-epileptic medicines.
Every 3 to 6 months for people established on lithium, following recommendations on using lithium in the NICE guideline on bipolar disorder. Follow the MHRA safety advice on valproate use by women and girls.
Consider monitoring prolactin levels annually if the person is taking a medicine that raises prolactin, and more regularly if they have symptoms.
Monitor thyroid function, renal function and calcium levels at least every 6 months for people established on lithium, following recommendations on using lithium in the NICE guideline on bipolar disorder.
Consider annual ECGs for everyone with complex psychosis in rehabilitation services, and more regularly if they are taking medicines, combinations of medicines or medicines above BNF or summary of product characteristics limits that may alter cardiac rhythm (for example, causing prolonged QT interval).
Be aware that people may be using non-prescription substances (for example, alcohol, smoking or drugs) to cope with their symptoms, which may affect their prescribed medicines.
Consider referring for a second opinion from a relevant specialist when treating people whose symptoms have not responded well to standard treatment, and after following recommendations in the NICE guideline on medicines optimisation.
Rehabilitation services should promote adherence to medicines in line with the NICE guideline on medicines adherence. Strategies to promote adherence could include avoiding complex medicine regimens and polypharmacy wherever possible.
Offer people the opportunity to manage their own medicines through a graduated self-management of medicines programme if they have been assessed as able to take part. Follow recommendations on self-management plans in the NICE guideline on medicines optimisation.
Be flexible in tailoring the self-management of medicines programme and choice of equipment to the person's needs and preferences. This could include using monitored dosage systems together with a reminder system (for examples, charts or alarms).
## Electroconvulsive therapy
See the NICE technology appraisal guidance on the use of electroconvulsive therapy.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on adjustments to mental health treatments in rehabilitation .
Full details of the evidence and the committee's discussion are in evidence review H: adjustments to standard treatment (recommendations 1.9.1 to 1.9.19) and evidence review K: activities of daily living (recommendations 1.9.20 to 1.9.22).
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# Physical healthcare
## Responsibilities of different healthcare providers
GPs should develop and use practice case registers to monitor the physical and mental health of people with complex psychosis in primary care.
For people having community rehabilitation, GPs should assume lead responsibility for the person's physical health needs, including health checks and treatment of physical health conditions, working collaboratively with the community mental health rehabilitation team and other services as relevant.
For people having inpatient rehabilitation, the rehabilitation team should ensure that health checks, treatment of physical health conditions and other healthcare needs are addressed.
## Coordinating physical healthcare
Nominate a professional from the rehabilitation service to provide continuity of physical healthcare across settings, liaising between the rehabilitation service, primary care, secondary mental health and secondary physical healthcare.
The nominated professional should work in collaboration with a healthcare professional to develop and oversee the physical healthcare plan, ensuring it is informed by the initial physical health check (see recommendation 1.7.3) and include:
health promotion interventions (see the section on healthy living, below)
routine screening through the national screening programmes (for example, cervical cancer) if the person is eligible
monitoring side effects of pharmacological treatments (see the section on pharmacological treatments)
monitoring of physical health (see the section on monitoring physical health, below)
monitoring of oral health
treatment plans for any risk factors or health conditions (see care and treatment for physical health conditions, below)
any reasonable adjustments needed for healthy living, screening, monitoring or treatments
the physical healthcare responsibilities for primary care, the rehabilitation service, other secondary mental health services and secondary physical healthcare.
Staff must follow the Mental Capacity Act 2005 when supporting people's physical health, including in primary and secondary physical healthcare screening, prevention, investigations and treatment.
## Healthy living
Offer people who smoke help to stop smoking, even if previous attempts have been unsuccessful.
Be aware of the potential significant impact of reducing cigarette smoking on the metabolism of other drugs, particularly clozapine. Follow recommendations 1.1.3.4 and 1.1.3.5 in the physical health section of NICE's guideline on psychosis and schizophrenia in adults.
Offer people a combined healthy eating and physical activity programme and support them to take part in it.
Give people clear and accessible information about any health risks related to their:
medicines (side effects)
lifestyle, including:
diet and physical activity
smoking, alcohol or illicit substance use
-ral hygiene
bone health
sexual and reproductive health.
Offer annual flu vaccination to people:
in inpatient rehabilitation services
in communal supported accommodation
who have a comorbid physical health condition (such as chronic respiratory disease, chronic heart disease or diabetes) that means they are more likely to develop serious complications from flu (see the section on clinical risk groups in NICE's guideline on flu vaccination).
Explain to people that family members or carers who support them may also be eligible for free flu vaccination (see the section on flu vaccination in carers in NICE's guideline on flu vaccination).
Support people to maintain good oral hygiene and access dental appointments in line with NICE's guideline on oral health promotion.
Consider providing advice and support for good sleep hygiene and maximise opportunities for healthy sleep. For example, for inpatients, avoid barriers to sleep such as environmental factors or intrusive night-time checks.
## Monitoring physical health
Offer people in rehabilitation services a routine physical health check at least annually. The annual physical health check should include:
body mass index
waist circumference
pulse and blood pressure
full blood count, HbA1c, blood lipid profile, renal function tests, liver function tests and thyroid function
smoking, alcohol or drug use
nutritional status, diet and level of physical activity
any movement disorders
sexual health
vision, hearing and podiatry
-ral inspection of general dental health. For additional physical health checks associated with pharmacological treatments, see the section on pharmacological treatments.
Give people the choice, whenever possible, to have their annual physical health check at their GP practice or by a trained professional at the rehabilitation service (see recommendation 1.10.5).
Ensure a copy of the results of the physical health check is available to the rehabilitation service, primary care, secondary mental healthcare and secondary physical healthcare as appropriate, and is recorded in the case notes. Discuss any important findings with the person.
## Care and treatment for physical health conditions
Use the annual physical health check in recommendation 1.10.15 to identify at the earliest opportunity people who:
have or are at high risk of cardiovascular disease (see the NICE guideline on cardiovascular disease)
have hypertension (see the NICE guideline on hypertension)
are obese or at risk of obesity (see the NICE guideline on obesity prevention)
have diabetes or are at high risk of diabetes (see the NICE guidelines on preventing type 2 diabetes, type 1 diabetes in adults: diagnosis and management and type 2 diabetes in adults: management)
are physically inactive (see the NICE guideline on physical activity)
have COPD (see the NICE guideline on chronic obstructive pulmonary disease). Offer treatment in line with NICE guidance, ideally in primary care.
Be alert to the possibility of infection with blood-borne diseases in people who could be at risk, for example because of homelessness, intravenous drug use or a history of sexually transmitted disease. For more information about those at risk and case identification, see the NICE guidelines on hepatitis B and C testing and HIV testing.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on physical healthcare .
Full details of the evidence and the committee's discussion are in evidence review C: prevalence of comorbidity (recommendations 1.10.1 to 1.10.3 and 1.10.19) and evidence review N: engagement in healthy living (recommendations 1.10.4 to 1.10.18).
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# Terms used in this guideline
## Behavioural activation
A low-intensity intervention using goal setting and activity schedules to encourage people to engage in activities they have previously avoided due to factors such as low mood or motivation.
## Cognitive remediation intervention
A manualised intervention to improve people's cognitive function.
## Commissioners
At the time of publication, the development of integrated care systems, integrated care providers and NHS provider collaboratives is changing the commissioning landscape in the English health and care system. This may be formalised within new legislation. All references to 'commissioners' and 'commissioning' in this guideline should therefore be read in that context, wherever the commissioning function may sit and however it may operate in the future NHS in England.
## Community mental health rehabilitation team
Teams providing specialist skills and care coordination to identify and address people's rehabilitation needs in the community. These teams can work in all community settings, but commonly work with people living in supported accommodation, often over many years, to enable their optimum level of functioning and independence.
## Community rehabilitation units
Inpatient rehabilitation units that are set outside hospital grounds. These units provide the full complement of multidisciplinary treatment and support for people with ongoing complex needs that prevent them from being discharged from a high-dependency rehabilitation unit directly to supported accommodation. They build on the progress made in the high-dependency inpatient rehabilitation unit and have a strong focus on promoting independent living skills and community participation. Most referrals come from high-dependency rehabilitation units or acute inpatient units. Community rehabilitation units can only care for detained people under the Mental Health Act 1983 if the unit is registered as a ward. If they are not registered as a ward, they can care for people who are voluntary or those subject to a community order (for example, a community treatment order, guardianship, or conditionally discharged Section 37/41). The expected length of stay in a community rehabilitation unit is 1 to 2 years.
## Complex psychosis
In this guideline, 'complex psychosis' refers to a primary diagnosis of a psychotic illness (this includes schizophrenia, bipolar affective disorder, psychotic depression, delusional disorders and schizoaffective disorder) with severe and treatment-resistant symptoms of psychosis and functional impairment.
People with complex psychosis usually also have 1 or more of the following:
cognitive impairments associated with their psychosis
coexisting mental health conditions (including substance misuse)
pre-existing neurodevelopmental disorders, such as autism spectrum disorder or attention deficit hyperactivity disorder
physical health problems, such as diabetes, cardiovascular disease or pulmonary conditions.
Together, these complex problems severely affect the person's social and everyday functioning, and mean they need a period of rehabilitation to enable their recovery and ensure they achieve their optimum level of independence.
## Floating outreach
Services providing support to people living in time-unlimited, usually self-contained, individual tenancies. Staff are based off-site and visit for a few hours per week, providing practical and emotional support, with the aim of reducing support over time to zero.
## Graduated self-management of medicines programme
Supporting a person to learn how to take and manage their own medicines. This usually involves them managing 1 day of medicines to begin with, with staff undertaking spot checks before progressing to managing 2 days, then 3 days and so on.
## High-dependency rehabilitation units
Inpatient rehabilitation units for people with complex psychosis whose symptoms have not yet been stabilised and whose associated risks and challenging behaviours remain problematic. These units aim to maximise benefits of medication, address physical health comorbidities, reduce challenging behaviours, re‑engage families and facilitate access to the community. Most people in high-dependency units are detained under the Mental Health Act 1983. Most (80%) referrals to high-dependency units are from acute inpatient units and 20% from forensic units, with only occasional referrals of people living in the community. The expected length of stay is around 1 year.
## Highly specialist rehabilitation units
Inpatient rehabilitation units for people with psychosis and comorbid conditions who need a specialist programme tailored to their specific comorbidity (such as acquired brain injury, severe personality disorder, autism spectrum disorder or Huntington's disease). Often, the complexity of the person's coexisting conditions is associated with greater support needs (more challenging behaviours and/or a greater risk to themselves and others) than people having treatment in a high-dependency rehabilitation unit. Referrals come from acute inpatient units or high-dependency rehabilitation units, and the expected length of stay is over 3 years.
## Individual Placement and Support (IPS) approach
A method of supporting people with severe mental health problems into work. IPS finds people a job quickly and then provides time-unlimited individualised support to keep the job and manage their mental health.
## Inpatient rehabilitation units
Units providing specialist inpatient care to people with complex psychosis. They can be based within a hospital or in the community.
## Local placement funding panel
A panel not specific to rehabilitation, who agree funding (health, social care or both) for people to receive treatment within area or out of area, for example in a nursing or residential care home, or in an inpatient rehabilitation unit. The panel has a commissioner and senior service managers, as well as clinicians (a senior rehabilitation practitioner plus possibly a senior clinician who works in general adult care, not specifically rehabilitation).
## Longer-term high-dependency rehabilitation units
These units provide longer-term inpatient rehabilitation for people with high levels of disability due to treatment-resistant symptoms and comorbid conditions that take more than 1 year to stabilise, and who have ongoing risks to others and/or challenging behaviours. The aims of longer-term high-dependency rehabilitation units are the same as for high-dependency rehabilitation units, and most referrals come from high-dependency rehabilitation units.
## Motivational interviewing
A person-centred psychologically informed approach that supports behavioural change by helping people explore and resolve ambivalence towards change.
## Out-of-area placements
A placement that provides treatment and support in an inpatient rehabilitation unit or supported accommodation outside the local area where a person usually lives, and/or outside the catchment area for the local authority that has responsibility for their housing. The placement may be away from the person's local area because there is no local service available, or because there are clinical or legal reasons that make local rehabilitation inappropriate for their needs, or because they prefer to have treatment outside their local area.
## Positive behaviour support
A behaviour management system that seeks to understand the reasons behind problematic behaviours and to find alternative ways to meet goals and needs.
## Psychologically informed approaches
Brief skills-based interventions that can be delivered by any staff member or service user who has had suitable training in the intervention. They include: guided self-help using online resources or workbooks; relaxation or mindfulness; stress workshops and behavioural activation groups.
## Recovery colleges
Peer-led education and training programmes for mental health service users. They provide education as a route to recovery, not as a form of therapy. The courses are co‑devised and co‑delivered by people with lived experience of mental illness and by mental health professionals.
## Recovery-orientated approach
There is no single definition of recovery for people with mental health problems, but the guiding principle is the belief that it is possible for someone to regain a meaningful life, despite serious mental illness. In this guideline, it refers to someone achieving the best quality of life they can, while living and coping with their symptoms. It is an ongoing process whereby the person is supported to build up their confidence and skills and resilience, through setting and achieving goals to minimise the impact of mental health problems on their everyday life.
## Residential care
Communal facilities, staffed 24 hours, where day-to-day needs are provided (including meals, supervision of medicines and cleaning), and placements are not time limited. People do not hold a tenancy in a residential care home.
## Supported accommodation
An umbrella term covering residential care, supported housing and floating outreach.
## Supported housing
Shared or individual self-contained, time-limited tenancies with staff based on site up to 24 hours a day who help the person to gain skills to move on to less supported accommodation. The intended length of stay is usually about 2 years but in practice, only around one-third of people move on in that time.
## Team formulation
A shared understanding of the issues that brought the person into rehabilitation services. It is their story, but draws on information from theory and research, as well as the experiences of the person, professionals and, where possible, others such as carers. It includes factors that made the person vulnerable to developing problems, factors that triggered the problems and factors that keep the problems going. A team formulation includes strengths and resources and points to ways that problems can be addressed.
## Transitional employment schemes
These schemes give people a supported occupation in which to gain pre-vocational work experiences and potentially prepare for mainstream employment. One of the original examples was the 'clubhouse' model of psychosocial rehabilitation developed at Fountain House in New York.
## Trauma-informed care
Care that is built on an understanding that anyone using services could have experienced psychosocial trauma and that this is likely to influence how they engage with care. Key principles include safety and avoiding re-traumatisation; relationship building; peer support; collaboration and mutuality; empowerment and choice; and an awareness of cultural, historical and gender issues.
## Treatment-resistant symptoms
Persistent symptoms that have not responded to the range of treatments (including pharmacological treatments) recommended in the NICE guidance for the person's condition.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Key recommendations for research
## Who should be offered rehabilitation?
What is the efficacy and cost effectiveness of rehabilitation services compared with treatment as usual for people with complex psychosis with residual disability, who are leaving early intervention services?
For a short explanation of why the committee made the recommendation for research, see the rationale on who should be offered rehabilitation .
Full details of the evidence and the committee's discussion are in evidence review D: effectiveness of rehabilitation services.
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## Peer-support interventions
How can peer-support interventions be used most effectively to support people with complex psychosis using rehabilitation services?
For a short explanation of why the committee made the recommendation for research, see the rationale on engagement in community activities, including leisure, education and work .
Full details of the evidence and the committee's discussion are in evidence review M: engagement in community activities.
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## Highly specialist and longer-term high-dependency rehabilitation units
What are the service and service user characteristics of highly specialist and longer-term high-dependency rehabilitation units that are associated with better outcomes?
For a short explanation of why the committee made the recommendation for research, see the rationale on rehabilitation in inpatient settings .
Full details of the evidence and the committee's discussion are in evidence review A: identifying people who would benefit most.
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## Structured group activities
What structured group activities are effective at improving interpersonal functioning (social skills) for people with complex psychosis?
For a short explanation of why the committee made the recommendation for research, see the rationale on interpersonal and social skills .
Full details of the evidence and the committee's discussion are in evidence review L: interpersonal functioning.
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## Inpatient rehabilitation provided by the independent sector
What is the clinical and cost effectiveness of inpatient rehabilitation provided by the independent sector compared with that provided by the NHS?
For a short explanation of why the committee made the recommendation for research, see the rationale on out-of-area placements .
Full details of the evidence and the committee's discussion are in evidence review E: comparative effectiveness of different types of rehabilitation services.
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# Other recommendations for research
## Integrated care systems
Is an integrated care system effective at promoting successful progress for people with complex psychosis to a more independent setting?
For a short explanation of why the committee made the recommendation for research, see the rationale on transitions .
Full details of the evidence and the committee's discussion are in evidence review R: supporting transitions.
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## Staff training interventions
What staff training interventions are effective at facilitating personal recovery for people with complex psychosis?
For a short explanation of why the committee made the recommendation for research, see the rationale on engagement in community activities, including leisure, education and work .
Full details of the evidence and the committee's discussion are in evidence review M: engagement in community activities.
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## Coexisting physical health conditions
What is the impact of coexisting physical health conditions on the mortality of people with complex psychosis?
For a short explanation of why the committee made the recommendation for research, see the rationale on assessment .
Full details of the evidence and the committee's discussion are in evidence review C: prevalence of comorbidity.
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## Medicines adherence
What interventions are effective to support medicines adherence for people with complex psychosis in supported accommodation?
For a short explanation of why the committee made the recommendation for research, see the rationale on adherence to medicines and helping people to manage their own medicines .
Full details of the evidence and the committee's discussion are in evidence review K: activities of daily living.
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## Tailored interventions
What tailored interventions (pharmaceutical and psychological) specific to rehabilitation are effective at equipping people with complex psychosis with the ability to live in the community?
For a short explanation of why the committee made the recommendation for research, see the rationale on interventions tailored to people in rehabilitation .
Full details of the evidence and the committee's discussion are in evidence review H: adjustments to standard treatment.
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## Risk of blood-borne virus infections
What are the risks that predict the development of blood-borne virus infections in people with complex psychosis in the UK?
For a short explanation of why the committee made the recommendation for research, see the rationale on care and treatment for physical health conditions .
Full details of the evidence and the committee's discussion are in evidence review C: prevalence of comorbidity.
Loading. Please wait.# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice and services.
# Who should be offered rehabilitation?
Recommendation 1.1.1
## Why the committee made the recommendation
Low to very low quality evidence from randomised controlled trials of rehabilitation in the community and observational studies of inpatient rehabilitation showed that rehabilitation was effective and cost effective for many people with complex psychosis. Qualitative evidence also showed that people with severe mental illness value rehabilitation.
There was moderate quality evidence that people who experienced a shorter duration of illness before rehabilitation, and who had lower psychopathology scores, were more likely to progress through the rehabilitation pathway to greater independence. However, the committee thought that everyone with treatment-resistant symptoms and functional impairments had the potential to benefit from rehabilitation, and that this applied regardless of whether they were living in inpatient or community settings.
The committee also highlighted the groups of people who, in their experience, are likely to have treatment-resistant symptoms and functional impairments.
The committee was aware that some people leaving early intervention services have significant residual disability, with persisting symptoms and functional impairment. However, it was not possible from the evidence to determine whether providing very early access to rehabilitation to these people could prevent repeated admissions and problems in daily living. The committee therefore made a research recommendation on who should be offered rehabilitation.
## How the recommendation might affect practice
Earlier access to rehabilitation should deliver more effective treatment sooner. This should reduce repeated admissions, enable earlier referral to less intensive (and cheaper) services and support more independent living. There may be some resource impact if more units are needed; however, most trusts in England have existing mental health rehabilitation units and half of trusts have community mental health rehabilitation teams who work with people after they have left hospital and moved to supported accommodation. In areas without these teams, community mental health teams already coordinate care. There will also be substantial savings from the repatriation of people placed out of area.
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# Overarching principles of rehabilitation
Recommendation 1.2.1
## Why the committee made the recommendation
There was qualitative evidence on the approaches, care, support and treatment that are valued by people using rehabilitation. A recovery-orientated approach was reported to be particularly valued and there was evidence that services adopting this approach to a greater extent were more successful in supporting people to progress along the rehabilitation pathway. The committee used this evidence along with their clinical knowledge and experience to recommend overarching principles to guide the delivery of rehabilitation services.
Based on the evidence, the committee noted that not everyone with complex psychosis will get better. However, in their experience, rehabilitation can be beneficial for everyone who has treatment-resistant symptoms, even if they do not regain the same level of function and continue to need a high level of support in the longer term.
## How the recommendation might affect practice
The committee agreed that the overarching principles will improve consistency of best practice and do not need any additional resources to deliver.
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# Organising the rehabilitation pathway, and the lead commissioner
Recommendations 1.3.1 to 1.3.9
## Why the committee made the recommendations
The evidence supported each locality having a defined rehabilitation pathway with access to a range of service components in different settings to provide the appropriate treatment and support that people need. The committee agreed that different levels of support, and usually both inpatient and community services, are needed to support people's full recovery. They noted it was important that these services were provided as locally as possible. The committee agreed that this would:
enable better integration between health and social care (because supported accommodation and housing are arranged at local authority level)
help to prevent inappropriate care, for example, people being unable to progress from inpatient units or out-of-area placements
provide options for appropriate aftercare for people who have been detained in hospital (a statutory obligation under the Mental Health Act 1983).
In the committee's view, the commissioning of rehabilitation services needs to take into account the mental health services that are already available and how services will work together to meet the population's needs. Currently, there is a lack of integration between services and a lack of clarity about who should be funding and commissioning them. The committee considered it essential that health and social care commissioners work together to commission services, to address people's overlapping health and social care needs. They acknowledged that to provide a full range of inpatient rehabilitation services, independent sector providers as well as those in the NHS may need to be involved.
Local authorities are required under the Health and Social Care Act (2012) to perform a joint strategic needs assessment to identify the health and social care needs of their population. The committee identified key groups that need to be included through a complementary local rehabilitation service needs assessment – people who are most likely to need local rehabilitation services, and those who might need highly specialist or longer-term rehabilitation services – to ensure services can be planned to help meet their needs.
The committee was aware that commissioning highly specialist services at the local level might not be feasible because there may not be enough people with very complex needs to warrant a dedicated unit. Therefore, they recommended local areas could work together to commission these services at a regional level.
The committee highlighted the need for flexibility within the rehabilitation pathway. People with complex psychosis do not always have a linear progression to recovery from needing high support to independence; some people may need continued support in the long term and some people may need more than 1 period of rehabilitation. It should be possible to accommodate this in the pathway.
Qualitative evidence showed that integration and collaborative working across teams and services was facilitated by a lead champion. This model of a lead commissioner is also recommended by NICE for people with learning disabilities and behaviour that challenges, who similarly have overlapping health and social care needs. Qualitative evidence, along with the experience of the committee, provided a number of attributes that would enable the lead commissioner to perform their role effectively.
## How the recommendations might affect practice
These recommendations largely reflect current practice in terms of joint commissioning. However, greater emphasis on an integrated rehabilitation pathway will likely see fewer people being referred to out-of-area placements and discharged from inpatient rehabilitation to community rehabilitation settings at a faster rate.
Economic evidence from a wider NHS and Personal Social Perspective shows that there may be a large cost saving from faster discharge rates that are appropriate to a person's illness and reduce inappropriate out-of-area placements. However, there may be a high resource impact for local authorities who are responsible for commissioning the provision of housing for people discharged from inpatient units. To some degree, this resource impact felt by local authorities would be offset by faster transitions to supported housing and floating support.
Providing more local inpatient facilities could potentially increase capital costs for some commissioners in the short term if those facilities do not currently exist. In the longer term, this would involve replacing costs incurred out of area with those incurred locally, so the move to more locally available services is expected to be cost neutral over time. Overall, the health benefits of people spending more time in contact with community-based services, and less in inpatient facilities, would offset any initial additional resource impact.
An appropriately skilled lead commissioner would facilitate local authorities working together with health and social care commissioners, which is current practice in some areas.
Return to recommendations
# Joint working
Recommendations 1.3.10 to 1.3.14
## Why the committee made the recommendations
The qualitative evidence identified barriers to integrating rehabilitation care pathways, which resonated with the committee's own experience. 'Siloes' of resources were discussed as a key barrier, and the committee noted that collaborations among services are hard to sustain unless they are underpinned by sufficient shared budgets. They also agreed that competitive funding among services is often not in the best interest of people in rehabilitation because it can discourage services from supporting a person to progress through the pathway. The committee agreed additional areas to highlight in the recommendation where the lead commissioner could help to address barriers to integration.
The committee agreed that because people with complex psychosis have a fluctuating illness, they need to be able to move seamlessly between services in the pathway depending on their needs. Based on consensus, the committee recommended measures to achieve this.
There was some qualitative evidence that some service users come to services passively because it is simply where they are 'sent to' next. Being able to visit a service before a placement begins helps people to make their own decisions and to feel more at ease about making the transition.
One study showed benefit of an integrated system to support transitions. The integrated system was a team of health and social care practitioners and informal carers for each person who met weekly to coordinate care, were able to communicate through a shared IT environment, and were trained to collaborate. Because the evidence was limited to 1 randomised controlled trial and there was no detail about what aspects of the intervention were effective, the committee could only recommend exploring ways to improve the sharing of information and IT systems.
To find out more about whether an integrated system involving a multidisciplinary team might help improve transitions and people's progress through the rehabilitation pathway towards greater independence, the committee also made a research recommendation on integrated care systems.
## How the recommendations might affect practice
Developing an integrated approach to rehabilitation is likely to be costly initially. Resources would be needed to set up services and underpin the collaboration between them (for example, systems to coordinate and communicate between services). However, an integrated rehabilitation pathway is likely to be cost effective in the longer term. Additional costs would be offset by the economic and health benefits of successful transitions and people receiving the correct level of support.
Visiting rehabilitation settings is common in some areas, and should not involve a high resource impact, unless the person needs significant support to attend the visit.
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# Working with other healthcare providers
Recommendations 1.3.15 to 1.3.17
## Why the committee made the recommendations
The evidence showed that people with severe mental illness are at increased risk of many comorbid conditions and substance misuse. The committee considered it crucial that services for mental and physical healthcare, social care and substance misuse develop local protocols to ensure appropriate services are available to people in rehabilitation. Based on their knowledge and experience, the committee recommended what these protocols should cover.
In the committee's experience, some people using rehabilitation services may need to start or restart treatment with clozapine. This requires strict monitoring and currently many of these people are admitted to hospital. However, it is possible to provide clozapine in the community with the right level of monitoring through an extended-hours service. The committee agreed that making clozapine available in the community would prevent unnecessary hospital admissions and is an important part of a successful rehabilitation service.
## How the recommendations might affect practice
Rehabilitation services should already be working with other providers to meet people's needs for physical healthcare and substance misuse services. However, if services and funding within an area are highly siloed, additional resources may be needed to enable this collaboration.
Although clozapine in the community is not available in all areas, most areas do have a team in place providing an extended-hours service for people with mental illness, for example a crisis resolution home treatment team. It may involve additional costs to fund the extra work for this team to provide clozapine at community level, but it could be balanced by cost savings resulting from better management of psychosis symptoms.
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# Improving access to rehabilitation
Recommendations 1.4.1 to 1.4.4
## Why the committee made the recommendations
In the committee's experience, many potential users of rehabilitation services and their families and carers are unaware of what services are available and how to access them. This was also reflected in the qualitative evidence.
Qualitative evidence found that factors like age, sex, physical health problems, race and ethnicity were barriers to accessing rehabilitation for many people, because services are often unequipped to meet specific needs associated with these groups. The evidence also found no significant association between successful progress in rehabilitation services and age, gender or ethnicity. The Equality Act 2010 requires services to be accessible regardless of these protected characteristics and the committee agreed everyone with complex psychosis should have access to rehabilitation services. They therefore provided examples for how these inequalities in access could be addressed.
The committee recommended supporting people to access legal advice about their immigration status if required, in case people might be concerned about being deported if they access services.
## How the recommendations might affect practice
The recommendations might have some resource impact, depending on how developed services are in this respect across different areas. For example, extra resources may be needed if outreach is needed to improve accessibility for minority groups. However, equal access and reasonable adjustments are requirements of the Equality Act 2010 and so should be standard practice and already considered in budgeting.
The recommendation to support people to access legal advice about their immigration status could require access to costly legal specialists; however, the committee noted this is currently being done in practice.
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# Delivering services within the rehabilitation pathway
Recommendations 1.5.1 to 1.5.16
## Why the committee made the recommendations
There was some evidence to support providing community rehabilitation through a multidisciplinary team and this was in line with the committee's experience. The committee also considered multidisciplinary working to be effective in inpatient rehabilitation services, so they recommended it for both inpatient and community settings. They used their own experience to recommend some of the core roles that would need to be included in the team. They also recommended other health professionals the team should have access to in order to meet the mental and physical healthcare needs of people with complex psychosis during rehabilitation. Input from welfare rights specialists was also thought to be important because people with complex psychosis will be on welfare benefits and are likely to need advice on their income. Speech and language therapist input would be needed to deal with the additional communication needs that can be experienced by this group. Physiotherapists would be needed to help people with mobility issues to engage in more physical activity to mitigate the physical health impact of a more sedentary lifestyle.
The evidence suggested that for every additional bed in an inpatient rehabilitation unit, there was an associated small decline in people's quality of care (as rated by Quality Indicator for Rehabilitative Care on living environment, therapeutic environment, promotion of self-management and autonomy and promotion of social integration). The committee agreed this finding was also relevant to supported accommodation. The committee could not specify the optimal size of inpatient units or supported accommodation because no absolute optimal size was indicated in the evidence, and units of varying size may be appropriate for different areas.
There was evidence that the quality of rehabilitative care (as measured using QuIRC for inpatient units and QuIRC‑SA for supported accommodation) was associated with better outcomes of rehabilitation, autonomy, experience of care and satisfaction for people using the service. This evidence came from inpatient units, community units and supported accommodation. The committee agreed that measuring the quality of rehabilitative care using currently available tools would help rehabilitation units to identify areas for improvement and ultimately lead to better rehabilitation services. They also recommended services consider joining a peer accreditation or quality improvement forum because rehabilitation services often exist in isolation, so it is important for them to share good practice with other practitioners.
There was evidence that multidisciplinary community team management increased participation in activities of daily living. The committee used their experience to extrapolate from this to recommend how community mental health rehabilitation teams should provide care and work together to support people in community rehabilitation. However, they acknowledged that this team's remit may vary in different areas depending on how other community-based services are organised.
The committee noted from their experience in practice that issues with mental capacity can cause delays to people moving to supported accommodation. They highlighted the need for staff to follow the Mental Capacity Act 2005 so that people can progress through the rehabilitation pathway.
The committee used qualitative evidence to highlight features of supported accommodation that are valued by people, The committee discussed the importance of supporting people to have autonomy, including to make potentially risky decisions, while still maintaining reasonable safety and helping people to avoid exploitation. The committee believed that in the long term, these recommendations would allow service users to live more sustainably and independently in the community, with fewer stressors and mental health relapses that lead to hospitalisation.
Evidence showed that rehabilitation units with an expected maximum length of stay were associated with better quality of care. The committee agreed that having an expected maximum length of stay could help prevent delays when people are ready to move on through the rehabilitation pathway. However, they also agreed this should not be treated as absolute; services need to be flexible and provide appropriate treatment and support tailored to each person's needs.
The committee noted that accepting a placement in inpatient rehabilitation could affect people's eligibility to receive particular benefits (for example housing benefit) and could affect people's existing tenancies with local authorities. The committee wanted providers to be aware of and advise people about these issues.
There was a lack of evidence about the characteristics of effective highly specialist or longer-term high-dependency inpatient services. People with particularly complex comorbid conditions whose care cannot be managed in less specialised settings often spend very long periods of time (sometimes many years) in highly specialist or longer-term inpatient rehabilitation services. The Care Quality Commission has raised concerns about quality of life for people in this group. It is important to understand the characteristics of services and service users that support successful progress through rehabilitation, so the committee made a research recommendation on highly specialist and longer-term high-dependency rehabilitation units.
Health economic modelling showed that providing rehabilitation locally was less costly than using out-of-area placements, which are often provided by the independent sector. Although no clinical outcomes were found in the accompanying systematic review, the model included data from the Care Quality Commission, which showed that people placed in out-of-area inpatient wards have a longer average stay on such wards than those placed in local wards. There is a large hypothetical overall cost saving from a wider NHS and Personal Social Services perspective which, in the model, is driven by a reduction in the rate of out-of-area placements and faster discharge rates to supported accommodation that enable more independent living.
The committee acknowledged that there were no relevant clinical outcomes or utility data to compute quality-adjusted life years, although it was their view that a person in supported accommodation would typically have improved activities of daily living. Reducing out-of-area placements would therefore lead to more people being appropriately discharged to supported accommodation, which would reduce costs and improve quality of life.
The committee was aware of evidence suggesting that for many people in out-of-area placements, it could be appropriate to offer rehabilitation in local inpatient units. Being in a local unit also makes it easier for people to maintain contact with their families, communities and local support networks or activities, such as peer support groups.
The committee shared anecdotal reports of people being in out-of-area placements for many years, without clinical oversight from the person's local area. To avoid this, they made recommendations with the aim of reducing out-of-area placements wherever possible, providing better support while people are in these placements and bringing them back to their local area as soon as possible. This included recommending time frames for reviewing out-of-area placements, which were based on committee consensus.
There was a lack of comparative evidence between services provided by the independent sector and the NHS. The committee acknowledged that the independent sector is an important provider of rehabilitation services; however, the services they provide are often a long way from where people live, and from the local area that funds their placement. Many independent units are locked, and lengths of stay are considerably longer (and therefore costlier) than in equivalent NHS services. There is little systematic and reliable evidence on the characteristics of users of these services or the effectiveness of these units, to establish if the longer stays are necessary. Given the potential for significant cost savings if the effectiveness in the 2 sectors were found to be the same, the committee made a research recommendation on inpatient rehabilitation provided by the independent sector.
## How the recommendations might affect practice
The recommendation for the multidisciplinary team to have access to additional healthcare professionals may have a resource impact for those teams without this access currently. However, because some teams already have access to these specialties, the committee did not think this would be a significant resource impact.
Not all supported accommodation services currently use the QuIRC‑SA so the recommendation may lead to a moderate change in practice. This tool is web-based, free to use and completed annually by a unit manager or senior staff member in around 90 minutes. Further investment may be needed to address gaps identified by these quality measures. However, the committee considered this would be justified by improved experience of care and better rehabilitation outcomes for service users.
The recommendation to advise people about the impact of rehabilitation placements on their tenancies could require access to welfare rights specialists, which could have a resource impact for services without this access currently.
The committee recognised that local authorities in some regions may need to invest significantly in the quality and variety of their supported accommodation to implement the recommendations on supported accommodation. However, the recommendations do recognise that commissioning decisions should be based on a local rehabilitation service needs assessment to reflect the needs of the local population. Nevertheless, local authorities often commission supported accommodation and therefore can specify quality metrics when tendering to providers.
There is likely to be some service reconfiguration required by the recommendations on out-of-area placements as people move back to local units. New rehabilitation units may need to be commissioned locally and there could be a substantial initial investment. However, in the long term, this would be expected to be largely cost neutral with respect to capital costs, as out-of-area facilities are replaced by local ones. Therefore, the committee argued that this 'investment' is currently already being spent on out-of-area placements so would not constitute additional funding in the long term. The committee did note though that any investment should be based on a local rehabilitation service needs assessment based on the needs of the local population.
The recommendation for a designated care manager may represent a change in practice in some areas. For areas that do not currently perform regular clinical review of people being sent out of area, this could represent an additional resource. However, if the review leads to people being brought back within area to a more cost-effective placement, this resource could be offset.
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# Recovery-orientated rehabilitation services
Recommendations 1.6.1 to 1.6.20
## Why the committee made the recommendations
Qualitative evidence showed that service users value a recovery-orientated approach to their care. This means helping people to work towards their aspirations and make the most of their abilities, while giving them support and encouragement wherever needed. The evidence suggested several key areas including activities of daily living, hobbies and interests, and vocational goals, where service users believed that services could help them work towards recovery.
Working collaboratively with people with complex psychosis to produce a care plan can be challenging because of diminished communication and mental capacity. Despite these challenges, planning care in collaboration with the service user is expected practice in UK mental health services. Guidance on mental capacity and communication needs is already provided in other NICE guidelines but the committee also agreed it was relevant to highlight the legal obligation to offer independent advocacy under the Care Act 2014 and to follow the NHS Accessible Information Standard when working with people in rehabilitation.
The committee considered staff training in recovery orientation to be essential to deliver an effective rehabilitation service. They also agreed that staff need to develop collaborative and non-judgemental relationships with people using the service. There was qualitative evidence that staff sometimes lack optimism or are overly risk-averse about the prospect of rehabilitation for some people, which can negatively affect a person's recovery. To address this, the committee recommended ways to encourage positive attitude changes to help staff retain hope and optimism, while acknowledging that not everyone will achieve full independence.
Qualitative evidence was supported by the committee's experience that service users from minority groups may experience language barriers and unconscious prejudice because of their minority status as well as because of their mental illness. This combination may produce its own unique barriers within services and the committee agreed staff should be aware of this.
The committee made the recommendation on supporting structured activities based on limited evidence combined with consensus. They saw structured group activities as a key aspect of rehabilitation (see recommendation 1.8.4) and agreed that all staff, not just certain staff such as occupational therapists, should be able to support these activities.
The committee also discussed safeguarding and risk, and agreed that all staff need to be trained to deal with risks relevant to the setting they are working in.
There is a high prevalence of substance misuse among the rehabilitation population. The committee thought it was essential that all staff are able to identify these problems and provide the right support.
Involving family members and carers in decision making can reduce isolation and increase support for people having rehabilitation. However, this can be complex for people with severe mental illness. Relationships may have broken down during the person's illness or the person may find it difficult to form new relationships and they may need additional support with this. A person's capacity or their wishes about other people's involvement can also change during their illness.
Laws and established NICE guidelines are already in place that cover involving family members and sharing information, as well as supporting families and helping people keep in contact with their home communities, and the committee either used or linked to these recommendations.
## How the recommendations might affect practice
The recommendations on staff competencies may have a resource impact in services that do not currently provide training. However, any additional resources may be offset by the benefits to service users of establishing a recovery-orientated rehabilitation service. Helping people with complex psychosis to engage with their family members or carers may be more resource-intensive than for people with less severe disease, because of the functional and communication problems people with complex psychosis may face. But these recommendations are derived from other NICE guidance so should reflect current practice.
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# Person-centred care planning through assessment and formulation
Recommendations 1.7.1 to 1.7.12
## Why the committee made the recommendations
The committee used evidence about rates of physical and mental health conditions and substance misuse in this population to recommend what to consider as part of the initial assessment when people enter the rehabilitation service. The committee also drew on their experience to provide details about what a structured comprehensive biopsychosocial needs assessment should cover to assess people's complex needs and comorbidities.
The committee agreed that baseline investigations before starting antipsychotic medicines recommended in the NICE guidelines on psychosis and schizophrenia in adults and bipolar disorder should form the core of the initial physical health check for people in rehabilitation services because most would be receiving antipsychotic medicines.
The committee also drew on the evidence identifying the most common physical and mental health comorbidities to highlight conditions that staff need to be alert for because these may contribute to higher mortality or complexity in rehabilitation in this population. The committee also agreed that more understanding is needed about the likely impact of physical comorbidities on mortality among people with complex psychosis, so they made a research recommendation on coexisting physical health conditions.
The committee agreed that the comorbid health conditions and other needs identified in the needs assessment could be used along with people's recovery goals to contribute to a healthcare plan that would reduce morbidity and mortality, and improve people's function and quality of life.
Quantitative evidence suggested that detailed and regularly updated care plans lead to better service user outcomes, especially when developed within a multidisciplinary team. The committee used this evidence, their own experience and other NICE guidelines to make further recommendations on good care planning. They decided that monthly reviews in inpatient rehabilitation, and 6-monthly reviews for people in community rehabilitation, would keep care plans relevant without being overly invasive.
## How the recommendations might affect practice
An initial needs assessment is already standard practice, but changes might be needed to align with recommendations on what the assessment should include. Physical health checks should also be standard practice, but the committee noted that monitoring and treatment of coexisting health problems was variable in this population so the recommendations should improve consistency of practice.
The recommendations on care planning should not have substantial resource implications. In some areas, additional staffing and training might be needed to enable more regular and thorough review, but in the long term these costs will be offset by more effective treatment, improved recovery and a reduced need for crisis teams, hospital beds and other services.
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# Rehabilitation programmes and interventions
Recommendations 1.8.1 to 1.8.19
## Why the committee made the recommendations
Based on evidence suggesting that interventions could improve daily living skills and, given the importance of these skills in recovery and quality of life, the committee recommended promoting interventions to improve these activities as highly as other types of interventions. In the committee's experience, this does not always happen in practice.
Based on their experience, the committee agreed that individualised support could improve daily living skills, for example by choosing activities that people enjoy and that motivate them. If a person is motivated, they might be more likely to engage in activities of daily living such as personal care or going out on public transport. Having access to areas such as kitchens and laundry was also agreed to be important so that people can practise their skills.
There was qualitative evidence that people in rehabilitation value structured group activities, and a randomised controlled trial found that taking part in them improves interpersonal functioning. This was in line with the committee's views, so they recommended these activities in both inpatient and community settings.
Based on the committee's experience, structured group activities need to be offered daily in inpatient settings and at least weekly in community settings to be effective, and people should have choice in what they do. Although there was no evidence on peer-supported activities, committee members had found these to be effective and agreed they could be an option.
Structured group activities are routinely provided by rehabilitation services, but the evidence base is fairly limited. The committee thought that more specific detail on the structured activities, and their efficacy, could help further inform practice. They therefore made a research recommendation on structured group activities.
The committee wanted to emphasise the importance of meaningful occupation and work in promoting recovery and helping to promote community inclusion, based on their own experience and the preferences expressed in the qualitative evidence. The committee highlighted a number of aims of community activities, and recommended a range of hobbies and leisure activities, as well as skill development opportunities.
Evidence from randomised controlled trials showed that Individual Placement and Support (IPS) increases engagement in employment for those interested in work, and this was supported by cost-effectiveness evidence from a health economic model. There was also evidence that adding cognitive remediation can increase the effectiveness of vocational rehabilitation. The committee recommended considering both of these interventions. They agreed, however, that some people may not be ready for mainstream employment and would benefit from alternatives to IPS such as transitional employment schemes.
The committee also discussed the role of partnerships with other organisations such as voluntary organisations and employment advice schemes. They agreed these could be an important route to engagement with employment or education.
The committee discussed peer-support interventions for engaging in community activities. Although these were widely valued by the committee, there was no directly relevant research to guide the development of peer support for community activities in complex psychosis and rehabilitation services. The committee therefore made a research recommendation on peer-support interventions.
The committee also discussed staff training interventions to mediate improvements in daily living skills, interpersonal skills and engagement in community activities, which are key areas of personal recovery in rehabilitation. However, no trials were found that assessed these interventions, so they made a research recommendation on staff training interventions.
There is a high prevalence of alcohol and substance misuse among the rehabilitation population. Because of limited evidence, the committee made recommendations based mainly on consensus and existing NICE guidance. They wanted to prevent a situation where substance misuse was occurring but rehabilitation staff viewed it as being outside their remit. The committee agreed that questions about substance use should be routine when people enter the rehabilitation service and that rehabilitation staff needed to know what their role should be in supporting people and providing substance misuse interventions.
## How the recommendations might affect practice
The committee noted that providing access to real-life settings for people to practise their daily living skills might be challenging in some services, because of the range of people's needs and risks within the service.
Structured group activities such as playing board games and watching DVDs do not have a high resource impact, but activities outside the rehabilitation setting could be more costly depending on the support needs of the group. Providing a named person to support engagement is unlikely to have significant resource impact, because an existing key worker or support worker might take on this role if it is not being done already, and no external provision would be needed.
The committee agreed that relatively few people with complex psychosis in rehabilitation services are ready to engage in paid employment so the recommendations for individual placement and support would have little impact on current IPS services. Cognitive remediation is not routinely added to vocational rehabilitation and this could lead to a change in practice in for some centres.
The recommendations call for greater awareness among rehabilitation staff about identifying and managing substance misuse, which could be incorporated into general training for all staff.
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# Adjustments to mental health treatments in rehabilitation
Recommendations 1.9.1 to 1.9.23
## Why the committee made the recommendations
The committee focused this section on people with symptoms of psychosis that are resistant to standard treatment because this population represents people using rehabilitation services. The committee recommended adjustments to standard treatments for psychosis described in other NICE guidance.
The evidence showed there were benefits and harms to each treatment option, so the committee agreed that treatments should always be discussed with the person. They were also aware that comorbidities, including other mental health conditions and autism spectrum disorder, can affect outcomes in people with complex psychosis. These comorbidities need to be identified and treated in line with NICE guidance.
There was some evidence from randomised controlled trials that for people with treatment-resistant psychosis, cognitive behavioural therapy (CBT) decreased positive psychosis symptoms compared with pharmacological therapy alone. Based on this evidence and their experience that people with complex psychosis are often too unwell to engage with CBT at earlier contacts with the rehabilitation service, the committee recommended that it should be continued in this treatment-resistant population.
In the committee's experience, some people in rehabilitation are not ready to engage with CBT. The committee discussed the importance of providing additional psychological interventions but could not recommend a specific intervention because of the lack of evidence. Instead they recommended interventions to consider and emphasised that these should be based on psychological assessment, formulation and consideration of each person's preferences.
The committee also wanted to acknowledge the importance of low-intensity psychological interventions. Despite the lack of evidence from trials, the committee decided that the option of providing all staff with skills in delivering these interventions should be considered in rehabilitation settings.
There was some evidence from randomised controlled trials supporting augmentation with the agents in recommendation 1.9.9 for reducing psychosis symptoms in people with schizophrenia refractory to clozapine. The evidence was limited by small sample sizes and information on adverse events was very sparse. However, given the lack of treatment options, and considering that current prescribing for this population is inconsistent, the committee decided that augmentation should be considered an option.
In general, the committee recommended classes of drug rather than individual drugs, but they specifically mentioned aripiprazole as an example when recommending augmentation with antipsychotics. The committee noted that amisulpride is more commonly prescribed than aripiprazole, but the evidence did not show a change in psychosis symptoms following amisulpride, while there was some evidence on the effectiveness of aripiprazole in reducing total psychosis symptoms. Although the evidence also showed that ziprasidone decreased psychosis symptoms, this drug is not licensed or available in the UK.
Given the safety profiles of these drugs and their potential interactions when combined, the committee recommended seeking advice from a psychiatrist specialising in treatment resistance or a specialist mental health pharmacist if needed.
The committee made recommendations on dosing and interactions with other substances based on their experience and knowledge about the safety of various therapeutic options. They recommended therapeutic plasma levels because this may be useful in checking non-adherence or to confirm toxicity or pharmacokinetic drug interactions.
The committee agreed it was important to measure drug levels regularly to assess adherence and guide dosing. There was a lack of evidence on how frequently this should be done, so the committee used their own knowledge and experience, as well as drawing on NICE's guideline on bipolar disorder for monitoring of people taking lithium.
The committee also agreed it was important to monitor the effects of specific medicines. However, again there was no evidence on how frequently to do this. Some antipsychotics increase prolactin, raising the risk of hyperprolactinaemia, and the committee discussed whether prolactin should be measured: before starting treatment with a drug that raises prolactin (as is common practice, and recommended in NICE's guideline on psychosis and schizophrenia in adults); only if a person has symptoms for hyperprolactinaemia; or at regular intervals. The consensus was to consider monitoring prolactin annually and more regularly if the person is symptomatic.
The committee also wanted to highlight the importance of electrocardiogram (ECG) monitoring. Antipsychotic medicines can cause cardiac abnormalities, for example lengthened QT interval on electrocardiography. Although the NICE guidelines on psychosis and schizophrenia in adults and bipolar disorder recommend ECGs only when starting antipsychotic medicines, the committee recommended considering ECGs annually (and more frequently for people with complex antipsychotic regimens or doses above BNF levels). They agreed this consideration was warranted for this population, many of whom have been on medicines long term, or combinations of medicines that may alter cardiac rhythm, or both. It is already common practice to perform ECGs if exceeding BNF limits for antipsychotics.
Evidence showed that medicines adherence was associated with successful progression in the rehabilitation pathway to more independent living. However, there was no evidence on specific interventions to improve adherence in people using rehabilitation services. The committee noted that people with a severe mental illness may find polypharmacy and complex regimens difficult to manage and so recommended avoiding these if possible.
Acknowledging the importance of self-management of medicines in people's recovery, the committee recommended opportunities to do this for those assessed as able to take part. Because of the lack of evidence on specific interventions to improve medicines adherence, they also made a research recommendation on medicine adherence for people in supported accommodation. They agreed that people in supported accommodation are likely to receive less support with taking medication than those in inpatient rehabilitation.
The committee noted that having psychological and pharmacological interventions specifically for people in rehabilitation, could improve their ability to live in the community. However, the existing evidence was not specific to rehabilitation settings and did not include all relevant outcomes, so the committee made a research recommendation on tailored interventions.
The committee was aware of other NICE guidance on electroconvulsive therapy and agreed it was appropriate to cross-refer to this.
## How the recommendations might affect practice
The recommendations on psychological therapy reflect current practice and should not involve additional resources.
The recommendations on pharmacological treatments will help to standardise practice across the NHS. They may lead to an increase in the prescription of aripiprazole as augmentation therapy, but this will not have a resource impact because the associated resource use and unit costs are marginally less costly than amisulpride.
The recommendation on increased monitoring of prolactin levels follows current practice.
There may be some resource impact from an increase in ECG monitoring, though the committee noted the Maudsley Prescribing Guidelines suggest that an ECG should be offered at least annually. Therefore, any resource impact would likely be small.
The overall impact of avoiding complex medical regimens and polypharmacy could be cost saving if adherence is improved and could lead to more successful progression through the rehabilitation pathway.
Return to recommendations
# Physical healthcare
Recommendations 1.10.1 to 1.10.19
## Why the committee made the recommendations
In the committee's experience, access to physical healthcare services is variable depending on the rehabilitation setting and they agreed it was crucial that people did not miss out on monitoring or treatment of their physical health. So the committee outlined the role that inpatient rehabilitation teams should play in physical healthcare, and also adapted existing recommendations on GP responsibilities (recommendations 1.10.1 and 1.10.2) from the NICE guideline on psychosis and schizophrenia in adults. These adapted recommendations were consistent with the evidence about physical comorbidities that the committee looked at.
Combining the limited evidence with their experiences of health promotion in rehabilitation services, the committee agreed that a single professional should coordinate people's physical healthcare. The committee did not specify the role of the professional (for example, a doctor, nurse, healthcare assistant or care coordinator) but the key point was to have a named person to maintain continuity.
The committee recommended the items that should be considered in physical healthcare plans based on their experience, and the evidence on comorbidities in people with severe mental illness.
The committee agreed that smoking was one of the most important modifiable risk factors in this population. They noted that people with complex psychosis using rehabilitation services may find accessing standard smoking cessation programmes difficult. Given the lack of evidence for a specific intervention in rehabilitation, and the need to be mindful of potential drug interactions, the committee agreed that the smoking cessation guidance in the NICE guideline on psychosis and schizophrenia in adults was applicable to the rehabilitation population.
Adverse lifestyle factors may be more prevalent in people with complex psychosis, for example they may be less physically active, which could place them at a higher risk of physical health problems such as obesity, cardiovascular disease, metabolic syndrome and diabetes. They therefore agreed that recommendation 1.1.3.1 about a combined healthy eating and physical activity programme from the NICE guideline on psychosis and schizophrenia in adults was also relevant to include for this population and was broadly supported by the evidence they looked at.
Given that adverse lifestyle factors may be more prevalent in people with complex psychosis, the committee made the recommendation about providing information on physical health risks based on both their knowledge and experience and evidence of the prevalence of comorbidities. The committee also noted that people with complex psychosis may have difficulty maintaining oral hygiene due to poor self‑care and may be at higher risk of substance misuse and sexual and reproductive health problems.
The committee also discussed the importance of good sleep for overall physical health and recovery. Although there was no evidence of specific interventions to improve sleep in the evidence or other NICE guidance, the committee agreed it would be good practice to provide advice and support for maintaining sleep hygiene, and practitioners should avoid environmental barriers that may hinder sleep.
The committee recommended an annual physical health check for people in rehabilitation services based on the physical health checks in NICE's guidelines on psychosis and schizophrenia in adults and bipolar disorder. They added assessments of sexual health, vision, hearing and podiatry, substance use and thyroid function. These additions were based on both their clinical experience and the evidence on comorbidities.
To increase uptake of this health check, the committee agreed it could be done either at the rehabilitation service by a nominated professional, or at the person's GP practice. Adapting recommendations from NICE's guideline on psychosis and schizophrenia in adults, the committee recommended discussing the results of the physical health check with the person and relevant practitioners.
The committee agreed that risk factors and physical or mental health conditions identified during the initial health check should be managed according to existing NICE guidance. For the treatment recommendation, the committee listed the same conditions as NICE's guideline on psychosis and schizophrenia but added chronic obstructive pulmonary disease (COPD) because of the high proportion of COPD in the population.
The recommendation to be alert to possible blood-borne diseases was based on evidence about the relatively high prevalence of hepatitis and HIV in people with severe mental illness. The committee agreed this may be related to homelessness, intravenous drug use or a history of sexually transmitted disease. They also agreed that more understanding is needed about the risks predicting blood-borne virus infection in this population so that strategies can be developed to address these, so they made a research recommendation on the risk of blood-borne virus infections.
## How the recommendations might affect practice
Limited evidence showed that it could be cost effective for physical healthcare to be coordinated by a nominated professional.
If the recommendations on physical health checks result in more people having these checks, there may be a resource impact. However, these costs may be offset in the longer term by the prevention of morbidity and future illness. Although the health checks are within existing NICE guidance and so should be common practice, the National Cardiac Audit Programme 2017 audit found that most people had not been assessed for all 5 cardiovascular health risk factors in the last year.
Treatment of physical health conditions according to NICE guidance should be current practice; however, the National Cardiac Audit Programme 2017 audit found many people with identified risk factors had not received appropriate interventions.
Return to recommendations# Context
Over 80% of people who are referred for mental health rehabilitation have a primary diagnosis of schizophrenia, schizoaffective disorder or other psychosis, around 8% have bipolar affective disorder, and the remaining 11% have other diagnoses. Around two‑thirds are men. Although people who need mental health rehabilitation have varied primary diagnoses, a common feature is the complex problems they experience. These have a severe, negative impact on the person's day-to-day functioning, including managing everyday activities and social, interpersonal and occupational functioning. These problems often make it impossible for people to be discharged from acute mental health inpatient care back to the community. Some people with these difficulties struggle to manage in the community and may benefit from mental health rehabilitation services.
The problems people may experience include 1 or more of the following:
treatment-resistant symptoms (for people with a primary diagnosis of psychosis, this may include 'positive' symptoms such as delusions and hallucinations and/or severe 'negative' symptoms that lead to problems with motivation)
specific cognitive impairments associated with severe psychosis that have a negative impact on organisational and social skills
coexisting mental health problems, such as severe anxiety, depressive or obsessive-compulsive symptoms, or substance misuse
physical health problems, such as diabetes, cardiovascular disease or pulmonary conditions
pre-existing neurodevelopmental disorders, for example autism spectrum disorder or attention deficit hyperactivity disorder.
Rehabilitation is essential to address these complex problems. For the vast majority of people, mental health rehabilitation leads to successful and sustained discharge from hospital and a meaningful, rewarding community life.
Although the mental health rehabilitation care pathway includes both inpatient and community services, there is significant national variation in how they are provided. In areas where there is a lack of local NHS rehabilitation services, people may receive treatment through the NHS or independent sector in the form of out-of-area placements. Since 2012, there have been many closures of NHS inpatient rehabilitation units across England and only half of trusts have a community rehabilitation team. Given that the users of these services have complex psychosis as described above, this suggests that many people do not have access to the specialist rehabilitation services they need, either locally or elsewhere.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nIn this guideline, 'complex psychosis' refers to a primary diagnosis of a psychotic illness (this includes schizophrenia, bipolar affective disorder, psychotic depression, delusional disorders and schizoaffective disorder) with severe and treatment-resistant symptoms of psychosis and functional impairment.\n\nPeople with complex psychosis usually also have 1\xa0or more of the following:\n\ncognitive impairments associated with their psychosis\n\ncoexisting mental health conditions (including substance misuse)\n\npre-existing neurodevelopmental disorders, such as autism spectrum disorder or attention deficit hyperactivity disorder\n\nphysical health problems, such as diabetes, cardiovascular disease or pulmonary conditions.\n\nTogether, these complex problems severely affect the person's social and everyday functioning, and mean they need a period of rehabilitation to enable their recovery and ensure they achieve their optimum level of independence.\n\nThe guideline does not cover people who have a primary diagnosis of a non-psychotic illness. However, rehabilitation practitioners can also provide advice to services outside the rehabilitation pathway on appropriate treatment and support, including specialist placements and tailored support packages, for people with other primary mental health diagnoses or neurodevelopmental conditions, such as personality disorders or autism spectrum disorder.\n\n# Who should be offered rehabilitation?\n\nOffer rehabilitation to people with complex psychosis:\n\nas soon as it is identified that they have treatment-resistant symptoms of psychosis and impairments affecting their social and everyday functioning\n\nwherever they are living, including in inpatient or community settings. In particular, this should include people who:\n\nhave experienced recurrent admissions or extended stays in acute inpatient or psychiatric units, either locally or out of area\n\nlive in 24‑hour staffed accommodation whose placement is breaking down.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on who should be offered rehabilitation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: identifying people who would benefit most and evidence review D: effectiveness of rehabilitation services.\n\nOther supporting information can be found in evidence review F: components of an effective rehabilitation pathway, evidence review J: rehabilitation approaches, care, support and treatment and evidence review Q: factors associated with successful transition.\n\nLoading. Please wait.\n\n# Overarching principles of rehabilitation\n\nRehabilitation services for people with complex psychosis should:\n\nbe embedded in a local comprehensive mental healthcare service\n\nprovide a recovery-orientated approach that has a shared ethos and agreed goals, a sense of hope and optimism, and aims to reduce stigma\n\ndeliver individualised, person-centred care through collaboration and shared decision making with service users and their carers involved\n\nbe offered in the least restrictive environment and aim to help people progress from more intensive support to greater independence through the rehabilitation pathway\n\nrecognise that not everyone returns to the same level of independence they had before their illness and may require supported accommodation (such as residential care, supported housing or floating outreach) in the long term.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on overarching principles of rehabilitation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review J: rehabilitation approaches, care, support and treatment.\n\nLoading. Please wait.\n\n# Organising the rehabilitation pathway\n\nAll local mental healthcare systems should include a defined rehabilitation pathway as part of their comprehensive service.\n\nUse the local joint strategic needs assessment to inform the commissioning of specific service components (see recommendation 1.3.4) that make up the rehabilitation pathway, to match the needs of the local population.\n\nConduct a local rehabilitation service needs assessment. This should include the number of people with complex psychosis who:\n\nare currently placed out of area for rehabilitation\n\nhave recurrent admissions or extended stays (for example, longer than 60\xa0days) in acute inpatient units and psychiatric intensive care units, either locally or out of area\n\nlive in highly supported (24‑hour staffed) accommodation\n\nare receiving care from forensic services but will need to continue their rehabilitation locally when risks or behaviours that challenge have been sufficiently addressed (for example, fire setting, physical or sexual aggression)\n\nare receiving care from early intervention for psychosis services and developing problems that are likely to require mental health rehabilitation services now or in the near future\n\nare physically frail and may need specialist support in their accommodation\n\nare young adults moving from children and young people's mental health services to adult mental health services.\n\nThe rehabilitation pathway should include the following components, as informed by the needs assessment:\n\nrehabilitation in the community, providing clinical care from a community mental health rehabilitation team to people living in supported accommodation (residential care, supported housing and floating outreach) and\n\nrehabilitation in inpatient settings, such as high-dependency rehabilitation units and/or community rehabilitation units.\n\nHealth and social care commissioners should work together with health services, local authorities, housing providers and other partners (third sector and independent sector providers, service users and their families and carers) to ensure that rehabilitation is provided as locally as possible for all those identified in the local rehabilitation service needs assessment.\n\nConsider jointly commissioning the most specialised services (including highly specialist rehabilitation units and longer-term high-dependency rehabilitation units) across areas to provide these services at a regional level for people with particularly complex needs.\n\nEnsure that the rehabilitation pathway is designed to provide flexibility, smooth transitions and support over the longer term, that enables people to:\n\njoin and leave the rehabilitation pathway at different points\n\nmove between parts of the pathway that provide higher or lower levels of support according to their changing needs\n\nspend different periods of time at different stages of the pathway according to need\n\nhave access to more than 1\xa0period of rehabilitation to progress successfully in their recovery and be swiftly referred back to the pathway if their needs increase and they would benefit from further rehabilitation.\n\n## The lead commissioner\n\nHealth and social care commissioners should jointly designate a lead commissioner to oversee the commissioning of the specific services that make up the defined rehabilitation pathway for people with complex psychosis.\n\nThe lead commissioner should:\n\nhave in‑depth knowledge and experience of commissioning services for people with psychosis and other severe mental health conditions\n\nhave knowledge of local rehabilitation services and partnerships\n\nbe familiar with best practice in rehabilitation.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on organising the rehabilitation pathway and the lead commissioner\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: identifying people who would benefit most and evidence review\xa0P: supported accommodation (recommendation 1.3.2 and 1.3.4); evidence review F: components of an effective rehabilitation pathway (recommendations 1.3.1, 1.3.3, 1.3.5, 1.3.6 and 1.3.7); and evidence review G: integrated rehabilitation care pathways involving multiple providers (recommendations 1.3.8 and 1.3.9).\n\nLoading. Please wait.\n\n## Joint working\n\nThe lead commissioner should work together with service providers to deliver an integrated rehabilitation pathway, by ensuring that:\n\nregular communication is supported between senior service managers and senior clinicians across providers of different services within the pathway\n\nbudgets and other resources are shared between local authorities and health services, so that local and regional rehabilitation services meet the local population's needs\n\nfunding mechanisms support collaboration between service providers and do not create unhelpful or perverse funding incentives that undermine people's progression through the rehabilitation pathway\n\nclinical records and care plans are shared between providers\n\nservice level agreements are developed so that relevant services and agencies can work together in a timely and flexible way, including for transitions between services (see recommendation 1.3.7)\n\nservices within the pathway are staffed by appropriately skilled staff\n\nthe remit for each of the services making up the pathway (see recommendation 1.3.1) is clearly specified, including the population they cover.\n\nThe lead commissioner and service providers should ensure that transitions in people's care between the rehabilitation service and other mental health teams or primary care are:\n\nguided by criteria that are clearly defined in local policy\n\nsupported by a group of local rehabilitation practitioners, with whom clinicians can discuss potential referrals and re-referrals and receive advice on appropriate treatment and support\n\nsupported by close collaboration, including comprehensive handovers or an individually tailored period of co‑working between services\n\nagreed with the person and their family or carers (as appropriate) and the clinicians involved in the person's care, at least 3\xa0months before the transition (unless a referral is urgent).\n\nThe lead commissioner and service providers should ensure that people have opportunities to visit potential supported accommodation before moving in to help them make an informed choice about the service.\n\nThe lead commissioner should think about ways to improve the sharing of information and IT\xa0systems between health and social care staff, particularly in relation to people placed out of area.\n\nFor more information on managing transitions, see the NICE guideline on transition between inpatient mental health settings and community or care home settings.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on joint working\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review G: integrated rehabilitation care pathways involving multiple providers (recommendation 1.3.10); evidence review Q: factors associated with successful transition (recommendations 1.3.11 and 1.3.12); evidence review B: barriers in accessing rehabilitation services (recommendation 1.3.13); and evidence review R: supporting transitions (recommendations 1.3.14).\n\nLoading. Please wait.\n\n## Working with other healthcare providers\n\nThe lead commissioner should oversee the agreement of local protocols and service level agreements with primary and secondary physical healthcare providers, for people having inpatient or community rehabilitation. These protocols should:\n\npromote access to national physical health screening programmes, health promotion, monitoring and interventions (see the section on physical healthcare)\n\nensure there is a system to monitor and report people's access to physical healthcare and outcomes that takes into account the increased physical health risks for specific subgroups, for example the higher prevalence of metabolic syndrome and diabetes in people from black, Asian and minority ethnic groups\n\nensure that any physical health conditions are assessed and treated (see the section on physical healthcare)\n\nensure practitioners in primary care, secondary physical care and rehabilitation services work collaboratively and flexibly, drawing together the necessary expertise and capacity to manage physical health conditions\n\nensure that the processes of the Mental Capacity Act (including Court of Protection decisions) do not delay care and treatment.\n\nThe lead commissioner should agree local protocols with specialist substance misuse services for people having inpatient or community rehabilitation who have substance misuse problems. These should:\n\ndefine local arrangements and the content of care to ensure people can get support from local substance misuse services\n\ninclude in‑reach arrangements for people in inpatient rehabilitation services\n\nmonitor and review access to substance misuse services and outcomes.\n\nThe lead commissioner should agree a local protocol with the community mental health service to enable clozapine to be started or restarted in the community. This protocol should:\n\nbe drawn up by, or in consultation with, the community mental health services pharmacist\n\ninclude all relevant safety checks\n\ninclude informing the person's GP.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on working with other healthcare providers\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: prevalence of comorbidity (recommendation 1.3.15); evidence review O: substance misuse (recommendation 1.3.16); and evidence review H: adjustments to standard treatment (recommendation 1.3.17).\n\nLoading. Please wait.\n\n# Improving access to rehabilitation\n\nThe lead commissioner and service providers should provide information about the local rehabilitation pathway and how it is accessed to health and social care practitioners, people who may benefit from rehabilitation and their families and carers.\n\nThe lead commissioner should work together with service providers to ensure that everyone with complex psychosis has access to rehabilitation services regardless of age, gender, ethnicity and other characteristics protected by the Equality Act 2010, and should actively monitor and report on access at least every 6\xa0months.\n\nIf any differences are found in rates of access for specific groups of people (for example, women or ethnic groups) compared with anticipated rates, these should be addressed, for example through:\n\nproviding bespoke services for specific groups, such as women-only services\n\nproviding outreach into other services that work with under-served groups, or home visiting\n\nproviding tailored information and advocacy.\n\nService providers should support people to access legal advice about their immigration status if required.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on improving access to rehabilitation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: barriers in accessing rehabilitation services.\n\nLoading. Please wait.\n\n# Delivering services within the rehabilitation pathway\n\n## Multidisciplinary teams\n\nInpatient and community rehabilitation services for people with complex psychosis should be staffed by multidisciplinary teams comprising a range of professionals with skills and competence in mental health rehabilitation, including:\n\nrehabilitation psychiatrists\n\npractitioner psychologists\n\nnurses\n\noccupational therapists\n\nsocial workers\n\napproved mental health professionals\n\nsupport workers (including peer support workers)\n\nspecialist mental health pharmacists.\n\nThe multidisciplinary team should have access to physical exercise coaches, vocational trainers, welfare rights specialists, dietitians or nutritionists, podiatrists, speech and language therapists and physiotherapists.\n\n## Size of accommodation\n\nCommissioners and providers of inpatient rehabilitation services and supported accommodation should be aware of the benefits to people of providing rehabilitation in smaller facilities, for example for promoting self-management, autonomy and social integration.\n\n## Service quality improvement\n\nConsider using tools to support quality improvement such as the Quality Indicator for Rehabilitative Care (QuIRC) for inpatient rehabilitation units, and the QuIRC-Supported Accommodation (QuIRC‑SA) for supported accommodation.\n\nConsider joining a peer accreditation or quality improvement forum.\n\n## Rehabilitation in the community\n\nFor people with complex psychosis who are living in supported accommodation, specialist clinical care should be provided by a multidisciplinary community mental health rehabilitation team whose work is integrated within an overall framework for the delivery of community mental health services. This team should:\n\ncoordinate the person's care and hold overall clinical responsibility for the person's mental health while they are living in the community\n\nprovide a designated care coordinator for each person but operate with a shared team caseload approach; this involves discussing people's care together at regular team meetings to pool and agree ideas about care and treatment\n\nmake the majority of contacts with the person in their home or community settings rather than where the team is based\n\nwork closely with staff at the person's supported accommodation to tailor people's care plans to their needs (see recommendation 1.7.7) and make clear which staff are responsible for providing different parts of the person's treatment and support as part of their rehabilitation\n\nsupport and oversee the person's progression through the rehabilitation pathway by:\n\n\n\nincreasing the intensity of treatment and support during periods of relapse\n\nproviding ongoing contact and support during any periods of acute inpatient care\n\nenabling the person's discharge home at the earliest opportunity\n\nadjusting care plans to enable the person to gain the skills and confidence to manage in more independent accommodation\n\n\n\nliaise with the person's GP about their physical healthcare\n\nliaise with the relevant service when the person is ready to be discharged from the team to ensure a smooth transition.\n\nSenior clinicians in the community mental health rehabilitation team should work with commissioners and supported accommodation providers to:\n\nhold an overview of the local mental health supported accommodation services, including current vacancies and the quality of care provided\n\nensure that the rehabilitation pathway continues to develop in line with changes in the needs of the local population.\n\nCommunity mental health rehabilitation teams should include as part of their team the staff who are designated care managers for people placed out of area.\n\nTo avoid unnecessary delays, staff should understand when and how to assess people's mental capacity in relation to decisions about moving to supported accommodation. Staff must follow the necessary steps set out in the Mental Capacity Act to enable this move. Also see the NICE guideline on decision making and mental capacity.\n\nSupported accommodation services should:\n\nprovide support appropriate to the person's mental and physical health needs\n\npromote stability and avoid unnecessary moves\n\nbe in a familiar place close to the person's social and cultural networks, if this is clinically appropriate\n\ninclude support with tasks such as managing money and everyday living while encouraging independence and participation in society\n\ngive the person the option (if they are eligible) to have a personal budget or direct payment so they can choose and control their social care and support (for more information on personal budgets and direct payments, see the NICE guideline on people's experience in adult social care services)\n\ngive the person a safe place that feels like their own\n\nrecognise and safeguard individual vulnerability, risk, loneliness and exploitation.\n\n## Rehabilitation in inpatient settings\n\nInpatient rehabilitation services should have an expected maximum length of stay (which should be used as a guide rather than an absolute) to reduce the chance of people becoming 'institutionalised'.\n\nService providers should advise people about the impact of being in inpatient rehabilitation services for an extended period of time on their welfare benefits and the tenure of any existing housing tenancy.\n\n## Out-of-area placements\n\nOut-of-area placements should be limited to people with particularly complex needs. This could include:\n\npeople with psychosis and brain injury, or psychosis and autism spectrum disorder, who need treatment in a highly specialist rehabilitation unit or\n\npeople who have a clear clinical or legal requirement to receive treatment outside their home area.\n\nOut-of-area placements should only be provided after a local placement funding panel (including a rehabilitation practitioner, a senior service manager and local commissioner) has confirmed that the person's care cannot be provided locally.\n\nA designated care manager (or 'out-of-area placement review officer') based within the community mental health rehabilitation team, should review the person's placement after the first 3\xa0months and then every 6\xa0months, to ensure it still meets their needs. This should include:\n\nreviewing the person's progress with them and the multidisciplinary team at their placement\n\nagreeing the necessary steps to help the person progress in their recovery so they can transfer to an appropriate placement in their local area at the earliest opportunity (also see the recommendations on maintaining links with the community in the hospital discharge section of the NICE guideline on transition between inpatient mental health settings and community or care home settings).\n\nWhen people are placed in out-of-area rehabilitation services, provide an explanation in writing to the person (and their family or carers, as appropriate):\n\nwhy they have been placed out of area\n\nthe steps that will be taken so they can return to their local area\n\nhow their family or carers will be helped to keep in contact\n\nthe advocacy support available to help them.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on delivering services within the rehabilitation pathway\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review E: comparative effectiveness of different types of rehabilitation services (recommendations 1.5.1, 1.5.2, 1.5.6 to 1.5.8 and 1.5.13 to 1.5.16); evidence review F: components of an effective rehabilitation pathway (recommendations 1.5.3 to 1.5.5, 1.5.11); evidence review P: supported accommodation (recommendations 1.5.10 and 1.5.12); and evidence review R: supporting transitions (recommendation 1.5.9).\n\nLoading. Please wait.\n\n# Recovery-orientated rehabilitation services\n\nStaff in rehabilitation services should aim to foster people's autonomy, help them take an active part in treatment decisions and support self‑management.\n\nStaff should build on people's strengths and encourage hope and optimism by:\n\nhelping people choose and work towards personal goals, based on their skills, aspirations and motivations\n\ndeveloping and maintaining continuity of individual therapeutic relationships wherever possible\n\nhelping them find meaningful occupations (including work, leisure or education) and build support networks using voluntary, health, social care and mainstream resources\n\nhelping people to gain skills to manage both their everyday activities and their mental health, including moving towards self-management of medication (see the recommendations on helping people to manage their own medicines)\n\nproviding opportunities for sharing experiences with peers\n\nencouraging positive risk-taking\n\ndeveloping people's self-esteem and confidence\n\nvalidating people's achievements and celebrating their progress\n\nrecognising that people vary in their experiences and progress at different rates\n\nimproving people's understanding of their experiences and the treatment and support that may help them – for example, through accessible written information, face-to-face discussions and group work.\n\n## Supporting people to make decisions\n\nEnsure staff in rehabilitation services follow recommendations on communication needs in the section on co-production and enabling people to make decisions in NICE's guideline on people's experience in adult social care services.\n\nStaff must meet people's communication needs as set out in the NHS Accessible Information Standard.\n\nEnsure staff in rehabilitation services follow recommendations in the NICE guideline on decision making and mental capacity.\n\nProvide support to people, if they need it, to express their views, preferences and aspirations about their care and support in line with recommendations in the NICE guideline on people's experience in adult social care services.\n\nLocal authorities must, in line with the Care Act 2014, provide independent advocacy to enable people to participate in:\n\ncare and support needs assessment and\n\ncare planning and\n\nthe implementation process and review where they would otherwise have substantial difficulty in doing so.\n\n## Universal staff competencies\n\nThese recommendations apply to all staff working in the services described in recommendation\xa01.3.4.\n\nEnsure that staff training emphasises recovery principles so that all rehabilitation staff work with a recovery-orientated approach.\n\nStaff should establish and maintain non-judgemental, collaborative relationships with people with complex psychosis.\n\nProvide support for staff to acknowledge and manage any feelings of pessimism about people's potential for recovery. Support could include helping staff to share experiences and frustrations with each other, for example through supervision, reflective practice and peer support groups.\n\nEnsure that staff attend appropriate diversity training and have the skills and competence to deliver non-discriminatory practice. They should understand that people may experience stigma resulting from their mental health condition, which could add to the stigma that people in a minority group (for example people from black, Asian and minority ethnic groups) may already experience.\n\nEnsure that all staff are trained and skilled in supporting structured group activities and promoting daily living skills.\n\nEnsure that staff have skills and competence in risk assessment and management to an appropriate level for the service they work in. For example, staff in high-dependency units should be able to work with people who have a history of, or currently present with, serious risks to themselves or others.\n\nRehabilitation services should ensure that their healthcare staff are competent to recognise and care for people with psychosis and coexisting substance misuse.\n\n## Maintaining and supporting social networks\n\nDiscuss with the person whether, and how, they want their family or carers to be involved in their care. Discuss this at regular intervals to take account of any changes in circumstances.\n\nEnsure that staff receive training in the skills needed to negotiate and work with families and carers, and also in managing issues relating to information sharing and confidentiality.\n\nRespect the rights and needs of carers alongside the person's right to confidentiality. Review the person's consent to share information with family members, carers and other services during their rehabilitation. Follow recommendations on involving families and carers in NICE's guideline on service user experience in adult mental health services.\n\nGive families and carers information about support services in their area that can address their emotional, practical and other needs (this is particularly important if the person is accessing rehabilitation services for the first time).\n\nFor advice for adult carers about how to get a formal assessment of their own needs, follow recommendations in the NICE guideline on supporting adult carers.\n\nEnable the person to maintain links with their home community by:\n\nsupporting them to maintain relationships with family and friends, for example, by finding ways to help with transport\n\nhelping them to stay in touch with social and recreational contacts\n\nhelping them to keep links with employment, education and their local community. This is particularly important if people are in an out-of-area placement.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on recovery-orientated rehabilitation services\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review J: rehabilitation approaches, care, support and treatment (recommendations 1.6.1, 1.6.2 and 1.6.8); evidence review I: collaborative care planning (recommendations 1.6.3 to 1.6.7 and 1.6.15 to 1.6.20); evidence review B: barriers in accessing rehabilitation services (recommendations 1.6.9 to 1.6.11); evidence review K: activities of daily living (recommendation 1.6.12); evidence review A: identifying people who would benefit most (recommendation 1.6.13); and evidence review O: substance misuse (recommendation 1.6.14).\n\nLoading. Please wait.\n\n# Person-centred care planning through assessment and formulation\n\n## Assessment\n\nDecember 2022:\n The MHRA has issued new safety advice on risks associated with valproate for anyone under 55.\n\nOffer people a comprehensive biopsychosocial needs assessment by a multidisciplinary team within 4\xa0weeks of entering the rehabilitation service.\n\nInclude the following as part of the comprehensive assessment:\n\nsystematic assessment of primary and coexisting mental health problems\n\npsychiatric history, including past admissions and treatments, responses to treatment, adverse effects from medicines, and medication adherence\n\nmedicines reconciliation by a specialist mental health pharmacist (see the section on medicines reconciliation in NICE's guideline on medicines optimisation)\n\nvulnerabilities, including self-neglect, exploitation and abuse, and the person's risk of harm to themselves (including suicide) and others\n\nphysical health and wellbeing through a physical health check (see recommendation 1.7.3)\n\ndevelopmental history from birth, including milestones; relationships with peers; and problems at school (identifying any problems with social or cognitive functioning, motor development and skills or coexisting neurodevelopmental conditions)\n\noccupational and educational history, including educational attainment and reason for leaving any employment\n\nsocial history, including accommodation history (noting the highest level of independence); culture, ethnicity and spirituality; leisure activities; and finances\n\nsmoking, alcohol and illicit substance use\n\npsychological and psychosocial history, including relationships, life history, experiences of abuse and trauma, coping strategies, strengths, resiliency, and previous psychological or psychosocial interventions\n\ncurrent social network, including any caring responsibilities\n\ncurrent skills in activities of daily living\n\ncurrent cognitive function, including any communication needs\n\nthe person's capacity to give informed consent for their treatment in line with the Mental Capacity Act\xa02005.\n\nThe initial physical health check in the comprehensive assessment by the rehabilitation service should include:\n\nbody mass index\n\nwaist circumference\n\nfull blood count\n\npulse and blood pressure\n\nglycosylated haemoglobin (HbA1c), blood lipid profile, liver function tests, renal function tests and thyroid function\n\nprolactin levels (for people on medicines that raise prolactin levels).\n\nrenal function tests and calcium levels (for people on lithium)\n\ndrug levels where appropriate, for example mood stabilising or anti-epileptic medicines, lithium and clozapine; do not offer valproate to women of childbearing potential, unless other options are unsuitable and the pregnancy prevention programme is in place (follow the Medicines and Healthcare Products Regulatory Agency [MHRA] safety advice on valproate use by women and girls)\n\nelectrocardiogram (ECG)\n\nsmoking, alcohol and illicit substance use\n\nnutritional status, diet and level of physical activity\n\ncontinence and constipation (particularly if the person is on clozapine)\n\nany movement disorders\n\nsexual health\n\nvision, hearing and podiatry\n\noral inspection of general dental health\n\nany difficulties with swallowing.\n\nBe aware that people with complex psychosis are more likely to have multiple comorbidities, both mental and physical.\n\nBe aware that people with complex psychosis have a higher prevalence of the following mental health conditions (which may contribute to complexity in rehabilitation):\n\nanxiety (see the NICE guideline on generalised anxiety disorder and panic disorder in adults)\n\nattention deficit hyperactivity disorder (see the NICE guideline on attention deficit hyperactivity disorder)\n\nautism spectrum disorder (see the NICE guidelines on autism spectrum disorder in under 19s: recognition, referral and diagnosis, autism spectrum disorder in under 19s: support and management and autism spectrum disorder in adults)\n\nborderline personality disorder (see the NICE guidelines on borderline personality disorder and antisocial personality disorder)\n\ncognitive impairments (including acquired brain disorders)\n\ndepression (see the NICE guideline on depression in adults)\n\nspeech, language and communication disorders.\n\nBe aware that people with complex psychosis have a higher prevalence of the following physical health conditions (which may contribute to higher mortality in this population):\n\ncardiovascular disease\n\nchronic obstructive pulmonary disease (COPD)\n\ndental problems and poor oral health\n\ndiabetes\n\nmetabolic syndrome\n\nobesity\n\nosteoporosis\n\nsubstance misuse.See the section on care and treatment for physical health conditions for links to other relevant NICE guidance.\n\n## Care planning and review\n\nUse the results of the comprehensive assessment to make a team formulation to inform treatment and care planning. The care plan should:\n\nbe developed collaboratively with the person\n\ncover the areas of need identified during assessment (see recommendation 1.7.2), including both mental and physical health (for physical healthcare planning, see the section on responsibilities of different healthcare providers)\n\ninclude the person's personal recovery goals\n\nclarify actions and responsibilities for staff, the person themselves and their family or carers (where relevant).\n\nConsider using accessible formatting to support the person in jointly developing their care plan, regardless of whether or not they have identified communication and information needs.\n\nReview people's progress and care plans with them at multidisciplinary care review meetings at least:\n\nevery month in the inpatient rehabilitation service\n\nevery 6\xa0months in the community.\n\nIncorporate both staff-rated and service user-rated measurements of the person's progress into their care plan reviews, so that their support can be adjusted if needed.\n\nUpdate care plans according to changes in the person's needs after these meetings and between meetings as needed. At every meeting or review, consider and plan with the person their transition to the next step in the rehabilitation pathway.\n\nEnsure that care plans are shared with the person and everyone involved in the person's care (for example, clinicians, supported accommodation staff, and the person's family or carers, if the person agrees) at:\n\neach review\n\neach transition point in the rehabilitation pathway\n\nat discharge from the service. For more on care plans and assessment before discharge, see recommendations 1.5.20 and 1.5.21 in the NICE guideline on transition between inpatient mental health settings and community or care home settings.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on person-centred care planning through assessment and formulation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: prevalence of comorbidity (recommendations 1.7.1 to 1.7.6) and evidence review I: collaborative care planning (recommendations 1.7.7 to 1.7.12).\n\nLoading. Please wait.\n\n# Rehabilitation programmes and interventions\n\n## Daily living skills\n\nRehabilitation services should develop a culture that promotes activities to improve daily living skills as highly as other interventions (for example, medicines).\n\nProvide activities to help people with complex psychosis develop and maintain daily living skills such as self-care, laundry, shopping, budgeting, using public transport, cooking and communicating (including using digital technology).\n\nSupport people to engage in activities to develop or improve their daily living skills by:\n\nmaking a plan with each person that focuses on their needs and regularly reviews their goals\n\nproviding activities they enjoy and that motivate them\n\nenabling them to practise their skills in risk-managed real life, such as kitchens and laundry rooms, wherever possible.\n\n## Interpersonal and social skills\n\nOffer structured group activities (social, leisure or occupational) aimed at improving interpersonal skills. These could be peer-led or peer-supported and should be offered:\n\ndaily in inpatient rehabilitation services\n\nat least weekly in community settings.\n\nOffer regular opportunities to discuss the choice of group activities, for example by inviting everyone in the inpatient unit or supported accommodation service to a 'community meeting'.\n\nOffer regular one-to-one sessions with a named member of staff to help the person plan and review their activity programme. The person could be:\n\nthe primary nurse in inpatient rehabilitation or\n\nthe person's care coordinator or keyworker in community rehabilitation services.\n\n## Engagement in community activities, including leisure, education and work\n\nProgrammes to engage people in community activities should:\n\nbe flexible and make reasonable adjustments to accommodate the person's illness and fluctuating needs\n\nbe individualised\n\ndevelop structure and purpose in the person's day\n\naim to increase their sense of identity, belonging and social inclusion in the community\n\ninvolve peer support\n\nrecognise people's skills and strengths.\n\nOffer people the chance to be involved in a range of activities that they enjoy, tailored to their level of ability and wellness.\n\nOffer people a range of educational and skill development opportunities, for example, recovery colleges and mainstream adult education settings, which build confidence and may lead to qualifications if the person wishes.\n\nFor people who would like to work towards mainstream employment, consider referring them to supported employment that uses the Individual Placement and Support approach.\n\nTake into account and advise people about the impact of supported employment on their welfare benefits.\n\nFor people who are not ready to return to paid employment, consider alternatives such as transitional employment schemes and volunteering.\n\nConsider providing a cognitive remediation intervention alongside vocational rehabilitation services.\n\nDevelop partnerships, for example with voluntary organisations and local employment advice schemes, to increase opportunities for support to prepare people for work or education.\n\n## Substance misuse\n\nAsk people about their substance use (alcohol and illicit substances) when they enter the rehabilitation service.\n\nAssess people's readiness to address their substance misuse, for example, through motivational interviewing.\n\nRehabilitation services should work with specialist substance misuse services to support people in line with NICE guidelines on:\n\ncoexisting severe mental illness (psychosis) and substance misuse: assessment and management in healthcare settings\n\ncoexisting severe mental illness and substance misuse: community health and social care services\n\nalcohol-use disorders: diagnosis, assessment and management of harmful drinking (high-risk drinking) and alcohol dependence.\n\nRehabilitation services should offer support and substance misuse interventions that aim to:\n\nsupport harm reduction\n\nchange behaviour\n\nhelp people develop coping strategies\n\nimprove engagement with substance misuse services\n\nprevent relapse.\n\nSubstance misuse services should provide reasonable adjustments to help people use specialist substance misuse services, for example, by providing in‑reach services to people in the inpatient rehabilitation service.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on rehabilitation programmes and interventions\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review K: activities of daily living (recommendations 1.8.1 to 1.8.3); evidence review L: interpersonal functioning (recommendations 1.8.4 to 1.8.6); evidence review M: engagement in community activities and evidence review J: rehabilitation approaches, care, support and treatment (recommendations 1.8.7 to 1.8.14); and evidence review O: substance misuse (recommendations 1.8.15 to 1.8.19).\n\nLoading. Please wait.\n\n# Adjustments to mental health treatments in rehabilitation\n\nFor standard pharmacological and non-pharmacological treatments, follow recommendations in these sections of the NICE guideline on psychosis and schizophrenia in adults:\n\nchoice of antipsychotic medication (section\xa01.3.5)\n\nhow to use antipsychotic medication (section\xa01.3.6)\n\nhow to deliver psychological interventions (section\xa01.3.7)\n\nsubsequent acute episodes of psychosis or schizophrenia and referral in crisis (section\xa01.4). Also see the NICE guideline on bipolar disorder, in particular section\xa01.10 on how to use medication.\n\nDiscuss all mental health treatment options with people in line with the recommendations in NICE's guideline on shared decision making.\n\nRoutinely monitor for and treat other coexisting mental health conditions, including depression, obsessive-compulsive disorder, anxiety, substance misuse, and risk of suicide (for guidance on these conditions, see NICE's web page on mental health and behavioural conditions).\n\nFor people diagnosed with a coexisting autism spectrum disorder, follow recommendations in the NICE guideline on autism spectrum disorder in adults.\n\nFollow the recommendations on medicines-related communication systems when people move from one care setting to another in the NICE guideline on medicines optimisation.\n\n## Psychological therapies\n\nContinue to offer people with complex psychosis individual cognitive behavioural therapy (CBT) and family intervention as recommended by the NICE guideline on psychosis and schizophrenia in adults. Follow the recommendations on delivery and monitoring in the section of that guideline on psychological interventions.\n\nConsider additional psychological interventions, especially for people who are not ready to engage in CBT. Use psychological assessment and formulation to identify the most appropriate therapeutic intervention, guided by the person's preferences. Interventions could include:\n\nthose focusing on learned behaviours and how context influences behaviour\n\nmindfulness approaches where people can be supported to focus on and attend to present experiences\n\napproaches that include a focus on wider systems such as families or ward environments and their impact on the person.\n\nConsider training all rehabilitation staff in psychologically informed approaches such as motivational interviewing, positive behaviour support, behavioural activation, trauma-informed care, and simple techniques for supporting people who are having troubling thoughts and feelings.\n\n## Pharmacological treatments\n\nDecember 2022:\n The MHRA has issued new safety advice on risks associated with valproate for anyone under 55.\n\nFor people with complex psychosis whose symptoms have not responded adequately to an optimised dose of clozapine alone, consider augmenting clozapine with the following, depending on target symptoms:\n\nan antipsychotic, for example aripiprazole for schizophrenia and related psychoses and/or\n\na mood stabiliser for psychosis with significant affective symptoms and/or\n\nan antidepressant if there are significant depressive symptoms in addition to the psychotic condition. Be aware of potential drug interactions and note that not all combinations of treatments may be in accordance with UK marketing authorisations. Any off-licence prescribing should be communicated in writing with the person's GP. Seek specialist advice if needed, for example from another psychiatrist specialising in treatment-resistant symptoms or a specialist mental health pharmacist. Do not offer valproate to women of childbearing potential, unless other options are unsuitable and the pregnancy prevention programme is in place. Follow the MHRA safety advice on valproate use by women and girls.\n\nOptimise the dosage (as tolerated) of medicines used to manage complex psychosis (see recommendations 1.9.1 and 1.9.9) according to the BNF and therapeutic plasma levels in the first instance.\n\nOnly use multiple medicines, or doses above BNF or summary of product characteristics limits, to treat complex psychosis:\n\nif this is agreed and documented by the multidisciplinary team and the person (and their family, carer or advocate, as appropriate)\n\nas a limited therapeutic trial, returning to conventional dosages or monotherapy after 3\xa0months, unless the clinical benefits of higher doses or combined therapy clearly outweigh the risks\n\nif the medicines are being used to treat specific symptoms that are disabling or distressing\n\nafter taking into account drug interactions and side effects, for example be cautious when adding an antidepressant to clozapine for someone who has experienced symptoms of mania\n\nif systems and processes are in place for monitoring the person's response to treatment and side effects (monitoring may include physical examination, ECG and appropriate haematological tests).\n\nRegularly review medicines used to manage complex psychosis and monitor effectiveness, adverse effects and drug interactions, including monitoring for constipation for those taking clozapine. Follow recommendations in the NICE guidelines on medicines optimisation and multimorbidity.\n\nIf pharmacological treatment is not effective, consider stopping the medicine:\n\nfollowing a thorough review of treatment\n\nafter agreeing and documenting the decision at a meeting with a multidisciplinary team and the person (and their family, carer or advocate, as appropriate)\n\nwith caution, particularly if the person has been on the medicine for many years\n\nby reducing the dose slowly and closely monitoring the person for symptoms of relapse.\n\nMonitor drug levels to check adherence and guide dosing:\n\nAt least annually and as needed for clozapine and mood stabilising anti-epileptic medicines.\n\nEvery 3 to 6\xa0months for people established on lithium, following recommendations on using lithium in the NICE guideline on bipolar disorder. Follow the MHRA safety advice on valproate use by women and girls.\n\nConsider monitoring prolactin levels annually if the person is taking a medicine that raises prolactin, and more regularly if they have symptoms.\n\nMonitor thyroid function, renal function and calcium levels at least every 6\xa0months for people established on lithium, following recommendations on using lithium in the NICE guideline on bipolar disorder.\n\nConsider annual ECGs for everyone with complex psychosis in rehabilitation services, and more regularly if they are taking medicines, combinations of medicines or medicines above BNF or summary of product characteristics limits that may alter cardiac rhythm (for example, causing prolonged QT interval).\n\nBe aware that people may be using non-prescription substances (for example, alcohol, smoking or drugs) to cope with their symptoms, which may affect their prescribed medicines.\n\nConsider referring for a second opinion from a relevant specialist when treating people whose symptoms have not responded well to standard treatment, and after following recommendations in the NICE guideline on medicines optimisation.\n\nRehabilitation services should promote adherence to medicines in line with the NICE guideline on medicines adherence. Strategies to promote adherence could include avoiding complex medicine regimens and polypharmacy wherever possible.\n\nOffer people the opportunity to manage their own medicines through a graduated self-management of medicines programme if they have been assessed as able to take part. Follow recommendations on self-management plans in the NICE guideline on medicines optimisation.\n\nBe flexible in tailoring the self-management of medicines programme and choice of equipment to the person's needs and preferences. This could include using monitored dosage systems together with a reminder system (for examples, charts or alarms).\n\n## Electroconvulsive therapy\n\nSee the NICE technology appraisal guidance on the use of electroconvulsive therapy.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on adjustments to mental health treatments in rehabilitation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review H: adjustments to standard treatment (recommendations 1.9.1 to 1.9.19) and evidence review K: activities of daily living (recommendations 1.9.20 to 1.9.22).\n\nLoading. Please wait.\n\n# Physical healthcare\n\n## Responsibilities of different healthcare providers\n\nGPs should develop and use practice case registers to monitor the physical and mental health of people with complex psychosis in primary care.\n\nFor people having community rehabilitation, GPs should assume lead responsibility for the person's physical health needs, including health checks and treatment of physical health conditions, working collaboratively with the community mental health rehabilitation team and other services as relevant.\n\nFor people having inpatient rehabilitation, the rehabilitation team should ensure that health checks, treatment of physical health conditions and other healthcare needs are addressed.\n\n## Coordinating physical healthcare\n\nNominate a professional from the rehabilitation service to provide continuity of physical healthcare across settings, liaising between the rehabilitation service, primary care, secondary mental health and secondary physical healthcare.\n\nThe nominated professional should work in collaboration with a healthcare professional to develop and oversee the physical healthcare plan, ensuring it is informed by the initial physical health check (see recommendation 1.7.3) and include:\n\nhealth promotion interventions (see the section on healthy living, below)\n\nroutine screening through the national screening programmes (for example, cervical cancer) if the person is eligible\n\nmonitoring side effects of pharmacological treatments (see the section on pharmacological treatments)\n\nmonitoring of physical health (see the section on monitoring physical health, below)\n\nmonitoring of oral health\n\ntreatment plans for any risk factors or health conditions (see care and treatment for physical health conditions, below)\n\nany reasonable adjustments needed for healthy living, screening, monitoring or treatments\n\nthe physical healthcare responsibilities for primary care, the rehabilitation service, other secondary mental health services and secondary physical healthcare.\n\nStaff must follow the Mental Capacity Act 2005 when supporting people's physical health, including in primary and secondary physical healthcare screening, prevention, investigations and treatment.\n\n## Healthy living\n\nOffer people who smoke help to stop smoking, even if previous attempts have been unsuccessful.\n\nBe aware of the potential significant impact of reducing cigarette smoking on the metabolism of other drugs, particularly clozapine. Follow recommendations 1.1.3.4 and 1.1.3.5 in the physical health section of NICE's guideline on psychosis and schizophrenia in adults.\n\nOffer people a combined healthy eating and physical activity programme and support them to take part in it.\n\nGive people clear and accessible information about any health risks related to their:\n\nmedicines (side effects)\n\nlifestyle, including:\n\n\n\ndiet and physical activity\n\nsmoking, alcohol or illicit substance use\n\noral hygiene\n\nbone health\n\nsexual and reproductive health.\n\n\n\nOffer annual flu vaccination to people:\n\nin inpatient rehabilitation services\n\nin communal supported accommodation\n\nwho have a comorbid physical health condition (such as chronic respiratory disease, chronic heart disease or diabetes) that means they are more likely to develop serious complications from flu (see the section on clinical risk groups in NICE's guideline on flu vaccination).\n\nExplain to people that family members or carers who support them may also be eligible for free flu vaccination (see the section on flu vaccination in carers in NICE's guideline on flu vaccination).\n\nSupport people to maintain good oral hygiene and access dental appointments in line with NICE's guideline on oral health promotion.\n\nConsider providing advice and support for good sleep hygiene and maximise opportunities for healthy sleep. For example, for inpatients, avoid barriers to sleep such as environmental factors or intrusive night-time checks.\n\n## Monitoring physical health\n\nOffer people in rehabilitation services a routine physical health check at least annually. The annual physical health check should include:\n\nbody mass index\n\nwaist circumference\n\npulse and blood pressure\n\nfull blood count, HbA1c, blood lipid profile, renal function tests, liver function tests and thyroid function\n\nsmoking, alcohol or drug use\n\nnutritional status, diet and level of physical activity\n\nany movement disorders\n\nsexual health\n\nvision, hearing and podiatry\n\noral inspection of general dental health. For additional physical health checks associated with pharmacological treatments, see the section on pharmacological treatments.\n\nGive people the choice, whenever possible, to have their annual physical health check at their GP practice or by a trained professional at the rehabilitation service (see recommendation 1.10.5).\n\nEnsure a copy of the results of the physical health check is available to the rehabilitation service, primary care, secondary mental healthcare and secondary physical healthcare as appropriate, and is recorded in the case notes. Discuss any important findings with the person.\n\n## Care and treatment for physical health conditions\n\nUse the annual physical health check in recommendation 1.10.15 to identify at the earliest opportunity people who:\n\nhave or are at high risk of cardiovascular disease (see the NICE guideline on cardiovascular disease)\n\nhave hypertension (see the NICE guideline on hypertension)\n\nare obese or at risk of obesity (see the NICE guideline on obesity prevention)\n\nhave diabetes or are at high risk of diabetes (see the NICE guidelines on preventing type\xa02 diabetes, type 1 diabetes in adults: diagnosis and management and\xa0type 2 diabetes in adults: management)\n\nare physically inactive (see the NICE guideline on physical activity)\n\nhave COPD (see the NICE guideline on chronic obstructive pulmonary disease). Offer treatment in line with NICE guidance, ideally in primary care.\n\nBe alert to the possibility of infection with blood-borne diseases in people who could be at risk, for example because of homelessness, intravenous drug use or a history of sexually transmitted disease. For more information about those at risk and case identification, see the NICE guidelines on hepatitis\xa0B and\xa0C testing and HIV testing.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on physical healthcare\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: prevalence of comorbidity (recommendations 1.10.1 to 1.10.3 and 1.10.19) and evidence review N: engagement in healthy living (recommendations 1.10.4 to 1.10.18).\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\n## Behavioural activation\n\nA low-intensity intervention using goal setting and activity schedules to encourage people to engage in activities they have previously avoided due to factors such as low mood or motivation.\n\n## Cognitive remediation intervention\n\nA manualised intervention to improve people's cognitive function.\n\n## Commissioners\n\nAt the time of publication, the development of integrated care systems, integrated care providers and NHS provider collaboratives is changing the commissioning landscape in the English health and care system. This may be formalised within new legislation. All references to 'commissioners' and 'commissioning' in this guideline should therefore be read in that context, wherever the commissioning function may sit and however it may operate in the future NHS in England.\n\n## Community mental health rehabilitation team\n\nTeams providing specialist skills and care coordination to identify and address people's rehabilitation needs in the community. These teams can work in all community settings, but commonly work with people living in supported accommodation, often over many years, to enable their optimum level of functioning and independence.\n\n## Community rehabilitation units\n\nInpatient rehabilitation units that are set outside hospital grounds. These units provide the full complement of multidisciplinary treatment and support for people with ongoing complex needs that prevent them from being discharged from a high-dependency rehabilitation unit directly to supported accommodation. They build on the progress made in the high-dependency inpatient rehabilitation unit and have a strong focus on promoting independent living skills and community participation. Most referrals come from high-dependency rehabilitation units or acute inpatient units. Community rehabilitation units can only care for detained people under the Mental Health Act 1983 if the unit is registered as a ward. If they are not registered as a ward, they can care for people who are voluntary or those subject to a community order (for example, a community treatment order, guardianship, or conditionally discharged Section\xa037/41). The expected length of stay in a community rehabilitation unit is 1\xa0to\xa02\xa0years.\n\n## Complex psychosis\n\nIn this guideline, 'complex psychosis' refers to a primary diagnosis of a psychotic illness (this includes schizophrenia, bipolar affective disorder, psychotic depression, delusional disorders and schizoaffective disorder) with severe and treatment-resistant symptoms of psychosis and functional impairment.\n\nPeople with complex psychosis usually also have 1\xa0or more of the following:\n\ncognitive impairments associated with their psychosis\n\ncoexisting mental health conditions (including substance misuse)\n\npre-existing neurodevelopmental disorders, such as autism spectrum disorder or attention deficit hyperactivity disorder\n\nphysical health problems, such as diabetes, cardiovascular disease or pulmonary conditions.\n\nTogether, these complex problems severely affect the person's social and everyday functioning, and mean they need a period of rehabilitation to enable their recovery and ensure they achieve their optimum level of independence.\n\n## Floating outreach\n\nServices providing support to people living in time-unlimited, usually self-contained, individual tenancies. Staff are based off-site and visit for a few hours per week, providing practical and emotional support, with the aim of reducing support over time to zero.\n\n## Graduated self-management of medicines programme\n\nSupporting a person to learn how to take and manage their own medicines. This usually involves them managing 1\xa0day of medicines to begin with, with staff undertaking spot checks before progressing to managing 2\xa0days, then 3\xa0days and so on.\n\n## High-dependency rehabilitation units\n\nInpatient rehabilitation units for people with complex psychosis whose symptoms have not yet been stabilised and whose associated risks and challenging behaviours remain problematic. These units aim to maximise benefits of medication, address physical health comorbidities, reduce challenging behaviours, re‑engage families and facilitate access to the community. Most people in high-dependency units are detained under the Mental Health Act 1983. Most (80%) referrals to high-dependency units are from acute inpatient units and 20% from forensic units, with only occasional referrals of people living in the community. The expected length of stay is around 1\xa0year.\n\n## Highly specialist rehabilitation units\n\nInpatient rehabilitation units for people with psychosis and comorbid conditions who need a specialist programme tailored to their specific comorbidity (such as acquired brain injury, severe personality disorder, autism spectrum disorder or Huntington's disease). Often, the complexity of the person's coexisting conditions is associated with greater support needs (more challenging behaviours and/or a greater risk to themselves and others) than people having treatment in a high-dependency rehabilitation unit. Referrals come from acute inpatient units or high-dependency rehabilitation units, and the expected length of stay is over 3\xa0years.\n\n## Individual Placement and Support (IPS) approach\n\nA method of supporting people with severe mental health problems into work. IPS finds people a job quickly and then provides time-unlimited individualised support to keep the job and manage their mental health.\n\n## Inpatient rehabilitation units\n\nUnits providing specialist inpatient care to people with complex psychosis. They can be based within a hospital or in the community.\n\n## Local placement funding panel\n\nA panel not specific to rehabilitation, who agree funding (health, social care or both) for people to receive treatment within area or out of area, for example in a nursing or residential care home, or in an inpatient rehabilitation unit. The panel has a commissioner and senior service managers, as well as clinicians (a senior rehabilitation practitioner plus possibly a senior clinician who works in general adult care, not specifically rehabilitation).\n\n## Longer-term high-dependency rehabilitation units\n\nThese units provide longer-term inpatient rehabilitation for people with high levels of disability due to treatment-resistant symptoms and comorbid conditions that take more than 1\xa0year to stabilise, and who have ongoing risks to others and/or challenging behaviours. The aims of longer-term high-dependency rehabilitation units are the same as for high-dependency rehabilitation units, and most referrals come from high-dependency rehabilitation units.\n\n## Motivational interviewing\n\nA person-centred psychologically informed approach that supports behavioural change by helping people explore and resolve ambivalence towards change.\n\n## Out-of-area placements\n\nA placement that provides treatment and support in an inpatient rehabilitation unit or supported accommodation outside the local area where a person usually lives, and/or outside the catchment area for the local authority that has responsibility for their housing. The placement may be away from the person's local area because there is no local service available, or because there are clinical or legal reasons that make local rehabilitation inappropriate for their needs, or because they prefer to have treatment outside their local area.\n\n## Positive behaviour support\n\nA behaviour management system that seeks to understand the reasons behind problematic behaviours and to find alternative ways to meet goals and needs.\n\n## Psychologically informed approaches\n\nBrief skills-based interventions that can be delivered by any staff member or service user who has had suitable training in the intervention. They include: guided self-help using online resources or workbooks; relaxation or mindfulness; stress workshops and behavioural activation groups.\n\n## Recovery colleges\n\nPeer-led education and training programmes for mental health service users. They provide education as a route to recovery, not as a form of therapy. The courses are co‑devised and co‑delivered by people with lived experience of mental illness and by mental health professionals.\n\n## Recovery-orientated approach\n\nThere is no single definition of recovery for people with mental health problems, but the guiding principle is the belief that it is possible for someone to regain a meaningful life, despite serious mental illness. In this guideline, it refers to someone achieving the best quality of life they can, while living and coping with their symptoms. It is an ongoing process whereby the person is supported to build up their confidence and skills and resilience, through setting and achieving goals to minimise the impact of mental health problems on their everyday life.\n\n## Residential care\n\nCommunal facilities, staffed 24\xa0hours, where day-to-day needs are provided (including meals, supervision of medicines and cleaning), and placements are not time limited. People do not hold a tenancy in a residential care home.\n\n## Supported accommodation\n\nAn umbrella term covering residential care, supported housing and floating outreach.\n\n## Supported housing\n\nShared or individual self-contained, time-limited tenancies with staff based on site up to 24\xa0hours a day who help the person to gain skills to move on to less supported accommodation. The intended length of stay is usually about 2\xa0years but in practice, only around one-third of people move on in that time.\n\n## Team formulation\n\nA shared understanding of the issues that brought the person into rehabilitation services. It is their story, but draws on information from theory and research, as well as the experiences of the person, professionals and, where possible, others such as carers. It includes factors that made the person vulnerable to developing problems, factors that triggered the problems and factors that keep the problems going. A team formulation includes strengths and resources and points to ways that problems can be addressed.\n\n## Transitional employment schemes\n\nThese schemes give people a supported occupation in which to gain pre-vocational work experiences and potentially prepare for mainstream employment. One of the original examples was the 'clubhouse' model of psychosocial rehabilitation developed at Fountain House in New York.\n\n## Trauma-informed care\n\nCare that is built on an understanding that anyone using services could have experienced psychosocial trauma and that this is likely to influence how they engage with care. Key principles include safety and avoiding re-traumatisation; relationship building; peer support; collaboration and mutuality; empowerment and choice; and an awareness of cultural, historical and gender issues.\n\n## Treatment-resistant symptoms\n\nPersistent symptoms that have not responded to the range of treatments (including pharmacological treatments) recommended in the NICE guidance for the person's condition.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Who should be offered rehabilitation?\n\nWhat is the efficacy and cost effectiveness of rehabilitation services compared with treatment as usual for people with complex psychosis with residual disability, who are leaving early intervention services?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on who should be offered rehabilitation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: effectiveness of rehabilitation services.\n\nLoading. Please wait.\n\n## Peer-support interventions\n\nHow can peer-support interventions be used most effectively to support people with complex psychosis using rehabilitation services?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on engagement in community activities, including leisure, education and work\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review M: engagement in community activities.\n\nLoading. Please wait.\n\n## Highly specialist and longer-term high-dependency rehabilitation units\n\nWhat are the service and service user characteristics of highly specialist and longer-term high-dependency rehabilitation units that are associated with better outcomes?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on rehabilitation in inpatient settings\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: identifying people who would benefit most.\n\nLoading. Please wait.\n\n## Structured group activities\n\nWhat structured group activities are effective at improving interpersonal functioning (social skills) for people with complex psychosis?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on interpersonal and social skills\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review L: interpersonal functioning.\n\nLoading. Please wait.\n\n## Inpatient rehabilitation provided by the independent sector\n\nWhat is the clinical and cost effectiveness of inpatient rehabilitation provided by the independent sector compared with that provided by the NHS?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on out-of-area placements\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review E: comparative effectiveness of different types of rehabilitation services.\n\nLoading. Please wait.\n\n# Other recommendations for research\n\n## Integrated care systems\n\nIs an integrated care system effective at promoting successful progress for people with complex psychosis to a more independent setting?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on transitions\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review R: supporting transitions.\n\nLoading. Please wait.\n\n## Staff training interventions\n\nWhat staff training interventions are effective at facilitating personal recovery for people with complex psychosis?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on engagement in community activities, including leisure, education and work\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review M: engagement in community activities.\n\nLoading. Please wait.\n\n## Coexisting physical health conditions\n\nWhat is the impact of coexisting physical health conditions on the mortality of people with complex psychosis?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on assessment\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: prevalence of comorbidity.\n\nLoading. Please wait.\n\n## Medicines adherence\n\nWhat interventions are effective to support medicines adherence for people with complex psychosis in supported accommodation?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on adherence to medicines and helping people to manage their own medicines\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review K: activities of daily living.\n\nLoading. Please wait.\n\n## Tailored interventions\n\nWhat tailored interventions (pharmaceutical and psychological) specific to rehabilitation are effective at equipping people with complex psychosis with the ability to live in the community?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on interventions tailored to people in rehabilitation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review H: adjustments to standard treatment.\n\nLoading. Please wait.\n\n## Risk of blood-borne virus infections\n\nWhat are the risks that predict the development of blood-borne virus infections in people with complex psychosis in the UK?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on care and treatment for physical health conditions\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: prevalence of comorbidity.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice and services.\n\n# Who should be offered rehabilitation?\n\nRecommendation 1.1.1\n\n## Why the committee made the recommendation\n\nLow to very low quality evidence from randomised controlled trials of rehabilitation in the community and observational studies of inpatient rehabilitation showed that rehabilitation was effective and cost effective for many people with complex psychosis. Qualitative evidence also showed that people with severe mental illness value rehabilitation.\n\nThere was moderate quality evidence that people who experienced a shorter duration of illness before rehabilitation, and who had lower psychopathology scores, were more likely to progress through the rehabilitation pathway to greater independence. However, the committee thought that everyone with treatment-resistant symptoms and functional impairments had the potential to benefit from rehabilitation, and that this applied regardless of whether they were living in inpatient or community settings.\n\nThe committee also highlighted the groups of people who, in their experience, are likely to have treatment-resistant symptoms and functional impairments.\n\nThe committee was aware that some people leaving early intervention services have significant residual disability, with persisting symptoms and functional impairment. However, it was not possible from the evidence to determine whether providing very early access to rehabilitation to these people could prevent repeated admissions and problems in daily living. The committee therefore made a research recommendation on who should be offered rehabilitation.\n\n## How the recommendation might affect practice\n\nEarlier access to rehabilitation should deliver more effective treatment sooner. This should reduce repeated admissions, enable earlier referral to less intensive (and cheaper) services and support more independent living. There may be some resource impact if more units are needed; however, most trusts in England have existing mental health rehabilitation units and half of trusts have community mental health rehabilitation teams who work with people after they have left hospital and moved to supported accommodation. In areas without these teams, community mental health teams already coordinate care. There will also be substantial savings from the repatriation of people placed out of area.\n\nReturn to recommendations\n\n# Overarching principles of rehabilitation\n\nRecommendation 1.2.1\n\n## Why the committee made the recommendation\n\nThere was qualitative evidence on the approaches, care, support and treatment that are valued by people using rehabilitation. A recovery-orientated approach was reported to be particularly valued and there was evidence that services adopting this approach to a greater extent were more successful in supporting people to progress along the rehabilitation pathway. The committee used this evidence along with their clinical knowledge and experience to recommend overarching principles to guide the delivery of rehabilitation services.\n\nBased on the evidence, the committee noted that not everyone with complex psychosis will get better. However, in their experience, rehabilitation can be beneficial for everyone who has treatment-resistant symptoms, even if they do not regain the same level of function and continue to need a high level of support in the longer term.\n\n## How the recommendation might affect practice\n\nThe committee agreed that the overarching principles will improve consistency of best practice and do not need any additional resources to deliver.\n\nReturn to recommendations\n\n# Organising the rehabilitation pathway, and the lead commissioner\n\nRecommendations 1.3.1 to 1.3.9\n\n## Why the committee made the recommendations\n\nThe evidence supported each locality having a defined rehabilitation pathway with access to a range of service components in different settings to provide the appropriate treatment and support that people need. The committee agreed that different levels of support, and usually both inpatient and community services, are needed to support people's full recovery. They noted it was important that these services were provided as locally as possible. The committee agreed that this would:\n\nenable better integration between health and social care (because supported accommodation and housing are arranged at local authority level)\n\nhelp to prevent inappropriate care, for example, people being unable to progress from inpatient units or out-of-area placements\n\nprovide options for appropriate aftercare for people who have been detained in hospital (a statutory obligation under the Mental Health Act\xa01983).\n\nIn the committee's view, the commissioning of rehabilitation services needs to take into account the mental health services that are already available and how services will work together to meet the population's needs. Currently, there is a lack of integration between services and a lack of clarity about who should be funding and commissioning them. The committee considered it essential that health and social care commissioners work together to commission services, to address people's overlapping health and social care needs. They acknowledged that to provide a full range of inpatient rehabilitation services, independent sector providers as well as those in the NHS may need to be involved.\n\nLocal authorities are required under the Health and Social Care Act (2012) to perform a joint strategic needs assessment to identify the health and social care needs of their population. The committee identified key groups that need to be included through a complementary local rehabilitation service needs assessment – people who are most likely to need local rehabilitation services, and those who might need highly specialist or longer-term rehabilitation services – to ensure services can be planned to help meet their needs.\n\nThe committee was aware that commissioning highly specialist services at the local level might not be feasible because there may not be enough people with very complex needs to warrant a dedicated unit. Therefore, they recommended local areas could work together to commission these services at a regional level.\n\nThe committee highlighted the need for flexibility within the rehabilitation pathway. People with complex psychosis do not always have a linear progression to recovery from needing high support to independence; some people may need continued support in the long term and some people may need more than 1\xa0period of rehabilitation. It should be possible to accommodate this in the pathway.\n\nQualitative evidence showed that integration and collaborative working across teams and services was facilitated by a lead champion. This model of a lead commissioner is also recommended by NICE for people with learning disabilities and behaviour that challenges, who similarly have overlapping health and social care needs. Qualitative evidence, along with the experience of the committee, provided a number of attributes that would enable the lead commissioner to perform their role effectively.\n\n## How the recommendations might affect practice\n\nThese recommendations largely reflect current practice in terms of joint commissioning. However, greater emphasis on an integrated rehabilitation pathway will likely see fewer people being referred to out-of-area placements and discharged from inpatient rehabilitation to community rehabilitation settings at a faster rate.\n\nEconomic evidence from a wider NHS and Personal Social Perspective shows that there may be a large cost saving from faster discharge rates that are appropriate to a person's illness and reduce inappropriate out-of-area placements. However, there may be a high resource impact for local authorities who are responsible for commissioning the provision of housing for people discharged from inpatient units. To some degree, this resource impact felt by local authorities would be offset by faster transitions to supported housing and floating support.\n\nProviding more local inpatient facilities could potentially increase capital costs for some commissioners in the short term if those facilities do not currently exist. In the longer term, this would involve replacing costs incurred out of area with those incurred locally, so the move to more locally available services is expected to be cost neutral over time. Overall, the health benefits of people spending more time in contact with community-based services, and less in inpatient facilities, would offset any initial additional resource impact.\n\nAn appropriately skilled lead commissioner would facilitate local authorities working together with health and social care commissioners, which is current practice in some areas.\n\nReturn to recommendations\n\n# Joint working\n\nRecommendations 1.3.10 to 1.3.14\n\n## Why the committee made the recommendations\n\nThe qualitative evidence identified barriers to integrating rehabilitation care pathways, which resonated with the committee's own experience. 'Siloes' of resources were discussed as a key barrier, and the committee noted that collaborations among services are hard to sustain unless they are underpinned by sufficient shared budgets. They also agreed that competitive funding among services is often not in the best interest of people in rehabilitation because it can discourage services from supporting a person to progress through the pathway. The committee agreed additional areas to highlight in the recommendation where the lead commissioner could help to address barriers to integration.\n\nThe committee agreed that because people with complex psychosis have a fluctuating illness, they need to be able to move seamlessly between services in the pathway depending on their needs. Based on consensus, the committee recommended measures to achieve this.\n\nThere was some qualitative evidence that some service users come to services passively because it is simply where they are 'sent to' next. Being able to visit a service before a placement begins helps people to make their own decisions and to feel more at ease about making the transition.\n\nOne study showed benefit of an integrated system to support transitions. The integrated system was a team of health and social care practitioners and informal carers for each person who met weekly to coordinate care, were able to communicate through a shared IT environment, and were trained to collaborate. Because the evidence was limited to 1 randomised controlled trial and there was no detail about what aspects of the intervention were effective, the committee could only recommend exploring ways to improve the sharing of information and IT systems.\n\nTo find out more about whether an integrated system involving a multidisciplinary team might help improve transitions and people's progress through the rehabilitation pathway towards greater independence, the committee also made a research recommendation on integrated care systems.\n\n## How the recommendations might affect practice\n\nDeveloping an integrated approach to rehabilitation is likely to be costly initially. Resources would be needed to set up services and underpin the collaboration between them (for example, systems to coordinate and communicate between services). However, an integrated rehabilitation pathway is likely to be cost effective in the longer term. Additional costs would be offset by the economic and health benefits of successful transitions and people receiving the correct level of support.\n\nVisiting rehabilitation settings is common in some areas, and should not involve a high resource impact, unless the person needs significant support to attend the visit.\n\nReturn to recommendations\n\n# Working with other healthcare providers\n\nRecommendations 1.3.15 to 1.3.17\n\n## Why the committee made the recommendations\n\nThe evidence showed that people with severe mental illness are at increased risk of many comorbid conditions and substance misuse. The committee considered it crucial that services for mental and physical healthcare, social care and substance misuse develop local protocols to ensure appropriate services are available to people in rehabilitation. Based on their knowledge and experience, the committee recommended what these protocols should cover.\n\nIn the committee's experience, some people using rehabilitation services may need to start or restart treatment with clozapine. This requires strict monitoring and currently many of these people are admitted to hospital. However, it is possible to provide clozapine in the community with the right level of monitoring through an extended-hours service. The committee agreed that making clozapine available in the community would prevent unnecessary hospital admissions and is an important part of a successful rehabilitation service.\n\n## How the recommendations might affect practice\n\nRehabilitation services should already be working with other providers to meet people's needs for physical healthcare and substance misuse services. However, if services and funding within an area are highly siloed, additional resources may be needed to enable this collaboration.\n\nAlthough clozapine in the community is not available in all areas, most areas do have a team in place providing an extended-hours service for people with mental illness, for example a crisis resolution home treatment team. It may involve additional costs to fund the extra work for this team to provide clozapine at community level, but it could be balanced by cost savings resulting from better management of psychosis symptoms.\n\nReturn to recommendations\n\n# Improving access to rehabilitation\n\nRecommendations 1.4.1 to 1.4.4\n\n## Why the committee made the recommendations\n\nIn the committee's experience, many potential users of rehabilitation services and their families and carers are unaware of what services are available and how to access them. This was also reflected in the qualitative evidence.\n\nQualitative evidence found that factors like age, sex, physical health problems, race and ethnicity were barriers to accessing rehabilitation for many people, because services are often unequipped to meet specific needs associated with these groups. The evidence also found no significant association between successful progress in rehabilitation services and age, gender or ethnicity. The Equality Act 2010 requires services to be accessible regardless of these protected characteristics and the committee agreed everyone with complex psychosis should have access to rehabilitation services. They therefore provided examples for how these inequalities in access could be addressed.\n\nThe committee recommended supporting people to access legal advice about their immigration status if required, in case people might be concerned about being deported if they access services.\n\n## How the recommendations might affect practice\n\nThe recommendations might have some resource impact, depending on how developed services are in this respect across different areas. For example, extra resources may be needed if outreach is needed to improve accessibility for minority groups. However, equal access and reasonable adjustments are requirements of the Equality Act 2010 and so should be standard practice and already considered in budgeting.\n\nThe recommendation to support people to access legal advice about their immigration status could require access to costly legal specialists; however, the committee noted this is currently being done in practice.\n\nReturn to recommendations\n\n# Delivering services within the rehabilitation pathway\n\nRecommendations 1.5.1 to 1.5.16\n\n## Why the committee made the recommendations\n\nThere was some evidence to support providing community rehabilitation through a multidisciplinary team and this was in line with the committee's experience. The committee also considered multidisciplinary working to be effective in inpatient rehabilitation services, so they recommended it for both inpatient and community settings. They used their own experience to recommend some of the core roles that would need to be included in the team. They also recommended other health professionals the team should have access to in order to meet the mental and physical healthcare needs of people with complex psychosis during rehabilitation. Input from welfare rights specialists was also thought to be important because people with complex psychosis will be on welfare benefits and are likely to need advice on their income. Speech and language therapist input would be needed to deal with the additional communication needs that can be experienced by this group. Physiotherapists would be needed to help people with mobility issues to engage in more physical activity to mitigate the physical health impact of a more sedentary lifestyle.\n\nThe evidence suggested that for every additional bed in an inpatient rehabilitation unit, there was an associated small decline in people's quality of care (as rated by Quality Indicator for Rehabilitative Care [QuIRC] on living environment, therapeutic environment, promotion of self-management and autonomy and promotion of social integration). The committee agreed this finding was also relevant to supported accommodation. The committee could not specify the optimal size of inpatient units or supported accommodation because no absolute optimal size was indicated in the evidence, and units of varying size may be appropriate for different areas.\n\nThere was evidence that the quality of rehabilitative care (as measured using QuIRC for inpatient units and QuIRC‑SA for supported accommodation) was associated with better outcomes of rehabilitation, autonomy, experience of care and satisfaction for people using the service. This evidence came from inpatient units, community units and supported accommodation. The committee agreed that measuring the quality of rehabilitative care using currently available tools would help rehabilitation units to identify areas for improvement and ultimately lead to better rehabilitation services. They also recommended services consider joining a peer accreditation or quality improvement forum because rehabilitation services often exist in isolation, so it is important for them to share good practice with other practitioners.\n\nThere was evidence that multidisciplinary community team management increased participation in activities of daily living. The committee used their experience to extrapolate from this to recommend how community mental health rehabilitation teams should provide care and work together to support people in community rehabilitation. However, they acknowledged that this team's remit may vary in different areas depending on how other community-based services are organised.\n\nThe committee noted from their experience in practice that issues with mental capacity can cause delays to people moving to supported accommodation. They highlighted the need for staff to follow the Mental Capacity Act\xa02005 so that people can progress through the rehabilitation pathway.\n\nThe committee used qualitative evidence to highlight features of supported accommodation that are valued by people, The committee discussed the importance of supporting people to have autonomy, including to make potentially risky decisions, while still maintaining reasonable safety and helping people to avoid exploitation. The committee believed that in the long term, these recommendations would allow service users to live more sustainably and independently in the community, with fewer stressors and mental health relapses that lead to hospitalisation.\n\nEvidence showed that rehabilitation units with an expected maximum length of stay were associated with better quality of care. The committee agreed that having an expected maximum length of stay could help prevent delays when people are ready to move on through the rehabilitation pathway. However, they also agreed this should not be treated as absolute; services need to be flexible and provide appropriate treatment and support tailored to each person's needs.\n\nThe committee noted that accepting a placement in inpatient rehabilitation could affect people's eligibility to receive particular benefits (for example housing benefit) and could affect people's existing tenancies with local authorities. The committee wanted providers to be aware of and advise people about these issues.\n\nThere was a lack of evidence about the characteristics of effective highly specialist or longer-term high-dependency inpatient services. People with particularly complex comorbid conditions whose care cannot be managed in less specialised settings often spend very long periods of time (sometimes many years) in highly specialist or longer-term inpatient rehabilitation services. The Care Quality Commission has raised concerns about quality of life for people in this group. It is important to understand the characteristics of services and service users that support successful progress through rehabilitation, so the committee made a research recommendation on highly specialist and longer-term high-dependency rehabilitation units.\n\nHealth economic modelling showed that providing rehabilitation locally was less costly than using out-of-area placements, which are often provided by the independent sector. Although no clinical outcomes were found in the accompanying systematic review, the model included data from the Care Quality Commission, which showed that people placed in out-of-area inpatient wards have a longer average stay on such wards than those placed in local wards. There is a large hypothetical overall cost saving from a wider NHS and Personal Social Services perspective which, in the model, is driven by a reduction in the rate of out-of-area placements and faster discharge rates to supported accommodation that enable more independent living.\n\nThe committee acknowledged that there were no relevant clinical outcomes or utility data to compute quality-adjusted life years, although it was their view that a person in supported accommodation would typically have improved activities of daily living. Reducing out-of-area placements would therefore lead to more people being appropriately discharged to supported accommodation, which would reduce costs and improve quality of life.\n\nThe committee was aware of evidence suggesting that for many people in out-of-area placements, it could be appropriate to offer rehabilitation in local inpatient units. Being in a local unit also makes it easier for people to maintain contact with their families, communities and local support networks or activities, such as peer support groups.\n\nThe committee shared anecdotal reports of people being in out-of-area placements for many years, without clinical oversight from the person's local area. To avoid this, they made recommendations with the aim of reducing out-of-area placements wherever possible, providing better support while people are in these placements and bringing them back to their local area as soon as possible. This included recommending time frames for reviewing out-of-area placements, which were based on committee consensus.\n\nThere was a lack of comparative evidence between services provided by the independent sector and the NHS. The committee acknowledged that the independent sector is an important provider of rehabilitation services; however, the services they provide are often a long way from where people live, and from the local area that funds their placement. Many independent units are locked, and lengths of stay are considerably longer (and therefore costlier) than in equivalent NHS services. There is little systematic and reliable evidence on the characteristics of users of these services or the effectiveness of these units, to establish if the longer stays are necessary. Given the potential for significant cost savings if the effectiveness in the 2\xa0sectors were found to be the same, the committee made a research recommendation on inpatient rehabilitation provided by the independent sector.\n\n## How the recommendations might affect practice\n\nThe recommendation for the multidisciplinary team to have access to additional healthcare professionals may have a resource impact for those teams without this access currently. However, because some teams already have access to these specialties, the committee did not think this would be a significant resource impact.\n\nNot all supported accommodation services currently use the QuIRC‑SA so the recommendation may lead to a moderate change in practice. This tool is web-based, free to use and completed annually by a unit manager or senior staff member in around 90\xa0minutes. Further investment may be needed to address gaps identified by these quality measures. However, the committee considered this would be justified by improved experience of care and better rehabilitation outcomes for service users.\n\nThe recommendation to advise people about the impact of rehabilitation placements on their tenancies could require access to welfare rights specialists, which could have a resource impact for services without this access currently.\n\nThe committee recognised that local authorities in some regions may need to invest significantly in the quality and variety of their supported accommodation to implement the recommendations on supported accommodation. However, the recommendations do recognise that commissioning decisions should be based on a local rehabilitation service needs assessment to reflect the needs of the local population. Nevertheless, local authorities often commission supported accommodation and therefore can specify quality metrics when tendering to providers.\n\nThere is likely to be some service reconfiguration required by the recommendations on out-of-area placements as people move back to local units. New rehabilitation units may need to be commissioned locally and there could be a substantial initial investment. However, in the long term, this would be expected to be largely cost neutral with respect to capital costs, as out-of-area facilities are replaced by local ones. Therefore, the committee argued that this 'investment' is currently already being spent on out-of-area placements so would not constitute additional funding in the long term. The committee did note though that any investment should be based on a local rehabilitation service needs assessment based on the needs of the local population.\n\nThe recommendation for a designated care manager may represent a change in practice in some areas. For areas that do not currently perform regular clinical review of people being sent out of area, this could represent an additional resource. However, if the review leads to people being brought back within area to a more cost-effective placement, this resource could be offset.\n\nReturn to recommendations\n\n# Recovery-orientated rehabilitation services\n\nRecommendations 1.6.1 to 1.6.20\n\n## Why the committee made the recommendations\n\nQualitative evidence showed that service users value a recovery-orientated approach to their care. This means helping people to work towards their aspirations and make the most of their abilities, while giving them support and encouragement wherever needed. The evidence suggested several key areas including activities of daily living, hobbies and interests, and vocational goals, where service users believed that services could help them work towards recovery.\n\nWorking collaboratively with people with complex psychosis to produce a care plan can be challenging because of diminished communication and mental capacity. Despite these challenges, planning care in collaboration with the service user is expected practice in UK mental health services. Guidance on mental capacity and communication needs is already provided in other NICE guidelines but the committee also agreed it was relevant to highlight the legal obligation to offer independent advocacy under the Care Act 2014 and to follow the NHS Accessible Information Standard when working with people in rehabilitation.\n\nThe committee considered staff training in recovery orientation to be essential to deliver an effective rehabilitation service. They also agreed that staff need to develop collaborative and non-judgemental relationships with people using the service. There was qualitative evidence that staff sometimes lack optimism or are overly risk-averse about the prospect of rehabilitation for some people, which can negatively affect a person's recovery. To address this, the committee recommended ways to encourage positive attitude changes to help staff retain hope and optimism, while acknowledging that not everyone will achieve full independence.\n\nQualitative evidence was supported by the committee's experience that service users from minority groups may experience language barriers and unconscious prejudice because of their minority status as well as because of their mental illness. This combination may produce its own unique barriers within services and the committee agreed staff should be aware of this.\n\nThe committee made the recommendation on supporting structured activities based on limited evidence combined with consensus. They saw structured group activities as a key aspect of rehabilitation (see recommendation\xa01.8.4) and agreed that all staff, not just certain staff such as occupational therapists, should be able to support these activities.\n\nThe committee also discussed safeguarding and risk, and agreed that all staff need to be trained to deal with risks relevant to the setting they are working in.\n\nThere is a high prevalence of substance misuse among the rehabilitation population. The committee thought it was essential that all staff are able to identify these problems and provide the right support.\n\nInvolving family members and carers in decision making can reduce isolation and increase support for people having rehabilitation. However, this can be complex for people with severe mental illness. Relationships may have broken down during the person's illness or the person may find it difficult to form new relationships and they may need additional support with this. A person's capacity or their wishes about other people's involvement can also change during their illness.\n\nLaws and established NICE guidelines are already in place that cover involving family members and sharing information, as well as supporting families and helping people keep in contact with their home communities, and the committee either used or linked to these recommendations.\n\n## How the recommendations might affect practice\n\nThe recommendations on staff competencies may have a resource impact in services that do not currently provide training. However, any additional resources may be offset by the benefits to service users of establishing a recovery-orientated rehabilitation service. Helping people with complex psychosis to engage with their family members or carers may be more resource-intensive than for people with less severe disease, because of the functional and communication problems people with complex psychosis may face. But these recommendations are derived from other NICE guidance so should reflect current practice.\n\nReturn to recommendations\n\n# Person-centred care planning through assessment and formulation\n\nRecommendations 1.7.1 to 1.7.12\n\n## Why the committee made the recommendations\n\nThe committee used evidence about rates of physical and mental health conditions and substance misuse in this population to recommend what to consider as part of the initial assessment when people enter the rehabilitation service. The committee also drew on their experience to provide details about what a structured comprehensive biopsychosocial needs assessment should cover to assess people's complex needs and comorbidities.\n\nThe committee agreed that baseline investigations before starting antipsychotic medicines recommended in the NICE guidelines on psychosis and schizophrenia in adults and bipolar disorder should form the core of the initial physical health check for people in rehabilitation services because most would be receiving antipsychotic medicines.\n\nThe committee also drew on the evidence identifying the most common physical and mental health comorbidities to highlight conditions that staff need to be alert for because these may contribute to higher mortality or complexity in rehabilitation in this population. The committee also agreed that more understanding is needed about the likely impact of physical comorbidities on mortality among people with complex psychosis, so they made a research recommendation on coexisting physical health conditions.\n\nThe committee agreed that the comorbid health conditions and other needs identified in the needs assessment could be used along with people's recovery goals to contribute to a healthcare plan that would reduce morbidity and mortality, and improve people's function and quality of life.\n\nQuantitative evidence suggested that detailed and regularly updated care plans lead to better service user outcomes, especially when developed within a multidisciplinary team. The committee used this evidence, their own experience and other NICE guidelines to make further recommendations on good care planning. They decided that monthly reviews in inpatient rehabilitation, and 6-monthly reviews for people in community rehabilitation, would keep care plans relevant without being overly invasive.\n\n## How the recommendations might affect practice\n\nAn initial needs assessment is already standard practice, but changes might be needed to align with recommendations on what the assessment should include. Physical health checks should also be standard practice, but the committee noted that monitoring and treatment of coexisting health problems was variable in this population so the recommendations should improve consistency of practice.\n\nThe recommendations on care planning should not have substantial resource implications. In some areas, additional staffing and training might be needed to enable more regular and thorough review, but in the long term these costs will be offset by more effective treatment, improved recovery and a reduced need for crisis teams, hospital beds and other services.\n\nReturn to recommendations\n\n# Rehabilitation programmes and interventions\n\nRecommendations 1.8.1 to 1.8.19\n\n## Why the committee made the recommendations\n\nBased on evidence suggesting that interventions could improve daily living skills and, given the importance of these skills in recovery and quality of life, the committee recommended promoting interventions to improve these activities as highly as other types of interventions. In the committee's experience, this does not always happen in practice.\n\nBased on their experience, the committee agreed that individualised support could improve daily living skills, for example by choosing activities that people enjoy and that motivate them. If a person is motivated, they might be more likely to engage in activities of daily living such as personal care or going out on public transport. Having access to areas such as kitchens and laundry was also agreed to be important so that people can practise their skills.\n\nThere was qualitative evidence that people in rehabilitation value structured group activities, and a randomised controlled trial found that taking part in them improves interpersonal functioning. This was in line with the committee's views, so they recommended these activities in both inpatient and community settings.\n\nBased on the committee's experience, structured group activities need to be offered daily in inpatient settings and at least weekly in community settings to be effective, and people should have choice in what they do. Although there was no evidence on peer-supported activities, committee members had found these to be effective and agreed they could be an option.\n\nStructured group activities are routinely provided by rehabilitation services, but the evidence base is fairly limited. The committee thought that more specific detail on the structured activities, and their efficacy, could help further inform practice. They therefore made a research recommendation on structured group activities.\n\nThe committee wanted to emphasise the importance of meaningful occupation and work in promoting recovery and helping to promote community inclusion, based on their own experience and the preferences expressed in the qualitative evidence. The committee highlighted a number of aims of community activities, and recommended a range of hobbies and leisure activities, as well as skill development opportunities.\n\nEvidence from randomised controlled trials showed that Individual Placement and Support (IPS) increases engagement in employment for those interested in work, and this was supported by cost-effectiveness evidence from a health economic model. There was also evidence that adding cognitive remediation can increase the effectiveness of vocational rehabilitation. The committee recommended considering both of these interventions. They agreed, however, that some people may not be ready for mainstream employment and would benefit from alternatives to IPS such as transitional employment schemes.\n\nThe committee also discussed the role of partnerships with other organisations such as voluntary organisations and employment advice schemes. They agreed these could be an important route to engagement with employment or education.\n\nThe committee discussed peer-support interventions for engaging in community activities. Although these were widely valued by the committee, there was no directly relevant research to guide the development of peer support for community activities in complex psychosis and rehabilitation services. The committee therefore made a research recommendation on peer-support interventions.\n\nThe committee also discussed staff training interventions to mediate improvements in daily living skills, interpersonal skills and engagement in community activities, which are key areas of personal recovery in rehabilitation. However, no trials were found that assessed these interventions, so they made a research recommendation on staff training interventions.\n\nThere is a high prevalence of alcohol and substance misuse among the rehabilitation population. Because of limited evidence, the committee made recommendations based mainly on consensus and existing NICE guidance. They wanted to prevent a situation where substance misuse was occurring but rehabilitation staff viewed it as being outside their remit. The committee agreed that questions about substance use should be routine when people enter the rehabilitation service and that rehabilitation staff needed to know what their role should be in supporting people and providing substance misuse interventions.\n\n## How the recommendations might affect practice\n\nThe committee noted that providing access to real-life settings for people to practise their daily living skills might be challenging in some services, because of the range of people's needs and risks within the service.\n\nStructured group activities such as playing board games and watching DVDs do not have a high resource impact, but activities outside the rehabilitation setting could be more costly depending on the support needs of the group. Providing a named person to support engagement is unlikely to have significant resource impact, because an existing key worker or support worker might take on this role if it is not being done already, and no external provision would be needed.\n\nThe committee agreed that relatively few people with complex psychosis in rehabilitation services are ready to engage in paid employment so the recommendations for individual placement and support would have little impact on current IPS services. Cognitive remediation is not routinely added to vocational rehabilitation and this could lead to a change in practice in for some centres.\n\nThe recommendations call for greater awareness among rehabilitation staff about identifying and managing substance misuse, which could be incorporated into general training for all staff.\n\nReturn to recommendations\n\n# Adjustments to mental health treatments in rehabilitation\n\nRecommendations 1.9.1 to 1.9.23\n\n## Why the committee made the recommendations\n\nThe committee focused this section on people with symptoms of psychosis that are resistant to standard treatment because this population represents people using rehabilitation services. The committee recommended adjustments to standard treatments for psychosis described in other NICE guidance.\n\nThe evidence showed there were benefits and harms to each treatment option, so the committee agreed that treatments should always be discussed with the person. They were also aware that comorbidities, including other mental health conditions and autism spectrum disorder, can affect outcomes in people with complex psychosis. These comorbidities need to be identified and treated in line with NICE guidance.\n\nThere was some evidence from randomised controlled trials that for people with treatment-resistant psychosis, cognitive behavioural therapy (CBT) decreased positive psychosis symptoms compared with pharmacological therapy alone. Based on this evidence and their experience that people with complex psychosis are often too unwell to engage with CBT at earlier contacts with the rehabilitation service, the committee recommended that it should be continued in this treatment-resistant population.\n\nIn the committee's experience, some people in rehabilitation are not ready to engage with CBT. The committee discussed the importance of providing additional psychological interventions but could not recommend a specific intervention because of the lack of evidence. Instead they recommended interventions to consider and emphasised that these should be based on psychological assessment, formulation and consideration of each person's preferences.\n\nThe committee also wanted to acknowledge the importance of low-intensity psychological interventions. Despite the lack of evidence from trials, the committee decided that the option of providing all staff with skills in delivering these interventions should be considered in rehabilitation settings.\n\nThere was some evidence from randomised controlled trials supporting augmentation with the agents in recommendation\xa01.9.9 for reducing psychosis symptoms in people with schizophrenia refractory to clozapine. The evidence was limited by small sample sizes and information on adverse events was very sparse. However, given the lack of treatment options, and considering that current prescribing for this population is inconsistent, the committee decided that augmentation should be considered an option.\n\nIn general, the committee recommended classes of drug rather than individual drugs, but they specifically mentioned aripiprazole as an example when recommending augmentation with antipsychotics. The committee noted that amisulpride is more commonly prescribed than aripiprazole, but the evidence did not show a change in psychosis symptoms following amisulpride, while there was some evidence on the effectiveness of aripiprazole in reducing total psychosis symptoms. Although the evidence also showed that ziprasidone decreased psychosis symptoms, this drug is not licensed or available in the UK.\n\nGiven the safety profiles of these drugs and their potential interactions when combined, the committee recommended seeking advice from a psychiatrist specialising in treatment resistance or a specialist mental health pharmacist if needed.\n\nThe committee made recommendations on dosing and interactions with other substances based on their experience and knowledge about the safety of various therapeutic options. They recommended therapeutic plasma levels because this may be useful in checking non-adherence or to confirm toxicity or pharmacokinetic drug interactions.\n\nThe committee agreed it was important to measure drug levels regularly to assess adherence and guide dosing. There was a lack of evidence on how frequently this should be done, so the committee used their own knowledge and experience, as well as drawing on NICE's guideline on bipolar disorder for monitoring of people taking lithium.\n\nThe committee also agreed it was important to monitor the effects of specific medicines. However, again there was no evidence on how frequently to do this. Some antipsychotics increase prolactin, raising the risk of hyperprolactinaemia, and the committee discussed whether prolactin should be measured: before starting treatment with a drug that raises prolactin (as is common practice, and recommended in NICE's guideline on psychosis and schizophrenia in adults); only if a person has symptoms for hyperprolactinaemia; or at regular intervals. The consensus was to consider monitoring prolactin annually and more regularly if the person is symptomatic.\n\nThe committee also wanted to highlight the importance of electrocardiogram (ECG) monitoring. Antipsychotic medicines can cause cardiac abnormalities, for example lengthened QT interval on electrocardiography. Although the NICE guidelines on psychosis and schizophrenia in adults and bipolar disorder recommend ECGs only when starting antipsychotic medicines, the committee recommended considering ECGs annually (and more frequently for people with complex antipsychotic regimens or doses above BNF levels). They agreed this consideration was warranted for this population, many of whom have been on medicines long term, or combinations of medicines that may alter cardiac rhythm, or both. It is already common practice to perform ECGs if exceeding BNF limits for antipsychotics.\n\nEvidence showed that medicines adherence was associated with successful progression in the rehabilitation pathway to more independent living. However, there was no evidence on specific interventions to improve adherence in people using rehabilitation services. The committee noted that people with a severe mental illness may find polypharmacy and complex regimens difficult to manage and so recommended avoiding these if possible.\n\nAcknowledging the importance of self-management of medicines in people's recovery, the committee recommended opportunities to do this for those assessed as able to take part. Because of the lack of evidence on specific interventions to improve medicines adherence, they also made a research recommendation on medicine adherence for people in supported accommodation. They agreed that people in supported accommodation are likely to receive less support with taking medication than those in inpatient rehabilitation.\n\nThe committee noted that having psychological and pharmacological interventions specifically for people in rehabilitation, could improve their ability to live in the community. However, the existing evidence was not specific to rehabilitation settings and did not include all relevant outcomes, so the committee made a research recommendation on tailored interventions.\n\nThe committee was aware of other NICE guidance on electroconvulsive therapy and agreed it was appropriate to cross-refer to this.\n\n## How the recommendations might affect practice\n\nThe recommendations on psychological therapy reflect current practice and should not involve additional resources.\n\nThe recommendations on pharmacological treatments will help to standardise practice across the NHS. They may lead to an increase in the prescription of aripiprazole as augmentation therapy, but this will not have a resource impact because the associated resource use and unit costs are marginally less costly than amisulpride.\n\nThe recommendation on increased monitoring of prolactin levels follows current practice.\n\nThere may be some resource impact from an increase in ECG monitoring, though the committee noted the Maudsley Prescribing Guidelines suggest that an ECG should be offered at least annually. Therefore, any resource impact would likely be small.\n\nThe overall impact of avoiding complex medical regimens and polypharmacy could be cost saving if adherence is improved and could lead to more successful progression through the rehabilitation pathway.\n\nReturn to recommendations\n\n# Physical healthcare\n\nRecommendations 1.10.1 to 1.10.19\n\n## Why the committee made the recommendations\n\nIn the committee's experience, access to physical healthcare services is variable depending on the rehabilitation setting and they agreed it was crucial that people did not miss out on monitoring or treatment of their physical health. So the committee outlined the role that inpatient rehabilitation teams should play in physical healthcare, and also adapted existing recommendations on GP responsibilities (recommendations\xa01.10.1 and 1.10.2) from the NICE guideline on psychosis and schizophrenia in adults. These adapted recommendations were consistent with the evidence about physical comorbidities that the committee looked at.\n\nCombining the limited evidence with their experiences of health promotion in rehabilitation services, the committee agreed that a single professional should coordinate people's physical healthcare. The committee did not specify the role of the professional (for example, a doctor, nurse, healthcare assistant or care coordinator) but the key point was to have a named person to maintain continuity.\n\nThe committee recommended the items that should be considered in physical healthcare plans based on their experience, and the evidence on comorbidities in people with severe mental illness.\n\nThe committee agreed that smoking was one of the most important modifiable risk factors in this population. They noted that people with complex psychosis using rehabilitation services may find accessing standard smoking cessation programmes difficult. Given the lack of evidence for a specific intervention in rehabilitation, and the need to be mindful of potential drug interactions, the committee agreed that the smoking cessation guidance in the NICE guideline on psychosis and schizophrenia in adults was applicable to the rehabilitation population.\n\nAdverse lifestyle factors may be more prevalent in people with complex psychosis, for example they may be less physically active, which could place them at a higher risk of physical health problems such as obesity, cardiovascular disease, metabolic syndrome and diabetes. They therefore agreed that recommendation 1.1.3.1 about a combined healthy eating and physical activity programme from the NICE guideline on psychosis and schizophrenia in adults was also relevant to include for this population and was broadly supported by the evidence they looked at.\n\nGiven that adverse lifestyle factors may be more prevalent in people with complex psychosis, the committee made the recommendation about providing information on physical health risks based on both their knowledge and experience and evidence of the prevalence of comorbidities. The committee also noted that people with complex psychosis may have difficulty maintaining oral hygiene due to poor self‑care and may be at higher risk of substance misuse and sexual and reproductive health problems.\n\nThe committee also discussed the importance of good sleep for overall physical health and recovery. Although there was no evidence of specific interventions to improve sleep in the evidence or other NICE guidance, the committee agreed it would be good practice to provide advice and support for maintaining sleep hygiene, and practitioners should avoid environmental barriers that may hinder sleep.\n\nThe committee recommended an annual physical health check for people in rehabilitation services based on the physical health checks in NICE's guidelines on psychosis and schizophrenia in adults and bipolar disorder. They added assessments of sexual health, vision, hearing and podiatry, substance use and thyroid function. These additions were based on both their clinical experience and the evidence on comorbidities.\n\nTo increase uptake of this health check, the committee agreed it could be done either at the rehabilitation service by a nominated professional, or at the person's GP practice. Adapting recommendations from NICE's guideline on psychosis and schizophrenia in adults, the committee recommended discussing the results of the physical health check with the person and relevant practitioners.\n\nThe committee agreed that risk factors and physical or mental health conditions identified during the initial health check should be managed according to existing NICE guidance. For the treatment recommendation, the committee listed the same conditions as NICE's guideline on psychosis and schizophrenia but added chronic obstructive pulmonary disease (COPD) because of the high proportion of COPD in the population.\n\nThe recommendation to be alert to possible blood-borne diseases was based on evidence about the relatively high prevalence of hepatitis and HIV in people with severe mental illness. The committee agreed this may be related to homelessness, intravenous drug use or a history of sexually transmitted disease. They also agreed that more understanding is needed about the risks predicting blood-borne virus infection in this population so that strategies can be developed to address these, so they made a research recommendation on the risk of blood-borne virus infections.\n\n## How the recommendations might affect practice\n\nLimited evidence showed that it could be cost effective for physical healthcare to be coordinated by a nominated professional.\n\nIf the recommendations on physical health checks result in more people having these checks, there may be a resource impact. However, these costs may be offset in the longer term by the prevention of morbidity and future illness. Although the health checks are within existing NICE guidance and so should be common practice, the National Cardiac Audit Programme 2017 audit found that most people had not been assessed for all 5 cardiovascular health risk factors in the last year.\n\nTreatment of physical health conditions according to NICE guidance should be current practice; however, the National Cardiac Audit Programme 2017 audit found many people with identified risk factors had not received appropriate interventions.\n\nReturn to recommendations", 'Context': "Over 80% of people who are referred for mental health rehabilitation have a primary diagnosis of schizophrenia, schizoaffective disorder or other psychosis, around 8% have bipolar affective disorder, and the remaining 11% have other diagnoses. Around two‑thirds are men. Although people who need mental health rehabilitation have varied primary diagnoses, a common feature is the complex problems they experience. These have a severe, negative impact on the person's day-to-day functioning, including managing everyday activities and social, interpersonal and occupational functioning. These problems often make it impossible for people to be discharged from acute mental health inpatient care back to the community. Some people with these difficulties struggle to manage in the community and may benefit from mental health rehabilitation services.\n\nThe problems people may experience include 1\xa0or more of the following:\n\ntreatment-resistant symptoms (for people with a primary diagnosis of psychosis, this may include 'positive' symptoms such as delusions and hallucinations and/or severe 'negative' symptoms that lead to problems with motivation)\n\nspecific cognitive impairments associated with severe psychosis that have a negative impact on organisational and social skills\n\ncoexisting mental health problems, such as severe anxiety, depressive or obsessive-compulsive symptoms, or substance misuse\n\nphysical health problems, such as diabetes, cardiovascular disease or pulmonary conditions\n\npre-existing neurodevelopmental disorders, for example autism spectrum disorder or attention deficit hyperactivity disorder.\n\nRehabilitation is essential to address these complex problems. For the vast majority of people, mental health rehabilitation leads to successful and sustained discharge from hospital and a meaningful, rewarding community life.\n\nAlthough the mental health rehabilitation care pathway includes both inpatient and community services, there is significant national variation in how they are provided. In areas where there is a lack of local NHS rehabilitation services, people may receive treatment through the NHS or independent sector in the form of out-of-area placements. Since 2012, there have been many closures of NHS inpatient rehabilitation units across England and only half of trusts have a community rehabilitation team. Given that the users of these services have complex psychosis as described above, this suggests that many people do not have access to the specialist rehabilitation services they need, either locally or elsewhere."}
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https://www.nice.org.uk/guidance/ng181
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This guideline covers mental health rehabilitation for adults with complex psychosis. It aims to ensure people can have rehabilitation when they need it and promotes a positive approach to long-term recovery. It includes recommendations on organising rehabilitation services, assessment and care planning, delivering programmes and interventions, and meeting people’s physical healthcare needs.
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54bb0526ad17be26bcbe8661a4c8048f26433610
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nice
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Deep brain stimulation for refractory epilepsy in adults
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Deep brain stimulation for refractory epilepsy in adults
Evidence-based recommendations on deep brain stimulation for refractory epilepsy in adults. This involves implanting an electrical stimulator in the brain.
# Recommendations
Evidence on the safety and efficacy of deep brain stimulation for refractory epilepsy in adults differs according to the site of stimulation:
For anterior thalamic targets the evidence is limited in quantity and quality, therefore this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE website.
For targets other than the anterior thalamus the evidence is inadequate in quantity and quality, therefore this procedure should only be used in the context of research. Find out what only in research means on the NICE website.
Clinicians wishing to do deep brain stimulation of anterior thalamic targets for refractory epilepsy in adults should:
Inform the clinical governance leads in their NHS trusts.
Give patients clear written information to support shared decision making, including NICE's information for the public.
Ensure that patients understand the procedure's safety and efficacy, as well as any uncertainties about these.
Audit and review clinical outcomes of all patients having the procedure. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).
Patient selection should be done by a multidisciplinary team experienced in managing epilepsy including a neurologist, neurophysiologist and neurosurgeon.
The procedure should only be done in neurosurgery centres that specialise in managing epilepsy.
Further research should describe patient selection and clearly define the target area of the brain. Outcomes should include reduction in seizure frequency and improvement in the epilepsy seizure outcome scale, quality of life, reduction in concomitant medication and hospital admissions.# The condition, current treatments and procedure
# The condition
Epilepsy is a neurological condition characterised by episodes of abnormal electrical activity in the brain which cause recurrent seizures. The seizures can be focal or generalised.
# Current treatments
The main treatment for epilepsy is anti-epileptic drugs taken to prevent or reduce the occurrence of seizures. However, many people have drug-resistant (refractory) epilepsy. They experience frequent seizures and are at risk of status epilepticus and sudden unexpected death in epilepsy.
Surgery may be considered for refractory epilepsy. Surgical options include open surgical resection (such as lesionectomy, anterior temporal lobectomy or hemispherectomy) or disconnection (such as multiple subpial transection or corpus callosotomy), neuroablation (using stereotactic radiosurgery, radiofrequency thermocoagulation or MRI-guided focused ultrasound) or neuromodulation (such as cranial nerve stimulation, deep brain stimulation or closed loop stimulation).
# The procedure
Deep brain stimulation involves implanting electrodes into specific target areas of the brain. Although the mechanisms of action are not fully understood, the aim of the procedure is to reduce or suppress seizure frequency. A potential advantage of the procedure is its reversibility. It is an option for some patients with medically refractory epilepsy when resective surgery is not indicated.
The procedure is done using general or local anaesthesia. A stereotactic frame may be used. Imaging (MRI or CT) is used to identify the target area of the brain (most commonly the anterior nucleus of the thalamus but may include the centromedian thalamic nucleus, hippocampus and nucleus accumbens). One or more small holes are drilled in the skull and electrodes are implanted into the target area.
A neurostimulator is surgically placed into a subcutaneous pocket below the clavicle. The electrodes are connected to the neurostimulator by leads that are tunnelled under the skin of the neck and scalp. Postoperative imaging is usually used to confirm the location of the electrodes. A handheld remote-control programming unit is used to turn the neurostimulator on or off, adjust stimulation parameters, and monitor activity.
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{'Recommendations': "Evidence on the safety and efficacy of deep brain stimulation for refractory epilepsy in adults differs according to the site of stimulation:\n\nFor anterior thalamic targets the evidence is limited in quantity and quality, therefore this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE website.\n\nFor targets other than the anterior thalamus the evidence is inadequate in quantity and quality, therefore this procedure should only be used in the context of research. Find out what only in research means on the NICE website.\n\nClinicians wishing to do deep brain stimulation of anterior thalamic targets for refractory epilepsy in adults should:\n\nInform the clinical governance leads in their NHS trusts.\n\nGive patients clear written information to support shared decision making, including NICE's information for the public.\n\nEnsure that patients understand the procedure's safety and efficacy, as well as any uncertainties about these.\n\nAudit and review clinical outcomes of all patients having the procedure. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).\n\nPatient selection should be done by a multidisciplinary team experienced in managing epilepsy including a neurologist, neurophysiologist and neurosurgeon.\n\nThe procedure should only be done in neurosurgery centres that specialise in managing epilepsy.\n\nFurther research should describe patient selection and clearly define the target area of the brain. Outcomes should include reduction in seizure frequency and improvement in the epilepsy seizure outcome scale, quality of life, reduction in concomitant medication and hospital admissions.", 'The condition, current treatments and procedure': '# The condition\n\nEpilepsy is a neurological condition characterised by episodes of abnormal electrical activity in the brain which cause recurrent seizures. The seizures can be focal or generalised.\n\n# Current treatments\n\nThe main treatment for epilepsy is anti-epileptic drugs taken to prevent or reduce the occurrence of seizures. However, many people have drug-resistant (refractory) epilepsy. They experience frequent seizures and are at risk of status epilepticus and sudden unexpected death in epilepsy.\n\nSurgery may be considered for refractory epilepsy. Surgical options include open surgical resection (such as lesionectomy, anterior temporal lobectomy or hemispherectomy) or disconnection (such as multiple subpial transection or corpus callosotomy), neuroablation (using stereotactic radiosurgery, radiofrequency thermocoagulation or MRI-guided focused ultrasound) or neuromodulation (such as cranial nerve stimulation, deep brain stimulation or closed loop stimulation).\n\n# The procedure\n\nDeep brain stimulation involves implanting electrodes into specific target areas of the brain. Although the mechanisms of action are not fully understood, the aim of the procedure is to reduce or suppress seizure frequency. A potential advantage of the procedure is its reversibility. It is an option for some patients with medically refractory epilepsy when resective surgery is not indicated.\n\nThe procedure is done using general or local anaesthesia. A stereotactic frame may be used. Imaging (MRI or CT) is used to identify the target area of the brain (most commonly the anterior nucleus of the thalamus but may include the centromedian thalamic nucleus, hippocampus and nucleus accumbens). One or more small holes are drilled in the skull and electrodes are implanted into the target area.\n\nA neurostimulator is surgically placed into a subcutaneous pocket below the clavicle. The electrodes are connected to the neurostimulator by leads that are tunnelled under the skin of the neck and scalp. Postoperative imaging is usually used to confirm the location of the electrodes. A handheld remote-control programming unit is used to turn the neurostimulator on or off, adjust stimulation parameters, and monitor activity.'}
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https://www.nice.org.uk/guidance/ipg678
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Evidence-based recommendations on deep brain stimulation for refractory epilepsy in adults. This involves implanting an electrical stimulator in the brain.
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b6a54116bdc252095c84c50469a382979ea63f90
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nice
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Implanted vagus nerve stimulation for treatment-resistant depression
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Implanted vagus nerve stimulation for treatment-resistant depression
Evidence-based recommendations on vagus nerve stimulation for treatment-resistant depression in adults. This involves implanting an electrical stimulator under the skin of the chest and connecting it by wires to the vagus nerve.
# Recommendations
Evidence on the safety of implanted vagus nerve stimulation for treatment-resistant depression raises no major safety concerns, but there are frequent, well-recognised side effects. Evidence on its efficacy is limited in quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE website.
Clinicians wishing to do implanted vagus nerve stimulation for treatment-resistant depression should:
Inform the clinical governance leads in their NHS trusts.
Give patients clear written information to support shared decision making, including NICE's information for the public.
Ensure that patients understand the procedure's safety and efficacy, as well as any uncertainties about these.
Audit and review clinical outcomes of all patients having the procedure. NICE has identified relevant audit criteria and is developing an audit tool (which is for use at local discretion).
NICE encourages further research into implanted vagus nerve stimulation for treatment-resistant depression, in the form of randomised controlled trials with a placebo or sham stimulation arm. Studies should report details of patient selection. Outcomes should include validated depression rating scales, patient-reported quality of life, time to onset of effect and duration of effect, and any changes in concurrent treatments.# The condition, current treatments and procedure
# The condition
Depression is characterised by low mood, loss of interest and enjoyment in life, and a range of associated emotional, cognitive, physical and behavioural symptoms. Depression is treatment-resistant when symptoms have not improved after at least 2 standard treatments.
# Current treatments
The diagnosis and management of depression is described in the NICE guideline for depression in adults and the NICE guideline for depression in children and young people. Standard treatment for depression includes antidepressants or psychological therapies (including cognitive behavioural therapies) or a combination of both. In severe depression when multiple treatments have failed, electroconvulsive therapy or other forms of neurostimulation are sometimes used.
# The procedure
The aim of implanted vagus nerve stimulation for treatment-resistant depression is to reduce symptoms and improve mood by periodic stimulation of the vagus nerve.
The procedure is done using general or local anaesthesia. An incision is made on the left side of the neck and the left vagus nerve is identified. A stimulator electrode is put around the nerve and the leads of the electrode are guided under the skin to the left chest wall. They are attached to a pulse generator unit, which is implanted into a subcutaneous pocket. The stimulator settings can be adjusted or turned off using an external (wireless) programming device.
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{'Recommendations': "Evidence on the safety of implanted vagus nerve stimulation for treatment-resistant depression raises no major safety concerns, but there are frequent, well-recognised side effects. Evidence on its efficacy is limited in quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE website.\n\nClinicians wishing to do implanted vagus nerve stimulation for treatment-resistant depression should:\n\nInform the clinical governance leads in their NHS trusts.\n\nGive patients clear written information to support shared decision making, including NICE's information for the public.\n\nEnsure that patients understand the procedure's safety and efficacy, as well as any uncertainties about these.\n\nAudit and review clinical outcomes of all patients having the procedure. NICE has identified relevant audit criteria and is developing an audit tool (which is for use at local discretion).\n\nNICE encourages further research into implanted vagus nerve stimulation for treatment-resistant depression, in the form of randomised controlled trials with a placebo or sham stimulation arm. Studies should report details of patient selection. Outcomes should include validated depression rating scales, patient-reported quality of life, time to onset of effect and duration of effect, and any changes in concurrent treatments.", 'The condition, current treatments and procedure': '# The condition\n\nDepression is characterised by low mood, loss of interest and enjoyment in life, and a range of associated emotional, cognitive, physical and behavioural symptoms. Depression is treatment-resistant when symptoms have not improved after at least 2\xa0standard treatments.\n\n# Current treatments\n\nThe diagnosis and management of depression is described in the NICE guideline for depression in adults and the NICE guideline for depression in children and young people. Standard treatment for depression includes antidepressants or psychological therapies (including cognitive behavioural therapies) or a combination of both. In severe depression when multiple treatments have failed, electroconvulsive therapy or other forms of neurostimulation are sometimes used.\n\n# The procedure\n\nThe aim of implanted vagus nerve stimulation for treatment-resistant depression is to reduce symptoms and improve mood by periodic stimulation of the vagus nerve.\n\nThe procedure is done using general or local anaesthesia. An incision is made on the left side of the neck and the left vagus nerve is identified. A stimulator electrode is put around the nerve and the leads of the electrode are guided under the skin to the left chest wall. They are attached to a pulse generator unit, which is implanted into a subcutaneous pocket. The stimulator settings can be adjusted or turned off using an external (wireless) programming device.'}
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https://www.nice.org.uk/guidance/ipg679
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Evidence-based recommendations on vagus nerve stimulation for treatment-resistant depression in adults. This involves implanting an electrical stimulator under the skin of the chest and connecting it by wires to the vagus nerve.
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7ccf28388ad4a3f4f4bc44bc95cf40f51ed722e2
|
nice
|
Entrectinib for treating NTRK fusion-positive solid tumours
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Entrectinib for treating NTRK fusion-positive solid tumours
Evidence-based recommendations on entrectinib (Rozlytrek) for treating neurotrophic tyrosine receptor kinase (NTRK) fusion-positive solid tumours in adults and children over 12 years.
# Recommendations
Entrectinib is recommended for use within the Cancer Drugs Fund as an option for treating neurotrophic tyrosine receptor kinase (NTRK) fusion-positive solid tumours in adults and children 12 years and older if:
the disease is locally advanced or metastatic or surgery could cause severe health problems and
they have not had an NTRK inhibitor before and
they have no satisfactory treatment options.It is recommended only if the conditions in the managed access agreement for entrectinib are followed.
This recommendation is not intended to affect treatment with entrectinib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. For children and young people, this decision should be made jointly by the clinician and the child or young person or their parents or carers.
Why the committee made these recommendations
There is no standard treatment for NTRK fusion-positive solid tumours, so current treatment is based on where in the body the cancer starts. Entrectinib is a histology-independent treatment. This means that it targets a genetic alteration, NTRK gene fusion, that is found in many different tumour types irrespective of where the cancer starts.
Evidence from trials suggests that tumours with NTRK gene fusions shrink in response to entrectinib, but longer follow up is needed. It is difficult to know how well entrectinib works because it has not been compared with other treatments in trials. Also, there is evidence that entrectinib works well for some types of NTRK fusion-positive tumour, but little or no evidence for other types.
The cost-effectiveness estimates for entrectinib are uncertain because of limitations in the data. Some of these estimates are higher than what NICE normally considers an acceptable use of NHS resources so entrectinib cannot be recommended for routine use in the NHS.
Collecting more data on entrectinib would help to address some of the uncertainty in the evidence. Entrectinib has the potential to be cost effective given the company's commercial offer as part of a managed access agreement and using the diagnostic testing costs provided by NHS England. Therefore, entrectinib is recommended for use in the Cancer Drugs Fund.# Information about entrectinib
# Marketing authorisation indication
Entrectinib (Rozlytrek, Roche) is indicated as monotherapy for the 'treatment of adult and paediatric patients 12 years of age and older, with solid tumours expressing a neurotrophic tyrosine receptor kinase (NTRK) gene fusion:
who have a disease that is locally advanced, metastatic or where surgical resection is likely to result in severe morbidity and
who have not received a prior NTRK inhibitor
who have no satisfactory treatment options'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price for entrectinib is £5,160.00 per 90‑tablet pack of 200 mg tablets (excluding VAT, company submission). The company has a commercial arrangement. This makes entrectinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Roche, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that it was appropriate to include people with primary central nervous system (CNS) tumours and children in the population included in the economic modelling (issue 8, see technical report page 35).
It recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, table 12, page 61), and took these into account in its decision making. It discussed the following issues (issues 1 to 7 and 9 to 23), which were outstanding after the technical engagement stage.
# NTRK gene fusions
## Entrectinib targets a genetic mutation rather than a tumour type and there are challenges in appraising it
Traditional oncology approaches treat tumours based on their type. More recently, targeted therapies based on the tumour's genetic information have been used for some indications. Entrectinib targets solid tumours with a neurotrophic tyrosine receptor kinase (NTRK) gene fusion. Because many tumour types respond to it, the company considers entrectinib to be 'tumour-agnostic' or 'histology-independent'. NTRK gene fusions may be able to drive tumour growth, so targeting treatment to the cause of the disease could mean higher rates of response to therapy and potentially better outcomes. The committee accepted that it was expected to appraise entrectinib within its marketing authorisation using the framework currently set out by NICE. But it recognised the challenges of appraising histology-independent treatments within the NICE single technology appraisal process.
## The prevalence of NTRK gene fusions in England is unknown but collecting further data could help address this
The prevalence of NTRK gene fusions is uncertain. Estimates reported in the literature are between 0.25% and 0.31% in adults and between 0.34% and 0.49% in children and young people. NTRK gene fusions have high prevalence in some rare cancers such as mammary analogue secretory carcinoma, infantile fibrosarcoma and secretory breast cancer. But there is low prevalence in some of the more common cancers such as colorectal cancer and non-small-cell lung cancer. The company submission included a calculated prevalence estimate for each tumour type based on a weighting of prevalence estimates from the literature and data held by the company. The company provided data from the Foundation Medicine Incorporated (FMI) dataset that included data based on next generation sequencing of adult and children's solid tumour samples using the FMI next generation sequencing platform. The ERG estimated the prevalence of NTRK fusions in each tumour type included in the database. There is considerable variation between tumour types, with prevalence estimates ranging from less than 1% to 100% for the tumour types included in the dataset. The committee understood that the ERG's estimates were more likely to be generalisable to clinical practice because they were sourced from a large database and seemed to be the most robust data available currently. The committee concluded that the prevalence estimates from the FMI database were reasonable for decision making but recognised that there was some uncertainty around the true prevalence of NTRK gene fusions in England. Further data collection in clinical practice could mitigate some of this uncertainty.
## NTRK fusion-positive solid tumours are not well characterised and the prognostic effect of NTRK gene fusions is unknown
Everyone included in the entrectinib trials had an NTRK fusion-positive tumour and 20.4% of the entrectinib efficacy population had CNS metastases. Only a small proportion of people in the comparator dataset were likely to have NTRK gene fusions and the prevalence of CNS metastases in the comparator population was unknown. The company included a scenario analysis in its submission. In the analysis the company applied a hazard ratio calculated from published overall survival data on people with colorectal cancer who had either an NTRK, receptor tyrosine kinase (ROS1) or anaplastic lymphoma kinase (ALK) genetic alteration. It used this to adjust the comparator data to account for people with NTRK fusion-positive solid tumours potentially having a poorer prognosis than people with solid tumours that were not NTRK fusion-positive. At the technical engagement stage the company provided a systematic literature review that did not find any further evidence to support its claim that people with NTRK fusion-positive solid tumours have a worse prognosis than people with tumours without the genetic alteration. The committee agreed that there was not enough evidence available about whether NTRK gene fusions affect prognosis. The company also did a scenario analysis to adjust for the effect of CNS metastases in the comparator arm. The ERG explained that the prevalence of CNS metastases in the comparator data was not widely reported in the clinical trials so any adjustment to the comparator arm was uncertain. It was not possible to report characteristics that are commonly prognostic such as age and Eastern Cooperative Oncology Group performance status, so the committee considered it uncertain whether the 2 arms were comparable. The committee considered that it would be appropriate to adjust the analysis to include factors that are known to affect prognosis but concluded that the evidence was too limited to do so.
# Treatment pathway and comparator
## There is no defined clinical pathway for people with NTRK fusion-positive solid tumours
There is no defined clinical pathway for people with NTRK fusion-positive solid tumours. Treatment currently follows care guidelines for specific tumour types. The committee understood that genomic testing to identify NTRK gene fusions was not routinely carried out for all of the different tumour types (see section 3.8). Until routine genomic testing is established in clinical practice, the people most likely to benefit from targeted therapy cannot be offered different treatment options to people with the same type of solid tumour but without the NTRK gene fusion. Some of the tumour types with NTRK gene fusions have an established treatment pathway with many treatment options available, such as colorectal cancer and non-small-cell lung cancer. However, other tumour types, including mammary analogue secretory carcinoma and cholangiocarcinoma, have few treatment options available for locally advanced and metastatic disease. The patient experts noted that for quadruple negative gastrointestinal stromal tumours there were no standard treatment options. They explained that people who have a solid tumour with a gene alteration would want a targeted treatment. The aim of treatment for some inoperable tumour types would be to shrink the solid tumour so that surgery might be a treatment option. The committee concluded that people with NTRK fusion-positive solid tumours would value new treatment options.
## Entrectinib is positioned as last-line therapy in the treatment pathway
The marketing authorisation specifies that entrectinib should only be used if there are no satisfactory treatment options, that is, for which clinical benefit has not been established, or when such treatment options have been exhausted. The Cancer Drugs Fund clinical lead explained that entrectinib should be used after all NHS commissioned treatments, because these treatments have an established clinical benefit. The company submission was broader than the marketing authorisation because for some tumour types (soft-tissue sarcoma, pancreatic cancer, non-small-cell lung cancer, breast cancer, thyroid cancer, colorectal cancer and neuroendocrine carcinomas) people had treatment before other treatments for locally advanced or metastatic disease. This was because the submission was developed before input from the regulator on the wording of the marketing authorisation. In the entrectinib clinical trials, a large proportion of patients had entrectinib for untreated disease or after 1 previous treatment. The clinical experts explained that if people with NTRK fusion-positive solid tumours had to have treatment with all NHS commissioned therapies before entrectinib then the solid tumours were more likely to be resistant to treatment. Entrectinib would be a treatment option for fewer people if it was used as a last-line therapy because some people would not be well enough to have it after other treatment options. The clinical experts noted that oncologists prefer to use targeted therapies as early as possible in the treatment pathway. The committee noted that entrectinib's clinical trial evidence may not be generalisable to its use in clinical practice as a last-line treatment option. The Cancer Drugs Fund clinical lead explained that people with rarer cancers that have a high prevalence of NTRK gene fusions may be more likely to have entrectinib as an earlier-line treatment option given that other treatment options are limited (see section 3.4) or may not have an established clinical benefit. This would be different for people with tumour types that have an established treatment pathway and different treatment options. For these tumour types it is likely that, for locally advanced or metastatic solid tumours, entrectinib will be a treatment option only after all NHS commissioned treatments in the treatment pathway.
## Best supportive care is the appropriate comparator
The company's clinical trials were single arm, so did not include a comparator arm (see section 3.11). The ERG explained that because the wording of the marketing authorisation was broader at the time of the company's submission, it was reasonable to include NICE-recommended treatments as comparators for some tumour sites. Entrectinib should be positioned as a treatment option after all NHS commissioned treatments (see section 3.5) so the committee noted that the appropriate comparator should be best supportive care. Best supportive care was included as a treatment option in the company's blended comparator arm for colorectal cancer, thyroid cancer and neuroendocrine tumours only. For some of these tumour sites NICE-recommended treatments were also included as treatment options. The committee concluded that best supportive care was the appropriate comparator for the appraisal given that the marketing authorisation stated that entrectinib should only be used if there are no satisfactory treatment options.
# Diagnosis
## The diagnostic pathway for NTRK fusions has implications for identifying patients and on diagnosis costs
All solid tumour types can potentially have an NTRK gene fusion although they are rare in common tumour types (see section 3.2). Therefore, many people would need screening to identify who would benefit from entrectinib. Currently, NTRK testing is not routinely done in the NHS for all solid tumours. However, it is available for mammary analogue secretory carcinoma and secretory breast carcinoma with immunohistochemistry techniques (a method using antibodies to detect the gene fusion protein). Whole genome sequencing (a method of determining the whole DNA sequence of a cancer, used for discovering mutations) can also identify NTRK gene fusions and it is available for children's cancers and sarcomas. However, confirmation of the results with another DNA or RNA test is needed (for example next generation sequencing, which is a faster method of sequencing targeted regions of the cancer's DNA). The committee concluded that the diagnostic pathway for NTRK gene fusions was important, with implications for identifying patients and on costs of diagnosis.
## The diagnostic pathway is uncertain until NHS England establishes a national service for genomic testing of all advanced solid tumours
The Cancer Drugs Fund clinical lead explained that NHS England is currently establishing a national service for cancer genomic testing to replace all local testing. It involves setting up 7 laboratory hubs across England to do genomic testing by next generation sequencing and interpret all results. Until the laboratory hubs are fully established, next generation sequencing will be done after all NHS commissioned treatment options have been tried. When the hubs are fully established, next generation sequencing to identify gene alterations, including NTRK gene fusions, will be done when locally advanced or metastatic solid tumours are first diagnosed. The Cancer Drugs Fund clinical lead estimated that 100,000 solid tumours would be tested per year once the service is fully established. He noted that other targeted therapies would likely become available soon for different diseases and genomic testing would also be needed before these treatments are used. The committee acknowledged the ongoing developments in genomic testing practice to identify NTRK fusion-positive solid tumours. It considered that the rapid change to the diagnostic testing pathway being led by NHS England was a unique situation. The committee concluded that the diagnostic testing pathway was uncertain until NHS England establishes a national service for cancer genomic testing.
## Diagnostic techniques will improve as the genomic laboratory hubs validate their techniques and NTRK gene fusions are better characterised
Because the genomic laboratory hubs were not yet operational, there was no single representative NHS-based test that would allow measurement of diagnostic accuracy. The Cancer Drugs Fund clinical lead explained that the genomic laboratory hubs were putting a lot of resources into ensuring high diagnostic accuracy in their testing procedures. The committee noted that high sensitivity and specificity of a diagnostic test minimises the risk of false results. If specificity was not high then there was a greater chance of a solid tumour testing positive for an NTRK gene fusion when an NTRK gene fusion was not present. Solid tumours that do not have an NTRK gene fusion are not expected to respond to entrectinib and this could result in poorer clinical outcomes than with a different treatment option. High diagnostic accuracy is particularly important when screening tumour types that have a known low prevalence of NTRK gene fusions such as lung and colorectal cancer. The clinical experts explained that it was essential that a combined DNA and RNA-based next generation sequencing panel is used in clinical practice to identify people with NTRK fusion-positive solid tumours. This was because a DNA-based panel may identify NTRK gene fusions that, when treated with entrectinib, would not lead to the expected clinical outcomes. They explained the importance of correctly interpreting the results of the genomic test to identify the significant NTRK gene fusions. The committee noted that the genomic laboratory hubs were very aware of the importance of high diagnostic accuracy, especially given that some tumour types have very low prevalence of NTRK gene fusions. The committee considered that this is an evolving field and that diagnostic techniques would improve as the genomic laboratory hubs validate their techniques and NTRK gene fusions are better characterised (see section 3.3). The committee concluded that diagnostic accuracy was very important and that a period of access in the Cancer Drugs Fund could allow the genomic laboratory hubs to implement testing more quickly.
# Clinical evidence
## NTRK gene fusions have been identified in primary CNS and children's tumours so including them in the population is appropriate
The marketing authorisation includes people with primary CNS tumours and children (on 28 May 2020, the Committee for Medicinal Products for Human Use announced that this would be children over 12 years). The company updated its submission at the technical engagement stage. It used data from 5 adults with primary CNS tumours and 7 children with NTRK gene fusions in the efficacy population that were included in the company's clinical trials. The committee considered it appropriate to include these data in the analysis because it increased the generalisability of the evidence base to the population likely to be seen in clinical practice. The population of children included in the clinical trial was small and it did not represent all children's tumours that were known to have NTRK gene fusions. Some patients in the trials were under 12 years and it is likely that many children in clinical practice will be under 12 years, so would not be eligible for entrectinib because of the marketing authorisation's age restriction. However, the committee considered these results would likely be comparable with results from older children. It noted also that there was considerable uncertainty because of the very low number of children in the trials and distribution of tumour types. The committee concluded that it was appropriate to include people with primary CNS tumours and children in the analyses because they are part of the population covered by entrectinib's marketing authorisation.
## The key clinical evidence comes from a pooled analysis of 4 single-arm clinical trials and is appropriate for decision making
The company did a pooled analysis of results for 54 adults from 3 clinical trials (ALKA, STARTRK‑1 and STARTRK‑2) in its original submission. STARTRK‑2 is an ongoing phase 2 basket trial for people aged 18 years and over with advanced or metastatic solid tumours that have an NTRK, ROS1 or ALK gene fusion. Basket trials are trials that include patients who have different types of cancer but the same gene mutation. The baskets in the STARTRK‑2 study were based on molecular targets (ALK, ROS1 and NTRK) rather than on tumour type for each molecular target. The ERG noted that this was different to a typical basket trial design. STARTRK‑2 contributed 51 patients to the pooled analysis. ALKA contributed 1 patient to the pooled analysis and STARTRK‑1 contributed 2 patients. Both ALKA and STARTRK‑1 are ongoing phase 1 ascending dose and dose escalation studies. At the technical engagement stage the company updated its entrectinib dataset to include 66 people (see section 3.10). The children's data were collected in the STARTRK‑NG trial, a dose escalation and expansion study evaluating the effect of entrectinib in children, adolescent and young adults aged 2 to 22 years. The committee noted the small patient numbers from each of the trials making up the pooled analysis, and that the trials were single arm and did not include a control group. The Cancer Drugs Fund clinical lead considered it reasonable to pool the 4 entrectinib studies to maximise the patient numbers included in the analyses. The clinical trial evidence included only 13 tumour types: sarcoma, non-small-cell lung cancer, mammary analogue secretory carcinoma, breast, thyroid, colorectal cancer, neuroendocrine tumours, pancreatic cancer, gynaecological cancers, cholangiocarcinoma, CNS primary, infantile fibrosarcoma and paediatric melanoma. Also, each tumour type was represented by between 1 and 13 patients. Given the rarity of the gene fusion, the committee considered that the evidence base was appropriate for decision making. But it acknowledged that further data collection was possible because the company's trials were ongoing.
## Entrectinib could be clinically effective, but its survival benefit is difficult to measure because of limitations in the trial data
The pooled analysis of 66 people across 13 tumour types (see section 3.11) showed a clinically relevant overall response rate across tumour types (exact results are confidential and cannot be reported here). However, there was considerable uncertainty about the extent to which the response translated into clinically meaningful survival benefits. At the most recent data-cut, median follow up was short and the survival data were immature. Also, the number of patients with specific cancers was very small so there was uncertainty in the robustness of all survival data. The Cancer Drugs Fund clinical lead noted that entrectinib was active in patients with CNS metastases with a similar response rate in the brain to that seen systemically in all patients in the pooled analysis. However, the small patient numbers and short follow up were noted. The committee saw that there was no direct evidence of entrectinib's effectiveness compared with established management. It concluded that entrectinib could be clinically effective, but the limited data for each of the tumour types, the immature survival data and the lack of trial data directly comparing entrectinib with established management meant the size of this benefit was difficult to measure.
## The population eligible for entrectinib is broader than the trial population so entrectinib's clinical effectiveness in some groups is unknown
There was limited evidence available on tumour types that have NTRK fusions. The clinical evidence for entrectinib was limited to the 13 tumour types included in the company's clinical trials. The ERG's clinical advisers suggested that it was plausible that NTRK gene fusions could be present in over 400 tumour types. The ERG used a Bayesian hierarchical modelling framework (see section 3.15) to explore the expected probability of response to entrectinib in tumour types not represented in the trial data. The results showed a very wide confidence interval around the probability of response for tumour types not included in the trial. This showed the high uncertainty around the response (exact results are confidential and cannot be reported here). The committee considered that the lack of any data for many other tumour sites meant there was substantial uncertainty about entrectinib's clinical and cost effectiveness for all those potentially eligible for treatment as defined by the marketing authorisation. The committee acknowledged that the ERG's analysis gave a reasonable estimate of the response rates for tumour types for which there were no data. It understood that the uncertainty would only be resolved through further data collection, including for other tumour types not already included in the clinical trials. But it noted that patient numbers could still be a limitation. The committee understood the challenges of appraising a histology-independent treatment when the population covered by the marketing authorisation was broader than the evidence base. It concluded that there was uncertainty about entrectinib's clinical effectiveness for tumour types that were not included in the clinical trials. Until further data are reported, the clinical benefit of using entrectinib in the NHS cannot be confirmed.
## The company assumes the same response to entrectinib for all tumour types but this is inappropriate
There are several biological reasons why heterogeneity, or a difference, in tumour response to entrectinib might be seen. For example, tumour response might be different by histology, by NTRK gene fusion or fusion partner, by the presence of codrivers of the disease and by age (for example, for children's indications). The company assumed that each of the solid tumour types would have the same response rate when treated with entrectinib and generated a pooled response estimate across each of the tumour types included in the efficacy dataset. This approach did not take into account the potential for heterogeneity in response across different tumour types and fusion partner. There was considerable uncertainty in the level of heterogeneity in response rates across tumour types (exact results are confidential and cannot be reported here). The company did not explore any alternatives to this assumption. The committee concluded that it was not appropriate to assume that the same level of response would be seen across all tumour types eligible for treatment with entrectinib.
## The ERG's approach explores heterogeneity in tumour response, but more data would help investigate this further
The ERG used a statistical modelling framework, Bayesian hierarchical modelling, to explore the potential heterogeneity in response across the 13 tumour types included in the company's dataset. This used the tumour type to define each basket and allowed borrowing of information across baskets by assuming that response rates were exchangeable, rather than the same across baskets. Tumour types with few patients borrowed more information than tumour types with more patients. Using this method, the ERG found that the estimated mean response rate across all tumour types was similar to the response rate seen when the company assumed an equal response. The company made the data available for survival outcomes by tumour type for the ERG to do this analysis on the progression-free and overall survival data. The ERG considered the survival data not to be robust enough to explore variability in overall and progression-free survival so these data could not be included in the company's partitioned survival model. The ERG noted that it was unclear whether the Bayesian hierarchical modelling would give useful survival estimates given the small number of patients with each of the tumour types and that the data were immature. The ERG's analyses showed the potential for heterogeneity between tumour types but had small patient numbers in each of the tumour types included in the analysis. The committee acknowledged that the results of the ERG's Bayesian hierarchical modelling approach were similar to the company's approach (see section 3.14). The committee considered the wide confidence intervals around the response estimate and the possibility that some tumour types could have response rates that differed significantly from the pooled estimate. It understood that further data collection would increase the patient numbers for each of the tumour types and this would help improve the robustness of the analysis. More mature survival data would allow heterogeneity in the survival outcomes to be explored. The response estimates were similar when some adjustment for heterogeneity was included (the ERG's Bayesian hierarchical modelling approach) and when it was not (the company's approach). The committee concluded that this is an outstanding uncertainty that needs to be explored further when more data are available.
## The trial population is not generalisable to the population in clinical practice in England
The company assumed that the distribution of the 13 tumour sites in its dataset reflected the distributions seen in clinical practice in England. The most frequently represented solid tumour types in the trial evidence were sarcomas, non-small-cell lung cancer, salivary gland tumours (mammary analogue secretory carcinoma) and breast cancer. The company used this distribution to estimate a weighted set of outcomes for the comparator arm in its base-case analysis. The ERG was concerned that the estimate of cost effectiveness was being driven by the proportion of tumour types included in the company's dataset. The Cancer Drugs Fund clinical lead highlighted that the distribution of tumour types in the population in England who would have treatment would differ significantly from that in the entrectinib clinical trial population. In particular, he noted the high proportion of people included in the entrectinib clinical trials who had mammary analogue secretory carcinoma. The ERG estimated the yearly prevalence of NTRK fusion-positive solid tumours in England. It noted that secretory breast carcinoma, sarcoma and mammary analogue secretory carcinoma were over-represented in the company's dataset. The ERG determined an alternative distribution of tumour types using the FMI database, which the committee considered the most appropriate source of data (see section 3.2). The ERG considered this dataset to be more representative of clinical practice because it was based on a larger sample than the company's original estimate. The company did not provide the data needed for the ERG to adjust the distribution of tumour types in the entrectinib arm as well as the comparator arm. At the technical engagement stage the company noted that the likely distribution of NTRK gene fusion-positive tumour types in England may only be definitively known once comprehensive next generation sequencing-based testing was implemented in an unbiased way for all advanced and metastatic cancer diagnoses. The committee recalled that there was uncertainty in the analysis about the distribution of tumour types in the company's and ERG's analyses (see section 3.14 and section 3.15). The committee concluded that the trial population was not generalisable to the population who would have entrectinib in clinical practice in England.
# Indirect treatment comparison
## The company's approach to the comparator arm is pragmatic, but other methods should be considered
The company constructed a comparator arm to compare clinical effectiveness between entrectinib and established management. It generated a comparator arm by identifying overall and progression-free survival data for established management. It did this by searching NICE Pathways for NICE‑recommended comparators for each of the tumour types included in the entrectinib clinical trials. Median progression-free and overall survival for each tumour type were averaged and then pooled to calculate mean overall progression-free and overall survival across all tumour types, weighted by the distribution of each tumour type in the trial population. For some tumour types tumour-site specific data were not available, so an average from the other tumour types was used. The ERG considered the company's methods to identify, select and combine the comparator data to be inappropriate. It considered the comparator data in the company model to be highly unreliable. The ERG considered the company's approach to be intuitive, but the comparator population:
was not consistent with the entrectinib population for CNS metastases and other potential prognostic factors (see section 3.3)
did not reflect the population seen in clinical practice if the comparators had not been selected at the appropriate line of treatment (see section 3.6).The ERG suggested 2 further approaches, a previous line of treatment approach (see section 3.18) and a response-based approach (see section 3.19). The committee recognised the difficulty in constructing a comparator arm for this appraisal. It concluded that the company's original approach was pragmatic but other methods should also be considered in the committee's decision making.
## The company's previous line of treatment approach is a reasonable alternative to generating comparator data
The company did a previous line of treatment analysis (referred to by the company as an intra-patient analysis) at the technical engagement stage. This was as a confirmatory analysis to their original pooled comparator approach. The company assessed the time to next treatment for 31 patients included in the STARTRK‑2 study who had a treatment before entrectinib. The time to next treatment for the treatment administered directly before entrectinib was considered to be a proxy for progression-free survival. The company acknowledged that this may have overestimated progression-free survival because treatment was unlikely to start exactly at the point of progression with the previous treatment. The company overcame the limitation that 10 patients included in this analysis did not have a documented reason for stopping treatment by doing the same analysis for those who did have a documented reason. The results showed that the median time to next treatment was broadly similar to the median progression-free survival estimate derived for the company's blended comparator using its pooled approach. The ERG acknowledged that the company's previous line of treatment analysis may have produced a more reliable progression-free survival estimate in the comparator arm than the original modelled comparator or the ERG's response-based analysis (see section 3.19). But the ERG highlighted that there were 2 assumptions that must hold for this analysis to be valid, which it considered to be strong and hard to verify. The ERG also highlighted that to understand the effect of this modelling approach on the incremental cost-effectiveness ratio (ICER), the data would need to be included in the economic model and an extrapolation function applied. The committee was aware of the limitations of this approach. But, it concluded that it was a reasonable alternative to generating the comparator data and should also be considered in the committee's decision making.
## The ERG's exploratory response-based approach is limited by the generalisability of the trial data to clinical practice
The results of the ERG's response-based approach were presented as an exploratory analysis. This approach involved taking the survival data for the people whose tumours did not respond from the entrectinib dataset and using these data for the comparator arm. The company considered the number of people whose tumours did not respond to be too small to provide a meaningful comparator sample. So, the ERG's method had some issues, including:
the people whose tumours did not respond potentially having a different prognosis to those whose tumours did respond
whether the effect of different subsequent therapies could be included in the clinical data
the generalisability of the population to the population likely seen in clinical practice, particularly given that the clinical trial population was not generalisable (see section 3.16)
entrectinib being given at earlier points in the treatment pathway in the clinical trials than it would be in clinical practice (see section 3.5).The committee understood that, as with the other approaches, data availability was an issue given the small patient numbers in the entrectinib clinical trials and the immaturity of the data. It concluded that the ERG's exploratory response-based approach was a reasonable alternative to generate comparator data. Additional data would help improve its robustness, but issues around generalisability could not be resolved, which was a major limitation of this analysis. The committee concluded that this approach was a reasonable alternative to generating comparator data. But, because of the limitations in generalisability, it was suitable only for exploratory analysis with current data.
# Economic model
## All modelling approaches for decision making are uncertain
The company presented a 3‑state partitioned survival model (progression-free, progressed disease and death) to estimate the cost effectiveness of entrectinib compared with established management. The model used data on overall and progression-free survival from the entrectinib clinical trials for the entrectinib arm. The established management arm was modelled using the data from the company's approach to modelling the comparator arm (see section 3.17). The company's model did not account for tumour types not represented in the entrectinib clinical trials (see section 3.15). The committee noted that the different approaches and methods used to construct the comparator arm for this appraisal (see section 3.17, section 3.18 and section 3.19) would affect the choice of model structure. The ERG explained that a major limitation of the company's model structure was that it could not account for tumour types not included in the entrectinib clinical trials (see section 3.15). Also, it did not have the functionality to produce an ICER for each tumour type individually, so produced only a single ICER. The ERG did some exploratory analysis using a response-based model. This approach distinguished between people whose tumours responded to treatment and people whose tumours did not respond for clinical effectiveness inputs as well as for health-related quality of life and the costs of care. The ERG's response-based approach used data from people whose tumours did not respond as a proxy for people not having an active treatment. Survival in the entrectinib arm was estimated as a weighted average of survival for the people whose tumours responded and those whose tumours did not, weighted by the estimated response rate derived from the ERG's Bayesian hierarchical model (see section 3.15). The ERG's response-based model allowed for results to be generated for each tumour type individually and could also account for tumour types that were not included in the entrectinib clinical trials. The committee considered that when more data were available the different model structures could be explored more fully. It concluded that each of the modelling approaches had limitations and uncertainties.
# Survival extrapolations
## The company's exponential extrapolation is appropriate to model overall and progression-free survival, but other extrapolations are also plausible
The entrectinib clinical trials are ongoing so data on overall survival were incomplete. To extrapolate overall survival for entrectinib and the established management comparator arm, the company fitted an exponential curve to the data. The ERG preferred the Weibull distribution to extrapolate overall and progression-free survival data because it gave a more clinically plausible balance between pre- and post-progression survival. The ERG explained that there was no difference in statistical fit between this distribution and the exponential distribution to extrapolate overall and progression-free survival. The exponential distribution gave a longer duration of survival in the post-progressed health state than in the pre-progressed health state. At the technical engagement stage the company did a scenario analysis using the proxy Weibull distribution in the comparator arm and the Weibull distribution in the entrectinib arm. The ERG explained that the most appropriate method to generate the extrapolated survival curves for the comparator arm would have been to extract the Kaplan–Meier curves from each of the source NICE technology appraisals included in the company's pooled comparator arm and to use the committee's most appropriate distribution for each of the appraisals. The committee noted that the survival data from the clinical trials were very immature and this made it challenging to select the most appropriate extrapolation function. The committee concluded that the exponential extrapolation was appropriate but other extrapolation functions were also plausible. It also noted that the trials were ongoing and follow-up survival data could reduce this uncertainty if all plausible extrapolations are considered after a period of further data collection.
# Utility values in the economic models
## The company's utility estimates are unlikely to be generalisable to clinical practice given entrectinib's position in the treatment pathway
The company's utility value in the pre-progressed health state in the entrectinib arm was taken from the EQ‑5D‑3L data from the STARTRK‑2 study. The utility values for the comparator arm were derived from a single NICE technology appraisal for each tumour type included in the entrectinib clinical trials. A single utility value was calculated for each health state by calculating the average utility value, weighted by the distribution of tumour types included in the clinical trial; 0.73 for progression-free and 0.59 for progressed disease. The company considered its utility value for the progressed disease health state derived from the STARTRK‑2 EQ‑5D‑3L data to be implausible because it was higher than the pre-progressed value. The same utility value was used in both arms for the progressed disease health state. In the STARTRK‑2 study a reasonable proportion of people had entrectinib as first-line treatment. The committee agreed that entrectinib's position was now as a last-line treatment option (see section 3.5). It recognised that the utility value in the pre-progressed health state may no longer be generalisable to clinical practice because it was likely to be an overestimate. The ERG also highlighted that the company's choice of NICE technology appraisal for the comparator arm utility value may have biased the cost-effectiveness analysis. This was because the selected utilities reflected a specific line of therapy and entrectinib's position was last line. The committee concluded that the utility estimates were unlikely to be generalisable to clinical practice because entrectinib's position in the treatment pathway was likely to be as a last-line treatment option.
## The size of difference in the pre-progressed utility values between arms is uncertain
The company used a higher utility value in the pre-progressed health state in the entrectinib arm (exact value is confidential and cannot be reported here) than in the comparator arm (0.73). The company justified this because entrectinib is an oral treatment with a more convenient administration and better safety profile than the comparators, which are mostly cytotoxic chemotherapies. Best supportive care was the appropriate comparator (see section 3.6) so entrectinib's safety profile compared with best supportive care was unlikely to give a higher utility score. The ERG highlighted the lack of evidence to justify the assumption to use different values in each arm for the pre-progressed health state. It considered there was considerable uncertainty about the size of any difference. The Cancer Drugs Fund clinical lead noted that equal utility values should be used in the progression-free health state. The committee recognised the uncertainty in the utility values given entrectinib's position in the treatment pathway as a last-line treatment option. It concluded that there was some uncertainty about the size of difference in the pre-progressed utility values between arms.
# Subsequent therapies
## It is not appropriate to include subsequent therapies in the analysis if entrectinib is a last-line treatment option
In the entrectinib clinical trial a reasonable number of people had subsequent therapy after entrectinib and this was included in the company's analysis. The subsequent therapies included targeted therapies. No subsequent therapies were included after established management in the comparator arm. The company modelled the duration of treatment with subsequent therapies from progression until death. The ERG considered it overly pessimistic to assume that people would have subsequent therapies from progression until death and instead assumed a treatment duration of 6 months, about half of the post-progression duration. The committee considered entrectinib's position in the treatment pathway as a last-line treatment option (see section 3.5). It agreed that if subsequent therapies were to be given after entrectinib, these would not be active treatments in which clinical benefit had been established. This was because these treatments would likely have been tried before entrectinib. The committee concluded that it was not appropriate to include subsequent therapies in the analysis if entrectinib was a last-line option in the treatment pathway.
# Resource use and costs
## It is appropriate to include diagnostic testing costs in the economic model
The company attempted to capture the diagnostic testing pathway and associated costs in its analysis. It included a 2‑stage approach to testing for cancers when biomarker screening is already done in clinical practice (for colorectal, non-small-cell lung, breast and thyroid cancers) or when no molecular testing is done (for neuroendocrine, pancreatic and gynaecological tumours and cholangiocarcinoma). This included an immunohistochemistry test, which if positive was followed by a next generation sequencing test. The ERG considered the company's approach to testing to be broadly plausible. For cancers that have whole genome sequencing (see section 3.7), the ERG's clinical advisers noted that an RNA-based next generation sequencing test would be needed after whole genome sequencing to confirm an NTRK fusion-positive tumour. The ERG did not consider it appropriate to include the costs of testing in the comparator arm for tests that did not identify NTRK gene fusions. It also noted that the costs of testing for NTRK gene fusions in lung cancer samples would be negligible beyond the cost of genomic testing already done in clinical practice. The committee acknowledged the difficulty in determining the potential diagnostic screening pathway and associated costs at a time when there are rapid developments in the NHS. The clinical experts explained that immunohistochemistry testing was considered to be the optimal screening method to identify NTRK fusion-positive tumours in European and US guidelines. The Cancer Drugs Fund clinical lead explained that NHS England does not intend to invest further in immunohistochemistry testing given the current service redesign towards a national service for genomic testing (see section 3.8). The committee concluded that the company's diagnostic testing approach was reasonable because it reflected current clinical practice but recognised that NHS England was rapidly moving towards a national service for cancer genomic testing. The committee understood that the NICE methods guide was not designed to address a system-wide change in diagnostic techniques and the cost of testing would depend on NHS England's testing strategy. The company included testing costs in its economic model for its 2‑step approach and the ERG explored the effect of including different testing strategies on entrectinib's cost effectiveness. The committee recognised that NHS England is rapidly moving towards a national service for cancer genomic testing and noted NHS England's proposal to implement next generation sequencing-based testing at diagnosis for all locally advanced or metastatic solid tumours. It agreed NHS England's cost per patient with an NTRK fusion-positive tumour should be included in the economic model. The committee understood that this proposal reflected the likely situation in the near future, once the changes to the diagnostic pathway had been established, but considered this approach to be appropriate for decision making. The committee concluded that it was appropriate to include diagnostic testing costs in the economic model.
## The economic model should include the costs of oral chemotherapy administration and drug wastage
The company did not include the costs of oral chemotherapy administration or drug wastage in its economic model. The Cancer Drugs Fund clinical lead noted that the oral chemotherapy administration costs should be included and the ERG incorporated them in its analyses after the technical engagement stage. The ERG added drug wastage to its analysis because a pack with a month's supply would be given to the person taking entrectinib and this would not be reused if treatment stopped before the pack was finished. The company acknowledged in its response to the technical engagement stage that there may be a small amount of drug wastage in clinical practice. However, the company highlighted that in its original submission a dose intensity of 100% was used. This was a conservative assumption because the mean observed dose in the clinical trials was lower. The committee concluded that drug wastage and the costs of oral chemotherapy administration should be included in the economic model, but it noted these did not have a significant effect on the cost-effectiveness estimates.
## The ERG's changes to costs are appropriate but there are some uncertainties
The company submission included a simplifying assumption for treatment administration costs and healthcare resource use that categorised the different types of treatment into 3 classes: oral, simple intravenous and complex intravenous interventions. The ERG noted that the infusion time varied significantly within the company's categories in its simplifying assumption and that the true effect of the administration costs was an uncertainty in the analysis. The ERG also identified some costs that had not been included in the company's progressed disease health state cost and noted that the company had used the BNF for the costs of the comparator treatments rather than the electronic market information tool (eMIT). The ERG considered the eMIT to be a more accurate and up-to-date indicator of treatment costs and the Cancer Drugs Fund clinical lead noted that this was the appropriate source of treatment costs. At the technical engagement stage the company did scenario analyses, including an updated progressed disease health state cost and comparator treatment costs sourced from the eMIT. The committee considered these scenario analyses to be appropriate for decision making but noted that there were some uncertainties around the administration costs included in the analyses.
# End of life
## Entrectinib has plausible potential to meet the end-of-life criteria
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The company proposed that entrectinib met these criteria for people with a short life expectancy (normally less than 24 months). The end-of-life criteria were not designed for histology-independent treatments and the committee was not shown the data needed to assess if entrectinib met the criteria for people with NTRK gene fusions specifically. Instead, the committee was shown life expectancy data for people with the relevant tumour type irrespective of NTRK gene fusion status and life extension data estimated from the model. It acknowledged the challenges with the data available, for example:
the distribution of tumour types in the trials (see section 3.16) and unrepresented tumour types not being included in the clinical evidence (see section 3.11)
the uncertainty around entrectinib's position in the treatment pathway (see section 3.5)
the limited survival data available (see section 3.12)
the prognostic importance of NTRK gene fusions (see section 3.3) and
the uncertainty about how the survival data was extrapolated (see section 3.21).The committee considered that most tumour types represented in the trials had overall survival estimates that would meet the short life expectancy criterion. It acknowledged that the overall survival estimates for people with thyroid and neuroendocrine tumours exceeded 24 months. But it considered the positioning of entrectinib as last-line therapy after all NHS commissioned treatments. The committee concluded that entrectinib has plausible potential to meet the end-of-life criterion for short life expectancy for most tumour types included in the entrectinib dataset, as most people with these tumour types have a life expectancy of less than 24 months. The committee noted the uncertainty associated with the short overall survival follow up in the entrectinib clinical trials and the small patient numbers for each tumour type. But it understood that both the company's and the ERG's modelling suggested that entrectinib was associated with an overall survival gain of over 3 months, irrespective of the choice of survival modelling. The committee concluded that entrectinib has plausible potential to meet the end-of-life criteria. But it acknowledged that there was uncertainty in determining both the life expectancy and the exact extension to life given the immaturity of the data and potential for heterogeneity across all of the different tumour types. Further data collection could resolve this uncertainty and the distribution of tumour sites likely to meet the life expectancy criterion.
# Cost-effectiveness results
## Entrectinib is not recommended for routine use in the NHS
The company's revised base case after the technical engagement stage gave a deterministic ICER of £49,358 per quality-adjusted life year (QALY) gained for entrectinib compared with established management. This included entrectinib's confidential simple discount but list prices for all other treatments. The company's revised base case included the NICE technical team's preference to include people with primary CNS tumours and children in the base-case population and included the costs of diagnostic testing. The revised base case did not include the committee's preferred assumptions to:
remove comparator arm testing costs that did not identify NTRK gene fusions and remove testing costs for lung cancer
use the prevalence estimates for the whole population rather than the population included in the entrectinib trials
include a confirmatory next generation sequencing test after whole genome sequencing
explore other plausible survival extrapolation distributions (for example the Weibull distribution for overall and progression-free survival)
remove second-line therapies in the comparator arm for breast and colorectal cancer and neuroendocrine tumours
include drug wastage or the costs of oral chemotherapy administration
use eMIT costs instead of BNF costs for the comparator treatment costs
use 6 months' duration of subsequent therapy after progression
include the revised cost of the progressed disease health state.The committee therefore agreed to use the analyses that included its preferred assumptions. These analyses also included:
a new commercial arrangement from the company (confidential so cannot be reported here)
diagnostic testing at the point of diagnosis of locally advanced or metastatic cancer costed per patient with an NTRK fusion-positive tumour, as provided by NHS England before the committee meeting.Based on the available evidence, the committee concluded that entrectinib (with the discount agreed in the commercial arrangement) had plausible potential for cost effectiveness if it met the end-of-life criteria. However, it also concluded that the ICER range on which it was basing its decision was associated with substantial uncertainty, particularly in the survival estimates and in modelling a population that was not generalisable to NHS clinical practice. The committee agreed this uncertainty needed to be accounted for in making its judgement about entrectinib's acceptability as an effective use of NHS resources. It acknowledged the ongoing NHS developments and that the company had asked that entrectinib was considered only for use within the Cancer Drugs Fund. The committee concluded that entrectinib could not be recommended for routine use in the NHS.
# Cancer Drugs Fund
## Further data collection could address uncertainties in the clinical and cost-effectiveness evidence
Having concluded that entrectinib could not be recommended for routine use, the committee then considered if it could be recommended for treating NTRK fusion-positive solid tumours within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum). The company expressed an interest in entrectinib being considered for funding through the Cancer Drugs Fund in its submission. The committee recognised that entrectinib is innovative (see section 3.32) and its use in clinical practice would help accelerate NHS England's developments in genomic testing (see section 3.9). The committee considered whether the clinical uncertainty associated with entrectinib's use could be addressed through collecting more data. More data from the entrectinib clinical trials are expected and the company also have other data collection activities ongoing. The committee agreed that:
The ongoing entrectinib clinical trials will provide more mature survival data for people already enrolled in the trials. They may recruit additional patients with solid tumours at sites not already included in the clinical trials, which will provide further data to explore the heterogeneity in response to treatment.
Real-world evidence collected within the Cancer Drugs Fund through Blueteq, SACT and the molecular dataset may provide further information on the prevalence of NTRK gene fusions, the distribution of tumour types in England, the screening pathway and testing costs and use of subsequent therapies.
Flatiron data (a US database of real-world clinical outcomes from cancer patients) and the Foundation Medicine genomic database (a US database of genetic data from samples of cancer tissue and blood) may provide data to further explore the heterogeneity in response to treatment and data to explore a matched cohort analysis to construct a comparator arm. It may also provide data to inform the decision about the end-of-life criteria.
A non-interventional study led by the European Thoracic Oncology Platform will collect utility data for prospective entrectinib patients and may provide data to help inform the decision about the end-of-life criteria.When entrectinib's European public assessment report is available, the managed access agreement may be updated to reflect any specific obligations that could inform the guidance review.
## Entrectinib meets the criteria to be included in the Cancer Drugs Fund
Data from the entrectinib trials showed that tumours in people having entrectinib may have good response rates, and there may be an improvement in overall and progression-free survival. The committee acknowledged that it had not seen evidence that fully reflected entrectinib's likely position in the treatment pathway, that is, as a last-line therapy, and that the evidence base was very uncertain. It noted that the company's revised base-case ICER including testing costs for entrectinib compared with established management was within what NICE considers a cost-effective use of NHS resources if end-of-life criteria are applied. The committee acknowledged that all the ICERs for entrectinib compared with established management were uncertain. But, taking the NHS developments around genetic testing and the company's commercial arrangement into account, it concluded that entrectinib had plausible potential to satisfy the criteria for routine use if this uncertainty could be reduced and genetic testing was fully established in clinical practice. The committee concluded that entrectinib met the criteria to be considered for inclusion in the Cancer Drugs Fund because it showed plausible potential for cost effectiveness at the end of the managed access agreement, when the diagnostic pathway would be fully operational in NHS England. It recommended entrectinib for use through the Cancer Drugs Fund as an option for people with NTRK fusion-positive solid tumours if the conditions in the managed access agreement were followed.
# Innovation
## Entrectinib is innovative and there are wider benefits to the NHS not captured in the analysis
The company considered entrectinib to be innovative. The patient and clinical experts agreed because it targets NTRK gene fusion, a new genomic target. The committee considered entrectinib to be innovative because it represents a major change in treating NTRK fusion-positive solid tumours. The committee understood that an important innovation is already underway in the NHS in developing more sophisticated strategies to improve genomic testing in clinical practice. These advances will likely help the uptake of treatments targeted to a gene alteration. The Cancer Drugs Fund clinical lead explained that histology-independent treatments entering the market are accelerating the advances in genomic testing in the NHS. It is estimated that 100,000 solid tumours will be tested per year once the genomic medicine service is fully established, thought to be within the next 2 years. The committee acknowledged that the improvements in genomic testing would bring wider benefits to the NHS and that these benefits have not been captured in the QALY calculation. The committee concluded that entrectinib would be beneficial for patients, but it had not been presented with any additional benefits that could be specifically attributed to entrectinib that were not captured in the measurement of the QALY.
# Equality considerations
## There are no equality issues relevant to the recommendations
The company did not highlight any equality issues. The Cancer Drugs Fund clinical lead noted that there may be issues about access to entrectinib. This is because the genomic testing needed to identify NTRK fusion-positive solid tumours is still being established as a national service (see section 3.8). The committee understood that any variation in access to genomic testing will be resolved in the next 1 to 2 years. The marketing authorisation specifies that entrectinib is a treatment for people of 12 years and over. The company explained that further data for children has been requested by the regulators. However, because the recommendations for entrectinib apply to the whole population in the marketing authorisation, the committee agreed that its recommendations do not have a different effect on people protected by the equality legislation than on the wider population. The committee concluded that there were no relevant equality issues.
|
{'Recommendations': "Entrectinib is recommended for use within the Cancer Drugs Fund as an option for treating neurotrophic tyrosine receptor kinase (NTRK) fusion-positive solid tumours in adults and children 12\xa0years and older if:\n\nthe disease is locally advanced or metastatic or surgery could cause severe health problems and\n\nthey have not had an NTRK inhibitor before and\n\nthey have no satisfactory treatment options.It is recommended only if the conditions in the managed access agreement for entrectinib are followed.\n\nThis recommendation is not intended to affect treatment with entrectinib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. For children and young people, this decision should be made jointly by the clinician and the child or young person or their parents or carers.\n\nWhy the committee made these recommendations\n\nThere is no standard treatment for NTRK fusion-positive solid tumours, so current treatment is based on where in the body the cancer starts. Entrectinib is a histology-independent treatment. This means that it targets a genetic alteration, NTRK gene fusion, that is found in many different tumour types irrespective of where the cancer starts.\n\nEvidence from trials suggests that tumours with NTRK gene fusions shrink in response to entrectinib, but longer follow up is needed. It is difficult to know how well entrectinib works because it has not been compared with other treatments in trials. Also, there is evidence that entrectinib works well for some types of NTRK fusion-positive tumour, but little or no evidence for other types.\n\nThe cost-effectiveness estimates for entrectinib are uncertain because of limitations in the data. Some of these estimates are higher than what NICE normally considers an acceptable use of NHS resources so entrectinib cannot be recommended for routine use in the NHS.\n\nCollecting more data on entrectinib would help to address some of the uncertainty in the evidence. Entrectinib has the potential to be cost effective given the company's commercial offer as part of a managed access agreement and using the diagnostic testing costs provided by NHS England. Therefore, entrectinib is recommended for use in the Cancer Drugs Fund.", 'Information about entrectinib': "# Marketing authorisation indication\n\nEntrectinib (Rozlytrek, Roche) is indicated as monotherapy for the 'treatment of adult and paediatric patients 12\xa0years of age and older, with solid tumours expressing a neurotrophic tyrosine receptor kinase (NTRK) gene fusion:\n\nwho have a disease that is locally advanced, metastatic or where surgical resection is likely to result in severe morbidity and\n\nwho have not received a prior NTRK inhibitor\n\nwho have no satisfactory treatment options'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price for entrectinib is £5,160.00 per 90‑tablet pack of 200\xa0mg tablets (excluding VAT, company submission). The company has a commercial arrangement. This makes entrectinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Roche, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that it was appropriate to include people with primary central nervous system (CNS) tumours and children in the population included in the economic modelling (issue\xa08, see technical report page\xa035).\n\nIt recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, table\xa012, page\xa061), and took these into account in its decision making. It discussed the following issues (issues 1\xa0to\xa07 and 9\xa0to\xa023), which were outstanding after the technical engagement stage.\n\n# NTRK gene fusions\n\n## Entrectinib targets a genetic mutation rather than a tumour type and there are challenges in appraising it\n\nTraditional oncology approaches treat tumours based on their type. More recently, targeted therapies based on the tumour's genetic information have been used for some indications. Entrectinib targets solid tumours with a neurotrophic tyrosine receptor kinase (NTRK) gene fusion. Because many tumour types respond to it, the company considers entrectinib to be 'tumour-agnostic' or 'histology-independent'. NTRK gene fusions may be able to drive tumour growth, so targeting treatment to the cause of the disease could mean higher rates of response to therapy and potentially better outcomes. The committee accepted that it was expected to appraise entrectinib within its marketing authorisation using the framework currently set out by NICE. But it recognised the challenges of appraising histology-independent treatments within the NICE single technology appraisal process.\n\n## The prevalence of NTRK gene fusions in England is unknown but collecting further data could help address this\n\nThe prevalence of NTRK gene fusions is uncertain. Estimates reported in the literature are between 0.25% and 0.31% in adults and between 0.34% and 0.49% in children and young people. NTRK gene fusions have high prevalence in some rare cancers such as mammary analogue secretory carcinoma, infantile fibrosarcoma and secretory breast cancer. But there is low prevalence in some of the more common cancers such as colorectal cancer and non-small-cell lung cancer. The company submission included a calculated prevalence estimate for each tumour type based on a weighting of prevalence estimates from the literature and data held by the company. The company provided data from the Foundation Medicine Incorporated (FMI) dataset that included data based on next generation sequencing of adult and children's solid tumour samples using the FMI next generation sequencing platform. The ERG estimated the prevalence of NTRK fusions in each tumour type included in the database. There is considerable variation between tumour types, with prevalence estimates ranging from less than 1% to 100% for the tumour types included in the dataset. The committee understood that the ERG's estimates were more likely to be generalisable to clinical practice because they were sourced from a large database and seemed to be the most robust data available currently. The committee concluded that the prevalence estimates from the FMI database were reasonable for decision making but recognised that there was some uncertainty around the true prevalence of NTRK gene fusions in England. Further data collection in clinical practice could mitigate some of this uncertainty.\n\n## NTRK fusion-positive solid tumours are not well characterised and the prognostic effect of NTRK gene fusions is unknown\n\nEveryone included in the entrectinib trials had an NTRK fusion-positive tumour and 20.4% of the entrectinib efficacy population had CNS metastases. Only a small proportion of people in the comparator dataset were likely to have NTRK gene fusions and the prevalence of CNS metastases in the comparator population was unknown. The company included a scenario analysis in its submission. In the analysis the company applied a hazard ratio calculated from published overall survival data on people with colorectal cancer who had either an NTRK, receptor tyrosine kinase (ROS1) or anaplastic lymphoma kinase (ALK) genetic alteration. It used this to adjust the comparator data to account for people with NTRK fusion-positive solid tumours potentially having a poorer prognosis than people with solid tumours that were not NTRK fusion-positive. At the technical engagement stage the company provided a systematic literature review that did not find any further evidence to support its claim that people with NTRK fusion-positive solid tumours have a worse prognosis than people with tumours without the genetic alteration. The committee agreed that there was not enough evidence available about whether NTRK gene fusions affect prognosis. The company also did a scenario analysis to adjust for the effect of CNS metastases in the comparator arm. The ERG explained that the prevalence of CNS metastases in the comparator data was not widely reported in the clinical trials so any adjustment to the comparator arm was uncertain. It was not possible to report characteristics that are commonly prognostic such as age and Eastern Cooperative Oncology Group performance status, so the committee considered it uncertain whether the 2\xa0arms were comparable. The committee considered that it would be appropriate to adjust the analysis to include factors that are known to affect prognosis but concluded that the evidence was too limited to do so.\n\n# Treatment pathway and comparator\n\n## There is no defined clinical pathway for people with NTRK fusion-positive solid tumours\n\nThere is no defined clinical pathway for people with NTRK fusion-positive solid tumours. Treatment currently follows care guidelines for specific tumour types. The committee understood that genomic testing to identify NTRK gene fusions was not routinely carried out for all of the different tumour types (see section\xa03.8). Until routine genomic testing is established in clinical practice, the people most likely to benefit from targeted therapy cannot be offered different treatment options to people with the same type of solid tumour but without the NTRK gene fusion. Some of the tumour types with NTRK gene fusions have an established treatment pathway with many treatment options available, such as colorectal cancer and non-small-cell lung cancer. However, other tumour types, including mammary analogue secretory carcinoma and cholangiocarcinoma, have few treatment options available for locally advanced and metastatic disease. The patient experts noted that for quadruple negative gastrointestinal stromal tumours there were no standard treatment options. They explained that people who have a solid tumour with a gene alteration would want a targeted treatment. The aim of treatment for some inoperable tumour types would be to shrink the solid tumour so that surgery might be a treatment option. The committee concluded that people with NTRK fusion-positive solid tumours would value new treatment options.\n\n## Entrectinib is positioned as last-line therapy in the treatment pathway\n\nThe marketing authorisation specifies that entrectinib should only be used if there are no satisfactory treatment options, that is, for which clinical benefit has not been established, or when such treatment options have been exhausted. The Cancer Drugs Fund clinical lead explained that entrectinib should be used after all NHS commissioned treatments, because these treatments have an established clinical benefit. The company submission was broader than the marketing authorisation because for some tumour types (soft-tissue sarcoma, pancreatic cancer, non-small-cell lung cancer, breast cancer, thyroid cancer, colorectal cancer and neuroendocrine carcinomas) people had treatment before other treatments for locally advanced or metastatic disease. This was because the submission was developed before input from the regulator on the wording of the marketing authorisation. In the entrectinib clinical trials, a large proportion of patients had entrectinib for untreated disease or after 1\xa0previous treatment. The clinical experts explained that if people with NTRK fusion-positive solid tumours had to have treatment with all NHS commissioned therapies before entrectinib then the solid tumours were more likely to be resistant to treatment. Entrectinib would be a treatment option for fewer people if it was used as a last-line therapy because some people would not be well enough to have it after other treatment options. The clinical experts noted that oncologists prefer to use targeted therapies as early as possible in the treatment pathway. The committee noted that entrectinib's clinical trial evidence may not be generalisable to its use in clinical practice as a last-line treatment option. The Cancer Drugs Fund clinical lead explained that people with rarer cancers that have a high prevalence of NTRK gene fusions may be more likely to have entrectinib as an earlier-line treatment option given that other treatment options are limited (see section\xa03.4) or may not have an established clinical benefit. This would be different for people with tumour types that have an established treatment pathway and different treatment options. For these tumour types it is likely that, for locally advanced or metastatic solid tumours, entrectinib will be a treatment option only after all NHS commissioned treatments in the treatment pathway.\n\n## Best supportive care is the appropriate comparator\n\nThe company's clinical trials were single arm, so did not include a comparator arm (see section\xa03.11). The ERG explained that because the wording of the marketing authorisation was broader at the time of the company's submission, it was reasonable to include NICE-recommended treatments as comparators for some tumour sites. Entrectinib should be positioned as a treatment option after all NHS commissioned treatments (see section\xa03.5) so the committee noted that the appropriate comparator should be best supportive care. Best supportive care was included as a treatment option in the company's blended comparator arm for colorectal cancer, thyroid cancer and neuroendocrine tumours only. For some of these tumour sites NICE-recommended treatments were also included as treatment options. The committee concluded that best supportive care was the appropriate comparator for the appraisal given that the marketing authorisation stated that entrectinib should only be used if there are no satisfactory treatment options.\n\n# Diagnosis\n\n## The diagnostic pathway for NTRK fusions has implications for identifying patients and on diagnosis costs\n\nAll solid tumour types can potentially have an NTRK gene fusion although they are rare in common tumour types (see section\xa03.2). Therefore, many people would need screening to identify who would benefit from entrectinib. Currently, NTRK testing is not routinely done in the NHS for all solid tumours. However, it is available for mammary analogue secretory carcinoma and secretory breast carcinoma with immunohistochemistry techniques (a method using antibodies to detect the gene fusion protein). Whole genome sequencing (a method of determining the whole DNA sequence of a cancer, used for discovering mutations) can also identify NTRK gene fusions and it is available for children's cancers and sarcomas. However, confirmation of the results with another DNA or RNA test is needed (for example next generation sequencing, which is a faster method of sequencing targeted regions of the cancer's DNA). The committee concluded that the diagnostic pathway for NTRK gene fusions was important, with implications for identifying patients and on costs of diagnosis.\n\n## The diagnostic pathway is uncertain until NHS England establishes a national service for genomic testing of all advanced solid tumours\n\nThe Cancer Drugs Fund clinical lead explained that NHS England is currently establishing a national service for cancer genomic testing to replace all local testing. It involves setting up 7\xa0laboratory hubs across England to do genomic testing by next generation sequencing and interpret all results. Until the laboratory hubs are fully established, next generation sequencing will be done after all NHS commissioned treatment options have been tried. When the hubs are fully established, next generation sequencing to identify gene alterations, including NTRK gene fusions, will be done when locally advanced or metastatic solid tumours are first diagnosed. The Cancer Drugs Fund clinical lead estimated that 100,000\xa0solid tumours would be tested per year once the service is fully established. He noted that other targeted therapies would likely become available soon for different diseases and genomic testing would also be needed before these treatments are used. The committee acknowledged the ongoing developments in genomic testing practice to identify NTRK fusion-positive solid tumours. It considered that the rapid change to the diagnostic testing pathway being led by NHS England was a unique situation. The committee concluded that the diagnostic testing pathway was uncertain until NHS England establishes a national service for cancer genomic testing.\n\n## Diagnostic techniques will improve as the genomic laboratory hubs validate their techniques and NTRK gene fusions are better characterised\n\nBecause the genomic laboratory hubs were not yet operational, there was no single representative NHS-based test that would allow measurement of diagnostic accuracy. The Cancer Drugs Fund clinical lead explained that the genomic laboratory hubs were putting a lot of resources into ensuring high diagnostic accuracy in their testing procedures. The committee noted that high sensitivity and specificity of a diagnostic test minimises the risk of false results. If specificity was not high then there was a greater chance of a solid tumour testing positive for an NTRK gene fusion when an NTRK gene fusion was not present. Solid tumours that do not have an NTRK gene fusion are not expected to respond to entrectinib and this could result in poorer clinical outcomes than with a different treatment option. High diagnostic accuracy is particularly important when screening tumour types that have a known low prevalence of NTRK gene fusions such as lung and colorectal cancer. The clinical experts explained that it was essential that a combined DNA and RNA-based next generation sequencing panel is used in clinical practice to identify people with NTRK fusion-positive solid tumours. This was because a DNA-based panel may identify NTRK gene fusions that, when treated with entrectinib, would not lead to the expected clinical outcomes. They explained the importance of correctly interpreting the results of the genomic test to identify the significant NTRK gene fusions. The committee noted that the genomic laboratory hubs were very aware of the importance of high diagnostic accuracy, especially given that some tumour types have very low prevalence of NTRK gene fusions. The committee considered that this is an evolving field and that diagnostic techniques would improve as the genomic laboratory hubs validate their techniques and NTRK gene fusions are better characterised (see section\xa03.3). The committee concluded that diagnostic accuracy was very important and that a period of access in the Cancer Drugs Fund could allow the genomic laboratory hubs to implement testing more quickly.\n\n# Clinical evidence\n\n## NTRK gene fusions have been identified in primary CNS and children's tumours so including them in the population is appropriate\n\nThe marketing authorisation includes people with primary CNS tumours and children (on 28\xa0May\xa02020, the Committee for Medicinal Products for Human Use announced that this would be children over 12\xa0years). The company updated its submission at the technical engagement stage. It used data from 5\xa0adults with primary CNS tumours and 7\xa0children with NTRK gene fusions in the efficacy population that were included in the company's clinical trials. The committee considered it appropriate to include these data in the analysis because it increased the generalisability of the evidence base to the population likely to be seen in clinical practice. The population of children included in the clinical trial was small and it did not represent all children's tumours that were known to have NTRK gene fusions. Some patients in the trials were under 12\xa0years and it is likely that many children in clinical practice will be under 12\xa0years, so would not be eligible for entrectinib because of the marketing authorisation's age restriction. However, the committee considered these results would likely be comparable with results from older children. It noted also that there was considerable uncertainty because of the very low number of children in the trials and distribution of tumour types. The committee concluded that it was appropriate to include people with primary CNS tumours and children in the analyses because they are part of the population covered by entrectinib's marketing authorisation.\n\n## The key clinical evidence comes from a pooled analysis of 4\xa0single-arm clinical trials and is appropriate for decision making\n\nThe company did a pooled analysis of results for 54\xa0adults from 3\xa0clinical trials (ALKA, STARTRK‑1 and STARTRK‑2) in its original submission. STARTRK‑2 is an ongoing phase\xa02 basket trial for people aged 18\xa0years and over with advanced or metastatic solid tumours that have an NTRK, ROS1 or ALK gene fusion. Basket trials are trials that include patients who have different types of cancer but the same gene mutation. The baskets in the STARTRK‑2 study were based on molecular targets (ALK, ROS1 and NTRK) rather than on tumour type for each molecular target. The ERG noted that this was different to a typical basket trial design. STARTRK‑2 contributed 51\xa0patients to the pooled analysis. ALKA contributed 1\xa0patient to the pooled analysis and STARTRK‑1 contributed 2\xa0patients. Both ALKA and STARTRK‑1 are ongoing phase\xa01 ascending dose and dose escalation studies. At the technical engagement stage the company updated its entrectinib dataset to include 66\xa0people (see section\xa03.10). The children's data were collected in the STARTRK‑NG trial, a dose escalation and expansion study evaluating the effect of entrectinib in children, adolescent and young adults aged 2 to 22\xa0years. The committee noted the small patient numbers from each of the trials making up the pooled analysis, and that the trials were single arm and did not include a control group. The Cancer Drugs Fund clinical lead considered it reasonable to pool the 4\xa0entrectinib studies to maximise the patient numbers included in the analyses. The clinical trial evidence included only 13\xa0tumour types: sarcoma, non-small-cell lung cancer, mammary analogue secretory carcinoma, breast, thyroid, colorectal cancer, neuroendocrine tumours, pancreatic cancer, gynaecological cancers, cholangiocarcinoma, CNS primary, infantile fibrosarcoma and paediatric melanoma. Also, each tumour type was represented by between 1 and 13\xa0patients. Given the rarity of the gene fusion, the committee considered that the evidence base was appropriate for decision making. But it acknowledged that further data collection was possible because the company's trials were ongoing.\n\n## Entrectinib could be clinically effective, but its survival benefit is difficult to measure because of limitations in the trial data\n\nThe pooled analysis of 66\xa0people across 13\xa0tumour types (see section\xa03.11) showed a clinically relevant overall response rate across tumour types (exact results are confidential and cannot be reported here). However, there was considerable uncertainty about the extent to which the response translated into clinically meaningful survival benefits. At the most recent data-cut, median follow up was short and the survival data were immature. Also, the number of patients with specific cancers was very small so there was uncertainty in the robustness of all survival data. The Cancer Drugs Fund clinical lead noted that entrectinib was active in patients with CNS metastases with a similar response rate in the brain to that seen systemically in all patients in the pooled analysis. However, the small patient numbers and short follow up were noted. The committee saw that there was no direct evidence of entrectinib's effectiveness compared with established management. It concluded that entrectinib could be clinically effective, but the limited data for each of the tumour types, the immature survival data and the lack of trial data directly comparing entrectinib with established management meant the size of this benefit was difficult to measure.\n\n## The population eligible for entrectinib is broader than the trial population so entrectinib's clinical effectiveness in some groups is unknown\n\nThere was limited evidence available on tumour types that have NTRK fusions. The clinical evidence for entrectinib was limited to the 13\xa0tumour types included in the company's clinical trials. The ERG's clinical advisers suggested that it was plausible that NTRK gene fusions could be present in over 400\xa0tumour types. The ERG used a Bayesian hierarchical modelling framework (see section\xa03.15) to explore the expected probability of response to entrectinib in tumour types not represented in the trial data. The results showed a very wide confidence interval around the probability of response for tumour types not included in the trial. This showed the high uncertainty around the response (exact results are confidential and cannot be reported here). The committee considered that the lack of any data for many other tumour sites meant there was substantial uncertainty about entrectinib's clinical and cost effectiveness for all those potentially eligible for treatment as defined by the marketing authorisation. The committee acknowledged that the ERG's analysis gave a reasonable estimate of the response rates for tumour types for which there were no data. It understood that the uncertainty would only be resolved through further data collection, including for other tumour types not already included in the clinical trials. But it noted that patient numbers could still be a limitation. The committee understood the challenges of appraising a histology-independent treatment when the population covered by the marketing authorisation was broader than the evidence base. It concluded that there was uncertainty about entrectinib's clinical effectiveness for tumour types that were not included in the clinical trials. Until further data are reported, the clinical benefit of using entrectinib in the NHS cannot be confirmed.\n\n## The company assumes the same response to entrectinib for all tumour types but this is inappropriate\n\nThere are several biological reasons why heterogeneity, or a difference, in tumour response to entrectinib might be seen. For example, tumour response might be different by histology, by NTRK gene fusion or fusion partner, by the presence of codrivers of the disease and by age (for example, for children's indications). The company assumed that each of the solid tumour types would have the same response rate when treated with entrectinib and generated a pooled response estimate across each of the tumour types included in the efficacy dataset. This approach did not take into account the potential for heterogeneity in response across different tumour types and fusion partner. There was considerable uncertainty in the level of heterogeneity in response rates across tumour types (exact results are confidential and cannot be reported here). The company did not explore any alternatives to this assumption. The committee concluded that it was not appropriate to assume that the same level of response would be seen across all tumour types eligible for treatment with entrectinib.\n\n## The ERG's approach explores heterogeneity in tumour response, but more data would help investigate this further\n\nThe ERG used a statistical modelling framework, Bayesian hierarchical modelling, to explore the potential heterogeneity in response across the 13\xa0tumour types included in the company's dataset. This used the tumour type to define each basket and allowed borrowing of information across baskets by assuming that response rates were exchangeable, rather than the same across baskets. Tumour types with few patients borrowed more information than tumour types with more patients. Using this method, the ERG found that the estimated mean response rate across all tumour types was similar to the response rate seen when the company assumed an equal response. The company made the data available for survival outcomes by tumour type for the ERG to do this analysis on the progression-free and overall survival data. The ERG considered the survival data not to be robust enough to explore variability in overall and progression-free survival so these data could not be included in the company's partitioned survival model. The ERG noted that it was unclear whether the Bayesian hierarchical modelling would give useful survival estimates given the small number of patients with each of the tumour types and that the data were immature. The ERG's analyses showed the potential for heterogeneity between tumour types but had small patient numbers in each of the tumour types included in the analysis. The committee acknowledged that the results of the ERG's Bayesian hierarchical modelling approach were similar to the company's approach (see section\xa03.14). The committee considered the wide confidence intervals around the response estimate and the possibility that some tumour types could have response rates that differed significantly from the pooled estimate. It understood that further data collection would increase the patient numbers for each of the tumour types and this would help improve the robustness of the analysis. More mature survival data would allow heterogeneity in the survival outcomes to be explored. The response estimates were similar when some adjustment for heterogeneity was included (the ERG's Bayesian hierarchical modelling approach) and when it was not (the company's approach). The committee concluded that this is an outstanding uncertainty that needs to be explored further when more data are available.\n\n## The trial population is not generalisable to the population in clinical practice in England\n\nThe company assumed that the distribution of the 13\xa0tumour sites in its dataset reflected the distributions seen in clinical practice in England. The most frequently represented solid tumour types in the trial evidence were sarcomas, non-small-cell lung cancer, salivary gland tumours (mammary analogue secretory carcinoma) and breast cancer. The company used this distribution to estimate a weighted set of outcomes for the comparator arm in its base-case analysis. The ERG was concerned that the estimate of cost effectiveness was being driven by the proportion of tumour types included in the company's dataset. The Cancer Drugs Fund clinical lead highlighted that the distribution of tumour types in the population in England who would have treatment would differ significantly from that in the entrectinib clinical trial population. In particular, he noted the high proportion of people included in the entrectinib clinical trials who had mammary analogue secretory carcinoma. The ERG estimated the yearly prevalence of NTRK fusion-positive solid tumours in England. It noted that secretory breast carcinoma, sarcoma and mammary analogue secretory carcinoma were over-represented in the company's dataset. The ERG determined an alternative distribution of tumour types using the FMI database, which the committee considered the most appropriate source of data (see section\xa03.2). The ERG considered this dataset to be more representative of clinical practice because it was based on a larger sample than the company's original estimate. The company did not provide the data needed for the ERG to adjust the distribution of tumour types in the entrectinib arm as well as the comparator arm. At the technical engagement stage the company noted that the likely distribution of NTRK gene fusion-positive tumour types in England may only be definitively known once comprehensive next generation sequencing-based testing was implemented in an unbiased way for all advanced and metastatic cancer diagnoses. The committee recalled that there was uncertainty in the analysis about the distribution of tumour types in the company's and ERG's analyses (see section\xa03.14 and section\xa03.15). The committee concluded that the trial population was not generalisable to the population who would have entrectinib in clinical practice in England.\n\n# Indirect treatment comparison\n\n## The company's approach to the comparator arm is pragmatic, but other methods should be considered\n\nThe company constructed a comparator arm to compare clinical effectiveness between entrectinib and established management. It generated a comparator arm by identifying overall and progression-free survival data for established management. It did this by searching NICE Pathways for NICE‑recommended comparators for each of the tumour types included in the entrectinib clinical trials. Median progression-free and overall survival for each tumour type were averaged and then pooled to calculate mean overall progression-free and overall survival across all tumour types, weighted by the distribution of each tumour type in the trial population. For some tumour types tumour-site specific data were not available, so an average from the other tumour types was used. The ERG considered the company's methods to identify, select and combine the comparator data to be inappropriate. It considered the comparator data in the company model to be highly unreliable. The ERG considered the company's approach to be intuitive, but the comparator population:\n\nwas not consistent with the entrectinib population for CNS metastases and other potential prognostic factors (see section\xa03.3)\n\ndid not reflect the population seen in clinical practice if the comparators had not been selected at the appropriate line of treatment (see section\xa03.6).The ERG suggested 2\xa0further approaches, a previous line of treatment approach (see section\xa03.18) and a response-based approach (see section\xa03.19). The committee recognised the difficulty in constructing a comparator arm for this appraisal. It concluded that the company's original approach was pragmatic but other methods should also be considered in the committee's decision making.\n\n## The company's previous line of treatment approach is a reasonable alternative to generating comparator data\n\nThe company did a previous line of treatment analysis (referred to by the company as an intra-patient analysis) at the technical engagement stage. This was as a confirmatory analysis to their original pooled comparator approach. The company assessed the time to next treatment for 31\xa0patients included in the STARTRK‑2 study who had a treatment before entrectinib. The time to next treatment for the treatment administered directly before entrectinib was considered to be a proxy for progression-free survival. The company acknowledged that this may have overestimated progression-free survival because treatment was unlikely to start exactly at the point of progression with the previous treatment. The company overcame the limitation that 10\xa0patients included in this analysis did not have a documented reason for stopping treatment by doing the same analysis for those who did have a documented reason. The results showed that the median time to next treatment was broadly similar to the median progression-free survival estimate derived for the company's blended comparator using its pooled approach. The ERG acknowledged that the company's previous line of treatment analysis may have produced a more reliable progression-free survival estimate in the comparator arm than the original modelled comparator or the ERG's response-based analysis (see section\xa03.19). But the ERG highlighted that there were 2\xa0assumptions that must hold for this analysis to be valid, which it considered to be strong and hard to verify. The ERG also highlighted that to understand the effect of this modelling approach on the incremental cost-effectiveness ratio (ICER), the data would need to be included in the economic model and an extrapolation function applied. The committee was aware of the limitations of this approach. But, it concluded that it was a reasonable alternative to generating the comparator data and should also be considered in the committee's decision making.\n\n## The ERG's exploratory response-based approach is limited by the generalisability of the trial data to clinical practice\n\nThe results of the ERG's response-based approach were presented as an exploratory analysis. This approach involved taking the survival data for the people whose tumours did not respond from the entrectinib dataset and using these data for the comparator arm. The company considered the number of people whose tumours did not respond to be too small to provide a meaningful comparator sample. So, the ERG's method had some issues, including:\n\nthe people whose tumours did not respond potentially having a different prognosis to those whose tumours did respond\n\nwhether the effect of different subsequent therapies could be included in the clinical data\n\nthe generalisability of the population to the population likely seen in clinical practice, particularly given that the clinical trial population was not generalisable (see section\xa03.16)\n\nentrectinib being given at earlier points in the treatment pathway in the clinical trials than it would be in clinical practice (see section\xa03.5).The committee understood that, as with the other approaches, data availability was an issue given the small patient numbers in the entrectinib clinical trials and the immaturity of the data. It concluded that the ERG's exploratory response-based approach was a reasonable alternative to generate comparator data. Additional data would help improve its robustness, but issues around generalisability could not be resolved, which was a major limitation of this analysis. The committee concluded that this approach was a reasonable alternative to generating comparator data. But, because of the limitations in generalisability, it was suitable only for exploratory analysis with current data.\n\n# Economic model\n\n## All modelling approaches for decision making are uncertain\n\nThe company presented a 3‑state partitioned survival model (progression-free, progressed disease and death) to estimate the cost effectiveness of entrectinib compared with established management. The model used data on overall and progression-free survival from the entrectinib clinical trials for the entrectinib arm. The established management arm was modelled using the data from the company's approach to modelling the comparator arm (see section\xa03.17). The company's model did not account for tumour types not represented in the entrectinib clinical trials (see section\xa03.15). The committee noted that the different approaches and methods used to construct the comparator arm for this appraisal (see section\xa03.17, section\xa03.18 and section\xa03.19) would affect the choice of model structure. The ERG explained that a major limitation of the company's model structure was that it could not account for tumour types not included in the entrectinib clinical trials (see section\xa03.15). Also, it did not have the functionality to produce an ICER for each tumour type individually, so produced only a single ICER. The ERG did some exploratory analysis using a response-based model. This approach distinguished between people whose tumours responded to treatment and people whose tumours did not respond for clinical effectiveness inputs as well as for health-related quality of life and the costs of care. The ERG's response-based approach used data from people whose tumours did not respond as a proxy for people not having an active treatment. Survival in the entrectinib arm was estimated as a weighted average of survival for the people whose tumours responded and those whose tumours did not, weighted by the estimated response rate derived from the ERG's Bayesian hierarchical model (see section\xa03.15). The ERG's response-based model allowed for results to be generated for each tumour type individually and could also account for tumour types that were not included in the entrectinib clinical trials. The committee considered that when more data were available the different model structures could be explored more fully. It concluded that each of the modelling approaches had limitations and uncertainties.\n\n# Survival extrapolations\n\n## The company's exponential extrapolation is appropriate to model overall and progression-free survival, but other extrapolations are also plausible\n\nThe entrectinib clinical trials are ongoing so data on overall survival were incomplete. To extrapolate overall survival for entrectinib and the established management comparator arm, the company fitted an exponential curve to the data. The ERG preferred the Weibull distribution to extrapolate overall and progression-free survival data because it gave a more clinically plausible balance between pre- and post-progression survival. The ERG explained that there was no difference in statistical fit between this distribution and the exponential distribution to extrapolate overall and progression-free survival. The exponential distribution gave a longer duration of survival in the post-progressed health state than in the pre-progressed health state. At the technical engagement stage the company did a scenario analysis using the proxy Weibull distribution in the comparator arm and the Weibull distribution in the entrectinib arm. The ERG explained that the most appropriate method to generate the extrapolated survival curves for the comparator arm would have been to extract the Kaplan–Meier curves from each of the source NICE technology appraisals included in the company's pooled comparator arm and to use the committee's most appropriate distribution for each of the appraisals. The committee noted that the survival data from the clinical trials were very immature and this made it challenging to select the most appropriate extrapolation function. The committee concluded that the exponential extrapolation was appropriate but other extrapolation functions were also plausible. It also noted that the trials were ongoing and follow-up survival data could reduce this uncertainty if all plausible extrapolations are considered after a period of further data collection.\n\n# Utility values in the economic models\n\n## The company's utility estimates are unlikely to be generalisable to clinical practice given entrectinib's position in the treatment pathway\n\nThe company's utility value in the pre-progressed health state in the entrectinib arm was taken from the EQ‑5D‑3L data from the STARTRK‑2 study. The utility values for the comparator arm were derived from a single NICE technology appraisal for each tumour type included in the entrectinib clinical trials. A single utility value was calculated for each health state by calculating the average utility value, weighted by the distribution of tumour types included in the clinical trial; 0.73 for progression-free and 0.59 for progressed disease. The company considered its utility value for the progressed disease health state derived from the STARTRK‑2 EQ‑5D‑3L data to be implausible because it was higher than the pre-progressed value. The same utility value was used in both arms for the progressed disease health state. In the STARTRK‑2 study a reasonable proportion of people had entrectinib as first-line treatment. The committee agreed that entrectinib's position was now as a last-line treatment option (see section\xa03.5). It recognised that the utility value in the pre-progressed health state may no longer be generalisable to clinical practice because it was likely to be an overestimate. The ERG also highlighted that the company's choice of NICE technology appraisal for the comparator arm utility value may have biased the cost-effectiveness analysis. This was because the selected utilities reflected a specific line of therapy and entrectinib's position was last line. The committee concluded that the utility estimates were unlikely to be generalisable to clinical practice because entrectinib's position in the treatment pathway was likely to be as a last-line treatment option.\n\n## The size of difference in the pre-progressed utility values between arms is uncertain\n\nThe company used a higher utility value in the pre-progressed health state in the entrectinib arm (exact value is confidential and cannot be reported here) than in the comparator arm (0.73). The company justified this because entrectinib is an oral treatment with a more convenient administration and better safety profile than the comparators, which are mostly cytotoxic chemotherapies. Best supportive care was the appropriate comparator (see section\xa03.6) so entrectinib's safety profile compared with best supportive care was unlikely to give a higher utility score. The ERG highlighted the lack of evidence to justify the assumption to use different values in each arm for the pre-progressed health state. It considered there was considerable uncertainty about the size of any difference. The Cancer Drugs Fund clinical lead noted that equal utility values should be used in the progression-free health state. The committee recognised the uncertainty in the utility values given entrectinib's position in the treatment pathway as a last-line treatment option. It concluded that there was some uncertainty about the size of difference in the pre-progressed utility values between arms.\n\n# Subsequent therapies\n\n## It is not appropriate to include subsequent therapies in the analysis if entrectinib is a last-line treatment option\n\nIn the entrectinib clinical trial a reasonable number of people had subsequent therapy after entrectinib and this was included in the company's analysis. The subsequent therapies included targeted therapies. No subsequent therapies were included after established management in the comparator arm. The company modelled the duration of treatment with subsequent therapies from progression until death. The ERG considered it overly pessimistic to assume that people would have subsequent therapies from progression until death and instead assumed a treatment duration of 6\xa0months, about half of the post-progression duration. The committee considered entrectinib's position in the treatment pathway as a last-line treatment option (see section\xa03.5). It agreed that if subsequent therapies were to be given after entrectinib, these would not be active treatments in which clinical benefit had been established. This was because these treatments would likely have been tried before entrectinib. The committee concluded that it was not appropriate to include subsequent therapies in the analysis if entrectinib was a last-line option in the treatment pathway.\n\n# Resource use and costs\n\n## It is appropriate to include diagnostic testing costs in the economic model\n\nThe company attempted to capture the diagnostic testing pathway and associated costs in its analysis. It included a 2‑stage approach to testing for cancers when biomarker screening is already done in clinical practice (for colorectal, non-small-cell lung, breast and thyroid cancers) or when no molecular testing is done (for neuroendocrine, pancreatic and gynaecological tumours and cholangiocarcinoma). This included an immunohistochemistry test, which if positive was followed by a next generation sequencing test. The ERG considered the company's approach to testing to be broadly plausible. For cancers that have whole genome sequencing (see section\xa03.7), the ERG's clinical advisers noted that an RNA-based next generation sequencing test would be needed after whole genome sequencing to confirm an NTRK fusion-positive tumour. The ERG did not consider it appropriate to include the costs of testing in the comparator arm for tests that did not identify NTRK gene fusions. It also noted that the costs of testing for NTRK gene fusions in lung cancer samples would be negligible beyond the cost of genomic testing already done in clinical practice. The committee acknowledged the difficulty in determining the potential diagnostic screening pathway and associated costs at a time when there are rapid developments in the NHS. The clinical experts explained that immunohistochemistry testing was considered to be the optimal screening method to identify NTRK fusion-positive tumours in European and US guidelines. The Cancer Drugs Fund clinical lead explained that NHS England does not intend to invest further in immunohistochemistry testing given the current service redesign towards a national service for genomic testing (see section\xa03.8). The committee concluded that the company's diagnostic testing approach was reasonable because it reflected current clinical practice but recognised that NHS England was rapidly moving towards a national service for cancer genomic testing. The committee understood that the NICE methods guide was not designed to address a system-wide change in diagnostic techniques and the cost of testing would depend on NHS England's testing strategy. The company included testing costs in its economic model for its 2‑step approach and the ERG explored the effect of including different testing strategies on entrectinib's cost effectiveness. The committee recognised that NHS England is rapidly moving towards a national service for cancer genomic testing and noted NHS England's proposal to implement next generation sequencing-based testing at diagnosis for all locally advanced or metastatic solid tumours. It agreed NHS England's cost per patient with an NTRK fusion-positive tumour should be included in the economic model. The committee understood that this proposal reflected the likely situation in the near future, once the changes to the diagnostic pathway had been established, but considered this approach to be appropriate for decision making. The committee concluded that it was appropriate to include diagnostic testing costs in the economic model.\n\n## The economic model should include the costs of oral chemotherapy administration and drug wastage\n\nThe company did not include the costs of oral chemotherapy administration or drug wastage in its economic model. The Cancer Drugs Fund clinical lead noted that the oral chemotherapy administration costs should be included and the ERG incorporated them in its analyses after the technical engagement stage. The ERG added drug wastage to its analysis because a pack with a month's supply would be given to the person taking entrectinib and this would not be reused if treatment stopped before the pack was finished. The company acknowledged in its response to the technical engagement stage that there may be a small amount of drug wastage in clinical practice. However, the company highlighted that in its original submission a dose intensity of 100% was used. This was a conservative assumption because the mean observed dose in the clinical trials was lower. The committee concluded that drug wastage and the costs of oral chemotherapy administration should be included in the economic model, but it noted these did not have a significant effect on the cost-effectiveness estimates.\n\n## The ERG's changes to costs are appropriate but there are some uncertainties\n\nThe company submission included a simplifying assumption for treatment administration costs and healthcare resource use that categorised the different types of treatment into 3\xa0classes: oral, simple intravenous and complex intravenous interventions. The ERG noted that the infusion time varied significantly within the company's categories in its simplifying assumption and that the true effect of the administration costs was an uncertainty in the analysis. The ERG also identified some costs that had not been included in the company's progressed disease health state cost and noted that the company had used the BNF for the costs of the comparator treatments rather than the electronic market information tool (eMIT). The ERG considered the eMIT to be a more accurate and up-to-date indicator of treatment costs and the Cancer Drugs Fund clinical lead noted that this was the appropriate source of treatment costs. At the technical engagement stage the company did scenario analyses, including an updated progressed disease health state cost and comparator treatment costs sourced from the eMIT. The committee considered these scenario analyses to be appropriate for decision making but noted that there were some uncertainties around the administration costs included in the analyses.\n\n# End of life\n\n## Entrectinib has plausible potential to meet the end-of-life criteria\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The company proposed that entrectinib met these criteria for people with a short life expectancy (normally less than 24\xa0months). The end-of-life criteria were not designed for histology-independent treatments and the committee was not shown the data needed to assess if entrectinib met the criteria for people with NTRK gene fusions specifically. Instead, the committee was shown life expectancy data for people with the relevant tumour type irrespective of NTRK gene fusion status and life extension data estimated from the model. It acknowledged the challenges with the data available, for example:\n\nthe distribution of tumour types in the trials (see section\xa03.16) and unrepresented tumour types not being included in the clinical evidence (see section\xa03.11)\n\nthe uncertainty around entrectinib's position in the treatment pathway (see section\xa03.5)\n\nthe limited survival data available (see section\xa03.12)\n\nthe prognostic importance of NTRK gene fusions (see section\xa03.3) and\n\nthe uncertainty about how the survival data was extrapolated (see section\xa03.21).The committee considered that most tumour types represented in the trials had overall survival estimates that would meet the short life expectancy criterion. It acknowledged that the overall survival estimates for people with thyroid and neuroendocrine tumours exceeded 24\xa0months. But it considered the positioning of entrectinib as last-line therapy after all NHS commissioned treatments. The committee concluded that entrectinib has plausible potential to meet the end-of-life criterion for short life expectancy for most tumour types included in the entrectinib dataset, as most people with these tumour types have a life expectancy of less than 24\xa0months. The committee noted the uncertainty associated with the short overall survival follow up in the entrectinib clinical trials and the small patient numbers for each tumour type. But it understood that both the company's and the ERG's modelling suggested that entrectinib was associated with an overall survival gain of over 3\xa0months, irrespective of the choice of survival modelling. The committee concluded that entrectinib has plausible potential to meet the end-of-life criteria. But it acknowledged that there was uncertainty in determining both the life expectancy and the exact extension to life given the immaturity of the data and potential for heterogeneity across all of the different tumour types. Further data collection could resolve this uncertainty and the distribution of tumour sites likely to meet the life expectancy criterion.\n\n# Cost-effectiveness results\n\n## Entrectinib is not recommended for routine use in the NHS\n\nThe company's revised base case after the technical engagement stage gave a deterministic ICER of £49,358 per quality-adjusted life year (QALY) gained for entrectinib compared with established management. This included entrectinib's confidential simple discount but list prices for all other treatments. The company's revised base case included the NICE technical team's preference to include people with primary CNS tumours and children in the base-case population and included the costs of diagnostic testing. The revised base case did not include the committee's preferred assumptions to:\n\nremove comparator arm testing costs that did not identify NTRK gene fusions and remove testing costs for lung cancer\n\nuse the prevalence estimates for the whole population rather than the population included in the entrectinib trials\n\ninclude a confirmatory next generation sequencing test after whole genome sequencing\n\nexplore other plausible survival extrapolation distributions (for example the Weibull distribution for overall and progression-free survival)\n\nremove second-line therapies in the comparator arm for breast and colorectal cancer and neuroendocrine tumours\n\ninclude drug wastage or the costs of oral chemotherapy administration\n\nuse eMIT costs instead of BNF costs for the comparator treatment costs\n\nuse 6\xa0months' duration of subsequent therapy after progression\n\ninclude the revised cost of the progressed disease health state.The committee therefore agreed to use the analyses that included its preferred assumptions. These analyses also included:\n\na new commercial arrangement from the company (confidential so cannot be reported here)\n\ndiagnostic testing at the point of diagnosis of locally advanced or metastatic cancer costed per patient with an NTRK fusion-positive tumour, as provided by NHS England before the committee meeting.Based on the available evidence, the committee concluded that entrectinib (with the discount agreed in the commercial arrangement) had plausible potential for cost effectiveness if it met the end-of-life criteria. However, it also concluded that the ICER range on which it was basing its decision was associated with substantial uncertainty, particularly in the survival estimates and in modelling a population that was not generalisable to NHS clinical practice. The committee agreed this uncertainty needed to be accounted for in making its judgement about entrectinib's acceptability as an effective use of NHS resources. It acknowledged the ongoing NHS developments and that the company had asked that entrectinib was considered only for use within the Cancer Drugs Fund. The committee concluded that entrectinib could not be recommended for routine use in the NHS.\n\n# Cancer Drugs Fund\n\n## Further data collection could address uncertainties in the clinical and cost-effectiveness evidence\n\nHaving concluded that entrectinib could not be recommended for routine use, the committee then considered if it could be recommended for treating NTRK fusion-positive solid tumours within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum). The company expressed an interest in entrectinib being considered for funding through the Cancer Drugs Fund in its submission. The committee recognised that entrectinib is innovative (see section\xa03.32) and its use in clinical practice would help accelerate NHS England's developments in genomic testing (see section\xa03.9). The committee considered whether the clinical uncertainty associated with entrectinib's use could be addressed through collecting more data. More data from the entrectinib clinical trials are expected and the company also have other data collection activities ongoing. The committee agreed that:\n\nThe ongoing entrectinib clinical trials will provide more mature survival data for people already enrolled in the trials. They may recruit additional patients with solid tumours at sites not already included in the clinical trials, which will provide further data to explore the heterogeneity in response to treatment.\n\nReal-world evidence collected within the Cancer Drugs Fund through Blueteq, SACT and the molecular dataset may provide further information on the prevalence of NTRK gene fusions, the distribution of tumour types in England, the screening pathway and testing costs and use of subsequent therapies.\n\nFlatiron data (a US database of real-world clinical outcomes from cancer patients) and the Foundation Medicine genomic database (a US database of genetic data from samples of cancer tissue and blood) may provide data to further explore the heterogeneity in response to treatment and data to explore a matched cohort analysis to construct a comparator arm. It may also provide data to inform the decision about the end-of-life criteria.\n\nA non-interventional study led by the European Thoracic Oncology Platform will collect utility data for prospective entrectinib patients and may provide data to help inform the decision about the end-of-life criteria.When entrectinib's European public assessment report is available, the managed access agreement may be updated to reflect any specific obligations that could inform the guidance review.\n\n## Entrectinib meets the criteria to be included in the Cancer Drugs Fund\n\nData from the entrectinib trials showed that tumours in people having entrectinib may have good response rates, and there may be an improvement in overall and progression-free survival. The committee acknowledged that it had not seen evidence that fully reflected entrectinib's likely position in the treatment pathway, that is, as a last-line therapy, and that the evidence base was very uncertain. It noted that the company's revised base-case ICER including testing costs for entrectinib compared with established management was within what NICE considers a cost-effective use of NHS resources if end-of-life criteria are applied. The committee acknowledged that all the ICERs for entrectinib compared with established management were uncertain. But, taking the NHS developments around genetic testing and the company's commercial arrangement into account, it concluded that entrectinib had plausible potential to satisfy the criteria for routine use if this uncertainty could be reduced and genetic testing was fully established in clinical practice. The committee concluded that entrectinib met the criteria to be considered for inclusion in the Cancer Drugs Fund because it showed plausible potential for cost effectiveness at the end of the managed access agreement, when the diagnostic pathway would be fully operational in NHS England. It recommended entrectinib for use through the Cancer Drugs Fund as an option for people with NTRK fusion-positive solid tumours if the conditions in the managed access agreement were followed.\n\n# Innovation\n\n## Entrectinib is innovative and there are wider benefits to the NHS not captured in the analysis\n\nThe company considered entrectinib to be innovative. The patient and clinical experts agreed because it targets NTRK gene fusion, a new genomic target. The committee considered entrectinib to be innovative because it represents a major change in treating NTRK fusion-positive solid tumours. The committee understood that an important innovation is already underway in the NHS in developing more sophisticated strategies to improve genomic testing in clinical practice. These advances will likely help the uptake of treatments targeted to a gene alteration. The Cancer Drugs Fund clinical lead explained that histology-independent treatments entering the market are accelerating the advances in genomic testing in the NHS. It is estimated that 100,000 solid tumours will be tested per year once the genomic medicine service is fully established, thought to be within the next 2\xa0years. The committee acknowledged that the improvements in genomic testing would bring wider benefits to the NHS and that these benefits have not been captured in the QALY calculation. The committee concluded that entrectinib would be beneficial for patients, but it had not been presented with any additional benefits that could be specifically attributed to entrectinib that were not captured in the measurement of the QALY.\n\n# Equality considerations\n\n## There are no equality issues relevant to the recommendations\n\nThe company did not highlight any equality issues. The Cancer Drugs Fund clinical lead noted that there may be issues about access to entrectinib. This is because the genomic testing needed to identify NTRK fusion-positive solid tumours is still being established as a national service (see section\xa03.8). The committee understood that any variation in access to genomic testing will be resolved in the next 1\xa0to\xa02 years. The marketing authorisation specifies that entrectinib is a treatment for people of 12\xa0years and over. The company explained that further data for children has been requested by the regulators. However, because the recommendations for entrectinib apply to the whole population in the marketing authorisation, the committee agreed that its recommendations do not have a different effect on people protected by the equality legislation than on the wider population. The committee concluded that there were no relevant equality issues."}
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https://www.nice.org.uk/guidance/ta644
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Evidence-based recommendations on entrectinib (Rozlytrek) for treating neurotrophic tyrosine receptor kinase (NTRK) fusion-positive solid tumours in adults and children over 12 years.
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1bc2653ebfc34d34de4d6c4e2cdacf3aa804482a
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nice
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Entrectinib for treating ROS1-positive advanced non-small-cell lung cancer
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Entrectinib for treating ROS1-positive advanced non-small-cell lung cancer
Evidence-based recommendations on entrectinib (Rozlytrek) for ROS1-positive advanced non-small-cell lung cancer (NSCLC) in adults who have not had ROS1 inhibitors.
# Recommendations
Entrectinib is recommended, within its marketing authorisation, as an option for treating ROS1-positive advanced non-small-cell lung cancer (NSCLC) in adults who have not had ROS1 inhibitors. It is recommended only if the company provides entrectinib according to the commercial arrangement.
Why the committee made these recommendations
Evidence for entrectinib in ROS1-positive advanced NSCLC comes from a small study that did not compare entrectinib with anything else. It includes mostly people with previously treated disease. The evidence suggests that entrectinib is effective at shrinking tumours and slowing disease progression.
Two indirect comparisons of entrectinib, using evidence from a different kind of NSCLC, show that it is clinically effective compared with pemetrexed and platinum chemotherapy. But because the evidence is from a different population, this is uncertain.
However, the cost-effectiveness results are within the range NICE normally considers an acceptable use of NHS resources for end-of-life treatments. Therefore, entrectinib is recommended.# Information about entrectinib
# Marketing authorisation indication
Entrectinib (Rozlytrek, Roche) is indicated as monotherapy 'for the treatment of adult patients with ROS1-positive, advanced non-small cell lung cancer (NSCLC) not previously treated with ROS1 inhibitors'.
On 28 May 2020 the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorisation for the medicinal product entrectinib intended for the treatment of ROS1-positive advanced NSCLC.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price for entrectinib is £5,160 for a 90‑capsule pack of 200-mg capsules, and £860 for a 30‑capsule pack of 100-mg capsules (excluding VAT, company submission). The company has a commercial arrangement. This makes entrectinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Roche, a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:
Pemetrexed with a platinum drug (PEM+PLAT) was the key comparator in this appraisal. In line with NICE's position statement on appraising new cancer products: handling comparators and treatment sequences in the Cancer Drugs Fund, crizotinib was not a comparator in this appraisal (issue 1, see technical report pages 12 to 14).
The relevant population was the STARTRK‑2 subgroup of 78 patients who had:
a confirmed diagnosis of ROS1-positive non-small-cell lung cancer (NSCLC)
measurable disease at baseline
no minimum follow-up restriction
the licensed 600-mg entrectinib dose
no prior ROS1 inhibitor treatment.Analyses based on the STARTRK‑2 subgroup were appropriate for decision making (issue 2, see technical report pages 15 to 17).
STARTRK‑2, the key clinical trial, was a single-arm phase 2 basket trial. To compare entrectinib with PEM+PLAT, a matching-adjusted indirect comparison was done using data from the ASCEND‑4 trial in anaplastic lymphoma kinase (ALK)-positive NSCLC. The results of the matching-adjusted indirect comparison were appropriate for decision making. However, there was a high level of uncertainty in the resulting progression-free survival and overall survival estimates because the evidence was from ALK-positive NSCLC and because of differences in the treatments people had before and after entrectinib in the ASCEND‑4 and STARTRK‑2 trials. It was not possible to estimate the direction or size of the effect the uncertainty had on the matching-adjusted indirect comparison results (issue 3, see technical report pages 18 to 23).
The company modelled pemetrexed maintenance therapy only after pemetrexed with cisplatin in line with NICE's technology appraisal guidance on pemetrexed for non-squamous NSCLC. In its base case it assumed no maintenance therapy. The ASCEND‑4 trial was used to estimate progression-free survival with PEM+PLAT in the model. In that trial, pemetrexed maintenance therapy was used for approximately 8 cycles. To reflect current clinical practice and the clinical evidence (ASCEND‑4), the technical team considered results assuming that pemetrexed maintenance therapy was taken for 4, 6 or 8 cycles after an induction treatment with pemetrexed with either cisplatin or carboplatin (issue 6, see technical report pages 37 to 39).
The company assumed a range of subsequent treatments in its model and only some patients had subsequent treatments. The cost of subsequent treatments was applied as one-off cost in the model. To reflect UK clinical practice, the technical team assumed that PEM+PLAT was the next treatment for all patients who progressed on entrectinib and considered scenario analyses assuming that 60% and 70% of patients were having subsequent therapy (issue 7, see technical report pages 40 to 43).
The estimated progression-free survival utility value from STARTRK‑2 was 0.73. A utility value for post-progression survival was not available. Given that only one set of utility data came from the trial and that the regression model had not been implemented correctly, the utilities used in NICE's technology appraisal guidance on crizotinib for ROS1-positive advanced NSCLC (0.81 for progression-free survival and 0.66 for post-progression survival) were appropriate for decision making (issue 8, see technical report pages 44 to 45).
The healthcare costs based on values proposed by the ERG's clinical experts were appropriate for decision making (issue 9, see technical report pages 46 to 47).
If entrectinib cannot be recommended for routine commissioning because of clinical uncertainty, it would be suitable for inclusion in the Cancer Drugs Fund (issue 10, see technical report pages 48 to 49).The committee recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, table 2, page 51), and took these into account in its decision making. It discussed the following issues (issue 4 and 5), which were outstanding after the technical engagement stage.
# Treatment pathway
## ROS1-targeted treatment would be valued by both patients and clinicians
ROS1 is a rare mutation that occurs in less than 2% of people with NSCLC. The committee was aware that patients would welcome an oral treatment that can delay chemotherapy. The patient experts considered that there was a significant unmet need for treatment for ROS1-positive NSCLC, and especially for people with brain metastases. NICE's technology appraisal guidance on crizotinib for ROS1-positive advanced NSCLC recommends crizotinib for use within the Cancer Drugs Fund as an option for treating ROS1‑positive advanced NSCLC in adults. NICE's guideline on lung cancer diagnosis and management recommends pemetrexed with platinum chemotherapy (PEM+PLAT) on progression after crizotinib. In addition, NICE's technology appraisal guidance on pemetrexed for non-squamous NSCLC recommends maintenance treatment with pemetrexed for people whose disease did not directly progress after pemetrexed and cisplatin induction therapy. The committee was aware that pemetrexed maintenance is also used after pemetrexed and carboplatin induction therapy. In line with NICE's position statement on appraising new cancer products: handling comparators and treatment sequences in the Cancer Drugs Fund, PEM+PLAT was the main comparator in this appraisal, because crizotinib is not recommended for routine commissioning. The committee concluded that a ROS1-targeted treatment would be valued by both patients and clinicians.
# Clinical evidence
## Evidence is available from 3 clinical studies
The company based its analyses on 53 people with ROS1-positive advanced NSCLC from 2 phase 1 studies (ALKA and STARTRK‑1) and 1 phase 2 study (STARTRK‑2; excluding people who had less than 12‑month follow-up data from the analyses). During the technical engagement stage it was agreed that the STARTRK‑2 ROS1-positive NSCLC population was the relevant population for this appraisal. STARTRK‑2 is an ongoing single-arm, multicentre basket trial (that is, a trial that included patients who had different types of cancer but the same gene mutation). It recruited adults with advanced or metastatic solid tumours with various gene alterations (n=207) and included 78 people with ROS1-positive NSCLC. Most (73%) people had previous therapy for advanced disease and everyone had the licensed entrectinib dose. Data from the STARTRK‑2 subgroup (May 2018 enrolment data cut-off) were used in this appraisal (including the model). After the technical engagement stage, the company submitted updated analyses (May 2019 enrolment data cut-off) which confirmed the original results from the STARTRK‑2 subgroup. The results cannot be reported here because they are confidential. The company's pooled analyses from ALKA, STARTRK‑1, and STARTRK‑2 (including people with a minimum of 12 months' follow up) were also updated and are reported in the entrectinib summary of product characteristics. The updated pooled analyses included 94 people (not 53 as in the original dataset) because of longer follow up. No one was excluded from the updated analyses because of short follow up.
## Entrectinib shows a high overall response rate and slows disease progression
The primary efficacy endpoints in STARTRK‑2 were objective response rate and duration of response. The survival data are immature (not yet complete). The results cannot be reported because they are confidential. The updated pooled analyses (n=94; May 2019 enrolment data cut-off), reported an overall response rate of 73.4% (95% confidence interval 63.3 to 82.0). The median progression-free survival for entrectinib was 16.8 months (95% CI 12.0 to 21.4). The committee considered that the STARTRK‑2 subgroup was representative of NHS clinical practice. It noted that only a small number of people with ROS1-positive NSCLC were included in the basket trial and that the results were immature. However, the committee agreed that entrectinib produced a high overall response rate and slowed disease progression.
## Entrectinib shows a high intracranial overall response rate in people with brain metastases
Central nervous system metastases are common in advanced NSCLC. In the STARTRK‑2 subgroup, 45% of people had brain metastasis when they entered the study and 8 people (10%) had measurable lesions. The results cannot be reported because they are confidential. Pooled analyses (with a minimum of 6 months of follow up; n=161) reported an intracranial overall response rate of 79.2% (95% CI 57.8 to 92.9) in 19 of 24 people with measurable central nervous system lesions at the start of the trial (46 people had brain metastases at the start of the trial). The clinical experts noted the anticipated benefit of entrectinib for treating and preventing advanced disease with central nervous system metastases. The committee agreed that entrectinib showed a high intracranial overall response rate in people with measurable central nervous system lesions.
# Modelling of overall survival and progression-free survival
## Evidence of effectiveness of the comparator, pemetrexed, is only available in ALK-positive advanced NSCLC
In the absence of available data, the company used data from patients with ALK-positive disease as a proxy for ROS1-positive NSCLC. It explained that patients with ALK-positive and ROS1-positive NSCLC were similar in terms of demographics (for example, younger age, no or light smoking) and clinical characteristics (for example, adenocarcinoma histology). The company identified 2 studies that could be used for an indirect comparison of entrectinib with PEM+PLAT:
ASCEND‑4: an open-label, multicentre, randomised controlled trial comparing ceritinib with PEM+PLAT (with pemetrexed maintenance therapy) in ALK-positive advanced NSCLC (n=375).
PROFILE 1014: an open-label, multicentre, randomised controlled trial comparing crizotinib with PEM+PLAT (without pemetrexed maintenance therapy) in ALK-positive advanced NSCLC (n=343).In ASCEND‑4, approximately 43% of patients had ceritinib after PEM+PLAT. Most patients (84%) had crizotinib after PEM+PLAT in PROFILE 1014. The committee was concerned about using proxy data, however in this instance the ERG and clinical experts agreed that this was acceptable because no ROS1-positive evidence was available. However, the committee highlighted the uncertainty the proxy data introduced to the estimated results. The committee agreed to explore the proxy data in its decision making. However, it considered the estimates from the indirect comparison to be uncertain.
## Both the ERG's and the company's approaches have considerable limitations
An exponential distribution was applied to the STARTRK‑2 data to estimate overall survival and progression-free survival beyond the observed data. To estimate the overall survival and progression-free survival for PEM+PLAT, the company first did a matching-adjusted indirect comparison using entrectinib (STARTRK‑2; n=78) and crizotinib (PROFILE 1001; n=53) data in ROS1-positive NSCLC to estimate the crizotinib curve. Next, hazard ratios adjusted for crossover from PROFILE 1014 were applied to the crizotinib curve to estimate survival for PEM+PLAT. In PROFILE 1014 patients did not have pemetrexed maintenance therapy, as in UK clinical practice. The use of adjusted hazard ratios from PROFILE 1014 was critiqued during the technology appraisal of crizotinib for ROS1-positive advanced NSCLC and the proportional hazards assumption (the relative risk of an event is fixed irrespective of time) was not valid for progression-free survival, so any hazard ratios for progression-free survival should be interpreted with caution. Also, the ERG was concerned about the results from the matching-adjusted indirect comparison comparing entrectinib with crizotinib. The ERG considered that entrectinib and crizotinib have similar efficacy and preferred to assume the same progression-free survival and overall survival (a hazard ratio of 1 for both) in the company's approach. Because of the limitations of the company's approach, the ERG used a matching-adjusted indirect comparison of entrectinib (STARTRK‑2; n=78) and PEM+PLAT (ASCEND‑4; n=187) data to estimate the PEM+PLAT curve. ASCEND‑4 patients had pemetrexed maintenance therapy in line with UK clinical practice. However, because of the high crossover to ceritinib after PEM+PLAT (ASCEND‑4 results were not adjusted for crossover), the results likely overestimate overall survival and progression-free survival with PEM+PLAT compared with entrectinib. The committee agreed that both approaches have limitations but both should be considered for decision making.
## The committee considers the likely survival estimate to be between the 2 approaches
The progression-free survival results were similar using both approaches. Mean overall survival with entrectinib was the same because both approaches used entrectinib data from the STARTRK‑2 subgroup. The entrectinib results and survival gains cannot be reported because they are confidential. The estimated mean overall survival with PEM+PLAT was 39.2 months using the ERG's approach and 15.6 months using the company's approach. The clinical experts considered the ERG's approach to overestimate and the company's approach to underestimate survival with PEM+PLAT. They also noted that the post-progression survival gain with entrectinib in the company's approach was implausibly high. The clinical experts agreed that the most likely survival values are somewhere between the 2 approaches. The committee agreed with the clinical experts and decided to consider both approaches in its decision making.
# End of life
## Entrectinib meets both criteria to be considered a life-extending, end-of-life treatment compared with PEM+PLAT
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The company's estimate of PEM+PLAT survival was less than 24 months and the ERG's estimate more than 24 months (see section 3.7). The ERG's estimate was likely to be an overestimate because of people crossing over to have ceritinib in ASCEND‑4 (see section 3.6). Entrectinib survival gains using both approaches were more than 3 months (results are confidential and cannot be reported here). The committee was aware that NICE's guidance on crizotinib considered it to meet both criteria to be considered a life-extending, end-of-life treatment when compared with PEM+PLAT at a similar point in the clinical pathway. The company, ERG, and clinical experts agreed that the life expectancy of patients who had treatment with PEM+PLAT was typically less than 24 months. Also, they all agreed that entrectinib could be expected to extend life by more than 3 months when compared with PEM+PLAT. The committee concluded that entrectinib meets both of NICE's criteria to be considered a life-extending, end-of-life treatment when compared with PEM+PLAT.
# Cost-effectiveness estimates
## The cost-effectiveness estimates are within the range NICE normally considers an acceptable use of NHS resources for end-of-life treatments
The technical team's preferred incremental cost-effectiveness ratio (ICER) for entrectinib (with the commercial arrangement applied) compared with PEM+PLAT was in the range of £37,910 to £42,572 per quality-adjusted life year (QALY) gained (see table 1 of the technical report). Using the company's approach to estimate progression-free survival and overall survival (while keeping all other assumptions the same and assuming the same efficacy for entrectinib and crizotinib), the company's preferred base-case post-technical engagement ICER was in the range of £21,607 to £23,457 per QALY gained. The decision-making ICERs used by the committee, which took account of all available confidential discounts including discounts for comparators and follow-up treatments, were higher. But these still remained within the range NICE normally considers an acceptable use of NHS resources for end-of-life treatments. The clinical experts explained that the 2 approaches to modelling were likely to define the optimistic and pessimistic margins of survival benefit, with the true benefit lying somewhere in between (see section 3.7). The company also submitted some analyses using the updated clinical data (May 2019 enrolment data, see section 3.2). These analyses resulted in a small decrease in the company's and technical team's ICERs and confirmed the original results. Therefore, despite the immaturity and uncertainty with the data (see section 3.5), the committee was persuaded that the highest ICER for entrectinib compared with PEM+PLAT was likely to be below £50,000 per QALY gained.
## Entrectinib is recommended for routine commissioning
The committee concluded that entrectinib can be considered cost effective. Therefore it can be recommended for routine commissioning as an option for treating ROS1-positive advanced NSCLC.
|
{'Recommendations': 'Entrectinib is recommended, within its marketing authorisation, as an option for treating ROS1-positive advanced non-small-cell lung cancer (NSCLC) in adults who have not had ROS1 inhibitors. It is recommended only if the company provides entrectinib according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nEvidence for entrectinib in ROS1-positive advanced NSCLC comes from a small study that did not compare entrectinib with anything else. It includes mostly people with previously treated disease. The evidence suggests that entrectinib is effective at shrinking tumours and slowing disease progression.\n\nTwo indirect comparisons of entrectinib, using evidence from a different kind of NSCLC, show that it is clinically effective compared with pemetrexed and platinum chemotherapy. But because the evidence is from a different population, this is uncertain.\n\nHowever, the cost-effectiveness results are within the range NICE normally considers an acceptable use of NHS resources for end-of-life treatments. Therefore, entrectinib is recommended.', 'Information about entrectinib': "# Marketing authorisation indication\n\nEntrectinib (Rozlytrek, Roche) is indicated as monotherapy 'for the treatment of adult patients with ROS1-positive, advanced non-small cell lung cancer (NSCLC) not previously treated with ROS1 inhibitors'.\n\nOn 28 May 2020 the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorisation for the medicinal product entrectinib intended for the treatment of ROS1-positive advanced NSCLC.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price for entrectinib is £5,160 for a 90‑capsule pack of 200-mg capsules, and £860 for a 30‑capsule pack of 100-mg capsules (excluding VAT, company submission). The company has a commercial arrangement. This makes entrectinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Roche, a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:\n\nPemetrexed with a platinum drug (PEM+PLAT) was the key comparator in this appraisal. In line with NICE's position statement on appraising new cancer products: handling comparators and treatment sequences in the Cancer Drugs Fund, crizotinib was not a comparator in this appraisal (issue\xa01, see technical report pages 12\xa0to\xa014).\n\nThe relevant population was the STARTRK‑2 subgroup of 78\xa0patients who had:\n\n\n\na confirmed diagnosis of ROS1-positive non-small-cell lung cancer (NSCLC)\n\nmeasurable disease at baseline\n\nno minimum follow-up restriction\n\nthe licensed 600-mg entrectinib dose\n\nno prior ROS1 inhibitor treatment.Analyses based on the STARTRK‑2 subgroup were appropriate for decision making (issue\xa02, see technical report pages 15\xa0to\xa017).\n\n\n\nSTARTRK‑2, the key clinical trial, was a single-arm phase\xa02 basket trial. To compare entrectinib with PEM+PLAT, a matching-adjusted indirect comparison was done using data from the ASCEND‑4 trial in anaplastic lymphoma kinase (ALK)-positive NSCLC. The results of the matching-adjusted indirect comparison were appropriate for decision making. However, there was a high level of uncertainty in the resulting progression-free survival and overall survival estimates because the evidence was from ALK-positive NSCLC and because of differences in the treatments people had before and after entrectinib in the ASCEND‑4 and STARTRK‑2 trials. It was not possible to estimate the direction or size of the effect the uncertainty had on the matching-adjusted indirect comparison results (issue\xa03, see technical report pages 18\xa0to\xa023).\n\nThe company modelled pemetrexed maintenance therapy only after pemetrexed with cisplatin in line with NICE's technology appraisal guidance on pemetrexed for non-squamous NSCLC. In its base case it assumed no maintenance therapy. The ASCEND‑4 trial was used to estimate progression-free survival with PEM+PLAT in the model. In that trial, pemetrexed maintenance therapy was used for approximately 8\xa0cycles. To reflect current clinical practice and the clinical evidence (ASCEND‑4), the technical team considered results assuming that pemetrexed maintenance therapy was taken for 4,\xa06\xa0or\xa08 cycles after an induction treatment with pemetrexed with either cisplatin or carboplatin (issue\xa06, see technical report pages 37\xa0to\xa039).\n\nThe company assumed a range of subsequent treatments in its model and only some patients had subsequent treatments. The cost of subsequent treatments was applied as one-off cost in the model. To reflect UK clinical practice, the technical team assumed that PEM+PLAT was the next treatment for all patients who progressed on entrectinib and considered scenario analyses assuming that 60% and 70% of patients were having subsequent therapy (issue\xa07, see technical report pages 40\xa0to\xa043).\n\nThe estimated progression-free survival utility value from STARTRK‑2 was 0.73. A utility value for post-progression survival was not available. Given that only one set of utility data came from the trial and that the regression model had not been implemented correctly, the utilities used in NICE's technology appraisal guidance on crizotinib for ROS1-positive advanced NSCLC (0.81 for progression-free survival and 0.66 for post-progression survival) were appropriate for decision making (issue\xa08, see technical report pages 44\xa0to\xa045).\n\nThe healthcare costs based on values proposed by the ERG's clinical experts were appropriate for decision making (issue\xa09, see technical report pages 46\xa0to\xa047).\n\nIf entrectinib cannot be recommended for routine commissioning because of clinical uncertainty, it would be suitable for inclusion in the Cancer Drugs Fund (issue\xa010, see technical report pages\xa048 to\xa049).The committee recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, table\xa02, page\xa051), and took these into account in its decision making. It discussed the following issues (issue\xa04 and 5), which were outstanding after the technical engagement stage.\n\n# Treatment pathway\n\n## ROS1-targeted treatment would be valued by both patients and clinicians\n\nROS1 is a rare mutation that occurs in less than 2% of people with NSCLC. The committee was aware that patients would welcome an oral treatment that can delay chemotherapy. The patient experts considered that there was a significant unmet need for treatment for ROS1-positive NSCLC, and especially for people with brain metastases. NICE's technology appraisal guidance on crizotinib for ROS1-positive advanced NSCLC recommends crizotinib for use within the Cancer Drugs Fund as an option for treating ROS1‑positive advanced NSCLC in adults. NICE's guideline on\xa0lung cancer diagnosis and management recommends pemetrexed with platinum chemotherapy (PEM+PLAT) on progression after crizotinib. In addition, NICE's technology appraisal guidance on pemetrexed for non-squamous NSCLC recommends maintenance treatment with pemetrexed for people whose disease did not directly progress after pemetrexed and cisplatin induction therapy. The committee was aware that pemetrexed maintenance is also used after pemetrexed and carboplatin induction therapy. In line with NICE's position statement on appraising new cancer products: handling comparators and treatment sequences in the Cancer Drugs Fund, PEM+PLAT was the main comparator in this appraisal, because crizotinib is not recommended for routine commissioning. The committee concluded that a ROS1-targeted treatment would be valued by both patients and clinicians.\n\n# Clinical evidence\n\n## Evidence is available from 3 clinical studies\n\nThe company based its analyses on 53\xa0people with ROS1-positive advanced NSCLC from 2 phase\xa01 studies (ALKA and STARTRK‑1) and 1 phase\xa02 study (STARTRK‑2; excluding people who had less than 12‑month follow-up data from the analyses). During the technical engagement stage it was agreed that the STARTRK‑2 ROS1-positive NSCLC population was the relevant population for this appraisal. STARTRK‑2 is an ongoing single-arm, multicentre basket trial (that is, a trial that included patients who had different types of cancer but the same gene mutation). It recruited adults with advanced or metastatic solid tumours with various gene alterations (n=207) and included 78\xa0people with ROS1-positive NSCLC. Most (73%) people had previous therapy for advanced disease and everyone had the licensed entrectinib dose. Data from the STARTRK‑2 subgroup (May\xa02018 enrolment data cut-off) were used in this appraisal (including the model). After the technical engagement stage, the company submitted updated analyses (May\xa02019 enrolment data cut-off) which confirmed the original results from the STARTRK‑2 subgroup. The results cannot be reported here because they are confidential. The company's pooled analyses from ALKA, STARTRK‑1, and STARTRK‑2 (including people with a minimum of 12\xa0months' follow up) were also updated and are reported in the entrectinib summary of product characteristics. The updated pooled analyses included 94\xa0people (not 53 as in the original dataset) because of longer follow up. No one was excluded from the updated analyses because of short follow up.\n\n## Entrectinib shows a high overall response rate and slows disease progression\n\nThe primary efficacy endpoints in STARTRK‑2 were objective response rate and duration of response. The survival data are immature (not yet complete). The results cannot be reported because they are confidential. The updated pooled analyses (n=94; May\xa02019 enrolment data cut-off), reported an overall response rate of 73.4% (95%\xa0confidence interval [CI] 63.3\xa0to\xa082.0). The median progression-free survival for entrectinib was 16.8\xa0months (95%\xa0CI 12.0\xa0to\xa021.4). The committee considered that the STARTRK‑2 subgroup was representative of NHS clinical practice. It noted that only a small number of people with ROS1-positive NSCLC were included in the basket trial and that the results were immature. However, the committee agreed that entrectinib produced a high overall response rate and slowed disease progression.\n\n## Entrectinib shows a high intracranial overall response rate in people with brain metastases\n\nCentral nervous system metastases are common in advanced NSCLC. In the STARTRK‑2 subgroup, 45% of people had brain metastasis when they entered the study and 8\xa0people (10%) had measurable lesions. The results cannot be reported because they are confidential. Pooled analyses (with a minimum of 6\xa0months of follow up; n=161) reported an intracranial overall response rate of 79.2% (95%\xa0CI 57.8\xa0to\xa092.9) in 19 of 24\xa0people with measurable central nervous system lesions at the start of the trial (46\xa0people had brain metastases at the start of the trial). The clinical experts noted the anticipated benefit of entrectinib for treating and preventing advanced disease with central nervous system metastases. The committee agreed that entrectinib showed a high intracranial overall response rate in people with measurable central nervous system lesions.\n\n# Modelling of overall survival and progression-free survival\n\n## Evidence of effectiveness of the comparator, pemetrexed, is only available in ALK-positive advanced NSCLC\n\nIn the absence of available data, the company used data from patients with ALK-positive disease as a proxy for ROS1-positive NSCLC. It explained that patients with ALK-positive and ROS1-positive NSCLC were similar in terms of demographics (for example, younger age, no or light smoking) and clinical characteristics (for example, adenocarcinoma histology). The company identified 2\xa0studies that could be used for an indirect comparison of entrectinib with PEM+PLAT:\n\nASCEND‑4: an open-label, multicentre, randomised controlled trial comparing ceritinib with PEM+PLAT (with pemetrexed maintenance therapy) in ALK-positive advanced NSCLC (n=375).\n\nPROFILE\xa01014: an open-label, multicentre, randomised controlled trial comparing crizotinib with PEM+PLAT (without pemetrexed maintenance therapy) in ALK-positive advanced NSCLC (n=343).In ASCEND‑4, approximately 43% of patients had ceritinib after PEM+PLAT. Most patients (84%) had crizotinib after PEM+PLAT in PROFILE\xa01014. The committee was concerned about using proxy data, however in this instance the ERG and clinical experts agreed that this was acceptable because no ROS1-positive evidence was available. However, the committee highlighted the uncertainty the proxy data introduced to the estimated results. The committee agreed to explore the proxy data in its decision making. However, it considered the estimates from the indirect comparison to be uncertain.\n\n## Both the ERG's and the company's approaches have considerable limitations\n\nAn exponential distribution was applied to the STARTRK‑2 data to estimate overall survival and progression-free survival beyond the observed data. To estimate the overall survival and progression-free survival for PEM+PLAT, the company first did a matching-adjusted indirect comparison using entrectinib (STARTRK‑2; n=78) and crizotinib (PROFILE\xa01001; n=53) data in ROS1-positive NSCLC to estimate the crizotinib curve. Next, hazard ratios adjusted for crossover from PROFILE\xa01014 were applied to the crizotinib curve to estimate survival for PEM+PLAT. In PROFILE\xa01014 patients did not have pemetrexed maintenance therapy, as in UK clinical practice. The use of adjusted hazard ratios from PROFILE\xa01014 was critiqued during the technology appraisal of crizotinib for ROS1-positive advanced NSCLC and the proportional hazards assumption (the relative risk of an event is fixed irrespective of time) was not valid for progression-free survival, so any hazard ratios for progression-free survival should be interpreted with caution. Also, the ERG was concerned about the results from the matching-adjusted indirect comparison comparing entrectinib with crizotinib. The ERG considered that entrectinib and crizotinib have similar efficacy and preferred to assume the same progression-free survival and overall survival (a hazard ratio of 1 for both) in the company's approach. Because of the limitations of the company's approach, the ERG used a matching-adjusted indirect comparison of entrectinib (STARTRK‑2; n=78) and PEM+PLAT (ASCEND‑4; n=187) data to estimate the PEM+PLAT curve. ASCEND‑4 patients had pemetrexed maintenance therapy in line with UK clinical practice. However, because of the high crossover to ceritinib after PEM+PLAT (ASCEND‑4 results were not adjusted for crossover), the results likely overestimate overall survival and progression-free survival with PEM+PLAT compared with entrectinib. The committee agreed that both approaches have limitations but both should be considered for decision making.\n\n## The committee considers the likely survival estimate to be between the 2\xa0approaches\n\nThe progression-free survival results were similar using both approaches. Mean overall survival with entrectinib was the same because both approaches used entrectinib data from the STARTRK‑2 subgroup. The entrectinib results and survival gains cannot be reported because they are confidential. The estimated mean overall survival with PEM+PLAT was 39.2\xa0months using the ERG's approach and 15.6\xa0months using the company's approach. The clinical experts considered the ERG's approach to overestimate and the company's approach to underestimate survival with PEM+PLAT. They also noted that the post-progression survival gain with entrectinib in the company's approach was implausibly high. The clinical experts agreed that the most likely survival values are somewhere between the 2\xa0approaches. The committee agreed with the clinical experts and decided to consider both approaches in its decision making.\n\n# End of life\n\n## Entrectinib meets both criteria to be considered a life-extending, end-of-life treatment compared with PEM+PLAT\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The company's estimate of PEM+PLAT survival was less than 24\xa0months and the ERG's estimate more than 24\xa0months (see section\xa03.7). The ERG's estimate was likely to be an overestimate because of people crossing over to have ceritinib in ASCEND‑4 (see section\xa03.6). Entrectinib survival gains using both approaches were more than 3\xa0months (results are confidential and cannot be reported here). The committee was aware that NICE's guidance on crizotinib considered it to meet both criteria to be considered a life-extending, end-of-life treatment when compared with PEM+PLAT at a similar point in the clinical pathway. The company, ERG, and clinical experts agreed that the life expectancy of patients who had treatment with PEM+PLAT was typically less than 24\xa0months. Also, they all agreed that entrectinib could be expected to extend life by more than 3\xa0months when compared with PEM+PLAT. The committee concluded that entrectinib meets both of NICE's criteria to be considered a life-extending, end-of-life treatment when compared with PEM+PLAT.\n\n# Cost-effectiveness estimates\n\n## The cost-effectiveness estimates are within the range NICE normally considers an acceptable use of NHS resources for end-of-life treatments\n\nThe technical team's preferred incremental cost-effectiveness ratio (ICER) for entrectinib (with the commercial arrangement applied) compared with PEM+PLAT was in the range of £37,910 to £42,572 per quality-adjusted life year (QALY) gained (see table\xa01 of the technical report). Using the company's approach to estimate progression-free survival and overall survival (while keeping all other assumptions the same and assuming the same efficacy for entrectinib and crizotinib), the company's preferred base-case post-technical engagement ICER was in the range of £21,607 to £23,457 per QALY gained. The decision-making ICERs used by the committee, which took account of all available confidential discounts including discounts for comparators and follow-up treatments, were higher. But these still remained within the range NICE normally considers an acceptable use of NHS resources for end-of-life treatments. The clinical experts explained that the 2\xa0approaches to modelling were likely to define the optimistic and pessimistic margins of survival benefit, with the true benefit lying somewhere in between (see section\xa03.7). The company also submitted some analyses using the updated clinical data (May 2019 enrolment data, see section\xa03.2). These analyses resulted in a small decrease in the company's and technical team's ICERs and confirmed the original results. Therefore, despite the immaturity and uncertainty with the data (see section\xa03.5), the committee was persuaded that the highest ICER for entrectinib compared with PEM+PLAT was likely to be below £50,000 per QALY gained.\n\n## Entrectinib is recommended for routine commissioning\n\nThe committee concluded that entrectinib can be considered cost effective. Therefore it can be recommended for routine commissioning as an option for treating ROS1-positive advanced NSCLC."}
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https://www.nice.org.uk/guidance/ta643
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Evidence-based recommendations on entrectinib (Rozlytrek) for ROS1-positive advanced non-small-cell lung cancer (NSCLC) in adults who have not had ROS1 inhibitors.
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b68ef8efb7e793dd0ef9edae7fcf9554e8baef61
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nice
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Brentuximab vedotin in combination for untreated systemic anaplastic large cell lymphoma
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Brentuximab vedotin in combination for untreated systemic anaplastic large cell lymphoma
Evidence-based recommendations on brentuximab vedotin (Adcetris) with cyclophosphamide, doxorubicin and prednisone for untreated systemic anaplastic large cell lymphoma in adults.
# Recommendations
Brentuximab vedotin with cyclophosphamide, doxorubicin and prednisone (CHP) is recommended, within its marketing authorisation, as an option for untreated systemic anaplastic large cell lymphoma in adults. It is only recommended if the company provides brentuximab vedotin according to the commercial arrangement.
Why the committee made these recommendations
Standard care for untreated systemic anaplastic large cell lymphoma is cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP).
Clinical evidence shows that people with systemic anaplastic large cell lymphoma who have brentuximab vedotin with CHP live longer and have longer before their disease progresses than people who have CHOP.
There is uncertainty about the modelling, but the most likely cost-effectiveness estimate is within what NICE considers an acceptable use of NHS resources. Therefore, brentuximab vedotin with CHP is recommended.# Information about brentuximab vedotin
# Marketing authorisation indication
Brentuximab vedotin (Adcetris, Takeda) with cyclophosphamide, doxorubicin and prednisone (CHP) is indicated 'for adult patients with previously untreated systemic anaplastic large cell lymphoma (sALCL)'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The NHS list price of brentuximab vedotin is £2,500 per 50‑mg vial (excluding VAT; BNF online, accessed June 2020). Based on a mean of 6 cycles, the cost for an average patient is estimated at about £47,619, at list price. The company has a commercial arrangement. This makes brentuximab vedotin available to the NHS with a discount. The size of the discount is confidential. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Takeda, a review of this submission by the evidence review group (ERG), the technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:
the mean age of the systemic anaplastic large cell lymphoma (sALCL) population seen in the ECHELON-2 trial (52 years) was appropriate for the economic model
the time-to-death utility model approach was preferable to the health-state utility method for this appraisal
it was appropriate to cap the patient utility values in the model so that they cannot exceed the age-adjusted utility values for the general population
the mean number of cycles of brentuximab vedotin monotherapy was 6 when used second line for relapsed or refractory sALCL
the joint modelling approach was acceptable for this appraisal
excluding costs for grades 3 and 4 peripheral neuropathy was appropriate.
The committee recognised that there were areas of uncertainty associated with the analyses presented and took these into account in its decision making. It discussed the choice of model used to estimate progression-free survival and overall survival (see technical report, pages 13 to 17), which was outstanding after the technical engagement stage.
# Clinical need
## People would welcome a new first-line treatment option
The patient and clinical experts explained that there is a considerable unmet need for people with sALCL. Current treatments are often difficult to tolerate, cause significant side effects and are often given as inpatient treatment. The patient experts described their experiences of disease relapse after cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) and other previous treatments and the lack of alternatives. They noted that after treatment with brentuximab vedotin plus cyclophosphamide, doxorubicin and prednisone (CHP) they experienced an improvement in their symptoms and had fewer side effects. Brentuximab vedotin with CHP is given in an outpatient setting, reducing the time in hospital. The committee concluded that brentuximab vedotin with CHP would be welcomed as a new treatment option for people with sALCL.
# Clinical management
## Brentuximab vedotin with CHP will replace CHOP for untreated sALCL
The clinical experts noted that standard care for untreated sALCL is CHOP, but few patients have disease that is in complete remission. Of those that do, many have disease that relapses in the first year. The clinical lead for the Cancer Drugs Fund advised that a more effective first-line treatment is needed and that, if recommended, brentuximab vedotin with CHP would replace current treatment for sALCL in the NHS. The clinical experts agreed that brentuximab vedotin with CHP would be a useful first-line treatment since it may give a durable response. They explained that for people whose disease relapses, brentuximab vedotin monotherapy would still be an option at a later stage in the treatment pathway. The only exception would be people whose sALCL did not respond to previous treatment with brentuximab vedotin. The clinical experts agreed that brentuximab vedotin with CHP could quickly replace CHOP for people with untreated sALCL because of its clinical advantages. Based on comments from the clinical experts and the clinical lead for the Cancer Drugs Fund, the committee concluded that brentuximab vedotin with CHP would replace CHOP for sALCL in the NHS.
# Clinical evidence
## Brentuximab vedotin with CHP improves progression-free survival and overall survival compared with CHOP
The clinical evidence for brentuximab vedotin with CHP came from ECHELON‑2. This was a randomised controlled trial of 452 people with CD30-positive peripheral T‑cell lymphoma, comparing brentuximab vedotin and CHP with CHOP. The median follow up for the progression-free survival analysis was 36.2 months (95% confidence interval 35.9 to 41.8), and for the overall survival analysis was 42.1 months (95% CI 40.4 to 43.8). The committee noted that 70% of the patients in ECHELON‑2 had a diagnosis of sALCL, which is higher than would be expected in clinical practice in the NHS. The company clarified that this was because of a regulatory requirement of the European Medicines Agency. The company presented analyses from the subgroup of patients with sALCL. This subgroup's objective response rate, measured by independent review facility assessment, was 88% (95% CI 81.6 to 92.3) for people in the brentuximab vedotin with CHP arm compared with 71% (95% CI 62.9 to 77.8) for people in the CHOP arm (p=0.0001). Brentuximab vedotin with CHP statistically significantly reduced the risk of a progression event compared with CHOP (stratified hazard ratio 0.59 ; p=0.0031). Overall survival was also statistically significantly improved for brentuximab vedotin with CHP compared with CHOP (HR 0.54 , p=0.0096). There were 70% of patients in the CHOP arm who had second-line brentuximab vedotin after progression. This meant the treatment effect was likely to be underestimated for the brentuximab vedotin with CHP arm. The committee concluded that brentuximab vedotin with CHP improves progression-free survival and overall survival compared with current standard care, CHOP.
# Survival extrapolation
## There are uncertainties about the company model for progression-free survival and overall survival
The company applied standard parametric functions to the available data from ECHELON‑2 to estimate progression-free survival and overall survival. It selected the generalised gamma curve for both progression-free survival and overall survival in the sALCL population. This was based on statistical fit and advice from clinical experts. The company submission noted that the shape of the generalised gamma hazard function matched what would be seen clinically in people with sALCL. People were at an increased risk of dying or having their disease progress during the first 18 to 24 months, but after that the risk declined quickly. This characteristic prognosis for sALCL was confirmed by the clinical experts. The committee noted that a similarly shaped hazard function could also be associated with the log-normal extrapolation, and to a lesser extent the log-logistic extrapolation. The clinical experts agreed that people in the CHOP arm of ECHELON‑2 appeared to do better than was expected in clinical practice. They suggested that this could be because of the inclusion and exclusion criteria of the trial. The clinical experts informed the committee that the number of people with sALCL seen in clinical practice is relatively small. This makes it difficult to select an overall survival extrapolation for the CHOP arm. The clinical experts agreed that real-world experience suggests that people would have less optimistic outcomes than suggested by the generalised gamma curve, and that it could be closer to the log-normal extrapolation. The committee concluded that there were considerable uncertainties about how the company modelled progression-free survival and overall survival.
## The committee would have preferred to see alternative survival models explored but accepts the available analyses
The standard parametric curves that were fitted to the data varied considerably. This was partly because of the high degree of censoring in the progression-free survival and overall survival data (the event of interest was not seen at the end of trial follow up). Also, most of the long-term projections of progression-free survival and overall survival were highly influenced by general population mortality constraints (adjusted for excess risk of mortality in long-term survivors). These were informed by the general population mortality for England and Wales. The company submission assumed that people whose disease is in long-term remission had a small reduction in life expectancy compared with the general population. This reflected slightly increased rates of cardiac toxicity and other malignancies. The company submission further noted that UK clinical expert opinion predicted a reduced survival of between 3% and 10%, relative to the general population. To reflect this in its analysis, the company applied a mortality multiplier of 1.19 in its base case, reflecting a 5% increased mortality risk. The ERG considered that 1.28 was more appropriate for its base case, representing a 6.5% increased mortality risk. This was the midpoint of the clinical expert estimates referenced in the company submission. In the company's model, the time points at which the background mortality risk took over from the parametric model risk differed depending on the progression-free survival and overall survival model selected. When the generalised gamma model was selected, the general population mortality took over from 12 years in the brentuximab vedotin with CHP arm, and 13 years in the CHOP arm. The committee noted that it was unusual for background mortality to take effect at such an early stage in an economic model with a 45‑year time horizon, and that it is applied to more than half of the patients in each treatment group. This means the model assumed that there is a cure, or 'near cure', for anyone still alive after these time points. The clinical experts noted that a person presenting 5 years after first-line treatment with brentuximab vedotin and CHP would be considered to have equally low risk of relapsing as someone who had CHOP. The assumed cure point varied a lot between the different parametric models. So, the committee agreed that the standard parametric extrapolations were uncertain and that alternative models, such as spline or mixture cure rate models, should have been more fully explored by the company. However, the incremental cost-effectiveness ratios (ICERs) for brentuximab vedotin with CHP were within what NICE considers cost effective even under pessimistic assumptions. Therefore the committee concluded that it would consider the available analyses.
# Cost-effectiveness analysis
## The company's base-case ICER for brentuximab vedotin with CHP is less than £30,000 per QALY gained
NICE's guide to the methods of technology appraisal notes that above a most plausible ICER of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. Therefore, because of the uncertainty in the survival extrapolations (see sections 3.4 and 3.5), the committee agreed that an acceptable ICER would be around the lower end of the £20,000 to £30,000 per QALY gained range. The company's base-case ICER for brentuximab vedotin plus CHP compared with CHOP was £21,192 per QALY gained (including the simple discount patient access scheme).
## The ERG's base-case ICER for brentuximab vedotin is less than £30,000 per QALY gained
The ERG agreed with the company base case on all points. It only had minor changes to the model to correct the implementation of the time-to-death approach, and adjust the mortality multiplier (see section 3.5). The selection of the generalised gamma model for both progression-free survival and overall survival represented the most conservative effect on the cost-effectiveness results, with all other parametric extrapolations generating lower ICERs. The committee was reassured that the cost-effectiveness results for brentuximab vedotin with CHP represented the most conservative scenario, but had concerns about the uncertainty of these parametric extrapolations. It agreed that it was important to explore different assumptions about duration of treatment effect. In the company base case, the treatment effect duration was 13 years (the time point when the hazard switches to that of the general population in both groups). The ERG also produced a scenario analysis. This showed the effect on the ICER of varying the time point at which the relative treatment effect in the brentuximab vedotin with CHP arm was assumed to be equal to that in the CHOP arm. If the relative treatment benefit of brentuximab vedotin with CHP was removed at 5 years (approximately corresponding to the point when the trial data end), the ICER remained broadly consistent with that in both the ERG and company base cases. The committee considered the standard parametric extrapolations to be uncertain. It concluded that the assumption that brentuximab vedotin with CHP had no additional relative clinical benefit over CHOP after 5 years was preferable for decision making. The corresponding ICER for brentuximab vedotin plus CHP compared with CHOP was £23,446 per QALY gained (including the simple discount patient access scheme). The committee concluded that brentuximab vedotin with CHP could be considered a cost-effective use of NHS resources.
# Innovation
## The model adequately captures the benefits of brentuximab vedotin with CHP
The company considered brentuximab vedotin with CHP to be innovative because it is a targeted treatment that has shown novel efficacy in the first-line treatment of sALCL. The clinical experts noted that it is expected to replace CHOP, which has been the standard treatment for about 30 years. The committee recognised the additional benefits to people with sALCL related to how the treatment is given and the associated improvements to quality of life. However, it concluded that it had not been presented with any additional evidence of benefits that were not captured in the measurement of the QALYs and the resulting cost-effectiveness estimates.
# Other factors
No equality or social value judgement issues were identified. The company did not make a case for brentuximab vedotin with CHP satisfying the end-of-life criteria. This was because people with sALCL are expected to live for more than 24 months.
# Conclusion
## Brentuximab vedotin with CHP is recommended for routine commissioning
The committee acknowledged the need for a better treatment option for adults with untreated sALCL. The most plausible ICER for brentuximab vedotin plus CHP compared with CHOP was £23,446 per QALY gained (including the simple discount patient access scheme). The committee concluded that brentuximab vedotin with CHP could be considered a cost-effective use of NHS resources. Therefore, it was recommended as an option for untreated sALCL.
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{'Recommendations': 'Brentuximab vedotin with cyclophosphamide, doxorubicin and prednisone (CHP) is recommended, within its marketing authorisation, as an option for untreated systemic anaplastic large cell lymphoma in adults. It is only recommended if the company provides brentuximab vedotin according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nStandard care for untreated systemic anaplastic large cell lymphoma is cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP).\n\nClinical evidence shows that people with systemic anaplastic large cell lymphoma who have brentuximab vedotin with CHP live longer and have longer before their disease progresses than people who have CHOP.\n\nThere is uncertainty about the modelling, but the most likely cost-effectiveness estimate is within what NICE considers an acceptable use of NHS resources. Therefore, brentuximab vedotin with CHP is recommended.', 'Information about brentuximab vedotin': "# Marketing authorisation indication\n\nBrentuximab vedotin (Adcetris, Takeda) with cyclophosphamide, doxorubicin and prednisone (CHP) is indicated 'for adult patients with previously untreated systemic anaplastic large cell lymphoma (sALCL)'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe NHS list price of brentuximab vedotin is £2,500 per 50‑mg vial (excluding VAT; BNF online, accessed June 2020). Based on a mean of 6\xa0cycles, the cost for an average patient is estimated at about £47,619, at list price. The company has a commercial arrangement. This makes brentuximab vedotin available to the NHS with a discount. The size of the discount is confidential. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Takeda, a review of this submission by the evidence review group (ERG), the technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:\n\nthe mean age of the systemic anaplastic large cell lymphoma (sALCL) population seen in the ECHELON-2 trial (52\xa0years) was appropriate for the economic model\n\nthe time-to-death utility model approach was preferable to the health-state utility method for this appraisal\n\nit was appropriate to cap the patient utility values in the model so that they cannot exceed the age-adjusted utility values for the general population\n\nthe mean number of cycles of brentuximab vedotin monotherapy was\xa06 when used second line for relapsed or refractory sALCL\n\nthe joint modelling approach was acceptable for this appraisal\n\nexcluding costs for grades\xa03 and\xa04 peripheral neuropathy was appropriate.\n\nThe committee recognised that there were areas of uncertainty associated with the analyses presented and took these into account in its decision making. It discussed the choice of model used to estimate progression-free survival and overall survival (see technical report, pages\xa013 to\xa017), which was outstanding after the technical engagement stage.\n\n# Clinical need\n\n## People would welcome a new first-line treatment option\n\nThe patient and clinical experts explained that there is a considerable unmet need for people with sALCL. Current treatments are often difficult to tolerate, cause significant side effects and are often given as inpatient treatment. The patient experts described their experiences of disease relapse after cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) and other previous treatments and the lack of alternatives. They noted that after treatment with brentuximab vedotin plus cyclophosphamide, doxorubicin and prednisone (CHP) they experienced an improvement in their symptoms and had fewer side effects. Brentuximab vedotin with CHP is given in an outpatient setting, reducing the time in hospital. The committee concluded that brentuximab vedotin with CHP would be welcomed as a new treatment option for people with sALCL.\n\n# Clinical management\n\n## Brentuximab vedotin with CHP will replace CHOP for untreated sALCL\n\nThe clinical experts noted that standard care for untreated sALCL is CHOP, but few patients have disease that is in complete remission. Of those that do, many have disease that relapses in the first year. The clinical lead for the Cancer Drugs Fund advised that a more effective first-line treatment is needed and that, if recommended, brentuximab vedotin with CHP would replace current treatment for sALCL in the NHS. The clinical experts agreed that brentuximab vedotin with CHP would be a useful first-line treatment since it may give a durable response. They explained that for people whose disease relapses, brentuximab vedotin monotherapy would still be an option at a later stage in the treatment pathway. The only exception would be people whose sALCL did not respond to previous treatment with brentuximab vedotin. The clinical experts agreed that brentuximab vedotin with CHP could quickly replace CHOP for people with untreated sALCL because of its clinical advantages. Based on comments from the clinical experts and the clinical lead for the Cancer Drugs Fund, the committee concluded that brentuximab vedotin with CHP would replace CHOP for sALCL in the NHS.\n\n# Clinical evidence\n\n## Brentuximab vedotin with CHP improves progression-free survival and overall survival compared with CHOP\n\nThe clinical evidence for brentuximab vedotin with CHP came from ECHELON‑2. This was a randomised controlled trial of 452\xa0people with CD30-positive peripheral T‑cell lymphoma, comparing brentuximab vedotin and CHP with CHOP. The median follow up for the progression-free survival analysis was 36.2\xa0months (95% confidence interval [CI]\xa035.9\xa0to\xa041.8), and for the overall survival analysis was 42.1\xa0months (95%\xa0CI\xa040.4\xa0to\xa043.8). The committee noted that 70% of the patients in ECHELON‑2 had a diagnosis of sALCL, which is higher than would be expected in clinical practice in the NHS. The company clarified that this was because of a regulatory requirement of the European Medicines Agency. The company presented analyses from the subgroup of patients with sALCL. This subgroup's objective response rate, measured by independent review facility assessment, was 88% (95%\xa0CI\xa081.6\xa0to\xa092.3) for people in the brentuximab vedotin with CHP arm compared with 71% (95%\xa0CI\xa062.9\xa0to\xa077.8) for people in the CHOP arm (p=0.0001). Brentuximab vedotin with CHP statistically significantly reduced the risk of a progression event compared with CHOP (stratified hazard ratio [HR]\xa00.59 [95%\xa0CI\xa00.42\xa0to\xa00.84]; p=0.0031). Overall survival was also statistically significantly improved for brentuximab vedotin with CHP compared with CHOP (HR\xa00.54 [95%\xa0CI\xa00.337\xa0to\xa00.867], p=0.0096). There were 70% of patients in the CHOP arm who had second-line brentuximab vedotin after progression. This meant the treatment effect was likely to be underestimated for the brentuximab vedotin with CHP arm. The committee concluded that brentuximab vedotin with CHP improves progression-free survival and overall survival compared with current standard care, CHOP.\n\n# Survival extrapolation\n\n## There are uncertainties about the company model for progression-free survival and overall survival\n\nThe company applied standard parametric functions to the available data from ECHELON‑2 to estimate progression-free survival and overall survival. It selected the generalised gamma curve for both progression-free survival and overall survival in the sALCL population. This was based on statistical fit and advice from clinical experts. The company submission noted that the shape of the generalised gamma hazard function matched what would be seen clinically in people with sALCL. People were at an increased risk of dying or having their disease progress during the first 18\xa0to 24\xa0months, but after that the risk declined quickly. This characteristic prognosis for sALCL was confirmed by the clinical experts. The committee noted that a similarly shaped hazard function could also be associated with the log-normal extrapolation, and to a lesser extent the log-logistic extrapolation. The clinical experts agreed that people in the CHOP arm of ECHELON‑2 appeared to do better than was expected in clinical practice. They suggested that this could be because of the inclusion and exclusion criteria of the trial. The clinical experts informed the committee that the number of people with sALCL seen in clinical practice is relatively small. This makes it difficult to select an overall survival extrapolation for the CHOP arm. The clinical experts agreed that real-world experience suggests that people would have less optimistic outcomes than suggested by the generalised gamma curve, and that it could be closer to the log-normal extrapolation. The committee concluded that there were considerable uncertainties about how the company modelled progression-free survival and overall survival.\n\n## The committee would have preferred to see alternative survival models explored but accepts the available analyses\n\nThe standard parametric curves that were fitted to the data varied considerably. This was partly because of the high degree of censoring in the progression-free survival and overall survival data (the event of interest was not seen at the end of trial follow up). Also, most of the long-term projections of progression-free survival and overall survival were highly influenced by general population mortality constraints (adjusted for excess risk of mortality in long-term survivors). These were informed by the general population mortality for England and Wales. The company submission assumed that people whose disease is in long-term remission had a small reduction in life expectancy compared with the general population. This reflected slightly increased rates of cardiac toxicity and other malignancies. The company submission further noted that UK clinical expert opinion predicted a reduced survival of between 3% and 10%, relative to the general population. To reflect this in its analysis, the company applied a mortality multiplier of 1.19 in its base case, reflecting a 5% increased mortality risk. The ERG considered that 1.28 was more appropriate for its base case, representing a 6.5% increased mortality risk. This was the midpoint of the clinical expert estimates referenced in the company submission. In the company's model, the time points at which the background mortality risk took over from the parametric model risk differed depending on the progression-free survival and overall survival model selected. When the generalised gamma model was selected, the general population mortality took over from 12\xa0years in the brentuximab vedotin with CHP arm, and 13\xa0years in the CHOP arm. The committee noted that it was unusual for background mortality to take effect at such an early stage in an economic model with a 45‑year time horizon, and that it is applied to more than half of the patients in each treatment group. This means the model assumed that there is a cure, or 'near cure', for anyone still alive after these time points. The clinical experts noted that a person presenting 5\xa0years after first-line treatment with brentuximab vedotin and CHP would be considered to have equally low risk of relapsing as someone who had CHOP. The assumed cure point varied a lot between the different parametric models. So, the committee agreed that the standard parametric extrapolations were uncertain and that alternative models, such as spline or mixture cure rate models, should have been more fully explored by the company. However, the incremental cost-effectiveness ratios (ICERs) for brentuximab vedotin with CHP were within what NICE considers cost effective even under pessimistic assumptions. Therefore the committee concluded that it would consider the available analyses.\n\n# Cost-effectiveness analysis\n\n## The company's base-case ICER for brentuximab vedotin with CHP is less than £30,000 per QALY gained\n\nNICE's guide to the methods of technology appraisal notes that above a most plausible ICER of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. Therefore, because of the uncertainty in the survival extrapolations (see sections\xa03.4 and\xa03.5), the committee agreed that an acceptable ICER would be around the lower end of the £20,000 to £30,000 per QALY gained range. The company's base-case ICER for brentuximab vedotin plus CHP compared with CHOP was £21,192 per QALY gained (including the simple discount patient access scheme).\n\n## The ERG's base-case ICER for brentuximab vedotin is less than £30,000 per QALY gained\n\nThe ERG agreed with the company base case on all points. It only had minor changes to the model to correct the implementation of the time-to-death approach, and adjust the mortality multiplier (see section\xa03.5). The selection of the generalised gamma model for both progression-free survival and overall survival represented the most conservative effect on the cost-effectiveness results, with all other parametric extrapolations generating lower ICERs. The committee was reassured that the cost-effectiveness results for brentuximab vedotin with CHP represented the most conservative scenario, but had concerns about the uncertainty of these parametric extrapolations. It agreed that it was important to explore different assumptions about duration of treatment effect. In the company base case, the treatment effect duration was 13\xa0years (the time point when the hazard switches to that of the general population in both groups). The ERG also produced a scenario analysis. This showed the effect on the ICER of varying the time point at which the relative treatment effect in the brentuximab vedotin with CHP arm was assumed to be equal to that in the CHOP arm. If the relative treatment benefit of brentuximab vedotin with CHP was removed at 5\xa0years (approximately corresponding to the point when the trial data end), the ICER remained broadly consistent with that in both the ERG and company base cases. The committee considered the standard parametric extrapolations to be uncertain. It concluded that the assumption that brentuximab vedotin with CHP had no additional relative clinical benefit over CHOP after 5\xa0years was preferable for decision making. The corresponding ICER for brentuximab vedotin plus CHP compared with CHOP was £23,446 per QALY gained (including the simple discount patient access scheme). The committee concluded that brentuximab vedotin with CHP could be considered a cost-effective use of NHS resources.\n\n# Innovation\n\n## The model adequately captures the benefits of brentuximab vedotin with CHP\n\nThe company considered brentuximab vedotin with CHP to be innovative because it is a targeted treatment that has shown novel efficacy in the first-line treatment of sALCL. The clinical experts noted that it is expected to replace CHOP, which has been the standard treatment for about 30\xa0years. The committee recognised the additional benefits to people with sALCL related to how the treatment is given and the associated improvements to quality of life. However, it concluded that it had not been presented with any additional evidence of benefits that were not captured in the measurement of the QALYs and the resulting cost-effectiveness estimates.\n\n# Other factors\n\nNo equality or social value judgement issues were identified. The company did not make a case for brentuximab vedotin with CHP satisfying the end-of-life criteria. This was because people with sALCL are expected to live for more than 24\xa0months.\n\n# Conclusion\n\n## Brentuximab vedotin with CHP is recommended for routine commissioning\n\nThe committee acknowledged the need for a better treatment option for adults with untreated sALCL. The most plausible ICER for brentuximab vedotin plus CHP compared with CHOP was £23,446 per QALY gained (including the simple discount patient access scheme). The committee concluded that brentuximab vedotin with CHP could be considered a cost-effective use of NHS resources. Therefore, it was recommended as an option for untreated sALCL."}
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https://www.nice.org.uk/guidance/ta641
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Evidence-based recommendations on brentuximab vedotin (Adcetris) with cyclophosphamide, doxorubicin and prednisone for untreated systemic anaplastic large cell lymphoma in adults.
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37234e69c2c9e7608c4d124b8d7047131dce644b
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nice
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Gilteritinib for treating relapsed or refractory acute myeloid leukaemia
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Gilteritinib for treating relapsed or refractory acute myeloid leukaemia
Evidence-based recommendations on gilteritinib (Xospata) for relapsed or refractory FLT3-mutation-positive acute myeloid leukaemia in adults.
# Recommendations
Gilteritinib monotherapy is recommended as an option for treating relapsed or refractory FLT3‑mutation-positive acute myeloid leukaemia (AML) in adults only if the company provides gilteritinib according to the commercial arrangement.
Gilteritinib should not be given as maintenance therapy after a haematopoietic stem cell transplant.
These recommendations are not intended to affect treatment with gilteritinib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Relapsed or refractory FLT3‑mutation-positive AML is usually treated with salvage chemotherapy (a type of chemotherapy offered when a first course of chemotherapy has not worked, or the disease has come back after treatment). Gilteritinib is an alternative treatment taken as an oral tablet at home, which is an important quality-of-life benefit for patients.
Clinical evidence shows that people having gilteritinib live longer compared with people having salvage chemotherapy. However, there is considerable uncertainty about long-term survival, particularly after stem cell transplant. There is no robust evidence of further benefit if someone restarts gilteritinib after stem cell transplant when they have had it before the transplant.
Gilteritinib meets NICE's criteria for a life-extending treatment at the end of life. The most likely cost-effectiveness estimates are within the range that NICE normally considers an acceptable use of NHS resources for end-of-life treatments. Therefore, gilteritinib is recommended as an option for people with relapsed or refractory FLT3‑mutation-positive AML. However, if people then have a stem cell transplant, gilteritinib should not be restarted afterwards.# Information about gilteritinib
# Marketing authorisation indication
Gilteritinib (Xospata, Astellas Pharma) is indicated 'as monotherapy for the treatment of adult patients who have relapsed or refractory acute myeloid leukaemia (AML) with a FLT3 mutation'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price for gilteritinib is £14,188 per 28‑day pack (company submission). The company has a commercial arrangement. This makes gilteritinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Astellas Pharma, a review of this submission by the evidence review group (ERG), the technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
The appraisal committee discussed the following issues (issues 1, 2, 3, 4, 5, 7 and 8), which were outstanding after the technical engagement stage.
# New treatment option
## People with relapsed or refractory acute myeloid leukaemia would welcome a new treatment option
Acute myeloid leukaemia (AML) is a rapidly progressing form of leukaemia, often diagnosed after an emergency admission to hospital. The FLT3 mutation is associated with poorer outcomes, such as a higher risk of relapse. Current treatment for relapsed or refractory AML is limited. The condition is managed with salvage chemotherapy, which is administered as an inpatient treatment and is associated with side effects and debilitating complications. Gilteritinib is an oral tablet that is self-managed and can be taken at home. Patient experts explained that it would improve their quality of life if they could avoid the disruption and loss of autonomy associated with inpatient treatment. They explained that the potential for improved quality of life is important to them, as well as the potential for improved survival. The committee concluded that people with relapsed or refractory AML would welcome a new treatment that improves survival and quality of life, particularly one that is taken orally at home.
# Comparators
## The ADMIRAL trial provides the main clinical evidence for gilteritinib compared with salvage chemotherapy
The clinical evidence came from ADMIRAL, an open-label, randomised trial, which compared gilteritinib with the investigator's choice of salvage chemotherapy. The comparator arm included:
low-dose cytarabine (LoDAC)
azacytidine
mitoxantrone, etoposide and cytarabine (MEC)
fludarabine, idarubicin, granulocyte-colony stimulating factor and high-dose cytarabine (FLAG-IDA).The primary outcome measure in ADMIRAL was overall survival. In response to consultation the company provided updated data from the ADMIRAL study (September 2019 data cut). Treatment with gilteritinib increased median overall survival compared with salvage chemotherapy from 5.6 months to 9.3 months (hazard ratio 0.68; 95% confidence interval 0.53 to 0.88, p=0.0013). The committee concluded that salvage chemotherapy was an appropriate comparator.
## Best supportive care is a relevant comparator but the evidence presented to support its relative efficacy is not reliable
Best supportive care was not included as a comparator in ADMIRAL. The clinical experts noted that, in clinical practice, most people would have salvage chemotherapy. But they added that best supportive care is a relevant option in a small proportion of patients who choose not to have salvage chemotherapy because of toxicity and lack of fitness for treatment. Stakeholders at technical engagement considered that best supportive care could be a relevant option for 10% to 20% of patients in this population. The company included a blended comparator of salvage chemotherapy based on ADMIRAL in its economic model results. It did not include best supportive care as a comparator in its original base-case results. However, it did include it as a separate comparator in a scenario analysis by applying a hazard ratio of 2.86 to gilteritinib overall survival, informed by a naive indirect comparison. This was because there was no direct evidence comparing gilteritinib with best supportive care. The ERG had concerns about the methods, assumptions and sources used to inform the company's indirect comparison for best supportive care, including:
the indirect comparison assumes that LoDAC is equivalent to salvage chemotherapy
the source of the values used to calculate the hazard ratio between gilteritinib and best supportive care was unclear
proportional hazards are assumed, which may not be appropriate because it is not clear whether the assumption was assessed.The committee noted the ERG's concerns about the methods of including best supportive care and did not consider that the indirect comparison was reliable. After technical engagement, the company updated its analysis to include best supportive care in the blended comparator. This reduced the cost-effectiveness estimates. The ERG noted that the company's analysis assumed the characteristics of people receiving best supportive care are the same as for people receiving salvage chemotherapy, for example the stem cell transplant rate, which it considered was implausible. The company's updated base-case model, provided after consultation, also included best supportive care in the weighted comparator arm. It suggested that 20% of people have best supportive care and half of them could have gilteritinib. The company suggested that these people would have the same outcomes as the gilteritinib arm in ADMIRAL. It assumed in its model that people having best supportive care would not have stem cell transplant so the probability of receiving transplant in the weighted comparator group is reduced by 10%. The gilteritinib group stem cell transplant rate was unchanged. The ERG highlighted that this assumption meant that people who choose to have best supportive care would have the same likelihood of receiving stem cell transplant if they had had gilteritinib, which was unrealistic. The issues with the indirect treatment comparison and how it was applied in the model discussed at the first committee meeting remained. The committee concluded that best supportive care was a relevant comparator as well as salvage chemotherapy. But it agreed that the company's method of including best supportive care in the blended comparator was not appropriate and therefore accepted analyses comparing gilteritinib with salvage chemotherapy.
# Prior midostaurin use
## The proportion of people who would have received midostaurin in clinical practice in the NHS may be higher than the proportion in ADMIRAL
NICE technology appraisal guidance on midostaurin (another FLT3 inhibitor) recommends it for use in the NHS for newly diagnosed acute FLT3‑mutation-positive AML. In ADMIRAL, 13% of the gilteritinib group and 11.3% of the salvage chemotherapy groups had received prior FLT3 inhibitors. If, in clinical practice in the NHS, the proportion of people who have had prior midostaurin is higher than in ADMIRAL, the efficacy of gilteritinib may be different to that seen in the trial. The company presented a subgroup analysis of people in ADMIRAL who had had prior FLT3 inhibitors, such as midostaurin. The results showed that, for patients with no prior FLT3 inhibitor (n=325), gilteritinib statistically significantly improved overall survival (hazard ratio 0.620; 95% confidence interval 0.470 to 0.818). For the 46 patients with prior use of an FLT3 inhibitor, the treatment difference was not statistically significant (hazard ratio 0.705; 95% confidence interval 0.346 to 1.438). However, this subgroup analysis only included a small number of patients and may be unreliable. The clinical experts confirmed that they would give gilteritinib after midostaurin in clinical practice. They stated that gilteritinib is a more potent FLT3 inhibitor and they did not believe that prior exposure to midostaurin would affect response to gilteritinib, although this is uncertain. The clinical expert estimated that there were about 600 people a year in the NHS who have relapsed or refractory FLT3‑positive AML. Comments from technical engagement suggested that around 50% to 60% of patients with newly diagnosed FLT3‑positive AML may have midostaurin. The committee concluded that currently the proportion of people with relapsed or refractory disease who may have received prior midostaurin in clinical practice in the NHS is higher than the proportion in ADMIRAL.
# Cure assumptions
## The most plausible cure point is closer to 2 years than 3 years
In its original model, the company assumed that all patients who were alive at 3 years were 'cured', regardless of whether their disease had progressed or they had had a stem cell transplant. After 3 years, survival was modelled using an uplifted general population mortality rate (standardised mortality ratio of 2.0). The 3‑year cure assumption was based on NICE technology appraisal guidance on midostaurin, published literature, and clinical advice given to the company. The company did not present any evidence from ADMIRAL to support the cure assumption. The clinical expert suggested that most relapses would be within 12 months. The ERG noted that the Kaplan–Meier curves from ADMIRAL did not show a plateau, which would have suggested a cure. At technical engagement, stakeholders agreed that it was clinically plausible to assume that patients alive after 3 years were cured. However, after technical engagement the company updated its model to include a 2‑year cure point, instead of 3 years. It did not give evidence or a clear rationale for why it had changed the cure point. After consultation the company provided additional evidence to support the 2‑year cure point assumption in the model. It provided data from different studies to show the flattening of curves between 18 months and 24 months. However, some of these studies were not in the same population as the ADMIRAL trial. The clinical experts explained that a 2‑year cure point is clinically plausible. They explained that FLT3-positive AML is a highly aggressive form of AML and relapses occur early in this population, ranging from 6 months to 2 years. The experts also pointed out that mortality after 2 years is likely to be a late consequence of stem cell transplant. However, the committee noted that using a 2-year cure point appears to overestimate the long-term overall survival for the gilteritinib arm in the observed period of the trial. It also noted that there were 3 deaths after 2 years in the gilteritinib arm of the trial. The committee had concerns about applying a 2-year cure point, because the population in the evidence used to support the 2‑year cure point was different to the ADMIRAL trial, and because of the lack of good visual fit of the extrapolated 2-year cure to the Kaplan–Meier data. However, taking into account clinical expert advice, it concluded that a cure point between 2 years and 3 years was plausible, and it was more likely to be closer to 2 years.
# Gilteritinib effectiveness after haematopoietic stem cell transplant
## Data from ADMIRAL should be used to model post-stem cell transplant overall survival
In the company's model, post-stem cell transplant overall survival was based on a Gompertz curve fitted to data from a study by Evers et al. (2018). The company did not use ADMIRAL data for this group of patients from the company submission and the model because there was limited follow up and a small sample size. However, patients in the Evers study did not all have FLT3 mutations so were not directly comparable to the population who would be eligible for gilteritinib in clinical practice. The company also highlighted data from a study by Ustun et al., which it used in a scenario analysis. This study included people with FLT3‑positive AML but most people in the study did not have relapsed or refractory disease. The ERG highlighted the company's model's predictions and the proportion of patients alive at the end of the final data cut off from ADMIRAL. It said that, because of these, to meet the 3‑year cure rate from the company's original model, the majority of surviving (censored) patients in the ADMIRAL gilteritinib-treated stem cell transplant group would need to be considered 'cured'. The ERG considered that the ADMIRAL trial was the most relevant data source, and did an analysis using ADMIRAL data to inform overall survival for people who had a stem cell transplant, which it included in its base case. The ERG pooled both treatment groups from ADMIRAL and fitted a log-normal parametric curve to the data until the 3‑year cure point. At technical engagement, stakeholders agreed that the ADMIRAL data should be considered. The committee considered that the ADMIRAL trial was the most appropriate because it included the population relevant to this appraisal.
## The additional benefit of maintenance therapy included by the company is not relevant
To model overall survival for the post-stem cell transplant group, the company applied a hazard ratio to the Gompertz model (see section 3.6) to reflect an additional survival benefit associated with gilteritinib maintenance therapy after stem cell transplant. The company derived the hazard ratio from an indirect comparison using data from Evers 2018. The company acknowledged that the results from ADMIRAL (September 2018 data cut) do not show a favourable effect of gilteritinib after stem cell transplant. However, it noted that there were small patient numbers and high levels of censoring. The company believed that, if the patients with salvage chemotherapy were followed up for longer, a benefit of gilteritinib maintenance therapy would be seen. The ERG considered that the company's approach was inconsistent. The company did not use ADMIRAL data to model post-stem cell transplant overall survival but it did use it, with the data from Evers, to calculate the hazard ratio for the additional benefit of gilteritinib. The ERG did an analysis using a hazard ratio of 1 to indicate no additional benefit of maintenance therapy, which it included in its base case. The clinical experts and other stakeholders at technical engagement confirmed that gilteritinib would be used as maintenance therapy after stem cell transplant in clinical practice, although there is little evidence to support this practice. In response to consultation the company provided updated data from the ADMIRAL study that did not suggest a benefit for gilteritinib over chemotherapy for overall survival after stem cell transplant (hazard ratio 1.108; 95% confidence interval 0.53 to 2.29, p=0.7836). The company did not update the indirect comparison with the updated 2019 data. The committee had already concluded that ADMIRAL data should be used to model post-stem cell transplant overall survival, so agreed that the additional benefit of maintenance therapy included by the company was not relevant.
## There is no robust evidence of benefit from post-transplant maintenance gilteritinib therapy
In its response to consultation the company reintroduced the gilteritinib maintenance therapy hazard ratio (0.69) for overall survival based on the naive indirect comparison using data from Evers et al. (see section 3.6). The company provided new evidence from the ADMIRAL trial comparing the overall survival of people who restarted gilteritinib after stem cell transplant and those who did not (hazard ratio 0.46). However, in ADMIRAL people could only restart gilteritinib in certain conditions, such as being in complete remission after stem cell transplant. This might lead to selection bias because those patients may be fitter than those who would receive gilteritinib maintenance treatment in clinical practice. The clinical experts confirmed that, in clinical practice maintenance therapy is the preferred treatment strategy, but people may not have to be in complete remission to restart gilteritinib. Therefore, more people would be eligible for treatment than in the trial. The committee also noted that in this analysis, patients who had chemotherapy before stem cell transplant had better overall survival than those who had gilteritinib before stem cell transplant. The company acknowledged that the true hazard ratio was likely to be somewhere between 0.46 and 1. The committee also recalled the overall survival after stem cell transplant data from the trial, which did not show gilteritinib to be effective (see section 3.7). The committee was also aware that including a maintenance therapy hazard ratio leads to a survival projection that is more favourable than the observed gilteritinib data from the trial. It acknowledged that there is interaction in the model between the cure point and the hazard ratio associated with maintenance therapy. Using the company's maintenance hazard ratio (0.69) would mean that a later cure point (later than 2 years) would be required for the extrapolations to fit the observed data. Therefore, when combining these assumptions – as in the company's updated base case – model predictions extremely overestimate the overall survival for the gilteritinib arm. Although the committee understood there might be a clinical benefit to gilteritinib maintenance treatment after stem cell transplant, it did not see robust evidence supporting this benefit. It agreed that no change to its previous conclusion was needed and therefore concluded that an additional benefit of maintenance therapy and associated costs should not be included in the model. The committee also concluded that treatment with gilteritinib should not restart as maintenance therapy after stem cell transplant.
# Costs
## Wastage of 7 days' supply of gilteritinib should be accounted for in the model
In its original model, the company did not include wastage for gilteritinib. The ERG considered that tablets could be wasted in clinical practice, for example, if patients died or their disease progressed while they were on treatment. The ERG did an exploratory analysis to include 14 days' supply of wastage for all patients who died before the 3‑year cure point. After technical engagement, the company updated its model to include wastage for 7 days' supply of gilteritinib. The clinical expert explained that normally a 28‑day pack would be given to each patient at a time. Therefore, the committee considered that it was reasonable to assume 14 days' supply of gilteritinib may be wasted if someone died before the 3‑year cure point. In its response to consultation the company explained that most people would stop treatment in a managed way after consulting clinicians, therefore in the company's updated base case 7 days of wastage was used. Clinical experts confirmed that treatment is closely monitored and tests are done before dispensing a pack of gilteritinib. Because the disease is closely monitored, it is highly unlikely that someone's condition would deteriorate in the first 2 weeks after starting a new pack of gilteritinib. The experts also confirmed that compliance is good and that treatment with gilteritinib would usually stop after completing a course of therapy. The committee concluded that wastage of 7 days' supply of gilteritinib should be accounted for in the model.
## Drug costs should be applied in each cycle of the model
The company included the costs of gilteritinib and chemotherapy as one-off costs in the first cycle of the model. The ERG noted that this was an unconventional approach that meant:
discounting could not be applied properly
gilteritinib treatment duration was underestimated because some patients were still having gilteritinib at data cut off and this was not accounted for
treatment duration was not linked to progression.The ERG stated that, if the drug costs had been applied in each cycle, the incremental cost-effectiveness ratio (ICER) would likely increase, although it did not know by how much. The committee agreed that drug costs should have been applied in each cycle.
# Quality of life and costs associated with administration
## The benefit of taking an oral tablet at home compared with having chemotherapy in hospital should be captured in the model
At technical engagement, the clinical expert highlighted that a potential benefit of gilteritinib is that it is an oral treatment that does not need to be administered in hospital, whereas salvage chemotherapy requires an inpatient stay. The ERG noted that the difference in costs between the 2 treatments was reflected in the administration costs included in the model. However, the ERG noted that the model did not assume any difference in quality of life between the 2 treatments to account for the different methods of administration. After technical engagement, the company updated its model to include a disutility value of -0.044 for high-intensity chemotherapy, which was sourced from a study by Wehler et al. (2018), because it was difficult to collect patient-reported outcomes from people in the salvage chemotherapy group in ADMIRAL. The company also updated some of the hospital costs to reflect this issue. The costs associated with the observed number of hospitalisations in the trial were spread across the event-free survival interval, including time on and off treatment. The clinical and patient experts explained that the benefit of taking an oral tablet at home compared with having chemotherapy in hospital would be important to patients. The committee was concerned that the potential quality-of-life benefits of oral gilteritinib, with less time in hospital, compared with inpatient chemotherapy with frequent debilitating complications, had not been adequately addressed. In its response to consultation the company updated its model to include additional disutilities for the first 3 cycles for all chemotherapy regimens using the Wehler study as a source. It also included increased costs for high-intensity chemotherapy to reflect that people on salvage chemotherapy would need inpatient treatment for the entire first 1-month cycle. The committee accepted the inclusion of additional disutilities. It also heard from the ERG that the new costs were applied in an unusual way in the model, which would overestimate the costs rather than reflect the total number of hospitalisation days observed in the trial. The committee noted that it is likely that the company's new approach overestimates the true costs of hospitalisation for the high-intensity chemotherapy regimens. The committee agreed it was not presented with good enough quality evidence to be able to accept the updated cost figures. It concluded that the increased costs for high-intensity chemotherapy should be excluded from the model, but the additional disutilities should be included.
# End of life
## Gilteritinib meets the criteria to be considered as a life-extending treatment at the end of life
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. Median overall survival in the salvage chemotherapy group of ADMIRAL was 5.6 months. The clinical expert stated that median survival is around 2 to 3 months in this patient population, and the ERG's base case showed that modelled survival in the salvage chemotherapy and the best supportive care group was less than 2 years. Although the company's updated base case predicted that the mean overall survival in the blended comparator group was over 2 years, the committee agreed that this was likely to be because of the method the company used to model gilteritinib effectiveness after stem cell transplant (see section 3.6). Therefore, the committee concluded that the short life expectancy criterion was met. Both the company's and the ERG's base-case economic models showed that gilteritinib extended mean overall survival by over 3 months more than with salvage chemotherapy (in the ERG's model, 2.34 years more than best supportive care and 0.98 years more than salvage chemotherapy). ADMIRAL showed a median overall survival gain of 3.7 months for gilteritinib compared with salvage chemotherapy. The committee concluded that the extension to life criterion was also met, and that when its preferred assumptions were applied in the model, gilteritinib met the criteria to be considered as a life-extending treatment at the end of life.
# Cost-effectiveness results
## The company's updated base-case ICER is below £50,000 per QALY gained
The company submitted a revised base case after consultation. The ICER, incorporating corrections made by the ERG (it corrected some programming errors in the company's model, which resulted in a lower ICER), was £46,961 per quality-adjusted life year (QALY) gained, compared with combined salvage chemotherapy and best supportive care. All analyses include the patient access scheme for gilteritinib. However, the committee noted that the revised base case did not include all of its preferred assumptions. These were:
excluding best supportive care from the weighted comparator (see section 3.3)
including a cure point closer to 2 years than 3 years (see section 3.5)
excluding the gilteritinib maintenance therapy hazard ratio for overall survival and the cost of maintenance therapy from the model (see section 3.8)
including gilteritinib wastage of 7 days' supply (see section 3.9)
including drug costs in each cycle of the model (see section 3.10)
including additional disutilities during first 3 cycles for all chemotherapy regimens and excluding increased costs for high-intensity chemotherapy (see section 3.11).
## Gilteritinib is recommended as a treatment option
Applying the committee's preferred assumptions (see section 3.13) and including all commercial arrangements in the model resulted in an ICER which was below £50,000 per QALY gained for gilteritinib compared with salvage chemotherapy (the ICER is confidential and cannot be reported here). The committee acknowledged that the modelling may not have included all benefits for gilteritinib (see section 3.11), and that doing so could possibly reduce the cost-effectiveness estimate, although this was not sufficiently quantified in the model. Based on the evidence presented to it, the committee concluded that, with the discount agreed in the commercial arrangement, the most plausible ICER was within the range that NICE normally considers an acceptable use of NHS resources for a life-extending treatment at the end of life. Therefore, it recommended gilteritinib as an option for treating relapsed or refractory FLT3‑mutation-positive AML in adults, although people whose disease responds to gilteritinib and who then go on to have a stem cell transplant should not restart gilteritinib after transplant.
# Other factors
## There are no equality issues relevant to the recommendations
No equality or social value judgement issues were identified.
## The benefits of gilteritinib can be captured in the cost-effectiveness analysis
The company, professional organisations and clinical experts considered that gilteritinib was innovative because it would be the first oral monotherapy targeted for relapsed or refractory FLT3‑positive AML. The committee agreed that these were important benefits of gilteritinib, but it concluded that it had not been presented with evidence of any demonstrable and distinct substantial additional benefits that could not be captured in the measurement of QALYs.
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{'Recommendations': "Gilteritinib monotherapy is recommended as an option for treating relapsed or refractory FLT3‑mutation-positive acute myeloid leukaemia (AML) in adults only if the company provides gilteritinib according to the commercial arrangement.\n\nGilteritinib should not be given as maintenance therapy after a haematopoietic stem cell transplant.\n\nThese recommendations are not intended to affect treatment with gilteritinib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nRelapsed or refractory FLT3‑mutation-positive AML is usually treated with salvage chemotherapy (a type of chemotherapy offered when a first course of chemotherapy has not worked, or the disease has come back after treatment). Gilteritinib is an alternative treatment taken as an oral tablet at home, which is an important quality-of-life benefit for patients.\n\nClinical evidence shows that people having gilteritinib live longer compared with people having salvage chemotherapy. However, there is considerable uncertainty about long-term survival, particularly after stem cell transplant. There is no robust evidence of further benefit if someone restarts gilteritinib after stem cell transplant when they have had it before the transplant.\n\nGilteritinib meets NICE's criteria for a life-extending treatment at the end of life. The most likely cost-effectiveness estimates are within the range that NICE normally considers an acceptable use of NHS resources for end-of-life treatments. Therefore, gilteritinib is recommended as an option for people with relapsed or refractory FLT3‑mutation-positive AML. However, if people then have a stem cell transplant, gilteritinib should not be restarted afterwards.", 'Information about gilteritinib': "# Marketing authorisation indication\n\nGilteritinib (Xospata, Astellas Pharma) is indicated 'as monotherapy for the treatment of adult patients who have relapsed or refractory acute myeloid leukaemia (AML) with a FLT3 mutation'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price for gilteritinib is £14,188 per 28‑day pack (company submission). The company has a commercial arrangement. This makes gilteritinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Astellas Pharma, a review of this submission by the evidence review group (ERG), the technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee discussed the following issues (issues\xa01, 2, 3, 4, 5, 7 and\xa08), which were outstanding after the technical engagement stage.\n\n# New treatment option\n\n## People with relapsed or refractory acute myeloid leukaemia would welcome a new treatment option\n\nAcute myeloid leukaemia (AML) is a rapidly progressing form of leukaemia, often diagnosed after an emergency admission to hospital. The FLT3 mutation is associated with poorer outcomes, such as a higher risk of relapse. Current treatment for relapsed or refractory AML is limited. The condition is managed with salvage chemotherapy, which is administered as an inpatient treatment and is associated with side effects and debilitating complications. Gilteritinib is an oral tablet that is self-managed and can be taken at home. Patient experts explained that it would improve their quality of life if they could avoid the disruption and loss of autonomy associated with inpatient treatment. They explained that the potential for improved quality of life is important to them, as well as the potential for improved survival. The committee concluded that people with relapsed or refractory AML would welcome a new treatment that improves survival and quality of life, particularly one that is taken orally at home.\n\n# Comparators\n\n## The ADMIRAL trial provides the main clinical evidence for gilteritinib compared with salvage chemotherapy\n\nThe clinical evidence came from ADMIRAL, an open-label, randomised trial, which compared gilteritinib with the investigator's choice of salvage chemotherapy. The comparator arm included:\n\nlow-dose cytarabine (LoDAC)\n\nazacytidine\n\nmitoxantrone, etoposide and cytarabine (MEC)\n\nfludarabine, idarubicin, granulocyte-colony stimulating factor and high-dose cytarabine (FLAG-IDA).The primary outcome measure in ADMIRAL was overall survival. In response to consultation the company provided updated data from the ADMIRAL study (September 2019 data cut). Treatment with gilteritinib increased median overall survival compared with salvage chemotherapy from 5.6\xa0months to 9.3\xa0months (hazard ratio\xa00.68; 95% confidence interval 0.53\xa0to\xa00.88, p=0.0013). The committee concluded that salvage chemotherapy was an appropriate comparator.\n\n## Best supportive care is a relevant comparator but the evidence presented to support its relative efficacy is not reliable\n\nBest supportive care was not included as a comparator in ADMIRAL. The clinical experts noted that, in clinical practice, most people would have salvage chemotherapy. But they added that best supportive care is a relevant option in a small proportion of patients who choose not to have salvage chemotherapy because of toxicity and lack of fitness for treatment. Stakeholders at technical engagement considered that best supportive care could be a relevant option for 10% to 20% of patients in this population. The company included a blended comparator of salvage chemotherapy based on ADMIRAL in its economic model results. It did not include best supportive care as a comparator in its original base-case results. However, it did include it as a separate comparator in a scenario analysis by applying a hazard ratio of 2.86 to gilteritinib overall survival, informed by a naive indirect comparison. This was because there was no direct evidence comparing gilteritinib with best supportive care. The ERG had concerns about the methods, assumptions and sources used to inform the company's indirect comparison for best supportive care, including:\n\nthe indirect comparison assumes that LoDAC is equivalent to salvage chemotherapy\n\nthe source of the values used to calculate the hazard ratio between gilteritinib and best supportive care was unclear\n\nproportional hazards are assumed, which may not be appropriate because it is not clear whether the assumption was assessed.The committee noted the ERG's concerns about the methods of including best supportive care and did not consider that the indirect comparison was reliable. After technical engagement, the company updated its analysis to include best supportive care in the blended comparator. This reduced the cost-effectiveness estimates. The ERG noted that the company's analysis assumed the characteristics of people receiving best supportive care are the same as for people receiving salvage chemotherapy, for example the stem cell transplant rate, which it considered was implausible. The company's updated base-case model, provided after consultation, also included best supportive care in the weighted comparator arm. It suggested that 20% of people have best supportive care and half of them could have gilteritinib. The company suggested that these people would have the same outcomes as the gilteritinib arm in ADMIRAL. It assumed in its model that people having best supportive care would not have stem cell transplant so the probability of receiving transplant in the weighted comparator group is reduced by 10%. The gilteritinib group stem cell transplant rate was unchanged. The ERG highlighted that this assumption meant that people who choose to have best supportive care would have the same likelihood of receiving stem cell transplant if they had had gilteritinib, which was unrealistic. The issues with the indirect treatment comparison and how it was applied in the model discussed at the first committee meeting remained. The committee concluded that best supportive care was a relevant comparator as well as salvage chemotherapy. But it agreed that the company's method of including best supportive care in the blended comparator was not appropriate and therefore accepted analyses comparing gilteritinib with salvage chemotherapy.\n\n# Prior midostaurin use\n\n## The proportion of people who would have received midostaurin in clinical practice in the NHS may be higher than the proportion in ADMIRAL\n\nNICE technology appraisal guidance on midostaurin (another FLT3 inhibitor) recommends it for use in the NHS for newly diagnosed acute FLT3‑mutation-positive AML. In ADMIRAL, 13% of the gilteritinib group and 11.3% of the salvage chemotherapy groups had received prior FLT3 inhibitors. If, in clinical practice in the NHS, the proportion of people who have had prior midostaurin is higher than in ADMIRAL, the efficacy of gilteritinib may be different to that seen in the trial. The company presented a subgroup analysis of people in ADMIRAL who had had prior FLT3 inhibitors, such as midostaurin. The results showed that, for patients with no prior FLT3 inhibitor (n=325), gilteritinib statistically significantly improved overall survival (hazard ratio\xa00.620; 95% confidence interval 0.470\xa0to\xa00.818). For the 46\xa0patients with prior use of an FLT3 inhibitor, the treatment difference was not statistically significant (hazard ratio\xa00.705; 95% confidence interval 0.346\xa0to\xa01.438). However, this subgroup analysis only included a small number of patients and may be unreliable. The clinical experts confirmed that they would give gilteritinib after midostaurin in clinical practice. They stated that gilteritinib is a more potent FLT3 inhibitor and they did not believe that prior exposure to midostaurin would affect response to gilteritinib, although this is uncertain. The clinical expert estimated that there were about 600\xa0people a year in the NHS who have relapsed or refractory FLT3‑positive AML. Comments from technical engagement suggested that around 50% to 60% of patients with newly diagnosed FLT3‑positive AML may have midostaurin. The committee concluded that currently the proportion of people with relapsed or refractory disease who may have received prior midostaurin in clinical practice in the NHS is higher than the proportion in ADMIRAL.\n\n# Cure assumptions\n\n## The most plausible cure point is closer to 2\xa0years than 3\xa0years\n\nIn its original model, the company assumed that all patients who were alive at 3\xa0years were 'cured', regardless of whether their disease had progressed or they had had a stem cell transplant. After 3\xa0years, survival was modelled using an uplifted general population mortality rate (standardised mortality ratio of\xa02.0). The 3‑year cure assumption was based on NICE technology appraisal guidance on midostaurin, published literature, and clinical advice given to the company. The company did not present any evidence from ADMIRAL to support the cure assumption. The clinical expert suggested that most relapses would be within 12\xa0months. The ERG noted that the Kaplan–Meier curves from ADMIRAL did not show a plateau, which would have suggested a cure. At technical engagement, stakeholders agreed that it was clinically plausible to assume that patients alive after 3\xa0years were cured. However, after technical engagement the company updated its model to include a 2‑year cure point, instead of 3\xa0years. It did not give evidence or a clear rationale for why it had changed the cure point. After consultation the company provided additional evidence to support the 2‑year cure point assumption in the model. It provided data from different studies to show the flattening of curves between 18\xa0months and 24\xa0months. However, some of these studies were not in the same population as the ADMIRAL trial. The clinical experts explained that a 2‑year cure point is clinically plausible. They explained that FLT3-positive AML is a highly aggressive form of AML and relapses occur early in this population, ranging from 6\xa0months to 2\xa0years. The experts also pointed out that mortality after 2\xa0years is likely to be a late consequence of stem cell transplant. However, the committee noted that using a 2-year cure point appears to overestimate the long-term overall survival for the gilteritinib arm in the observed period of the trial. It also noted that there were 3\xa0deaths after 2\xa0years in the gilteritinib arm of the trial. The committee had concerns about applying a 2-year cure point, because the population in the evidence used to support the 2‑year cure point was different to the ADMIRAL trial, and because of the lack of good visual fit of the extrapolated 2-year cure to the Kaplan–Meier data. However, taking into account clinical expert advice, it concluded that a cure point between 2\xa0years and 3\xa0years was plausible, and it was more likely to be closer to 2\xa0years.\n\n# Gilteritinib effectiveness after haematopoietic stem cell transplant\n\n## Data from ADMIRAL should be used to model post-stem cell transplant overall survival\n\nIn the company's model, post-stem cell transplant overall survival was based on a Gompertz curve fitted to data from a study by Evers et al. (2018). The company did not use ADMIRAL data for this group of patients from the company submission and the model because there was limited follow up and a small sample size. However, patients in the Evers study did not all have FLT3 mutations so were not directly comparable to the population who would be eligible for gilteritinib in clinical practice. The company also highlighted data from a study by Ustun et al., which it used in a scenario analysis. This study included people with FLT3‑positive AML but most people in the study did not have relapsed or refractory disease. The ERG highlighted the company's model's predictions and the proportion of patients alive at the end of the final data cut off from ADMIRAL. It said that, because of these, to meet the 3‑year cure rate from the company's original model, the majority of surviving (censored) patients in the ADMIRAL gilteritinib-treated stem cell transplant group would need to be considered 'cured'. The ERG considered that the ADMIRAL trial was the most relevant data source, and did an analysis using ADMIRAL data to inform overall survival for people who had a stem cell transplant, which it included in its base case. The ERG pooled both treatment groups from ADMIRAL and fitted a log-normal parametric curve to the data until the 3‑year cure point. At technical engagement, stakeholders agreed that the ADMIRAL data should be considered. The committee considered that the ADMIRAL trial was the most appropriate because it included the population relevant to this appraisal.\n\n## The additional benefit of maintenance therapy included by the company is not relevant\n\nTo model overall survival for the post-stem cell transplant group, the company applied a hazard ratio to the Gompertz model (see section 3.6) to reflect an additional survival benefit associated with gilteritinib maintenance therapy after stem cell transplant. The company derived the hazard ratio from an indirect comparison using data from Evers 2018. The company acknowledged that the results from ADMIRAL (September 2018 data cut) do not show a favourable effect of gilteritinib after stem cell transplant. However, it noted that there were small patient numbers and high levels of censoring. The company believed that, if the patients with salvage chemotherapy were followed up for longer, a benefit of gilteritinib maintenance therapy would be seen. The ERG considered that the company's approach was inconsistent. The company did not use ADMIRAL data to model post-stem cell transplant overall survival but it did use it, with the data from Evers, to calculate the hazard ratio for the additional benefit of gilteritinib. The ERG did an analysis using a hazard ratio of\xa01 to indicate no additional benefit of maintenance therapy, which it included in its base case. The clinical experts and other stakeholders at technical engagement confirmed that gilteritinib would be used as maintenance therapy after stem cell transplant in clinical practice, although there is little evidence to support this practice. In response to consultation the company provided updated data from the ADMIRAL study that did not suggest a benefit for gilteritinib over chemotherapy for overall survival after stem cell transplant (hazard ratio\xa01.108; 95% confidence interval 0.53\xa0to\xa02.29, p=0.7836). The company did not update the indirect comparison with the updated 2019 data. The committee had already concluded that ADMIRAL data should be used to model post-stem cell transplant overall survival, so agreed that the additional benefit of maintenance therapy included by the company was not relevant.\n\n## There is no robust evidence of benefit from post-transplant maintenance gilteritinib therapy\n\nIn its response to consultation the company reintroduced the gilteritinib maintenance therapy hazard ratio (0.69) for overall survival based on the naive indirect comparison using data from Evers et al. (see section 3.6). The company provided new evidence from the ADMIRAL trial comparing the overall survival of people who restarted gilteritinib after stem cell transplant and those who did not (hazard ratio\xa00.46). However, in ADMIRAL people could only restart gilteritinib in certain conditions, such as being in complete remission after stem cell transplant. This might lead to selection bias because those patients may be fitter than those who would receive gilteritinib maintenance treatment in clinical practice. The clinical experts confirmed that, in clinical practice maintenance therapy is the preferred treatment strategy, but people may not have to be in complete remission to restart gilteritinib. Therefore, more people would be eligible for treatment than in the trial. The committee also noted that in this analysis, patients who had chemotherapy before stem cell transplant had better overall survival than those who had gilteritinib before stem cell transplant. The company acknowledged that the true hazard ratio was likely to be somewhere between 0.46\xa0and\xa01. The committee also recalled the overall survival after stem cell transplant data from the trial, which did not show gilteritinib to be effective (see section 3.7). The committee was also aware that including a maintenance therapy hazard ratio leads to a survival projection that is more favourable than the observed gilteritinib data from the trial. It acknowledged that there is interaction in the model between the cure point and the hazard ratio associated with maintenance therapy. Using the company's maintenance hazard ratio (0.69) would mean that a later cure point (later than 2\xa0years) would be required for the extrapolations to fit the observed data. Therefore, when combining these assumptions – as in the company's updated base case – model predictions extremely overestimate the overall survival for the gilteritinib arm. Although the committee understood there might be a clinical benefit to gilteritinib maintenance treatment after stem cell transplant, it did not see robust evidence supporting this benefit. It agreed that no change to its previous conclusion was needed and therefore concluded that an additional benefit of maintenance therapy and associated costs should not be included in the model. The committee also concluded that treatment with gilteritinib should not restart as maintenance therapy after stem cell transplant.\n\n# Costs\n\n## Wastage of 7\xa0days' supply of gilteritinib should be accounted for in the model\n\nIn its original model, the company did not include wastage for gilteritinib. The ERG considered that tablets could be wasted in clinical practice, for example, if patients died or their disease progressed while they were on treatment. The ERG did an exploratory analysis to include 14\xa0days' supply of wastage for all patients who died before the 3‑year cure point. After technical engagement, the company updated its model to include wastage for 7\xa0days' supply of gilteritinib. The clinical expert explained that normally a 28‑day pack would be given to each patient at a time. Therefore, the committee considered that it was reasonable to assume 14\xa0days' supply of gilteritinib may be wasted if someone died before the 3‑year cure point. In its response to consultation the company explained that most people would stop treatment in a managed way after consulting clinicians, therefore in the company's updated base case 7\xa0days of wastage was used. Clinical experts confirmed that treatment is closely monitored and tests are done before dispensing a pack of gilteritinib. Because the disease is closely monitored, it is highly unlikely that someone's condition would deteriorate in the first 2\xa0weeks after starting a new pack of gilteritinib. The experts also confirmed that compliance is good and that treatment with gilteritinib would usually stop after completing a course of therapy. The committee concluded that wastage of 7\xa0days' supply of gilteritinib should be accounted for in the model.\n\n## Drug costs should be applied in each cycle of the model\n\nThe company included the costs of gilteritinib and chemotherapy as one-off costs in the first cycle of the model. The ERG noted that this was an unconventional approach that meant:\n\ndiscounting could not be applied properly\n\ngilteritinib treatment duration was underestimated because some patients were still having gilteritinib at data cut off and this was not accounted for\n\ntreatment duration was not linked to progression.The ERG stated that, if the drug costs had been applied in each cycle, the incremental cost-effectiveness ratio (ICER) would likely increase, although it did not know by how much. The committee agreed that drug costs should have been applied in each cycle.\n\n# Quality of life and costs associated with administration\n\n## The benefit of taking an oral tablet at home compared with having chemotherapy in hospital should be captured in the model\n\nAt technical engagement, the clinical expert highlighted that a potential benefit of gilteritinib is that it is an oral treatment that does not need to be administered in hospital, whereas salvage chemotherapy requires an inpatient stay. The ERG noted that the difference in costs between the 2\xa0treatments was reflected in the administration costs included in the model. However, the ERG noted that the model did not assume any difference in quality of life between the 2\xa0treatments to account for the different methods of administration. After technical engagement, the company updated its model to include a disutility value of -0.044 for high-intensity chemotherapy, which was sourced from a study by Wehler et al. (2018), because it was difficult to collect patient-reported outcomes from people in the salvage chemotherapy group in ADMIRAL. The company also updated some of the hospital costs to reflect this issue. The costs associated with the observed number of hospitalisations in the trial were spread across the event-free survival interval, including time on and off treatment. The clinical and patient experts explained that the benefit of taking an oral tablet at home compared with having chemotherapy in hospital would be important to patients. The committee was concerned that the potential quality-of-life benefits of oral gilteritinib, with less time in hospital, compared with inpatient chemotherapy with frequent debilitating complications, had not been adequately addressed. In its response to consultation the company updated its model to include additional disutilities for the first 3\xa0cycles for all chemotherapy regimens using the Wehler study as a source. It also included increased costs for high-intensity chemotherapy to reflect that people on salvage chemotherapy would need inpatient treatment for the entire first 1-month cycle. The committee accepted the inclusion of additional disutilities. It also heard from the ERG that the new costs were applied in an unusual way in the model, which would overestimate the costs rather than reflect the total number of hospitalisation days observed in the trial. The committee noted that it is likely that the company's new approach overestimates the true costs of hospitalisation for the high-intensity chemotherapy regimens. The committee agreed it was not presented with good enough quality evidence to be able to accept the updated cost figures. It concluded that the increased costs for high-intensity chemotherapy should be excluded from the model, but the additional disutilities should be included.\n\n# End of life\n\n## Gilteritinib meets the criteria to be considered as a life-extending treatment at the end of life\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. Median overall survival in the salvage chemotherapy group of ADMIRAL was 5.6\xa0months. The clinical expert stated that median survival is around 2\xa0to 3\xa0months in this patient population, and the ERG's base case showed that modelled survival in the salvage chemotherapy and the best supportive care group was less than 2\xa0years. Although the company's updated base case predicted that the mean overall survival in the blended comparator group was over 2\xa0years, the committee agreed that this was likely to be because of the method the company used to model gilteritinib effectiveness after stem cell transplant (see section 3.6). Therefore, the committee concluded that the short life expectancy criterion was met. Both the company's and the ERG's base-case economic models showed that gilteritinib extended mean overall survival by over 3\xa0months more than with salvage chemotherapy (in the ERG's model, 2.34\xa0years more than best supportive care and 0.98\xa0years more than salvage chemotherapy). ADMIRAL showed a median overall survival gain of 3.7\xa0months for gilteritinib compared with salvage chemotherapy. The committee concluded that the extension to life criterion was also met, and that when its preferred assumptions were applied in the model, gilteritinib met the criteria to be considered as a life-extending treatment at the end of life.\n\n# Cost-effectiveness results\n\n## The company's updated base-case ICER is below £50,000 per QALY gained\n\nThe company submitted a revised base case after consultation. The ICER, incorporating corrections made by the ERG (it corrected some programming errors in the company's model, which resulted in a lower ICER), was £46,961 per quality-adjusted life year (QALY) gained, compared with combined salvage chemotherapy and best supportive care. All analyses include the patient access scheme for gilteritinib. However, the committee noted that the revised base case did not include all of its preferred assumptions. These were:\n\nexcluding best supportive care from the weighted comparator (see section 3.3)\n\nincluding a cure point closer to 2\xa0years than 3\xa0years (see section 3.5)\n\nexcluding the gilteritinib maintenance therapy hazard ratio for overall survival and the cost of maintenance therapy from the model (see section 3.8)\n\nincluding gilteritinib wastage of 7\xa0days' supply (see section 3.9)\n\nincluding drug costs in each cycle of the model (see section 3.10)\n\nincluding additional disutilities during first 3\xa0cycles for all chemotherapy regimens and excluding increased costs for high-intensity chemotherapy (see section 3.11).\n\n## Gilteritinib is recommended as a treatment option\n\nApplying the committee's preferred assumptions (see section 3.13) and including all commercial arrangements in the model resulted in an ICER which was below £50,000 per QALY gained for gilteritinib compared with salvage chemotherapy (the ICER is confidential and cannot be reported here). The committee acknowledged that the modelling may not have included all benefits for gilteritinib (see section 3.11), and that doing so could possibly reduce the cost-effectiveness estimate, although this was not sufficiently quantified in the model. Based on the evidence presented to it, the committee concluded that, with the discount agreed in the commercial arrangement, the most plausible ICER was within the range that NICE normally considers an acceptable use of NHS resources for a life-extending treatment at the end of life. Therefore, it recommended gilteritinib as an option for treating relapsed or refractory FLT3‑mutation-positive AML in adults, although people whose disease responds to gilteritinib and who then go on to have a stem cell transplant should not restart gilteritinib after transplant.\n\n# Other factors\n\n## There are no equality issues relevant to the recommendations\n\nNo equality or social value judgement issues were identified.\n\n## The benefits of gilteritinib can be captured in the cost-effectiveness analysis\n\nThe company, professional organisations and clinical experts considered that gilteritinib was innovative because it would be the first oral monotherapy targeted for relapsed or refractory FLT3‑positive AML. The committee agreed that these were important benefits of gilteritinib, but it concluded that it had not been presented with evidence of any demonstrable and distinct substantial additional benefits that could not be captured in the measurement of QALYs."}
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https://www.nice.org.uk/guidance/ta642
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Evidence-based recommendations on gilteritinib (Xospata) for relapsed or refractory FLT3-mutation-positive acute myeloid leukaemia in adults.
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3cf32a8858f715b6a159f0d7ffa43d3e9189b541
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nice
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Transcranial magnetic stimulation for obsessive-compulsive disorder
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Transcranial magnetic stimulation for obsessive-compulsive disorder
Evidence-based recommendations on transcranial magnetic stimulation for obsessive-compulsive disorder in adults. This involves pulsing electromagnetic energy through the skull to stimulate the brain.
# Recommendations
Evidence on the safety of transcranial magnetic stimulation for obsessive-compulsive disorder raises no major safety concerns. However, evidence on its efficacy is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE website.
Research should ideally be in the form of pre-registered, adequately powered, randomised controlled trials. It should report details of patient selection, including the use of concurrent therapies, type, duration and frequency of stimulation, and the intended target in the brain. Outcomes should include improvement in symptoms, quality of life and duration of effect.# The condition, current treatments and procedure
# The condition
Obsessive-compulsive disorder is a mental health condition in which a person has obsessive thoughts (repeated, unwanted and unpleasant thoughts, images or urges). The person feels compelled to carry out compulsive (repetitive) behaviours to try to relieve the unpleasant feelings brought on by the obsessive thoughts.
# Current treatments
NICE's clinical guideline on obsessive-compulsive disorder and body dysmorphic disorder describes the treatment of the disorder. Treatment options include psychological interventions and drug treatment (typically, selective serotonin reuptake inhibitors).
# The procedure
Transcranial magnetic stimulation (TMS) is done with the patient awake and sitting in a comfortable chair. The operator places an electromagnetic coil over a specific region of the head. The coil delivers electromagnetic pulses through the skull that stimulate neurons (brain cells) by inducing small electrical currents within the brain. Different areas of the brain may be targeted, and a variety of stimulation protocols may be used. Treatment with TMS usually comprises daily sessions lasting about 30 minutes, for a few weeks. The aim is to reduce the symptoms of obsessive-compulsive disorder.
In repetitive TMS (rTMS), repetitive pulses of electromagnetic energy are delivered at various frequencies (low or high) or stimulus intensities. The intensity of stimulation is usually titrated against the minimum intensity needed to elicit a motor response when stimulating the motor cortex, known as the motor threshold. Determining the motor threshold for rTMS can be done visually (such as by observing targeted hand muscle movements) or by using electromyography.
Conventional rTMS is repeated individual pulses at a pre-set interval (train of pulses), and theta-burst rTMS is repeated short bursts of pulses at a pre-set interval (train of bursts). Deep TMS stimulates deeper and broader brain regions compared with conventional rTMS.
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{'Recommendations': 'Evidence on the safety of transcranial magnetic stimulation for obsessive-compulsive disorder raises no major safety concerns. However, evidence on its efficacy is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE website.\n\nResearch should ideally be in the form of pre-registered, adequately powered, randomised controlled trials. It should report details of patient selection, including the use of concurrent therapies, type, duration and frequency of stimulation, and the intended target in the brain. Outcomes should include improvement in symptoms, quality of life and duration of effect.', 'The condition, current treatments and procedure': "# The condition\n\nObsessive-compulsive disorder is a mental health condition in which a person has obsessive thoughts (repeated, unwanted and unpleasant thoughts, images or urges). The person feels compelled to carry out compulsive (repetitive) behaviours to try to relieve the unpleasant feelings brought on by the obsessive thoughts.\n\n# Current treatments\n\nNICE's clinical guideline on obsessive-compulsive disorder and body dysmorphic disorder describes the treatment of the disorder. Treatment options include psychological interventions and drug treatment (typically, selective serotonin reuptake inhibitors).\n\n# The procedure\n\nTranscranial magnetic stimulation (TMS) is done with the patient awake and sitting in a comfortable chair. The operator places an electromagnetic coil over a specific region of the head. The coil delivers electromagnetic pulses through the skull that stimulate neurons (brain cells) by inducing small electrical currents within the brain. Different areas of the brain may be targeted, and a variety of stimulation protocols may be used. Treatment with TMS usually comprises daily sessions lasting about 30\xa0minutes, for a few weeks. The aim is to reduce the symptoms of obsessive-compulsive disorder.\n\nIn repetitive TMS (rTMS), repetitive pulses of electromagnetic energy are delivered at various frequencies (low or high) or stimulus intensities. The intensity of stimulation is usually titrated against the minimum intensity needed to elicit a motor response when stimulating the motor cortex, known as the motor threshold. Determining the motor threshold for rTMS can be done visually (such as by observing targeted hand muscle movements) or by using electromyography.\n\nConventional rTMS is repeated individual pulses at a pre-set interval (train of pulses), and theta-burst rTMS is repeated short bursts of pulses at a pre-set interval (train of bursts). Deep TMS stimulates deeper and broader brain regions compared with conventional rTMS."}
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https://www.nice.org.uk/guidance/ipg676
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Evidence-based recommendations on transcranial magnetic stimulation for obsessive-compulsive disorder in adults. This involves pulsing electromagnetic energy through the skull to stimulate the brain.
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4c700cc60465b7d85d47de532ac6a11cd8a98e5c
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nice
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Electrical stimulation to improve muscle strength in chronic respiratory conditions, chronic heart failure and chronic kidney disease
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Electrical stimulation to improve muscle strength in chronic respiratory conditions, chronic heart failure and chronic kidney disease
Evidence-based recommendations on electrical stimulation to improve muscle strength in chronic respiratory conditions, chronic heart failure and chronic kidney disease. This involves delivering electrical impulses to weakened muscles using electrodes placed on the skin.
# Recommendations
Evidence on the safety of electrical stimulation to improve muscle strength in chronic respiratory conditions, chronic heart failure and chronic kidney disease shows no major safety concerns.
For people who are having an acute exacerbation of their chronic condition and are unable to exercise, evidence of efficacy is adequate to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE website.
For people who are able to exercise, evidence on efficacy is inadequate in quality. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE website.
Further research should include long term, suitably powered and appropriately controlled randomised trials. These should report details of patient selection, and type and duration of treatment. Outcomes should include quality of life, social functioning and physiological measures.# The condition, current treatments and procedure
# The condition
Chronic respiratory conditions, chronic heart failure and chronic kidney disease can cause impaired muscle function and weakness.
# Current treatments
Rehabilitation is described in NICE's guidelines on rehabilitation after critical illness, chronic obstructive pulmonary disease and chronic heart failure. Management for muscle weakness or dysfunction caused by chronic respiratory conditions, chronic heart failure or chronic kidney disease includes lifestyle change, medication (including oxygen therapy), rehabilitation (such as pulmonary rehabilitation or cardiac rehabilitation) and treating the underlying conditions.
# The procedure
Electrical stimulation produces muscle contractions that aim to mimic exercise training. Small electrical impulses are applied to nerves supplying groups of muscles typically in either the arms or legs, using self-adhesive electrodes applied to the skin and connected to an electrical stimulator. This causes the muscles supplied by the nerve to contract and relax. A typical programme consists of 30 to 60 minutes of stimulation.
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{'Recommendations': 'Evidence on the safety of electrical stimulation to improve muscle strength in chronic respiratory conditions, chronic heart failure and chronic kidney disease shows no major safety concerns.\n\nFor people who are having an acute exacerbation of their chronic condition and are unable to exercise, evidence of efficacy is adequate to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE website.\n\nFor people who are able to exercise, evidence on efficacy is inadequate in quality. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE website.\n\nFurther research should include long term, suitably powered and appropriately controlled randomised trials. These should report details of patient selection, and type and duration of treatment. Outcomes should include quality of life, social functioning and physiological measures.', 'The condition, current treatments and procedure': "# The condition\n\nChronic respiratory conditions, chronic heart failure and chronic kidney disease can cause impaired muscle function and weakness.\n\n# Current treatments\n\nRehabilitation is described in NICE's guidelines on rehabilitation after critical illness, chronic obstructive pulmonary disease and chronic heart failure. Management for muscle weakness or dysfunction caused by chronic respiratory conditions, chronic heart failure or chronic kidney disease includes lifestyle change, medication (including oxygen therapy), rehabilitation (such as pulmonary rehabilitation or cardiac rehabilitation) and treating the underlying conditions.\n\n# The procedure\n\nElectrical stimulation produces muscle contractions that aim to mimic exercise training. Small electrical impulses are applied to nerves supplying groups of muscles typically in either the arms or legs, using self-adhesive electrodes applied to the skin and connected to an electrical stimulator. This causes the muscles supplied by the nerve to contract and relax. A typical programme consists of 30\xa0to 60\xa0minutes of stimulation."}
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https://www.nice.org.uk/guidance/ipg677
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Evidence-based recommendations on electrical stimulation to improve muscle strength in chronic respiratory conditions, chronic heart failure and chronic kidney disease. This involves delivering electrical impulses to weakened muscles using electrodes placed on the skin.
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24999c36573e0b1268f259eee4c146d24c7f69b0
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nice
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Treosulfan with fludarabine for malignant disease before allogeneic stem cell transplant
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Treosulfan with fludarabine for malignant disease before allogeneic stem cell transplant
Evidence-based recommendations on treosulfan (Trecondi) with fludarabine for conditioning treatment before allogeneic haematopoietic stem cell transplant for malignant diseases in people for whom a reduced intensity regimen would be suitable.
# Recommendations
Treosulfan with fludarabine is recommended as an option for conditioning treatment before allogeneic haematopoietic stem cell transplant (allo-HSCT) for people with malignant diseases for whom a reduced intensity regimen, such as low-dose busulfan with fludarabine, would be suitable.
Why the committee made these recommendations
People with malignant diseases having an allo-HSCT need to have conditioning treatment first to prepare their bone marrow. If they cannot tolerate high-intensity myeloablative conditioning, they can have reduced-intensity conditioning such as low-dose busulfan with fludarabine.
The clinical evidence compares treosulfan and fludarabine with low-dose busulfan and fludarabine. Not enough evidence was presented for children or for people who could tolerate a high-intensity myeloablative regimen, so it is not possible to make recommendations for these groups.
The evidence in people for whom reduced-intensity is the most appropriate conditioning regimen shows that people are less likely to die from the transplant or associated complications if they have treosulfan and fludarabine instead of busulfan and fludarabine. The risk of disease recurrence was similar after either treatment.
Treosulfan with fludarabine is more effective and costs less than low-dose busulfan with fludarabine in most analyses. Therefore, treosulfan with fludarabine is recommended as an option in the NHS for conditioning treatment for people who would normally have a reduced intensity regimen.# Information about treosulfan
# Marketing authorisation indication
Treosulfan (Trecondi, Medac) in combination with fludarabine (generic) is indicated 'as part of conditioning treatment prior to allogeneic haematopoietic stem cell transplantation (alloHSCT) in adult patients with malignant and non-malignant diseases, and in paediatric patients older than 1 month with malignant diseases'.
This appraisal focuses on malignant diseases only.
# Dosage in the marketing authorisation
The dosage schedule for treosulfan is available in the summary of product characteristics.
# Price
Treosulfan:
£494.40 per 5‑vial pack of 1 g powder for solution for injection (BNF online accessed December 2019)
£2,434.25 per 5‑vial pack of 5 g powder for solution for injection (BNF online accessed December 2019).
Fludarabine:
£155.00 per vial of 50 mg powder for solution for injection (BNF online accessed November 2019).# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Medac, a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that 1 issue was resolved during the technical engagement stage and agreed that it is reasonable to assume that allogeneic haematopoietic stem cell transplantation (allo-HSCT) practice is similar in England and Wales to other European countries.
It recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, table 2, page 36), and took these into account in its decision making. It discussed the following issues (issues 1, 2, 3, 5 and 6), which were outstanding after the technical engagement stage.
# Treatment pathway and clinical need
## Conditioning treatment is an essential but traumatic step before allo-HSCT
Allo-HSCT is a potentially curative therapy for more than 70 malignant diseases, such as acute myeloid leukaemia. Before having the transplant, people have conditioning treatment to prepare their bone marrow. Conditioning treatments are usually chemotherapy alone or chemotherapy with radiotherapy. High-intensity myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC) are 2 types of regimens. The clinical expert explained that the RIC regimens are usually interchangeable, and the commonest regimens are busulfan with fludarabine and melphalan with fludarabine. MAC regimens differ more and are associated with a higher toxicity. Therefore, MAC regimens would only be offered to people who are fit and healthy enough to tolerate them. The patient experts explained that the allo-HSCT process is long and involves an extended stay in hospital. They explained that conditioning treatment is a traumatic experience and can have a substantial psychological impact. Conditioning drugs given before a transplant remove the recipient's haematopoietic cells from the bone marrow. This can have powerful effects on the body. For many patients, the conditioning treatment is more challenging than the chemotherapy they have previously had. Transplant-related complications include increased mortality, graft-versus-host disease (with symptoms such as mouth blisters or skin rashes) and infections such as shingles or pneumonia. The clinical expert explained that it typically takes 12 to 24 months to recover from a transplant and for the immune system to recover. The committee concluded that conditioning treatment for allo-HSCT is an important part of the procedure that can be difficult to tolerate, but it is necessary to remove any remaining disease and prepare the bone marrow to receive and accept the transplant.
## There is a clinical need for effective conditioning treatments with reduced transplant-related toxicity
The clinical expert's written submission explained that conditioning treatments have a major impact on the success of the transplant. They are designed to reduce the risk of disease recurrence or rejection of the graft by the body. The transplant itself carries short- and longer-term risks in terms of mortality and morbidity. The aim is to minimise these, while not compromising the success of the transplant. Conditioning treatments therefore have an impact on the patient's survival, quality of life and wellbeing. Both the physical and major psychological effects of a transplant were particularly highlighted by the patient experts. The clinical expert explained that all conditioning treatments have immediate major side effects, but that they are essential for a successful transplant. The treatment must ablate the marrow enough to remove remaining disease and allow the transplant to be accepted. But it must also not be so toxic that the patient dies of transplant-related causes such as infection. The committee concluded that patients and healthcare professionals would welcome conditioning regimens that allow a successful transplant with reduced risks.
# Clinical evidence from MC-FludT-14-L trial 2
## MC-FludT-14-L trial 2 reflects UK allo-HSCT clinical practice
MC‑FludT‑14‑L trial 2 is a double-blind randomised clinical trial of treosulfan and fludarabine compared with low-dose busulfan and fludarabine in adults with acute myeloid leukaemia or myelodysplastic syndromes who were not eligible for high-intensity MAC regimens. No UK patients were included in the trial, and most patients were from Germany. The company explained that clinical practice in the UK is similar to that in other European countries included in the trial. In addition, 50 UK transplant centres are members of the European Society for Blood and Marrow Transplantation (EBMT) and work according to the EBMT guidelines. The clinical expert explained that the target population for treosulfan in the UK would be similar to the population in the trial; that is, people who would not be eligible for high-intensity MAC regimens. The committee concluded that allo-HSCT practice in MC‑FludT‑14‑L trial 2 is comparable to clinical practice in the UK for that group of people.
## Treosulfan with fludarabine reduces mortality relative to low-dose busulfan with fludarabine
Treosulfan is an alkylating agent. The company proposes it as a reduced-toxicity MAC, with lower toxicity than usual MAC regimens. The primary endpoint of MC‑FludT‑14‑L trial 2 was event-free survival. This composite endpoint defined an event as disease relapse, graft failure or death, whichever occurred first. Event-free survival at 24 months was 65.7% in the treosulfan arm and 51.2% in the busulfan arm (hazard ratio 0.64, 95% confidence interval 0.49 to 0.84). The disaggregated event-free survival results showed that the main benefit of treosulfan was on mortality, especially non-relapse mortality. It had limited effect on disease relapse rates. Relapse rates were 22.8% in the treosulfan arm and 25.4% in the busulfan arm (HR 0.82, 95% CI 0.59 to 1.16), death rates were 13.1% in the treosulfan arm and 19.8% in the busulfan arm (HR 0.63, 95% CI 0.41 to 0.97). The company explained that this is because of lower non-relapse mortality rates with treosulfan: patients are less likely to die from the transplant, associated infections or graft-versus-host disease. In the trial, the main causes of non-relapse deaths were infections and graft-versus-host disease (both causes combined: 13.9% for treosulfan compared with 21.5% for busulfan). The committee concluded that people eligible for low-dose busulfan with fludarabine have a lower mortality with treosulfan and fludarabine than with low-dose busulfan and fludarabine.
## Benefit and risk of increased toxicity have to be balanced in conditioning regimens
The committee heard that treosulfan is considered a reduced-intensity conditioning (RIC) regimen according to the European public assessment report, although the company stated that treosulfan is a reduced-toxicity MAC regimen. In MC‑FludT‑14‑L trial 2 the treosulfan dose was reduced from 14 mg per m2 to 10 mg per m2 because of increased infections after treosulfan treatment. The clinical expert believed that the 10 mg per m2 dose of treosulfan used in the trial was myeloablative although there is no clear-cut threshold for when a regimen becomes myeloablative. The main clinical consideration is toxicity. The benefit of reduced relapse needs to be balanced with the increased risk of death from toxicity. The committee concluded that the balance between benefit and risk is an important consideration for conditioning regimens.
# Cost effectiveness
## The company's economic model is suitable for decision making
The company submitted a partitioned survival model to estimate the cost effectiveness of treosulfan and fludarabine compared with low-dose busulfan and fludarabine. The committee considered that the model is suitable for decision making.
## Assuming a 5-year cure point to model mortality is plausible
The company used a cure point to model mortality, based on the rationale that allo-HSCT is potentially curative. In the company's base case, a fixed cure point of 5 years was assumed for people who had not relapsed 5 years after transplantation. The company explained that patients who survive allo-HSCT for at least 5 years are considered cured in clinical practice. The ERG tested the impact of changing the cure point. Results were similar to the base-case analysis except when the cure point was assumed to be 1 year, when treosulfan with fludarabine was dominated by busulfan with fludarabine (that is, it was less effective and cost more). The clinical expert explained that relapse is likely to occur in the first and second year after allo-HSCT, and that a cure point of 5 years was a robust assumption. The committee concluded that it was reasonable to assume that people who have not relapsed within 5 years of the transplant can be considered cured.
## Treosulfan with fludarabine is cost effective compared with low-dose busulfan with fludarabine, in patients otherwise eligible for low-dose busulfan with fludarabine
Treosulfan with fludarabine dominates busulfan with fludarabine; that is, it generates more quality-adjusted life years (QALYs) at a lower cost than busulfan in both the company's base case and ERG's preferred assumptions analyses. The committee concluded that treosulfan with fludarabine is cost effective compared with low-dose busulfan with fludarabine, in people who would otherwise be eligible for low-dose busulfan with fludarabine.
## Evidence in other patient populations
The committee considered the evidence for:
people who could tolerate high-intensity MAC regimens
children.The committee could not make a positive or negative recommendation for these groups, which were not included in MC‑FludT‑14‑L trial 2, because it needed more comparative evidence. The committee invites the company to provide more evidence.
## The evidence is only in people ineligible for high-intensity MAC
The company submitted evidence based on MC‑FludT‑14‑L trial 2, in which the patient population was not eligible for a high-intensity MAC regimen. The trial used 1 comparator, the reduced-intensity regimen of low-dose busulfan and fludarabine. Therefore, the company's submission only partially addressed the NICE scope, which included high-intensity regimens such as cyclophosphamide and irradiation, cyclophosphamide and busulfan. No evidence was submitted on treosulfan and fludarabine compared with other conditioning regimens (particularly high-intensity MAC regimens) and in patients who can tolerate high-intensity MAC regimens. The company explored 2 approaches to generate comparative evidence with other regimens, using registry analyses and indirect treatment comparison. The committee understood that randomised controlled trials were available, and some indirect treatment comparisons were feasible. However, the company did not include any indirect comparisons in the submission because it considered that they were unlikely to be reliable. The committee concluded that it could not make a positive or negative recommendation for people who could have a high-intensity MAC regimen because no comparative evidence was supplied.
## The only evidence in children is from a single-arm trial
The clinical evidence for treosulfan in children was from the single-arm MC‑FludT‑17‑M trial, which showed low mortality rates at 100 days and high overall survival and event-free survival at 12 months. No evidence of the efficacy of treosulfan in children compared with other regimens was submitted. The committee considered the evidence presented, and the apparent favourable outcomes in the single-arm trial. But the company did not attempt to compare the outcomes from the treosulfan-based regimen against those that might be expected with existing treatments. There was also no evidence presented on the relative costs of the alternatives. In the absence of any evidence on the relative clinical and cost effectiveness of a treosulfan-based regimen compared with other regimens, the committee could not make a recommendation, either positive or negative, about the use of treosulfan in conditioning regimens for children.
# Conclusion
## Treosulfan with fludarabine is clinically and cost effective as conditioning treatment before allo-HSCT for people with malignant diseases in whom a reduced-intensity regimen would be appropriate
Treosulfan with fludarabine is associated with reduced toxicity and mortality compared with a reduced-intensity regimen comprising low-dose busulfan with fludarabine. Treosulfan with fludarabine has been shown to be more effective and cost less than low-dose busulfan with fludarabine in people with malignant disease who would otherwise have a reduced-intensity conditioning regimen. Therefore, treosulfan with fludarabine is recommended as an option for conditioning treatment before an allo-HSCT for people with malignant diseases who would otherwise be eligible for low-dose busulfan with fludarabine.
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{'Recommendations': 'Treosulfan with fludarabine is recommended as an option for conditioning treatment before allogeneic haematopoietic stem cell transplant (allo-HSCT) for people with malignant diseases for whom a reduced intensity regimen, such as low-dose busulfan with fludarabine, would be suitable.\n\nWhy the committee made these recommendations\n\nPeople with malignant diseases having an allo-HSCT need to have conditioning treatment first to prepare their bone marrow. If they cannot tolerate high-intensity myeloablative conditioning, they can have reduced-intensity conditioning such as low-dose busulfan with fludarabine.\n\nThe clinical evidence compares treosulfan and fludarabine with low-dose busulfan and fludarabine. Not enough evidence was presented for children or for people who could tolerate a high-intensity myeloablative regimen, so it is not possible to make recommendations for these groups.\n\nThe evidence in people for whom reduced-intensity is the most appropriate conditioning regimen shows that people are less likely to die from the transplant or associated complications if they have treosulfan and fludarabine instead of busulfan and fludarabine. The risk of disease recurrence was similar after either treatment.\n\nTreosulfan with fludarabine is more effective and costs less than low-dose busulfan with fludarabine in most analyses. Therefore, treosulfan with fludarabine is recommended as an option in the NHS for conditioning treatment for people who would normally have a reduced intensity regimen.', 'Information about treosulfan': "# Marketing authorisation indication\n\nTreosulfan (Trecondi, Medac) in combination with fludarabine (generic) is indicated 'as part of conditioning treatment prior to allogeneic haematopoietic stem cell transplantation (alloHSCT) in adult patients with malignant and non-malignant diseases, and in paediatric patients older than 1\xa0month with malignant diseases'.\n\nThis appraisal focuses on malignant diseases only.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule for treosulfan is available in the summary of product characteristics.\n\n# Price\n\nTreosulfan:\n\n£494.40 per 5‑vial pack of 1\xa0g powder for solution for injection (BNF online accessed December\xa02019)\n\n£2,434.25 per 5‑vial pack of 5\xa0g powder for solution for injection (BNF online accessed December\xa02019).\n\nFludarabine:\n\n£155.00 per vial of 50\xa0mg powder for solution for injection (BNF online accessed November\xa02019).", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Medac, a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that 1\xa0issue was resolved during the technical engagement stage and agreed that it is reasonable to assume that allogeneic haematopoietic stem cell transplantation (allo-HSCT) practice is similar in England and Wales to other European countries.\n\nIt recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, table\xa02, page\xa036), and took these into account in its decision making. It discussed the following issues (issues 1,\xa02,\xa03,\xa05\xa0and\xa06), which were outstanding after the technical engagement stage.\n\n# Treatment pathway and clinical need\n\n## Conditioning treatment is an essential but traumatic step before allo-HSCT\n\nAllo-HSCT is a potentially curative therapy for more than 70\xa0malignant diseases, such as acute myeloid leukaemia. Before having the transplant, people have conditioning treatment to prepare their bone marrow. Conditioning treatments are usually chemotherapy alone or chemotherapy with radiotherapy. High-intensity myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC) are 2\xa0types of regimens. The clinical expert explained that the RIC regimens are usually interchangeable, and the commonest regimens are busulfan with fludarabine and melphalan with fludarabine. MAC regimens differ more and are associated with a higher toxicity. Therefore, MAC regimens would only be offered to people who are fit and healthy enough to tolerate them. The patient experts explained that the allo-HSCT process is long and involves an extended stay in hospital. They explained that conditioning treatment is a traumatic experience and can have a substantial psychological impact. Conditioning drugs given before a transplant remove the recipient's haematopoietic cells from the bone marrow. This can have powerful effects on the body. For many patients, the conditioning treatment is more challenging than the chemotherapy they have previously had. Transplant-related complications include increased mortality, graft-versus-host disease (with symptoms such as mouth blisters or skin rashes) and infections such as shingles or pneumonia. The clinical expert explained that it typically takes 12\xa0to\xa024 months to recover from a transplant and for the immune system to recover. The committee concluded that conditioning treatment for allo-HSCT is an important part of the procedure that can be difficult to tolerate, but it is necessary to remove any remaining disease and prepare the bone marrow to receive and accept the transplant.\n\n## There is a clinical need for effective conditioning treatments with reduced transplant-related toxicity\n\nThe clinical expert's written submission explained that conditioning treatments have a major impact on the success of the transplant. They are designed to reduce the risk of disease recurrence or rejection of the graft by the body. The transplant itself carries short- and longer-term risks in terms of mortality and morbidity. The aim is to minimise these, while not compromising the success of the transplant. Conditioning treatments therefore have an impact on the patient's survival, quality of life and wellbeing. Both the physical and major psychological effects of a transplant were particularly highlighted by the patient experts. The clinical expert explained that all conditioning treatments have immediate major side effects, but that they are essential for a successful transplant. The treatment must ablate the marrow enough to remove remaining disease and allow the transplant to be accepted. But it must also not be so toxic that the patient dies of transplant-related causes such as infection. The committee concluded that patients and healthcare professionals would welcome conditioning regimens that allow a successful transplant with reduced risks.\n\n# Clinical evidence from MC-FludT-14-L trial\xa02\n\n## MC-FludT-14-L trial 2 reflects UK allo-HSCT clinical practice\n\nMC‑FludT‑14‑L trial\xa02 is a double-blind randomised clinical trial of treosulfan and fludarabine compared with low-dose busulfan and fludarabine in adults with acute myeloid leukaemia or myelodysplastic syndromes who were not eligible for high-intensity MAC regimens. No UK patients were included in the trial, and most patients were from Germany. The company explained that clinical practice in the UK is similar to that in other European countries included in the trial. In addition, 50\xa0UK transplant centres are members of the European Society for Blood and Marrow Transplantation (EBMT) and work according to the EBMT guidelines. The clinical expert explained that the target population for treosulfan in the UK would be similar to the population in the trial; that is, people who would not be eligible for high-intensity MAC regimens. The committee concluded that allo-HSCT practice in MC‑FludT‑14‑L trial\xa02 is comparable to clinical practice in the UK for that group of people.\n\n## Treosulfan with fludarabine reduces mortality relative to low-dose busulfan with fludarabine\n\nTreosulfan is an alkylating agent. The company proposes it as a reduced-toxicity MAC, with lower toxicity than usual MAC regimens. The primary endpoint of MC‑FludT‑14‑L trial\xa02 was event-free survival. This composite endpoint defined an event as disease relapse, graft failure or death, whichever occurred first. Event-free survival at 24\xa0months was 65.7% in the treosulfan arm and 51.2% in the busulfan arm (hazard ratio [HR] 0.64, 95%\xa0confidence interval [CI] 0.49\xa0to\xa00.84). The disaggregated event-free survival results showed that the main benefit of treosulfan was on mortality, especially non-relapse mortality. It had limited effect on disease relapse rates. Relapse rates were 22.8% in the treosulfan arm and 25.4% in the busulfan arm (HR 0.82, 95%\xa0CI 0.59\xa0to\xa01.16), death rates were 13.1% in the treosulfan arm and 19.8% in the busulfan arm (HR 0.63, 95%\xa0CI 0.41\xa0to\xa00.97). The company explained that this is because of lower non-relapse mortality rates with treosulfan: patients are less likely to die from the transplant, associated infections or graft-versus-host disease. In the trial, the main causes of non-relapse deaths were infections and graft-versus-host disease (both causes combined: 13.9% for treosulfan compared with 21.5% for busulfan). The committee concluded that people eligible for low-dose busulfan with fludarabine have a lower mortality with treosulfan and fludarabine than with low-dose busulfan and fludarabine.\n\n## Benefit and risk of increased toxicity have to be balanced in conditioning regimens\n\nThe committee heard that treosulfan is considered a reduced-intensity conditioning (RIC) regimen according to the European public assessment report, although the company stated that treosulfan is a reduced-toxicity MAC regimen. In MC‑FludT‑14‑L trial\xa02 the treosulfan dose was reduced from 14\xa0mg\xa0per\xa0m2 to 10\xa0mg\xa0per\xa0m2 because of increased infections after treosulfan treatment. The clinical expert believed that the 10\xa0mg\xa0per\xa0m2 dose of treosulfan used in the trial was myeloablative although there is no clear-cut threshold for when a regimen becomes myeloablative. The main clinical consideration is toxicity. The benefit of reduced relapse needs to be balanced with the increased risk of death from toxicity. The committee concluded that the balance between benefit and risk is an important consideration for conditioning regimens.\n\n# Cost effectiveness\n\n## The company's economic model is suitable for decision making\n\nThe company submitted a partitioned survival model to estimate the cost effectiveness of treosulfan and fludarabine compared with low-dose busulfan and fludarabine. The committee considered that the model is suitable for decision making.\n\n## Assuming a 5-year cure point to model mortality is plausible\n\nThe company used a cure point to model mortality, based on the rationale that allo-HSCT is potentially curative. In the company's base case, a fixed cure point of 5\xa0years was assumed for people who had not relapsed 5\xa0years after transplantation. The company explained that patients who survive allo-HSCT for at least 5\xa0years are considered cured in clinical practice. The ERG tested the impact of changing the cure point. Results were similar to the base-case analysis except when the cure point was assumed to be 1\xa0year, when treosulfan with fludarabine was dominated by busulfan with fludarabine (that is, it was less effective and cost more). The clinical expert explained that relapse is likely to occur in the first and second year after allo-HSCT, and that a cure point of 5\xa0years was a robust assumption. The committee concluded that it was reasonable to assume that people who have not relapsed within 5\xa0years of the transplant can be considered cured.\n\n## Treosulfan with fludarabine is cost effective compared with low-dose busulfan with fludarabine, in patients otherwise eligible for low-dose busulfan with fludarabine\n\nTreosulfan with fludarabine dominates busulfan with fludarabine; that is, it generates more quality-adjusted life years (QALYs) at a lower cost than busulfan in both the company's base case and ERG's preferred assumptions analyses. The committee concluded that treosulfan with fludarabine is cost effective compared with low-dose busulfan with fludarabine, in people who would otherwise be eligible for low-dose busulfan with fludarabine.\n\n## Evidence in other patient populations\n\nThe committee considered the evidence for:\n\npeople who could tolerate high-intensity MAC regimens\n\nchildren.The committee could not make a positive or negative recommendation for these groups, which were not included in MC‑FludT‑14‑L trial\xa02, because it needed more comparative evidence. The committee invites the company to provide more evidence.\n\n## The evidence is only in people ineligible for high-intensity MAC\n\nThe company submitted evidence based on MC‑FludT‑14‑L trial\xa02, in which the patient population was not eligible for a high-intensity MAC regimen. The trial used 1\xa0comparator, the reduced-intensity regimen of low-dose busulfan and fludarabine. Therefore, the company's submission only partially addressed the NICE scope, which included high-intensity regimens such as cyclophosphamide and irradiation, cyclophosphamide and busulfan. No evidence was submitted on treosulfan and fludarabine compared with other conditioning regimens (particularly high-intensity MAC regimens) and in patients who can tolerate high-intensity MAC regimens. The company explored 2\xa0approaches to generate comparative evidence with other regimens, using registry analyses and indirect treatment comparison. The committee understood that randomised controlled trials were available, and some indirect treatment comparisons were feasible. However, the company did not include any indirect comparisons in the submission because it considered that they were unlikely to be reliable. The committee concluded that it could not make a positive or negative recommendation for people who could have a high-intensity MAC regimen because no comparative evidence was supplied.\n\n## The only evidence in children is from a single-arm trial\n\nThe clinical evidence for treosulfan in children was from the single-arm MC‑FludT‑17‑M trial, which showed low mortality rates at 100\xa0days and high overall survival and event-free survival at 12\xa0months. No evidence of the efficacy of treosulfan in children compared with other regimens was submitted. The committee considered the evidence presented, and the apparent favourable outcomes in the single-arm trial. But the company did not attempt to compare the outcomes from the treosulfan-based regimen against those that might be expected with existing treatments. There was also no evidence presented on the relative costs of the alternatives. In the absence of any evidence on the relative clinical and cost effectiveness of a treosulfan-based regimen compared with other regimens, the committee could not make a recommendation, either positive or negative, about the use of treosulfan in conditioning regimens for children.\n\n# Conclusion\n\n## Treosulfan with fludarabine is clinically and cost effective as conditioning treatment before allo-HSCT for people with malignant diseases in whom a reduced-intensity regimen would be appropriate\n\nTreosulfan with fludarabine is associated with reduced toxicity and mortality compared with a reduced-intensity regimen comprising low-dose busulfan with fludarabine. Treosulfan with fludarabine has been shown to be more effective and cost less than low-dose busulfan with fludarabine in people with malignant disease who would otherwise have a reduced-intensity conditioning regimen. Therefore, treosulfan with fludarabine is recommended as an option for conditioning treatment before an allo-HSCT for people with malignant diseases who would otherwise be eligible for low-dose busulfan with fludarabine."}
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https://www.nice.org.uk/guidance/ta640
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Evidence-based recommendations on treosulfan (Trecondi) with fludarabine for conditioning treatment before allogeneic haematopoietic stem cell transplant for malignant diseases in people for whom a reduced intensity regimen would be suitable.
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3dc9dbc5c0750c626b92ce0d34db37b6e2aa1d89
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nice
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Artificial iris insertion for acquired aniridia
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Artificial iris insertion for acquired aniridia
Evidence-based recommendations on artificial iris insertion for acquired aniridia. This involves inserting an artificial iris into the eye.
# Recommendations
Evidence on the safety and efficacy of artificial iris implant insertion for acquired aniridia is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE website.
Clinicians wishing to do artificial iris implant insertion for acquired aniridia should:
Inform the clinical governance leads in their NHS trusts.
Give patients clear information to support shared decision making, including NICE's information for the public.
Ensure that patients understand the procedure's safety and efficacy, as well as any uncertainties about these.
Audit and review clinical outcomes of all patients having the procedure. NICE has identified relevant audit criteria and developed an audit tool (which is for use at local discretion).
The procedure should only be done by ophthalmic surgeons with appropriate experience and training.
Research could include the use of observational data from cohort studies or high-quality case series. Studies should report details of patient selection and the type of implant used. Outcomes should include quality of life and other patient-reported outcomes.
NICE may update the guidance on publication of further evidence.# The condition, current treatments and procedure
# The condition
Acquired aniridia means the iris is either missing or incomplete as a result of trauma, surgery or laser treatment.
People with aniridia may be very light sensitive (photophobic) and report symptoms of glare. They may develop other eye problems such as glaucoma, cataract and corneal opacification. The degree of vision loss varies.
# Current treatments
Treatment includes contact lenses with iris prints and tinted spectacle lenses.
Surgical implantation of an artificial iris device may be an option for some people with complete or partial acquired aniridia.
# The procedure
There are different devices available, including a solid acrylic ring or segment and a flexible silicone disc, which can be custom-made for each patient. The implant has a defined pupil size, which offers a compromise between day and night vision.
The artificial iris implant is inserted using local or general anaesthesia. The exact details of the procedure vary according to the type of implant being used.
Flexible implants are rolled up and inserted through a cut about 3 mm long at the edge of the cornea, into the posterior chamber of the eye. They are then unfolded and fixed in the eye. If sutures are needed to hold the implant in place, a larger cut may be necessary. The implant insertion can be done on its own or at the time of cataract or lens fixation surgery.
Solid ring implants are typically inserted during cataract surgery along with an intraocular lens. In some patients, an iris reconstruction lens containing both an artificial iris and a lens is implanted. Depending on the condition of the eye, the lens and iris device may need to be sutured to the sclera.
The aim of artificial iris implant insertion is to improve visual acuity, reduce photophobia and glare, and improve the eye's appearance.
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{'Recommendations': "Evidence on the safety and efficacy of artificial iris implant insertion for acquired aniridia is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE website.\n\nClinicians wishing to do artificial iris implant insertion for acquired aniridia should:\n\nInform the clinical governance leads in their NHS trusts.\n\nGive patients clear information to support shared decision making, including NICE's information for the public.\n\nEnsure that patients understand the procedure's safety and efficacy, as well as any uncertainties about these.\n\nAudit and review clinical outcomes of all patients having the procedure. NICE has identified relevant audit criteria and developed an audit tool (which is for use at local discretion).\n\nThe procedure should only be done by ophthalmic surgeons with appropriate experience and training.\n\nResearch could include the use of observational data from cohort studies or high-quality case series. Studies should report details of patient selection and the type of implant used. Outcomes should include quality of life and other patient-reported outcomes.\n\nNICE may update the guidance on publication of further evidence.", 'The condition, current treatments and procedure': "# The condition\n\nAcquired aniridia means the iris is either missing or incomplete as a result of trauma, surgery or laser treatment.\n\nPeople with aniridia may be very light sensitive (photophobic) and report symptoms of glare. They may develop other eye problems such as glaucoma, cataract and corneal opacification. The degree of vision loss varies.\n\n# Current treatments\n\nTreatment includes contact lenses with iris prints and tinted spectacle lenses.\n\nSurgical implantation of an artificial iris device may be an option for some people with complete or partial acquired aniridia.\n\n# The procedure\n\nThere are different devices available, including a solid acrylic ring or segment and a flexible silicone disc, which can be custom-made for each patient. The implant has a defined pupil size, which offers a compromise between day and night vision.\n\nThe artificial iris implant is inserted using local or general anaesthesia. The exact details of the procedure vary according to the type of implant being used.\n\nFlexible implants are rolled up and inserted through a cut about 3\xa0mm long at the edge of the cornea, into the posterior chamber of the eye. They are then unfolded and fixed in the eye. If sutures are needed to hold the implant in place, a larger cut may be necessary. The implant insertion can be done on its own or at the time of cataract or lens fixation surgery.\n\nSolid ring implants are typically inserted during cataract surgery along with an intraocular lens. In some patients, an iris reconstruction lens containing both an artificial iris and a lens is implanted. Depending on the condition of the eye, the lens and iris device may need to be sutured to the sclera.\n\nThe aim of artificial iris implant insertion is to improve visual acuity, reduce photophobia and glare, and improve the eye's appearance."}
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https://www.nice.org.uk/guidance/ipg674
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Evidence-based recommendations on artificial iris insertion for acquired aniridia. This involves inserting an artificial iris into the eye.
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392414f72899714d3a86cf9ab69c9088f7cf2da2
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nice
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Artificial iris insertion for congenital aniridia
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Artificial iris insertion for congenital aniridia
Evidence-based recommendations on artificial iris insertion for congenital aniridia. This involves inserting an artificial iris into the eye.
# Recommendations
Evidence on the safety and efficacy of artificial iris implant insertion for congenital aniridia is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE website.
Research could include the use of observational data from cohort studies or high-quality case series. Studies should report details of patient selection and the type of implant used. Outcomes should include quality of life and other patient-reported outcomes.
NICE may update the guidance on publication of further evidence.# The condition, current treatments and procedure
# The condition
Congenital aniridia is a rare condition in which the iris has not formed properly, so it is missing or underdeveloped. It affects both eyes. The amount of iris tissue missing varies from person to person. Many people with congenital aniridia also have a part of their retina that is not fully developed, and many have nystagmus.
People with congenital aniridia may be very light sensitive (photophobic) and report symptoms of glare. They may develop other eye problems such as glaucoma, cataract and corneal opacification. The degree of vision loss varies.
# Current treatments
Treatment includes contact lenses with iris prints and tinted spectacle lenses.
Surgical implantation of an artificial iris device may be an option for some people with complete or partial congenital aniridia.
# The procedure
There are different devices available, including a solid acrylic ring or segment and a flexible silicone disc which can be custom-made for each patient. The implant has a defined pupil size, which offers a compromise between day and night vision.
The artificial iris implant is inserted using local or general anaesthesia. The exact details of the procedure vary according to the type of implant being used.
Flexible implants are rolled up and inserted through a cut about 3 mm long at the edge of the cornea, into the posterior chamber of the eye. They are then unfolded and fixed in the eye. If sutures are needed to hold the implant in place, a larger cut may be necessary. The implant insertion can be done on its own or at the time of cataract or lens fixation surgery.
Solid ring implants are typically inserted during cataract surgery along with an intraocular lens. In some patients, an iris reconstruction lens containing both an artificial iris and a lens is implanted. Depending on the condition of the eye, the lens and iris device may need to be sutured to the sclera.
The aim of artificial iris implant insertion is to improve visual acuity, reduce photophobia and glare, and improve the eye's appearance.
|
{'Recommendations': 'Evidence on the safety and efficacy of artificial iris implant insertion for congenital aniridia is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE website.\n\nResearch could include the use of observational data from cohort studies or high-quality case series. Studies should report details of patient selection and the type of implant used. Outcomes should include quality of life and other patient-reported outcomes.\n\nNICE may update the guidance on publication of further evidence.', 'The condition, current treatments and procedure': "# The condition\n\nCongenital aniridia is a rare condition in which the iris has not formed properly, so it is missing or underdeveloped. It affects both eyes. The amount of iris tissue missing varies from person to person. Many people with congenital aniridia also have a part of their retina that is not fully developed, and many have nystagmus.\n\nPeople with congenital aniridia may be very light sensitive (photophobic) and report symptoms of glare. They may develop other eye problems such as glaucoma, cataract and corneal opacification. The degree of vision loss varies.\n\n# Current treatments\n\nTreatment includes contact lenses with iris prints and tinted spectacle lenses.\n\nSurgical implantation of an artificial iris device may be an option for some people with complete or partial congenital aniridia.\n\n# The procedure\n\nThere are different devices available, including a solid acrylic ring or segment and a flexible silicone disc which can be custom-made for each patient. The implant has a defined pupil size, which offers a compromise between day and night vision.\n\nThe artificial iris implant is inserted using local or general anaesthesia. The exact details of the procedure vary according to the type of implant being used.\n\nFlexible implants are rolled up and inserted through a cut about 3\xa0mm long at the edge of the cornea, into the posterior chamber of the eye. They are then unfolded and fixed in the eye. If sutures are needed to hold the implant in place, a larger cut may be necessary. The implant insertion can be done on its own or at the time of cataract or lens fixation surgery.\n\nSolid ring implants are typically inserted during cataract surgery along with an intraocular lens. In some patients, an iris reconstruction lens containing both an artificial iris and a lens is implanted. Depending on the condition of the eye, the lens and iris device may need to be sutured to the sclera.\n\nThe aim of artificial iris implant insertion is to improve visual acuity, reduce photophobia and glare, and improve the eye's appearance."}
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https://www.nice.org.uk/guidance/ipg675
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Evidence-based recommendations on artificial iris insertion for congenital aniridia. This involves inserting an artificial iris into the eye.
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08fc091c61b56349df3878ec58c7d4cd80969b77
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nice
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Atezolizumab with carboplatin and etoposide for untreated extensive-stage small-cell lung cancer
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Atezolizumab with carboplatin and etoposide for untreated extensive-stage small-cell lung cancer
Evidence-based recommendations on atezolizumab (Tecentriq) for untreated extensive-stage small-cell lung cancer in adults.
# Recommendations
Atezolizumab with carboplatin and etoposide is recommended as an option for untreated extensive-stage small-cell lung cancer in adults, only if:
they have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and
the company provides atezolizumab according to the commercial arrangement.
When using ECOG performance status, healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect ECOG performance status and make any adjustments they consider appropriate.
These recommendations are not intended to affect treatment with atezolizumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
People with extensive-stage small-cell lung cancer have carboplatin and etoposide chemotherapy as their first treatment. Clinical trial evidence is in people with an ECOG status of 0 or 1 (that is, they are more able to do daily tasks and ordinary activities than those with poorer ECOG status). It suggests that atezolizumab with chemotherapy could help people to live longer without their disease progressing, and to live for longer compared with chemotherapy alone.
Atezolizumab meets NICE's criteria to be considered a life-extending treatment at the end of life. The cost-effectiveness estimates comparing atezolizumab and chemotherapy with chemotherapy alone are uncertain, but they are within what NICE normally considers an acceptable use of NHS resources. Because the clinical evidence is for people with an ECOG status of 0 or 1, atezolizumab with carboplatin and etoposide is only recommended for this group.# Information about atezolizumab with carboplatin and etoposide
# Marketing authorisation indication
Atezolizumab (Tecentriq, Roche) received a promising innovative medicine designation in November 2018 and a positive opinion from the Early Access to Medicines Scheme in June 2019.Having received a marketing authorisation in other cancer indications in 2017, on 26 July 2019, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending a variation to the terms of the marketing authorisation for the medicinal product atezolizumab. The CHMP adopted a new indication as follows: 'Tecentriq, in combination with carboplatin and etoposide, is indicated for the first-line treatment of adult patients with extensive-stage small-cell lung cancer (ES-SCLC)'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price of atezolizumab is £3,807.69 per 1,200 mg vial (excluding VAT; BNF online, accessed April 2019). The mean treatment cost of a course of treatment for a patient with ES‑SCLC is £32,798.39 for atezolizumab (at list price), £76.18 for carboplatin and £30.89 for etoposide.The company has a commercial arrangement. This makes atezolizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Roche, a review of this submission by the evidence review group (ERG), and the technical report developed by the NICE team through engagement with stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:
Carboplatin with etoposide is the most relevant comparator for this appraisal (issue 1, see technical report page 11).
Because carboplatin with etoposide is the most relevant comparator for this appraisal, clinical data from the IMpower133 trial is acceptable for decision making (issue 2, see technical report page 12).
The company's approach of using time-to-death to estimate utility values, using the ERG's preferred model, is acceptable for decision making (section 3.5; issue 3, see technical report page 16).
It is appropriate for disutilities associated with adverse events to be incorporated in the model (issue 4, see technical report page 18).
The committee recognised that there was remaining uncertainty associated with the analyses presented (see technical report page 19), and took this into account in its decision making. It discussed the issue of long-term survival estimates (issue 5, see technical report page 18), which was outstanding after the technical engagement stage. This included uncertainty about how long people having atezolizumab live, and how well the model fitted the trial data and predicted long-term survival. At the first appraisal committee meeting, the committee recommended that NICE requested further clarification and analyses from the company for the second meeting. It requested that this should include a revised cost-effectiveness model with further methods of estimating overall survival for both atezolizumab and comparator groups. After receiving new analyses and information from the company, the committee discussed the long-term survival estimates again. It also discussed treatment effect duration and end of life, which were outstanding issues after the first committee meeting. During consultation, the company updated the confidential discount. This altered the incremental cost-effectiveness ratios (ICERs) from the overall survival models for the atezolizumab arm, which the committee considered plausible. The committee considered these updated analyses in its final decision making.
# Clinical need and comparator
## There is an unmet need for treatment options in this disease
A patient expert highlighted that people diagnosed with extensive-stage small-cell lung cancer (ES‑SCLC) are often dismayed at their lack of treatment options, particularly compared with non-small-cell lung cancer (NSCLC). Treatment options have not changed for decades, and patients are aware of the success of immunotherapy for treating other cancers. After starting chemotherapy, people often feel better at first, but this may only last for a few months before their condition deteriorates. Any treatment that could extend life, even for a short period, would allow more time for advanced care planning. The patient expert commented that many people with this condition spend their last days in a hospital bed, meaning a worse quality of life for them and their family. More time to plan for end-of-life care could help to reduce the incidence of this. The committee noted that ES‑SCLC progresses rapidly, and the impact that this has on patients, and their friends and family. It agreed that an additional more effective treatment option would benefit people with untreated ES‑SCLC, and concluded that atezolizumab with carboplatin and etoposide would be a welcome treatment option.
## The most appropriate comparator is carboplatin and etoposide chemotherapy
The company submitted cost-effectiveness analyses comparing atezolizumab plus carboplatin and etoposide with carboplatin and etoposide This used Kaplan−Meier data from IMpower133 (see section 3.3). The company also provided an exploratory comparison with cisplatin and etoposide, but the clinical experts explained that fewer than 5% of people with untreated ES‑SCLC would be offered this. The committee agreed that the most appropriate comparator for this appraisal was chemotherapy consisting of carboplatin and etoposide.
# Clinical trial evidence
## Atezolizumab with chemotherapy improves overall and progression-free survival compared with chemotherapy, but the long-term benefit is uncertain
The clinical evidence for atezolizumab with carboplatin and etoposide came from IMpower133, a randomised placebo-controlled trial. It compared atezolizumab plus carboplatin and etoposide (atezolizumab combination therapy) with placebo plus carboplatin and etoposide (standard chemotherapy) in adults with untreated ES‑SCLC with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. At the April 2018 data-cut, median progression-free survival was 5.2 months for atezolizumab combination therapy and 4.3 months for standard chemotherapy (hazard ratio 0.77, 95% confidence interval 0.62 to 0.96). Overall survival data were provided from a later data-cut (January 2019). Median overall survival was 12.3 months for atezolizumab combination therapy and 10.3 months for standard chemotherapy (HR 0.76, 95% CI 0.60 to 0.95). The committee considered a Kaplan−Meier plot of overall survival from the January 2019 data-cut. It noted that the plots for the atezolizumab and placebo arms had almost come together by about 30 months, which could show that there is little overall survival benefit for the atezolizumab arm after this. The committee concluded that the trial data showed that atezolizumab combination therapy improves overall and progression-free survival compared with standard chemotherapy, but the long-term benefit on overall survival was uncertain.
## Data from IMpower133 are not generalisable to people with an ECOG performance status score of 2 or higher
IMpower133 only included people with a good ECOG performance status (0 or 1). The clinical experts commented that some people with untreated ES‑SCLC in the NHS in England are likely to have an ECOG performance status of 2 or higher, that is, a worse performance status. They stated that IMpower133 data should not be extrapolated to people with worse performance status because treatment effects can be very different for people with a larger disease burden. The clinical experts explained that a lower effectiveness of immunotherapies in general has been seen in people with a different disease (NSCLC) and an ECOG performance status of 2 or higher. The committee agreed that the treatment effect of atezolizumab with carboplatin and etoposide seen in IMpower133 should not be used to estimate the effectiveness of the treatment for people with worse performance status, and is not generalisable to people with this status in clinical practice in England. Therefore, the committee concluded that its decision should reflect the trial evidence.
# Economic model
## The company's time-to-death approach for estimating utility values in the model is accepted for this appraisal
The company used a time-to-death approach to get utility values for its base-case economic model. The committee had concerns about this approach. After new analyses was provided at technical engagement, the technical team favoured the ERG's preferred approach of using the ERG‑requested utility model with 'time-to-death categories 1 week earlier' to estimate utility values. Analysis done by the company during technical engagement showed that disease progression had little effect on the quality-of-life data from IMpower133. However, the clinical experts commented that they would expect a patient's quality of life to decrease after disease progression. The committee was concerned that EQ‑5D data for patients whose disease had progressed could be biased. This was because of informative censoring (that is, when quality of life after progression is measured before there is any decrease in quality of life caused by progression, or if people whose disease has progressed are less likely to complete quality-of-life questionnaires). Also, during the trial, quality-of-life data might no longer have been reliably collected once a patient's disease had progressed or they had stopped having treatment. The company commented that its updated time-to-death statistical model for estimating utility based on trial EQ‑5D data did include progression status. However, the committee considered that the problems around informative censoring remained. The company also highlighted that previous appraisals used this approach to estimate utility. However, the committee was aware that NICE technology appraisal guidance on pembrolizumab with carboplatin and paclitaxel for untreated metastatic squamous non-small-cell lung cancer preferred using progression-based utility values instead of a time-to-death based approach. The committee concluded that the company's time-to-death approach to estimate utilities was acceptable for this particular appraisal, given the specific circumstances, but this should not be considered the usual methodology for this disease.
## The duration of treatment benefit from the start of treatment is uncertain, but varying this duration has a small effect on the cost-effectiveness results
The committee requested investigation of the effect of reducing the duration of treatment benefit on model results. This is because, based on a Kaplan−Meier data plot of overall survival from IMpower133, there may be no treatment benefit from about 30 months (see section 3.3). The company presented scenario analyses for no treatment effect cut-off, as well as for 36, 48 and 60 months from the start of treatment. It chose to use a 60‑month effect cut-off in its base case. The ERG carried out an illustrative scenario with a cut-off of 30 months, which was about the maximum follow up in the trial. However, varying the treatment effect duration did not have a large effect on the ICER overall. The committee concluded that the company's preferred 60‑month treatment effect duration from starting treatment was plausible but uncertain because follow up was still short.
## Flexible methods of estimating overall survival are explored to identify the most appropriate model assumptions for decision making
In its original submission, the company used log-logistic extrapolations in its base-case model. It stated that the Weibull extrapolations were not appropriate for overall survival (the ERG's preferred approach at the time). This was because the company predicted that all people with ES‑SCLC did not survive past about 40 months. The company commented that several studies showed that people having standard care were alive after this time. It expected to see prolonged survival for people having atezolizumab, consistent with immunotherapeutic effects seen in other indications. The clinical experts commented that, while there is some evidence that immunotherapy causes prolonged remission for NSCLC, it is too early to see if this is the case for SCLC. The committee did not accept that observing a longer-term treatment effect in 1 disease would necessarily translate to another disease. Confirmatory long-term data are needed. The clinical experts also explained that, while some people with SCLC do survive for 5 years, this is mostly people with early-stage SCLC. Not everyone with ES‑SCLC would die from the condition by 5 years, but the proportion surviving by that point was likely to be fewer than 1%. The committee commented that neither the Weibull nor log-logistic models fitted the IMpower133 data very well, but were the least poor fitting of the parametric survival extrapolations used by the company. Also, looking at the hazard over time, there was a complex pattern which would have been clearer if a plot of hazard function over time had been provided. The committee concluded that the Weibull extrapolation for overall survival may be too pessimistic to reflect the chemotherapy-only group outcome, and the log-logistic may be too optimistic. It did not consider either approach suitable for decision making at the first appraisal committee meeting. It requested that the company provided new analyses exploring further methods for estimating mean overall survival. The committee considered that alternative, more flexible models may allow better representation of the available survival data and would provide a more robust basis for decision making.
## Restricted spline models may provide the best method for modelling atezolizumab with chemotherapy long-term overall survival
In response to the committee's request for new analyses with alternative models, the company provided plots of the hazard function over time. It commented that long-term hazards were decreasing, and that both groups in IMpower133 had different shaped curves before and after about 5 months. The company validated the new models with 8 consultant oncologists to understand how well the extrapolations reflected long-term overall survival in clinical practice. It presented a new base-case model with changed curve-fitting and extrapolation of overall survival. This was a hybrid model using Kaplan−Meier data then switching at 20 months to a log-logistic extrapolation for both the atezolizumab and the chemotherapy groups. The ERG stated that there was no compelling reason to choose a hybrid model of Kaplan−Meier data followed by extrapolation instead of a parametric curve extrapolation alone. The ERG preferred a log-logistic model for the chemotherapy group because it was the most plausible based on statistical fit, visual fit, decreasing hazards and 2.5% survival at 5 years. The committee agreed to use a log-logistic method for the chemotherapy arm, with a more flexible curve-fitting approach for the atezolizumab arm in its decision making. It considered that the chemotherapy group hazard reduced over time, but this was not reflected in the company's preferred hybrid modelling. It was concerned that the company's hybrid modelling was inappropriate because the event hazard rate had been applied for the whole model duration, rather than a hazard rate related to a specific cut-point in time. The committee concluded that the most appropriate overall survival model for the atezolizumab arm fitted to the whole curve (rather than just a section of it) and took into account the changing hazard profile over time. Therefore, the committee agreed that some of the spline-based models for the atezolizumab arm were most appropriate, but statistical criteria did not show that any one was a better choice than any other. It noted that, when using the 60‑month treatment effect duration (see section 3.6), the ICER generated with a log-logistic model for the chemotherapy arm and one of the preferred spline models for the atezolizumab arm would give an ICER of between £32,433 per quality-adjusted life year (QALY) gained and £48,770 per QALY gained when the revised patient access scheme was applied.
## The curve-fitting and extrapolation of overall survival has a large effect on the ICER
The company's new deterministic base case showed that the ICER for atezolizumab and chemotherapy compared with chemotherapy alone was £26,998 per QALY gained. All analyses included the revised patient access scheme for atezolizumab. The ERG preferred to use a log-logistic extrapolation for long-term survival for the chemotherapy arm. It considered several different plausible extrapolations for the atezolizumab arm, giving ICERs of between £25,567 and £48,770 per QALY gained for atezolizumab and chemotherapy compared with chemotherapy alone. The committee agreed that a log-logistic extrapolation was appropriate for the chemotherapy arm (see section 3.8). Also, it found that some of the flexible curves considered plausible fits to the trial data by the ERG and technical team for the atezolizumab group were more appropriate, particularly the spline-based models. These spline models gave a plausible ICER of between £32,433 per QALY gained and £48,770 per QALY gained for atezolizumab and chemotherapy compared with chemotherapy alone.
# End of life
## Restricted mean analysis of overall survival data from IMpower133 may support atezolizumab with chemotherapy meeting NICE's end-of-life criteria
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. A restricted mean analysis of the overall survival data from IMpower133 may help estimate the extent that atezolizumab with chemotherapy extends life compared with chemotherapy alone. The company explained that the restricted mean survival time increases with further data cuts and gets closer to NICE's end-of-life extension-to-life criterion. With the company's updated base case, the mean difference in overall survival was 4.93 months, which is above the 3 months threshold needed to meet the end-of-life criteria. The ERG explained that the restricted mean analysis showed that one of the end-of-life criteria might not be met if the difference in mean survival based on the trial data only is used to estimate increase in life expectancy. However, the difference in means is larger the later the cut-off, and the model predicted a gain in life expectancy of over 3 months using any of the log-logistic based models. The committee used the evidence on restricted mean analysis to discuss whether or not all end-of-life criteria were met.
## Atezolizumab with carboplatin and etoposide for ES-SCLC meets NICE's end-of-life criteria
Based on evidence from IMpower133 and clinical expert opinion, the committee concluded that the life expectancy of people with untreated ES‑SCLC would be under 24 months with current NHS treatment. The company's preferred economic model was a hybrid model using Kaplan−Meier data with log-logistic extrapolation from 20 months. This predicted a mean increase in survival of 4.93 months for atezolizumab with carboplatin and etoposide. The increase in median overall survival from IMpower133 was 2.0 months for atezolizumab compared with placebo (12.3 months compared with 10.3 months). The committee had concluded that there was uncertainty about the most appropriate method for estimating mean overall survival in this appraisal (see section 3.8). However, almost all the models for overall survival that it considered plausible gave a survival gain of 3 months or more for atezolizumab and chemotherapy compared with chemotherapy alone. So, the committee accepted that this criterion was met in this circumstance. It concluded that, on balance, with trial and modelled evidence, taking both mean and median survival into account, the NICE criteria for a treatment at the end of life were met.
# Other factors
## Healthcare professionals should consider ECOG performance status when implementing the recommendations
The committee considered whether its recommendations were associated with any potential issues related to equality. It concluded that healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect ECOG performance status and make any adjustments they consider appropriate.
## All relevant benefits of the treatment are captured in the QALY
Atezolizumab with carboplatin and etoposide may be innovative. However, all relevant benefits of the technology were captured in the QALY.
# Conclusion
## Atezolizumab with carboplatin and etoposide is recommended for untreated ES-SCLC in adults
The company provided multiple models of overall survival at the request of the committee and updated its base case, but the committee still found some remaining uncertainty around which of the more flexible models of overall survival was most appropriate. However, having considered the various models with different fits to the atezolizumab and chemotherapy arms that it found plausible (see section 3.8), the committee concluded that the range of plausible ICERs with the confidential discount was within the range considered cost effective for end-of-life treatments. The trial only included people with an ECOG performance status of 0 to 1, and the committee agreed that its recommendations should reflect the population in the trial. Therefore, it recommended atezolizumab with carboplatin and etoposide as an option for untreated ES‑SCLC in adults, only if they have an ECOG performance status of 0 or 1.
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{'Recommendations': "Atezolizumab with carboplatin and etoposide is recommended as an option for untreated extensive-stage small-cell lung cancer in adults, only if:\n\nthey have an Eastern Cooperative Oncology Group (ECOG) performance status of 0\xa0or\xa01, and\n\nthe company provides atezolizumab according to the commercial arrangement.\n\nWhen using ECOG performance status, healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect ECOG performance status and make any adjustments they consider appropriate.\n\nThese recommendations are not intended to affect treatment with atezolizumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nPeople with extensive-stage small-cell lung cancer have carboplatin and etoposide chemotherapy as their first treatment. Clinical trial evidence is in people with an ECOG status of 0\xa0or\xa01 (that is, they are more able to do daily tasks and ordinary activities than those with poorer ECOG status). It suggests that atezolizumab with chemotherapy could help people to live longer without their disease progressing, and to live for longer compared with chemotherapy alone.\n\nAtezolizumab meets NICE's criteria to be considered a life-extending treatment at the end of life. The cost-effectiveness estimates comparing atezolizumab and chemotherapy with chemotherapy alone are uncertain, but they are within what NICE normally considers an acceptable use of NHS resources. Because the clinical evidence is for people with an ECOG status of 0\xa0or\xa01, atezolizumab with carboplatin and etoposide is only recommended for this group.", 'Information about atezolizumab with carboplatin and etoposide': "# Marketing authorisation indication\n\nAtezolizumab (Tecentriq, Roche) received a promising innovative medicine designation in November 2018 and a positive opinion from the Early Access to Medicines Scheme in June 2019.Having received a marketing authorisation in other cancer indications in 2017, on 26\xa0July 2019, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending a variation to the terms of the marketing authorisation for the medicinal product atezolizumab. The CHMP adopted a new indication as follows: 'Tecentriq, in combination with carboplatin and etoposide, is indicated for the first-line treatment of adult patients with extensive-stage small-cell lung cancer (ES-SCLC)'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price of atezolizumab is £3,807.69 per 1,200\xa0mg vial (excluding VAT; BNF online, accessed April 2019). The mean treatment cost of a course of treatment for a patient with ES‑SCLC is £32,798.39 for atezolizumab (at list price), £76.18 for carboplatin and £30.89 for etoposide.The company has a commercial arrangement. This makes atezolizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Roche, a review of this submission by the evidence review group (ERG), and the technical report developed by the NICE team through engagement with stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:\n\nCarboplatin with etoposide is the most relevant comparator for this appraisal (issue\xa01, see technical report page\xa011).\n\nBecause carboplatin with etoposide is the most relevant comparator for this appraisal, clinical data from the IMpower133 trial is acceptable for decision making (issue\xa02, see technical report page\xa012).\n\nThe company's approach of using time-to-death to estimate utility values, using the ERG's preferred model, is acceptable for decision making (section\xa03.5; issue\xa03, see technical report page\xa016).\n\nIt is appropriate for disutilities associated with adverse events to be incorporated in the model (issue\xa04, see technical report page\xa018).\n\nThe committee recognised that there was remaining uncertainty associated with the analyses presented (see technical report page\xa019), and took this into account in its decision making. It discussed the issue of long-term survival estimates (issue\xa05, see technical report page\xa018), which was outstanding after the technical engagement stage. This included uncertainty about how long people having atezolizumab live, and how well the model fitted the trial data and predicted long-term survival. At the first appraisal committee meeting, the committee recommended that NICE requested further clarification and analyses from the company for the second meeting. It requested that this should include a revised cost-effectiveness model with further methods of estimating overall survival for both atezolizumab and comparator groups. After receiving new analyses and information from the company, the committee discussed the long-term survival estimates again. It also discussed treatment effect duration and end of life, which were outstanding issues after the first committee meeting. During consultation, the company updated the confidential discount. This altered the incremental cost-effectiveness ratios (ICERs) from the overall survival models for the atezolizumab arm, which the committee considered plausible. The committee considered these updated analyses in its final decision making.\n\n# Clinical need and comparator\n\n## There is an unmet need for treatment options in this disease\n\nA patient expert highlighted that people diagnosed with extensive-stage small-cell lung cancer (ES‑SCLC) are often dismayed at their lack of treatment options, particularly compared with non-small-cell lung cancer (NSCLC). Treatment options have not changed for decades, and patients are aware of the success of immunotherapy for treating other cancers. After starting chemotherapy, people often feel better at first, but this may only last for a few months before their condition deteriorates. Any treatment that could extend life, even for a short period, would allow more time for advanced care planning. The patient expert commented that many people with this condition spend their last days in a hospital bed, meaning a worse quality of life for them and their family. More time to plan for end-of-life care could help to reduce the incidence of this. The committee noted that ES‑SCLC progresses rapidly, and the impact that this has on patients, and their friends and family. It agreed that an additional more effective treatment option would benefit people with untreated ES‑SCLC, and concluded that atezolizumab with carboplatin and etoposide would be a welcome treatment option.\n\n## The most appropriate comparator is carboplatin and etoposide chemotherapy\n\nThe company submitted cost-effectiveness analyses comparing atezolizumab plus carboplatin and etoposide with carboplatin and etoposide This used Kaplan−Meier data from IMpower133 (see section\xa03.3). The company also provided an exploratory comparison with cisplatin and etoposide, but the clinical experts explained that fewer than 5% of people with untreated ES‑SCLC would be offered this. The committee agreed that the most appropriate comparator for this appraisal was chemotherapy consisting of carboplatin and etoposide.\n\n# Clinical trial evidence\n\n## Atezolizumab with chemotherapy improves overall and progression-free survival compared with chemotherapy, but the long-term benefit is uncertain\n\nThe clinical evidence for atezolizumab with carboplatin and etoposide came from IMpower133, a randomised placebo-controlled trial. It compared atezolizumab plus carboplatin and etoposide (atezolizumab combination therapy) with placebo plus carboplatin and etoposide (standard chemotherapy) in adults with untreated ES‑SCLC with an Eastern Cooperative Oncology Group (ECOG) performance status of 0\xa0or\xa01. At the April 2018 data-cut, median progression-free survival was 5.2\xa0months for atezolizumab combination therapy and 4.3\xa0months for standard chemotherapy (hazard ratio [HR]\xa00.77, 95% confidence interval [CI] 0.62\xa0to\xa00.96). Overall survival data were provided from a later data-cut (January 2019). Median overall survival was 12.3\xa0months for atezolizumab combination therapy and 10.3\xa0months for standard chemotherapy (HR\xa00.76, 95%\xa0CI 0.60\xa0to\xa00.95). The committee considered a Kaplan−Meier plot of overall survival from the January 2019 data-cut. It noted that the plots for the atezolizumab and placebo arms had almost come together by about 30\xa0months, which could show that there is little overall survival benefit for the atezolizumab arm after this. The committee concluded that the trial data showed that atezolizumab combination therapy improves overall and progression-free survival compared with standard chemotherapy, but the long-term benefit on overall survival was uncertain.\n\n## Data from IMpower133 are not generalisable to people with an ECOG performance status score of 2\xa0or higher\n\nIMpower133 only included people with a good ECOG performance status (0\xa0or\xa01). The clinical experts commented that some people with untreated ES‑SCLC in the NHS in England are likely to have an ECOG performance status of 2\xa0or higher, that is, a worse performance status. They stated that IMpower133 data should not be extrapolated to people with worse performance status because treatment effects can be very different for people with a larger disease burden. The clinical experts explained that a lower effectiveness of immunotherapies in general has been seen in people with a different disease (NSCLC) and an ECOG performance status of 2\xa0or higher. The committee agreed that the treatment effect of atezolizumab with carboplatin and etoposide seen in IMpower133 should not be used to estimate the effectiveness of the treatment for people with worse performance status, and is not generalisable to people with this status in clinical practice in England. Therefore, the committee concluded that its decision should reflect the trial evidence.\n\n# Economic model\n\n## The company's time-to-death approach for estimating utility values in the model is accepted for this appraisal\n\nThe company used a time-to-death approach to get utility values for its base-case economic model. The committee had concerns about this approach. After new analyses was provided at technical engagement, the technical team favoured the ERG's preferred approach of using the ERG‑requested utility model with 'time-to-death categories 1\xa0week earlier' to estimate utility values. Analysis done by the company during technical engagement showed that disease progression had little effect on the quality-of-life data from IMpower133. However, the clinical experts commented that they would expect a patient's quality of life to decrease after disease progression. The committee was concerned that EQ‑5D data for patients whose disease had progressed could be biased. This was because of informative censoring (that is, when quality of life after progression is measured before there is any decrease in quality of life caused by progression, or if people whose disease has progressed are less likely to complete quality-of-life questionnaires). Also, during the trial, quality-of-life data might no longer have been reliably collected once a patient's disease had progressed or they had stopped having treatment. The company commented that its updated time-to-death statistical model for estimating utility based on trial EQ‑5D data did include progression status. However, the committee considered that the problems around informative censoring remained. The company also highlighted that previous appraisals used this approach to estimate utility. However, the committee was aware that NICE technology appraisal guidance on pembrolizumab with carboplatin and paclitaxel for untreated metastatic squamous non-small-cell lung cancer preferred using progression-based utility values instead of a time-to-death based approach. The committee concluded that the company's time-to-death approach to estimate utilities was acceptable for this particular appraisal, given the specific circumstances, but this should not be considered the usual methodology for this disease.\n\n## The duration of treatment benefit from the start of treatment is uncertain, but varying this duration has a small effect on the cost-effectiveness results\n\nThe committee requested investigation of the effect of reducing the duration of treatment benefit on model results. This is because, based on a Kaplan−Meier data plot of overall survival from IMpower133, there may be no treatment benefit from about 30\xa0months (see section\xa03.3). The company presented scenario analyses for no treatment effect cut-off, as well as for 36,\xa048 and 60\xa0months from the start of treatment. It chose to use a 60‑month effect cut-off in its base case. The ERG carried out an illustrative scenario with a cut-off of 30\xa0months, which was about the maximum follow up in the trial. However, varying the treatment effect duration did not have a large effect on the ICER overall. The committee concluded that the company's preferred 60‑month treatment effect duration from starting treatment was plausible but uncertain because follow up was still short.\n\n## Flexible methods of estimating overall survival are explored to identify the most appropriate model assumptions for decision making\n\nIn its original submission, the company used log-logistic extrapolations in its base-case model. It stated that the Weibull extrapolations were not appropriate for overall survival (the ERG's preferred approach at the time). This was because the company predicted that all people with ES‑SCLC did not survive past about 40\xa0months. The company commented that several studies showed that people having standard care were alive after this time. It expected to see prolonged survival for people having atezolizumab, consistent with immunotherapeutic effects seen in other indications. The clinical experts commented that, while there is some evidence that immunotherapy causes prolonged remission for NSCLC, it is too early to see if this is the case for SCLC. The committee did not accept that observing a longer-term treatment effect in 1\xa0disease would necessarily translate to another disease. Confirmatory long-term data are needed. The clinical experts also explained that, while some people with SCLC do survive for 5\xa0years, this is mostly people with early-stage SCLC. Not everyone with ES‑SCLC would die from the condition by 5\xa0years, but the proportion surviving by that point was likely to be fewer than 1%. The committee commented that neither the Weibull nor log-logistic models fitted the IMpower133 data very well, but were the least poor fitting of the parametric survival extrapolations used by the company. Also, looking at the hazard over time, there was a complex pattern which would have been clearer if a plot of hazard function over time had been provided. The committee concluded that the Weibull extrapolation for overall survival may be too pessimistic to reflect the chemotherapy-only group outcome, and the log-logistic may be too optimistic. It did not consider either approach suitable for decision making at the first appraisal committee meeting. It requested that the company provided new analyses exploring further methods for estimating mean overall survival. The committee considered that alternative, more flexible models may allow better representation of the available survival data and would provide a more robust basis for decision making.\n\n## Restricted spline models may provide the best method for modelling atezolizumab with chemotherapy long-term overall survival\n\nIn response to the committee's request for new analyses with alternative models, the company provided plots of the hazard function over time. It commented that long-term hazards were decreasing, and that both groups in IMpower133 had different shaped curves before and after about 5\xa0months. The company validated the new models with 8\xa0consultant oncologists to understand how well the extrapolations reflected long-term overall survival in clinical practice. It presented a new base-case model with changed curve-fitting and extrapolation of overall survival. This was a hybrid model using Kaplan−Meier data then switching at 20\xa0months to a log-logistic extrapolation for both the atezolizumab and the chemotherapy groups. The ERG stated that there was no compelling reason to choose a hybrid model of Kaplan−Meier data followed by extrapolation instead of a parametric curve extrapolation alone. The ERG preferred a log-logistic model for the chemotherapy group because it was the most plausible based on statistical fit, visual fit, decreasing hazards and 2.5% survival at 5\xa0years. The committee agreed to use a log-logistic method for the chemotherapy arm, with a more flexible curve-fitting approach for the atezolizumab arm in its decision making. It considered that the chemotherapy group hazard reduced over time, but this was not reflected in the company's preferred hybrid modelling. It was concerned that the company's hybrid modelling was inappropriate because the event hazard rate had been applied for the whole model duration, rather than a hazard rate related to a specific cut-point in time. The committee concluded that the most appropriate overall survival model for the atezolizumab arm fitted to the whole curve (rather than just a section of it) and took into account the changing hazard profile over time. Therefore, the committee agreed that some of the spline-based models for the atezolizumab arm were most appropriate, but statistical criteria did not show that any one was a better choice than any other. It noted that, when using the 60‑month treatment effect duration (see section\xa03.6), the ICER generated with a log-logistic model for the chemotherapy arm and one of the preferred spline models for the atezolizumab arm would give an ICER of between £32,433 per quality-adjusted life year (QALY) gained and £48,770 per QALY gained when the revised patient access scheme was applied.\n\n## The curve-fitting and extrapolation of overall survival has a large effect on the ICER\n\nThe company's new deterministic base case showed that the ICER for atezolizumab and chemotherapy compared with chemotherapy alone was £26,998 per QALY gained. All analyses included the revised patient access scheme for atezolizumab. The ERG preferred to use a log-logistic extrapolation for long-term survival for the chemotherapy arm. It considered several different plausible extrapolations for the atezolizumab arm, giving ICERs of between £25,567 and £48,770 per QALY gained for atezolizumab and chemotherapy compared with chemotherapy alone. The committee agreed that a log-logistic extrapolation was appropriate for the chemotherapy arm (see section\xa03.8). Also, it found that some of the flexible curves considered plausible fits to the trial data by the ERG and technical team for the atezolizumab group were more appropriate, particularly the spline-based models. These spline models gave a plausible ICER of between £32,433 per QALY gained and £48,770 per QALY gained for atezolizumab and chemotherapy compared with chemotherapy alone.\n\n# End of life\n\n## Restricted mean analysis of overall survival data from IMpower133 may support atezolizumab with chemotherapy meeting NICE's end-of-life criteria\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. A restricted mean analysis of the overall survival data from IMpower133 may help estimate the extent that atezolizumab with chemotherapy extends life compared with chemotherapy alone. The company explained that the restricted mean survival time increases with further data cuts and gets closer to NICE's end-of-life extension-to-life criterion. With the company's updated base case, the mean difference in overall survival was 4.93\xa0months, which is above the 3\xa0months threshold needed to meet the end-of-life criteria. The ERG explained that the restricted mean analysis showed that one of the end-of-life criteria might not be met if the difference in mean survival based on the trial data only is used to estimate increase in life expectancy. However, the difference in means is larger the later the cut-off, and the model predicted a gain in life expectancy of over 3\xa0months using any of the log-logistic based models. The committee used the evidence on restricted mean analysis to discuss whether or not all end-of-life criteria were met.\n\n## Atezolizumab with carboplatin and etoposide for ES-SCLC meets NICE's end-of-life criteria\n\nBased on evidence from IMpower133 and clinical expert opinion, the committee concluded that the life expectancy of people with untreated ES‑SCLC would be under 24\xa0months with current NHS treatment. The company's preferred economic model was a hybrid model using Kaplan−Meier data with log-logistic extrapolation from 20\xa0months. This predicted a mean increase in survival of 4.93\xa0months for atezolizumab with carboplatin and etoposide. The increase in median overall survival from IMpower133 was 2.0\xa0months for atezolizumab compared with placebo (12.3\xa0months compared with 10.3\xa0months). The committee had concluded that there was uncertainty about the most appropriate method for estimating mean overall survival in this appraisal (see section\xa03.8). However, almost all the models for overall survival that it considered plausible gave a survival gain of 3\xa0months or more for atezolizumab and chemotherapy compared with chemotherapy alone. So, the committee accepted that this criterion was met in this circumstance. It concluded that, on balance, with trial and modelled evidence, taking both mean and median survival into account, the NICE criteria for a treatment at the end of life were met.\n\n# Other factors\n\n## Healthcare professionals should consider ECOG performance status when implementing the recommendations\n\nThe committee considered whether its recommendations were associated with any potential issues related to equality. It concluded that healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect ECOG performance status and make any adjustments they consider appropriate.\n\n## All relevant benefits of the treatment are captured in the QALY\n\nAtezolizumab with carboplatin and etoposide may be innovative. However, all relevant benefits of the technology were captured in the QALY.\n\n# Conclusion\n\n## Atezolizumab with carboplatin and etoposide is recommended for untreated ES-SCLC in adults\n\nThe company provided multiple models of overall survival at the request of the committee and updated its base case, but the committee still found some remaining uncertainty around which of the more flexible models of overall survival was most appropriate. However, having considered the various models with different fits to the atezolizumab and chemotherapy arms that it found plausible (see section\xa03.8), the committee concluded that the range of plausible ICERs with the confidential discount was within the range considered cost effective for end-of-life treatments. The trial only included people with an ECOG performance status of 0\xa0to\xa01, and the committee agreed that its recommendations should reflect the population in the trial. Therefore, it recommended atezolizumab with carboplatin and etoposide as an option for untreated ES‑SCLC in adults, only if they have an ECOG performance status of 0\xa0or\xa01."}
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https://www.nice.org.uk/guidance/ta638
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Evidence-based recommendations on atezolizumab (Tecentriq) for untreated extensive-stage small-cell lung cancer in adults.
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365f22b798bea8afd217ac0c1e27c4b8f040e945
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nice
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Atezolizumab with nab-paclitaxel for untreated PD-L1-positive, locally advanced or metastatic, triple-negative breast cancer
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Atezolizumab with nab-paclitaxel for untreated PD-L1-positive, locally advanced or metastatic, triple-negative breast cancer
Evidence-based recommendations on atezolizumab (Tecentriq) with nab‑paclitaxel for triple-negative, unresectable, PD‑L1‑positive, locally advanced or metastatic breast cancer in adults who have not had chemotherapy for metastatic disease.
# Recommendations
Atezolizumab with nab‑paclitaxel is recommended, within its marketing authorisation, for treating triple-negative, unresectable, locally advanced or metastatic breast cancer in adults whose tumours express PD‑L1 at a level of 1% or more and who have not had previous chemotherapy for metastatic disease. It is recommended only if the company provides atezolizumab according to the commercial arrangement.
Why the committee made these recommendations
There are currently no targeted or immunotherapy treatments for triple-negative breast cancer. The only treatment option is chemotherapy, usually with taxane monotherapy. Atezolizumab is the first immunotherapy to be approved for PD‑L1‑positive, triple-negative advanced breast cancer. It is used in combination with the chemotherapy agent, nab‑paclitaxel.
Clinical trial evidence shows that people having atezolizumab plus nab‑paclitaxel live longer before their condition gets worse than people having placebo plus nab‑paclitaxel. It also suggests that they live longer. There is no direct comparison of atezolizumab plus nab‑paclitaxel with taxanes that are used in the NHS, such as weekly paclitaxel. However, it is reasonable to assume that nab‑paclitaxel has a similar efficacy to weekly paclitaxel.
Atezolizumab plus nab‑paclitaxel is considered to be a life-extending treatment at the end of life. The cost-effectiveness estimates are within what NICE considers an acceptable use of NHS resources. Therefore, atezolizumab with nab‑paclitaxel is recommended.# Information about atezolizumab
# Marketing authorisation indication
Atezolizumab (Tecentriq, Roche) 'in combination with nab‑paclitaxel is indicated for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) whose tumours have PD‑L1 expression ≥ 1% and who have not received prior chemotherapy for metastatic disease'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price for atezolizumab is £2,665.38 per 840 mg/14 ml vial (excluding VAT, BNF online accessed April 2020). The company has a commercial arrangement, which makes atezolizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Roche, a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that 1 issue was resolved during the technical engagement stage, and agreed that:
The company's assumption that patients in the progression-free and progressed disease health states have an oncology appointment at 6 months and then every 2 months underestimates health-resource use in the NHS.
The ERG's assumption that patients in the NHS have a monthly oncology visit is more plausible and should be used for modelling health-resource use.It recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, section 1.2), and took these into account in its decision making. It discussed the following issues (issues 1, 2, 3, 4, 5, 6 and 7), which were outstanding after the technical engagement stage.
# Clinical need and treatment pathway
## The burden of triple-negative advanced breast cancer is high
The patient expert explained that triple-negative advanced breast cancer is a devastating condition, and has a huge negative effect on the quality of life of patients and their families. Progression of the condition may be more aggressive than in other types of breast cancer, and the outcomes can be worse. The prognosis is extremely poor and average survival for advanced disease is 12 to 18 months. The condition often affects people of a younger age who may have young children and caring responsibilities, and who have to rely on family members and friends to take on their caring responsibilities. The patient expert emphasised that the burden of the disease on the family is high, both emotionally and financially. The committee understood these factors. It recognised both the poor prognosis and the disease burden in people with triple-negative advanced breast cancer.
## Limited treatment options are available
The clinical and patient experts explained that, unlike in hormone receptor-positive or human epidermal growth factor receptor 2 (HER2)‑positive breast cancer, there are no specific targeted treatments for people with triple-negative advanced breast cancer. Currently, the only treatment option for people with triple-negative advanced breast cancer is chemotherapy, usually with a taxane. This has side effects including increased risk of infection, hair loss, sickness, nausea and fatigue. Atezolizumab is the first immunotherapy for PD‑L1‑positive, triple-negative breast cancer. It is also the first treatment to substantially improve outcomes for people with triple-negative breast cancer compared with taxane chemotherapy alone, so is considered to be a major breakthrough in managing the condition. The patient expert explained that the availability of a new treatment that increases progression-free survival compared with chemotherapy alone gives hope to people with the condition that they will be able to maintain a good quality life for as long as possible. The side effects of atezolizumab plus nab‑paclitaxel are manageable and allow people to have a reasonably good quality of life. The patient expert also explained that atezolizumab plus nab‑paclitaxel is available to some patients through the Early Access to Medicines Scheme, and that a negative recommendation would be devastating to patients and their families. The committee concluded that there is a very high unmet clinical need among people with triple-negative advanced breast cancer, and that the availability of a new immunotherapy is an important development in this condition.
# PD-L1 testing in triple-negative advanced breast cancer
## There would be no major barriers to introducing PD-L1 testing in people with triple-negative breast cancer
The marketing authorisation for atezolizumab specifies that it is indicated for the treatment of adults with unresectable, locally advanced or metastatic triple-negative breast cancer whose tumours have PD‑L1 expression at a level of 1% or more and who have not had previous chemotherapy for metastatic disease. Currently PD‑L1 testing is not part of routine clinical practice in triple-negative breast cancer. However, it is routinely carried out for people with other types of cancer such as non-small-cell lung cancer and urothelial carcinoma. The clinical experts and the Cancer Drugs Fund clinical lead explained that introducing PD‑L1 testing for people with triple-negative breast cancer would not be problematic, and that the currently used diagnostic tests could be used. Although additional training and resources would be needed, the testing would have a limited impact on the workflow in laboratories. The committee concluded that there would be no major barriers to introducing PD‑L1 testing in people with triple-negative breast cancer.
# Appropriate comparators
## Weekly paclitaxel is the most relevant comparator
The final scope specified 2 groups of comparators: anthracycline-based chemotherapy and single-agent taxanes (docetaxel and paclitaxel). The company did not present evidence comparing atezolizumab plus nab‑paclitaxel with anthracycline-based chemotherapy. It said this was because most people have anthracycline treatment for early breast cancer, and they are unlikely to be eligible for re-treatment at an advanced stage because anthracyclines have a lifetime maximum cumulative dose. The clinical experts explained that there is no standard of care in triple-negative advanced breast cancer but the most commonly used treatments are taxanes, particularly weekly paclitaxel. This is used because it has a more favourable toxicity profile than docetaxel so people are able tolerate treatment, and maintain a treatment response, for longer. The clinical experts agreed with the company that anthracycline-based chemotherapy regimens are not commonly used for advanced breast cancer. The committee concluded that weekly paclitaxel is the most relevant comparator.
## Nab-paclitaxel has similar efficacy to weekly paclitaxel and docetaxel
The clinical experts explained that nab‑paclitaxel, which is the form of paclitaxel used in the trial in both the intervention and comparator arms (see section 3.6), is not routinely used in UK clinical practice. However, it is considered to be broadly equivalent to the taxanes currently in routine use and may be used when people develop hypersensitivity to the conventional formulations of paclitaxel or docetaxel. The clinical experts explained that nab‑paclitaxel gives similar results compared with weekly paclitaxel, although it delivers a slightly higher dose of paclitaxel to the tissue because of its formulation. The licensing studies for nab‑paclitaxel showed no statistically significant difference in progression-free survival or overall survival between paclitaxel and nab‑paclitaxel in patients having their first treatment for metastatic breast cancer. In terms of overall survival, 1 clinical expert expected there to be no difference in survival outcomes between weekly paclitaxel and nab‑paclitaxel and the other expert considered that, if any difference exists at all, it would be marginal. The committee concluded that nab‑paclitaxel and weekly paclitaxel have broadly similar efficacy in advanced breast cancer.
# Clinical trial evidence from IMpassion130
## The results of IMpassion130 are generalisable to UK clinical practice
IMpassion130 is a double-blind randomised clinical trial comparing atezolizumab plus nab‑paclitaxel against placebo plus nab‑paclitaxel in people with triple-negative advanced breast cancer who have not had previous treatment for metastatic disease. Nine treatment centres in the UK (44 patients) were included in the trial. The company presented a subgroup analysis of patients with PD‑L1‑positive (that is, PD‑L1 expression level of 1% or more), triple-negative, advanced breast cancer. This subgroup represented 41% of the overall trial population. In the PD‑L1‑positive subgroup, 71% of patients had had previous treatment with anthracyclines and 21% of patients had metastatic disease at presentation. The clinical experts explained that these characteristics reflect the population who would be eligible for treatment with atezolizumab plus nab‑paclitaxel in the NHS. The committee concluded that the PD‑L1-positive subgroup of IMpassion130 is broadly generalisable to UK clinical practice.
## Atezolizumab plus nab-paclitaxel improves progression-free survival
The joint primary endpoints in IMpassion130 were progression-free survival and overall survival. The trial protocol specified that formal testing of statistical significance in the PD‑L1‑positive population could only occur if statistical significance was shown in the intention-to-treat population. For progression-free survival, at the first data cut in April 2018 (the definitive progression-free survival analysis), there was a statistically significant improvement with atezolizumab plus nab‑paclitaxel in both the intention-to-treat and the PD‑L1‑positive population. Median progression-free survival in the PD‑L1‑positive subgroup was 7.5 months in the atezolizumab plus nab‑paclitaxel arm and 5.0 months in the placebo plus nab‑paclitaxel arm (hazard ratio 0.62, 95% confidence interval 0.49 to 0.78). The committee concluded that atezolizumab plus nab‑paclitaxel improves progression-free survival compared with placebo plus nab‑paclitaxel.
## The evidence suggests that atezolizumab plus nab-paclitaxel increases overall survival in the PD-L1-positive subgroup
In the intention-to-treat population, the results for overall survival in the first interim analysis were not statistically significant, and formal testing of overall survival in the PD‑L1‑positive subgroup according to the trial protocol was not possible (see section 3.7). The company presented an informal analysis of overall survival in the PD‑L1‑positive subgroup. The median overall survival was 25.0 months compared with 15.5 months in the placebo plus nab‑paclitaxel population (hazard ratio 0.62, 95% confidence interval 0.45 to 0.86). The company explained that the final analysis for overall survival is expected in 2020. However, because the data are already relatively mature, the company does not expect that this will substantially reduce the clinical uncertainty. The committee concluded that the data suggest that atezolizumab plus nab‑paclitaxel increases overall survival in patients with triple-negative advanced breast cancer. However, it noted that the results were not from a formal analysis.
# Indirect comparison with taxanes
## The company's network meta-analysis is not reliable and lacks face validity
In the absence of a head-to-head trial comparing atezolizumab plus nab‑paclitaxel against weekly paclitaxel or docetaxel, the company presented a type of network meta-analysis (NMA) known as a population-adjusted indirect comparison. This method is used to link studies in unconnected networks. There were 7 trials in the overall-survival analysis and 8 in the progression-free survival analysis. The committee heard from the ERG that the methods used in the NMA were broadly appropriate. However, the ERG had concerns about the approach used to estimate the survival times, and the assumption that the results from patients with unknown PD‑L1 disease status were generalisable to the subgroup with PD‑L1‑positive disease. It was also concerned about the limited data on baseline characteristics on which the matching of studies could be based. Also, the results of the NMA were associated with high uncertainty because the credible intervals around the point estimates of the hazard ratios were very wide. The ERG advised that the results should be interpreted with caution. This made it difficult for the committee to assess whether the effectiveness of the treatments is different. It discussed the methodology used in the NMA and the steps taken to adjust for heterogeneity in patient characteristics among the trials. It heard that the company adjusted for a number of variables including age, Eastern Cooperative Oncology Group (ECOG) status, previous taxane use, the time from initial diagnosis to metastatic disease and the proportion of patients with metastases in the liver, other viscera or bone. The clinical experts confirmed that these are key characteristics that determine treatment response in this patient population. However, the trials did not all report the same patient characteristics and therefore different variables were adjusted in each study. The proportion of de novo metastases is also an important determinant of response to further treatments and prognosis, but this was not included in the NMA. The committee heard from the company that, in order to connect trials together in the NMA, they created virtual trials using observational data-analysis techniques in which patients in one study were propensity-score matched to patients in another study. The committee noted the importance of having the relevant data on patient characteristics in order for the match to be appropriate and the resulting 'virtual study' to be unbiased. The committee discussed the face validity of the NMA results. The NMA predicted higher overall survival for docetaxel and paclitaxel compared with nab‑paclitaxel in the first 5 months and then higher overall survival for nab‑paclitaxel after 5 months. The clinical experts confirmed that paclitaxel and nab‑paclitaxel are very similar, therefore such differences are unlikely. Using the results of the NMA, the cost-effectiveness model predicted much larger differences in overall survival between nab‑paclitaxel and paclitaxel than those expected by the clinical experts. Also, using the results of the NMA, the cost-effectiveness model predicted better overall survival with docetaxel than with paclitaxel, which is contrary to the expectations of the clinical experts. The committee appreciated that the company's NMA incorporated the very limited evidence available to estimate the relative effectiveness of the treatments. However, it thought that there was considerable heterogeneity among the trials that may not have been appropriately taken into account, given the limitations of the data. It also noted the poor face validity of the results. For these reasons, the committee concluded that there was great uncertainty in the NMA, and that the results were not robust and lacked face validity.
# Cost effectiveness
## Data from the nab-paclitaxel arm of IMpassion130 are appropriate for modelling the effectiveness of weekly paclitaxel
The company submitted a 3‑state partitioned survival model to estimate the cost effectiveness of atezolizumab plus nab‑paclitaxel compared against weekly paclitaxel or docetaxel. The approach used to model the relative effectiveness of these treatments was a key driver of the model results. The company used the results of its NMA to model the differences in effectiveness. However, because of the limitations of the NMA and the high uncertainty in the results (see section 3.9), the ERG did not consider the results of the NMA to be robust enough to use in the economic model. Because there was no clear evidence of a difference between nab‑paclitaxel, paclitaxel and docetaxel in terms of overall survival and progression-free survival, the ERG presented the results of a scenario analysis that assumed equal effectiveness between these treatments. It used data from the placebo plus nab‑paclitaxel arm of IMpassion130 as a proxy for the effectiveness of other taxane regimens. The committee considered which approach was more appropriate. It recalled its previous conclusions that the results of the NMA were not reliable and lacked face validity (see section 3.9), and the feedback from clinical experts that nab‑paclitaxel and weekly paclitaxel have broadly similar efficacy (see section 3.5). The company argued that this assumption was overly conservative and oversimplified the evidence. It also highlighted that using the NMA predicted a 0.197‑year difference in life years between nab‑paclitaxel and paclitaxel (which it believed to be a marginal difference) but has a big impact on the incremental cost-effectiveness ratio (ICER). The committee did not consider that the 10.27‑week life year gain predicted by the model was a trivial difference. It accepted that using data from the placebo plus nab‑paclitaxel arm of IMpassion130 as a proxy for the effectiveness of weekly paclitaxel was not a perfect approach. However, it considered a randomised, unbiased and contemporaneous comparison to be more reliable than the NMA, which was based on heterogenous and historical trial populations and associated with high uncertainty. The committee therefore concluded that the ERG's approach, using the control arm of IMpassion130 as a proxy for the effectiveness of weekly paclitaxel, was preferable.
# Treatment-effect duration
## Assuming a treatment waning effect is not appropriate
In IMpassion130, treatment was continued until disease progression or unacceptable toxicity. The median treatment duration was 26.4 weeks in the atezolizumab arm and 16.1 weeks in the placebo arm. The company assumed that a treatment benefit would be maintained for a lifetime horizon (assumed to be 15 years). The ERG considered that this assumption was implausible. It presented a scenario analysis in which it limited the treatment effect to 3 or 5 years from the start of treatment. However, the ERG acknowledged that there was a lack of evidence on the long-term treatment effect and these were arbitrary time points. The company explained that applying a 3‑year treatment benefit cap meant that patients still on treatment at 3 years (6% in the clinical trial) would experience no further benefit, which it did not consider to be clinically plausible. The committee noted that, in previous NICE appraisals in which a treatment duration cap was considered, a treatment stopping rule was applied in the analyses. However, the marketing authorisation for atezolizumab recommends that treatment should be continued until disease progression or unacceptable toxicity. The committee acknowledged that treatment-effect duration is an area of uncertainty. However, in the absence of evidence, the committee concluded that incorporating an arbitrary treatment waning effect was not appropriate.
# Treatment duration with paclitaxel
## Data on time to stopping treatment from the control arm of IMpassion130 may be more relevant for decision making
The company submitted additional evidence during technical engagement. This was because it considered that it had misinterpreted how weekly paclitaxel is administered in the NHS and had incorrectly assumed a maximum of 18 weeks or cycles of treatment. In its updated base-case model, it removed this treatment cap and assumed that patients have paclitaxel until disease progression. This reduced the ICER. The ERG commented that it had been given clinical advice suggesting that treatment beyond 6 months is unusual and that it does not exceed 10 months. Applying a 10‑month treatment cap in the model also decreased the ICER but had a more modest effect than the company's scenario. The clinical experts explained that there is variation in the duration of paclitaxel treatment in the NHS. In the past, it was common for treatment to continue for a fixed period. But now, patients are more likely to have paclitaxel until disease progression or unacceptable toxicity. They explained that, to extend the treatment period, side effects are often managed by dose reductions and dose 'holidays', so assuming full dosage for all patients until disease progression was not realistic. However, the committee also heard from the clinical experts that assuming an 18‑cycle cut-off point would be arbitrary and not supported by evidence. Their experience is that most chemotherapies stop working after 10 months. However, because there are no effective alternative treatments in this condition, it is common practice to continue treatment until there is evidence of no further benefit. The committee accepted that an 18‑cycle treatment cap does not reflect clinical practice in the NHS. However, it considered that the company's revised analysis, which assumed all patients on paclitaxel would have it at the full dose until disease progression, was not reliable because it did not account for dose reductions, or for variation in practice in the NHS. The committee concluded that the company's updated analysis overestimated average treatment duration with weekly paclitaxel and the associated costs. It suggested that, in the absence of robust real-world evidence, the treatment duration of weekly paclitaxel may have best been informed by the treatment duration in the nab‑paclitaxel control arm of IMpassion130 (see section 3.10). The committee concluded that average treatment duration with weekly paclitaxel was uncertain and would have best been informed by data on time to stopping treatment from the control arm of IMpassion130.
# Cost-effectiveness estimate
## The company's updated commercial arrangement reduced the ICER
Following consultation, the company updated its commercial arrangement and submitted an updated analysis that incorporated the committee's preferred assumptions (see section 3.10 and section 3.12). The ICER is not reported here to protect the confidentiality of the commercial arrangement. The committee noted that the commercial arrangement reduces the ICER for atezolizumab plus nab‑paclitaxel compared with weekly paclitaxel. However, it remains above the range normally considered cost effective (that is, £20,000 to £30,000 per quality-adjusted life year gained) for technologies that are not given special consideration as life-extending treatments for people with a short life expectancy.
# End of life
## End-of-life criteria are met
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. It considered that all scenario analyses presented by the company and the ERG indicated that atezolizumab plus nab‑paclitaxel offers more than 3 months' extension to life in a population that has a life expectancy of less than 24 months. Therefore, it concluded that atezolizumab plus nab‑paclitaxel fulfils the end-of-life criteria.
# Other factors
The company and clinical experts considered atezolizumab plus nab‑paclitaxel to be innovative, and a major breakthrough in managing triple-negative breast cancer. It is the first treatment to substantially improve outcomes compared with chemotherapy in this population. However, the committee considered that all relevant benefits associated with the drug were adequately captured in the model.
# Conclusion
## Atezolizumab plus nab-paclitaxel is recommended for PD-L1-positive, triple-negative advanced breast cancer
Clinical trial evidence has shown that atezolizumab plus nab‑paclitaxel increases progression-free survival and suggests it could increase overall survival compared with placebo plus nab‑paclitaxel. When the updated commercial offer and the greater weight assigned to QALYs at the end of life are taken into account, the ICER is acceptable. Therefore, atezolizumab plus nab‑paclitaxel is recommended for PD‑L1‑positive, triple-negative advanced breast cancer.
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{'Recommendations': 'Atezolizumab with nab‑paclitaxel is recommended, within its marketing authorisation, for treating triple-negative, unresectable, locally advanced or metastatic breast cancer in adults whose tumours express PD‑L1 at a level of\xa01% or more and who have not had previous chemotherapy for metastatic disease. It is recommended only if the company provides atezolizumab according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nThere are currently no targeted or immunotherapy treatments for triple-negative breast cancer. The only treatment option is chemotherapy, usually with taxane monotherapy. Atezolizumab is the first immunotherapy to be approved for PD‑L1‑positive, triple-negative advanced breast cancer. It is used in combination with the chemotherapy agent, nab‑paclitaxel.\n\nClinical trial evidence shows that people having atezolizumab plus nab‑paclitaxel live longer before their condition gets worse than people having placebo plus nab‑paclitaxel. It also suggests that they live longer. There is no direct comparison of atezolizumab plus nab‑paclitaxel with taxanes that are used in the NHS, such as weekly paclitaxel. However, it is reasonable to assume that nab‑paclitaxel has a similar efficacy to weekly paclitaxel.\n\nAtezolizumab plus nab‑paclitaxel is considered to be a life-extending treatment at the end of life. The cost-effectiveness estimates are within what NICE considers an acceptable use of NHS resources. Therefore, atezolizumab with nab‑paclitaxel is recommended.', 'Information about atezolizumab': "# Marketing authorisation indication\n\nAtezolizumab (Tecentriq, Roche) 'in combination with nab‑paclitaxel is indicated for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) whose tumours have PD‑L1 expression ≥\xa01% and who have not received prior chemotherapy for metastatic disease'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price for atezolizumab is £2,665.38 per 840\xa0mg/14\xa0ml vial (excluding VAT, BNF online accessed April\xa02020). The company has a commercial arrangement, which makes atezolizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Roche, a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that 1\xa0issue was resolved during the technical engagement stage, and agreed that:\n\nThe company's assumption that patients in the progression-free and progressed disease health states have an oncology appointment at 6\xa0months and then every 2\xa0months underestimates health-resource use in the NHS.\n\nThe ERG's assumption that patients in the NHS have a monthly oncology visit is more plausible and should be used for modelling health-resource use.It recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, section\xa01.2), and took these into account in its decision making. It discussed the following issues (issues 1,\xa02,\xa03,\xa04,\xa05,\xa06\xa0and\xa07), which were outstanding after the technical engagement stage.\n\n# Clinical need and treatment pathway\n\n## The burden of triple-negative advanced breast cancer is high\n\nThe patient expert explained that triple-negative advanced breast cancer is a devastating condition, and has a huge negative effect on the quality of life of patients and their families. Progression of the condition may be more aggressive than in other types of breast cancer, and the outcomes can be worse. The prognosis is extremely poor and average survival for advanced disease is 12\xa0to 18\xa0months. The condition often affects people of a younger age who may have young children and caring responsibilities, and who have to rely on family members and friends to take on their caring responsibilities. The patient expert emphasised that the burden of the disease on the family is high, both emotionally and financially. The committee understood these factors. It recognised both the poor prognosis and the disease burden in people with triple-negative advanced breast cancer.\n\n## Limited treatment options are available\n\nThe clinical and patient experts explained that, unlike in hormone receptor-positive or human epidermal growth factor receptor\xa02 (HER2)‑positive breast cancer, there are no specific targeted treatments for people with triple-negative advanced breast cancer. Currently, the only treatment option for people with triple-negative advanced breast cancer is chemotherapy, usually with a taxane. This has side effects including increased risk of infection, hair loss, sickness, nausea and fatigue. Atezolizumab is the first immunotherapy for PD‑L1‑positive, triple-negative breast cancer. It is also the first treatment to substantially improve outcomes for people with triple-negative breast cancer compared with taxane chemotherapy alone, so is considered to be a major breakthrough in managing the condition. The patient expert explained that the availability of a new treatment that increases progression-free survival compared with chemotherapy alone gives hope to people with the condition that they will be able to maintain a good quality life for as long as possible. The side effects of atezolizumab plus nab‑paclitaxel are manageable and allow people to have a reasonably good quality of life. The patient expert also explained that atezolizumab plus nab‑paclitaxel is available to some patients through the Early Access to Medicines Scheme, and that a negative recommendation would be devastating to patients and their families. The committee concluded that there is a very high unmet clinical need among people with triple-negative advanced breast cancer, and that the availability of a new immunotherapy is an important development in this condition.\n\n# PD-L1 testing in triple-negative advanced breast cancer\n\n## There would be no major barriers to introducing PD-L1 testing in people with triple-negative breast cancer\n\nThe marketing authorisation for atezolizumab specifies that it is indicated for the treatment of adults with unresectable, locally advanced or metastatic triple-negative breast cancer whose tumours have PD‑L1 expression at a level of 1%\xa0or more and who have not had previous chemotherapy for metastatic disease. Currently PD‑L1 testing is not part of routine clinical practice in triple-negative breast cancer. However, it is routinely carried out for people with other types of cancer such as non-small-cell lung cancer and urothelial carcinoma. The clinical experts and the Cancer Drugs Fund clinical lead explained that introducing PD‑L1 testing for people with triple-negative breast cancer would not be problematic, and that the currently used diagnostic tests could be used. Although additional training and resources would be needed, the testing would have a limited impact on the workflow in laboratories. The committee concluded that there would be no major barriers to introducing PD‑L1 testing in people with triple-negative breast cancer.\n\n# Appropriate comparators\n\n## Weekly paclitaxel is the most relevant comparator\n\nThe final scope specified 2\xa0groups of comparators: anthracycline-based chemotherapy and single-agent taxanes (docetaxel and paclitaxel). The company did not present evidence comparing atezolizumab plus nab‑paclitaxel with anthracycline-based chemotherapy. It said this was because most people have anthracycline treatment for early breast cancer, and they are unlikely to be eligible for re-treatment at an advanced stage because anthracyclines have a lifetime maximum cumulative dose. The clinical experts explained that there is no standard of care in triple-negative advanced breast cancer but the most commonly used treatments are taxanes, particularly weekly paclitaxel. This is used because it has a more favourable toxicity profile than docetaxel so people are able tolerate treatment, and maintain a treatment response, for longer. The clinical experts agreed with the company that anthracycline-based chemotherapy regimens are not commonly used for advanced breast cancer. The committee concluded that weekly paclitaxel is the most relevant comparator.\n\n## Nab-paclitaxel has similar efficacy to weekly paclitaxel and docetaxel\n\nThe clinical experts explained that nab‑paclitaxel, which is the form of paclitaxel used in the trial in both the intervention and comparator arms (see section\xa03.6), is not routinely used in UK clinical practice. However, it is considered to be broadly equivalent to the taxanes currently in routine use and may be used when people develop hypersensitivity to the conventional formulations of paclitaxel or docetaxel. The clinical experts explained that nab‑paclitaxel gives similar results compared with weekly paclitaxel, although it delivers a slightly higher dose of paclitaxel to the tissue because of its formulation. The licensing studies for nab‑paclitaxel showed no statistically significant difference in progression-free survival or overall survival between paclitaxel and nab‑paclitaxel in patients having their first treatment for metastatic breast cancer. In terms of overall survival, 1\xa0clinical expert expected there to be no difference in survival outcomes between weekly paclitaxel and nab‑paclitaxel and the other expert considered that, if any difference exists at all, it would be marginal. The committee concluded that nab‑paclitaxel and weekly paclitaxel have broadly similar efficacy in advanced breast cancer.\n\n# Clinical trial evidence from IMpassion130\n\n## The results of IMpassion130 are generalisable to UK clinical practice\n\nIMpassion130 is a double-blind randomised clinical trial comparing atezolizumab plus nab‑paclitaxel against placebo plus nab‑paclitaxel in people with triple-negative advanced breast cancer who have not had previous treatment for metastatic disease. Nine treatment centres in the UK (44\xa0patients) were included in the trial. The company presented a subgroup analysis of patients with PD‑L1‑positive (that is, PD‑L1 expression level of 1%\xa0or more), triple-negative, advanced breast cancer. This subgroup represented 41% of the overall trial population. In the PD‑L1‑positive subgroup, 71% of patients had had previous treatment with anthracyclines and 21% of patients had metastatic disease at presentation. The clinical experts explained that these characteristics reflect the population who would be eligible for treatment with atezolizumab plus nab‑paclitaxel in the NHS. The committee concluded that the PD‑L1-positive subgroup of IMpassion130 is broadly generalisable to UK clinical practice.\n\n## Atezolizumab plus nab-paclitaxel improves progression-free survival\n\nThe joint primary endpoints in IMpassion130 were progression-free survival and overall survival. The trial protocol specified that formal testing of statistical significance in the PD‑L1‑positive population could only occur if statistical significance was shown in the intention-to-treat population. For progression-free survival, at the first data cut in April\xa02018 (the definitive progression-free survival analysis), there was a statistically significant improvement with atezolizumab plus nab‑paclitaxel in both the intention-to-treat and the PD‑L1‑positive population. Median progression-free survival in the PD‑L1‑positive subgroup was 7.5\xa0months in the atezolizumab plus nab‑paclitaxel arm and 5.0\xa0months in the placebo plus nab‑paclitaxel arm (hazard ratio\xa00.62, 95%\xa0confidence interval 0.49\xa0to\xa00.78). The committee concluded that atezolizumab plus nab‑paclitaxel improves progression-free survival compared with placebo plus nab‑paclitaxel.\n\n## The evidence suggests that atezolizumab plus nab-paclitaxel increases overall survival in the PD-L1-positive subgroup\n\nIn the intention-to-treat population, the results for overall survival in the first interim analysis were not statistically significant, and formal testing of overall survival in the PD‑L1‑positive subgroup according to the trial protocol was not possible (see section\xa03.7). The company presented an informal analysis of overall survival in the PD‑L1‑positive subgroup. The median overall survival was 25.0\xa0months compared with 15.5\xa0months in the placebo plus nab‑paclitaxel population (hazard ratio\xa00.62, 95%\xa0confidence interval 0.45\xa0to\xa00.86). The company explained that the final analysis for overall survival is expected in 2020. However, because the data are already relatively mature, the company does not expect that this will substantially reduce the clinical uncertainty. The committee concluded that the data suggest that atezolizumab plus nab‑paclitaxel increases overall survival in patients with triple-negative advanced breast cancer. However, it noted that the results were not from a formal analysis.\n\n# Indirect comparison with taxanes\n\n## The company's network meta-analysis is not reliable and lacks face validity\n\nIn the absence of a head-to-head trial comparing atezolizumab plus nab‑paclitaxel against weekly paclitaxel or docetaxel, the company presented a type of network meta-analysis (NMA) known as a population-adjusted indirect comparison. This method is used to link studies in unconnected networks. There were 7\xa0trials in the overall-survival analysis and 8 in the progression-free survival analysis. The committee heard from the ERG that the methods used in the NMA were broadly appropriate. However, the ERG had concerns about the approach used to estimate the survival times, and the assumption that the results from patients with unknown PD‑L1 disease status were generalisable to the subgroup with PD‑L1‑positive disease. It was also concerned about the limited data on baseline characteristics on which the matching of studies could be based. Also, the results of the NMA were associated with high uncertainty because the credible intervals around the point estimates of the hazard ratios were very wide. The ERG advised that the results should be interpreted with caution. This made it difficult for the committee to assess whether the effectiveness of the treatments is different. It discussed the methodology used in the NMA and the steps taken to adjust for heterogeneity in patient characteristics among the trials. It heard that the company adjusted for a number of variables including age, Eastern Cooperative Oncology Group (ECOG) status, previous taxane use, the time from initial diagnosis to metastatic disease and the proportion of patients with metastases in the liver, other viscera or bone. The clinical experts confirmed that these are key characteristics that determine treatment response in this patient population. However, the trials did not all report the same patient characteristics and therefore different variables were adjusted in each study. The proportion of de novo metastases is also an important determinant of response to further treatments and prognosis, but this was not included in the NMA. The committee heard from the company that, in order to connect trials together in the NMA, they created virtual trials using observational data-analysis techniques in which patients in one study were propensity-score matched to patients in another study. The committee noted the importance of having the relevant data on patient characteristics in order for the match to be appropriate and the resulting 'virtual study' to be unbiased. The committee discussed the face validity of the NMA results. The NMA predicted higher overall survival for docetaxel and paclitaxel compared with nab‑paclitaxel in the first 5\xa0months and then higher overall survival for nab‑paclitaxel after 5\xa0months. The clinical experts confirmed that paclitaxel and nab‑paclitaxel are very similar, therefore such differences are unlikely. Using the results of the NMA, the cost-effectiveness model predicted much larger differences in overall survival between nab‑paclitaxel and paclitaxel than those expected by the clinical experts. Also, using the results of the NMA, the cost-effectiveness model predicted better overall survival with docetaxel than with paclitaxel, which is contrary to the expectations of the clinical experts. The committee appreciated that the company's NMA incorporated the very limited evidence available to estimate the relative effectiveness of the treatments. However, it thought that there was considerable heterogeneity among the trials that may not have been appropriately taken into account, given the limitations of the data. It also noted the poor face validity of the results. For these reasons, the committee concluded that there was great uncertainty in the NMA, and that the results were not robust and lacked face validity.\n\n# Cost effectiveness\n\n## Data from the nab-paclitaxel arm of IMpassion130 are appropriate for modelling the effectiveness of weekly paclitaxel\n\nThe company submitted a 3‑state partitioned survival model to estimate the cost effectiveness of atezolizumab plus nab‑paclitaxel compared against weekly paclitaxel or docetaxel. The approach used to model the relative effectiveness of these treatments was a key driver of the model results. The company used the results of its NMA to model the differences in effectiveness. However, because of the limitations of the NMA and the high uncertainty in the results (see section\xa03.9), the ERG did not consider the results of the NMA to be robust enough to use in the economic model. Because there was no clear evidence of a difference between nab‑paclitaxel, paclitaxel and docetaxel in terms of overall survival and progression-free survival, the ERG presented the results of a scenario analysis that assumed equal effectiveness between these treatments. It used data from the placebo plus nab‑paclitaxel arm of IMpassion130 as a proxy for the effectiveness of other taxane regimens. The committee considered which approach was more appropriate. It recalled its previous conclusions that the results of the NMA were not reliable and lacked face validity (see section\xa03.9), and the feedback from clinical experts that nab‑paclitaxel and weekly paclitaxel have broadly similar efficacy (see section\xa03.5). The company argued that this assumption was overly conservative and oversimplified the evidence. It also highlighted that using the NMA predicted a 0.197‑year difference in life years between nab‑paclitaxel and paclitaxel (which it believed to be a marginal difference) but has a big impact on the incremental cost-effectiveness ratio (ICER). The committee did not consider that the 10.27‑week life year gain predicted by the model was a trivial difference. It accepted that using data from the placebo plus nab‑paclitaxel arm of IMpassion130 as a proxy for the effectiveness of weekly paclitaxel was not a perfect approach. However, it considered a randomised, unbiased and contemporaneous comparison to be more reliable than the NMA, which was based on heterogenous and historical trial populations and associated with high uncertainty. The committee therefore concluded that the ERG's approach, using the control arm of IMpassion130 as a proxy for the effectiveness of weekly paclitaxel, was preferable.\n\n# Treatment-effect duration\n\n## Assuming a treatment waning effect is not appropriate\n\nIn IMpassion130, treatment was continued until disease progression or unacceptable toxicity. The median treatment duration was 26.4\xa0weeks in the atezolizumab arm and 16.1\xa0weeks in the placebo arm. The company assumed that a treatment benefit would be maintained for a lifetime horizon (assumed to be 15\xa0years). The ERG considered that this assumption was implausible. It presented a scenario analysis in which it limited the treatment effect to 3\xa0or 5\xa0years from the start of treatment. However, the ERG acknowledged that there was a lack of evidence on the long-term treatment effect and these were arbitrary time points. The company explained that applying a 3‑year treatment benefit cap meant that patients still on treatment at 3\xa0years (6%\xa0in the clinical trial) would experience no further benefit, which it did not consider to be clinically plausible. The committee noted that, in previous NICE appraisals in which a treatment duration cap was considered, a treatment stopping rule was applied in the analyses. However, the marketing authorisation for atezolizumab recommends that treatment should be continued until disease progression or unacceptable toxicity. The committee acknowledged that treatment-effect duration is an area of uncertainty. However, in the absence of evidence, the committee concluded that incorporating an arbitrary treatment waning effect was not appropriate.\n\n# Treatment duration with paclitaxel\n\n## Data on time to stopping treatment from the control arm of IMpassion130 may be more relevant for decision making\n\nThe company submitted additional evidence during technical engagement. This was because it considered that it had misinterpreted how weekly paclitaxel is administered in the NHS and had incorrectly assumed a maximum of 18\xa0weeks or cycles of treatment. In its updated base-case model, it removed this treatment cap and assumed that patients have paclitaxel until disease progression. This reduced the ICER. The ERG commented that it had been given clinical advice suggesting that treatment beyond 6\xa0months is unusual and that it does not exceed 10\xa0months. Applying a 10‑month treatment cap in the model also decreased the ICER but had a more modest effect than the company's scenario. The clinical experts explained that there is variation in the duration of paclitaxel treatment in the NHS. In the past, it was common for treatment to continue for a fixed period. But now, patients are more likely to have paclitaxel until disease progression or unacceptable toxicity. They explained that, to extend the treatment period, side effects are often managed by dose reductions and dose 'holidays', so assuming full dosage for all patients until disease progression was not realistic. However, the committee also heard from the clinical experts that assuming an 18‑cycle cut-off point would be arbitrary and not supported by evidence. Their experience is that most chemotherapies stop working after 10\xa0months. However, because there are no effective alternative treatments in this condition, it is common practice to continue treatment until there is evidence of no further benefit. The committee accepted that an 18‑cycle treatment cap does not reflect clinical practice in the NHS. However, it considered that the company's revised analysis, which assumed all patients on paclitaxel would have it at the full dose until disease progression, was not reliable because it did not account for dose reductions, or for variation in practice in the NHS. The committee concluded that the company's updated analysis overestimated average treatment duration with weekly paclitaxel and the associated costs. It suggested that, in the absence of robust real-world evidence, the treatment duration of weekly paclitaxel may have best been informed by the treatment duration in the nab‑paclitaxel control arm of IMpassion130 (see section\xa03.10). The committee concluded that average treatment duration with weekly paclitaxel was uncertain and would have best been informed by data on time to stopping treatment from the control arm of IMpassion130.\n\n# Cost-effectiveness estimate\n\n## The company's updated commercial arrangement reduced the ICER\n\nFollowing consultation, the company updated its commercial arrangement and submitted an updated analysis that incorporated the committee's preferred assumptions (see section\xa03.10 and section\xa03.12). The ICER is not reported here to protect the confidentiality of the commercial arrangement. The committee noted that the commercial arrangement reduces the ICER for atezolizumab plus nab‑paclitaxel compared with weekly paclitaxel. However, it remains above the range normally considered cost effective (that is, £20,000 to £30,000 per quality-adjusted life year [QALY] gained) for technologies that are not given special consideration as life-extending treatments for people with a short life expectancy.\n\n# End of life\n\n## End-of-life criteria are met\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. It considered that all scenario analyses presented by the company and the ERG indicated that atezolizumab plus nab‑paclitaxel offers more than 3\xa0months' extension to life in a population that has a life expectancy of less than 24\xa0months. Therefore, it concluded that atezolizumab plus nab‑paclitaxel fulfils the end-of-life criteria.\n\n# Other factors\n\nThe company and clinical experts considered atezolizumab plus nab‑paclitaxel to be innovative, and a major breakthrough in managing triple-negative breast cancer. It is the first treatment to substantially improve outcomes compared with chemotherapy in this population. However, the committee considered that all relevant benefits associated with the drug were adequately captured in the model.\n\n# Conclusion\n\n## Atezolizumab plus nab-paclitaxel is recommended for PD-L1-positive, triple-negative advanced breast cancer\n\nClinical trial evidence has shown that atezolizumab plus nab‑paclitaxel increases progression-free survival and suggests it could increase overall survival compared with placebo plus nab‑paclitaxel. When the updated commercial offer and the greater weight assigned to QALYs at the end of life are taken into account, the ICER is acceptable. Therefore, atezolizumab plus nab‑paclitaxel is recommended for PD‑L1‑positive, triple-negative advanced breast cancer."}
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https://www.nice.org.uk/guidance/ta639
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Evidence-based recommendations on atezolizumab (Tecentriq) with nab‑paclitaxel for triple-negative, unresectable, PD‑L1‑positive, locally advanced or metastatic breast cancer in adults who have not had chemotherapy for metastatic disease.
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292ca9b1899a6e65770a56384e5766dc67690d6a
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nice
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Intravascular lithotripsy for calcified coronary arteries during percutaneous coronary intervention
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Intravascular lithotripsy for calcified coronary arteries during percutaneous coronary intervention
Evidence-based recommendations on intravascular lithotripsy for calcified coronary arteries during percutaneous coronary intervention in adults. This involves breaking up the calcification with soundwaves.
# Recommendations
Evidence on the safety and efficacy of intravascular lithotripsy for calcified coronary arteries during percutaneous coronary intervention is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research.
Clinicians wishing to do intravascular lithotripsy for calcified coronary arteries during percutaneous coronary intervention should:
Inform the clinical governance leads in their NHS trusts.
Give patients clear information to support shared decision making, including NICE's information for the public.
Ensure that patients understand the procedure's safety and efficacy, as well as any uncertainties about these.
Enter details about all patients having intravascular lithotripsy for calcified coronary arteries during percutaneous coronary intervention onto the National Institute for Cardiovascular Outcomes Research (NICOR) database, and review local clinical outcomes.
The procedure should only be done by an experienced interventional cardiologist with specific training in the procedure.
Research could be a randomised controlled trial, comparing the procedure with current standard therapies, or an observational cohort study, including using registry data. Studies should include details of patient selection, the size and shape of the lesion, procedural success, minimal stent area and longer-term outcomes including survival.# The condition, current treatments and procedure
# The condition
Coronary artery calcification (intimal and medial calcifications) increases the complexity of percutaneous treatment strategies in coronary interventions. It contributes to arterial wall stiffness, suboptimal stent delivery and expansion, in-stent restenosis, high rates of stent thrombosis and the need for subsequent target lesion revascularisation after endovascular interventions.
# Current treatments
Standard endovascular treatment options for modifying calcification or plaques during percutaneous coronary intervention (PCI) include: balloon angioplasty using standard or super high-pressure non-compliant balloons; cutting or scoring balloons; and stenting with or without coronary atherectomy (such as excisional, rotational, orbital or laser atherectomy). The aim with these treatments is to allow optimal stent expansion and achieve maximal luminal gain. However, they may sometimes lead to localised wall injury, balloon rupture, or the risk of coronary vessel dissections or perforation.
# The procedure
In this procedure, shockwave intravascular lithotripsy is administered to the calcified coronary artery before stent deployment during PCI.
A percutaneous guidewire is passed from the radial or femoral artery into a coronary artery. Then, an intravascular lithotripsy catheter with embedded emitters enclosed in an integrated angioplasty balloon is passed and connected to an external generator with a connector cable. The catheter is advanced to the target lesion guided by radiopaque markers on the catheter. The balloon is then inflated with a saline and contrast solution to ensure contact with the vessel wall. The lithotripsy cycle is then activated. For every cycle, the catheter emits localised, high-energy, pulsatile, unfocused, circumferential, acoustic, sonic, pressure waves (lasting microseconds). These waves pass through the inflated balloon into the wall of the coronary artery. As the waves travel along the wall and the connective tissue, they disrupt calcium deposits (both intimal and medial calcium) by microfracturing the calcified lesions.
The cycle can be repeated until the lesion has been expanded sufficiently to allow optimal stent placement. Intravascular lithotripsy during PCI may improve stent delivery and expansion and modify focal intravascular calcium, while limiting localised injury to the endovascular surface.
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{'Recommendations': "Evidence on the safety and efficacy of intravascular lithotripsy for calcified coronary arteries during percutaneous coronary intervention is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research.\n\nClinicians wishing to do intravascular lithotripsy for calcified coronary arteries during percutaneous coronary intervention should:\n\nInform the clinical governance leads in their NHS trusts.\n\nGive patients clear information to support shared decision making, including NICE's information for the public.\n\nEnsure that patients understand the procedure's safety and efficacy, as well as any uncertainties about these.\n\nEnter details about all patients having intravascular lithotripsy for calcified coronary arteries during percutaneous coronary intervention onto the National Institute for Cardiovascular Outcomes Research (NICOR) database, and review local clinical outcomes.\n\nThe procedure should only be done by an experienced interventional cardiologist with specific training in the procedure.\n\nResearch could be a randomised controlled trial, comparing the procedure with current standard therapies, or an observational cohort study, including using registry data. Studies should include details of patient selection, the size and shape of the lesion, procedural success, minimal stent area and longer-term outcomes including survival.", 'The condition, current treatments and procedure': '# The condition\n\nCoronary artery calcification (intimal and medial calcifications) increases the complexity of percutaneous treatment strategies in coronary interventions. It contributes to arterial wall stiffness, suboptimal stent delivery and expansion, in-stent restenosis, high rates of stent thrombosis and the need for subsequent target lesion revascularisation after endovascular interventions.\n\n# Current treatments\n\nStandard endovascular treatment options for modifying calcification or plaques during percutaneous coronary intervention (PCI) include: balloon angioplasty using standard or super high-pressure non-compliant balloons; cutting or scoring balloons; and stenting with or without coronary atherectomy (such as excisional, rotational, orbital or laser atherectomy). The aim with these treatments is to allow optimal stent expansion and achieve maximal luminal gain. However, they may sometimes lead to localised wall injury, balloon rupture, or the risk of coronary vessel dissections or perforation.\n\n# The procedure\n\nIn this procedure, shockwave intravascular lithotripsy is administered to the calcified coronary artery before stent deployment during PCI.\n\nA percutaneous guidewire is passed from the radial or femoral artery into a coronary artery. Then, an intravascular lithotripsy catheter with embedded emitters enclosed in an integrated angioplasty balloon is passed and connected to an external generator with a connector cable. The catheter is advanced to the target lesion guided by radiopaque markers on the catheter. The balloon is then inflated with a saline and contrast solution to ensure contact with the vessel wall. The lithotripsy cycle is then activated. For every cycle, the catheter emits localised, high-energy, pulsatile, unfocused, circumferential, acoustic, sonic, pressure waves (lasting microseconds). These waves pass through the inflated balloon into the wall of the coronary artery. As the waves travel along the wall and the connective tissue, they disrupt calcium deposits (both intimal and medial calcium) by microfracturing the calcified lesions.\n\nThe cycle can be repeated until the lesion has been expanded sufficiently to allow optimal stent placement. Intravascular lithotripsy during PCI may improve stent delivery and expansion and modify focal intravascular calcium, while limiting localised injury to the endovascular surface.'}
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https://www.nice.org.uk/guidance/ipg673
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Evidence-based recommendations on intravascular lithotripsy for calcified coronary arteries during percutaneous coronary intervention in adults. This involves breaking up the calcification with soundwaves.
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253722dfa658a9509d16ddae8f15fd5f8d90ef2d
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nice
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Rezum for treating lower urinary tract symptoms secondary to benign prostatic hyperplasia
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Rezum for treating lower urinary tract symptoms secondary to benign prostatic hyperplasia
Evidence-based recommendations on Rezum for treating lower urinary tract symptoms secondary to benign prostatic hyperplasia.
# Recommendations
Evidence supports the case for adopting Rezum for treating lower urinary tract symptoms (LUTS) caused by benign prostatic hyperplasia (BPH) in the NHS. Rezum relieves LUTS and improves quality of life.
Rezum is a minimally invasive procedure. It should be considered as a treatment option for people with:
moderate to severe LUTS (International Prostate Symptoms Score typically 13 or over) and
a moderately enlarged prostate (typically between 30 cm3 and 80 cm3).
Cost modelling estimates that Rezum is cost saving compared with standard treatments such as transurethral resection of the prostate (TURP) and holmium laser enucleation of the prostate (HoLEP) by more than £550 per person over 4 years. Savings compared with UroLift are uncertain. This is because of uncertainty about some of the assumptions in the cost modelling for that comparison.
Why the committee made these recommendations
Rezum is a minimally invasive procedure that involves injecting steam to destroy excess prostate tissue. Clinical evidence shows that using the Rezum procedure relieves LUTS caused by BPH in men with moderate to severe symptoms who have a moderately enlarged prostate. Evidence also shows that using Rezum is associated with improved quality of life and a low risk of sexual dysfunction. Cost analyses suggest that when Rezum is used as an alternative to standard treatment, such as TURP or HoLEP, it is likely to lead to cost savings because it is done as day surgery with reduced operating and recovery costs.# The technology
# Technology
Rezum is water vapour (steam) therapy for treating lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). The technology uses water vapour to destroy excess prostate tissue with the aim of relieving symptoms.The water vapour is injected into the prostate through a single-use device attached to a urological endoscope. The process is intended to disrupt cell membranes, leading to cell death and shrinking the prostate. The intention is to relieve obstructive symptoms without interfering with surrounding tissues that might impair sexual function.The vapour is injected for 9 seconds during treatment. The number of times this has to be done in each lobe of the prostate depends on the length of the prostatic urethra. It can be customised to the configuration of the gland. A maximum number of 15 full injections can be done with each delivery device although fewer injections are needed for most treatments. The procedure is usually done in the NHS under general anaesthesia or local anaesthesia with sedation, and lasts up to 20 minutes.
# Innovative aspects
Rezum differs from other prostate treatments because it uses water vapour thermal energy. It does not use a laser and can be used to treat the median or middle lobe.
# Intended use
Rezum is intended for the treatment of prostates with volumes greater than 30 cm3 (equivalent to 30 g).
The instructions for use state that Rezum is contraindicated for patients:
with a urinary sphincter implant
who have a penile prosthesis.
# Costs
The typical cost of consumables for the Rezum procedure is estimated at £1,348 (excluding VAT) per treatment. The company supplies the generator, which is loaned free of charge. The company also provides servicing including maintenance and other services (such as software updates) free of charge.
For more details, see the website for Rezum.# Evidence
# Clinical evidence
## Relevant evidence comes from 4 studies presented in 10 publications, including 1 randomised controlled trial
Four studies were relevant to the decision problem in the scope:
randomised controlled trial (5 publications: McVary et al. 2019, McVary and Roehrborn 2018, Roehrborn et al. 2017, McVary et al. 2016a, McVary et al. 2016b)
prospective observational study (3 publications: Mynderse et al. 2015; Dixon et al. 2015, Dixon et al. 2016)
retrospective observational studies (Mollengarden et al. 2018, Darson et al. 2017).The randomised controlled trial was in 197 people with an International Prostate Symptom Score (IPSS) of 13 or more and an estimated prostate volume between 30 cm3 and 80 cm3, who did not have urinary retention and who had no previous surgical interventions for their prostate. The observational studies included people with prostate sizes from 20 cm3 to 110 cm3 who had the Rezum procedure. All are non-UK studies.
## The evidence suggests that Rezum is clinically effective
The Rezum II study showed that Rezum was associated with statistically significant improvements in lower urinary tract symptoms (LUTS) compared with sham at the 3‑month follow up. These improvements were maintained throughout 4 years of follow up. The treatment benefits of Rezum in relieving LUTS were also seen consistently in the observational studies. The incidence of sexual dysfunction after treatment with Rezum was low, with a few people reporting a decrease in ejaculatory function but little change in erectile function. Overall, the evidence base shows that Rezum is an effective treatment for LUTS in people with benign prostatic hyperplasia (BPH). Rezum also improved quality of life (McVary et al. 2019, Darson et al. 2017; Dixon et al. 2015 and 2016).
## There is no evidence that directly compares Rezum with other interventions for BPH
None of the included studies compared Rezum with other commonly used treatments for BPH. Clinical experts suggested that more invasive treatments such as transurethral resection of the prostate (TURP) were likely to be associated with a more substantial relief of urinary symptoms than Rezum. But there is currently no direct evidence to support this. Similarly, there are no direct comparisons of Rezum with UroLift, holmium laser enucleation of the prostate (HoLEP), or GreenLight laser. Expert opinion indicated that recruiting participants to clinical trials that directly compare different minimally invasive and invasive treatments is challenging because people often say they prefer to avoid more invasive treatment.
## An indirect comparison suggests that Rezum is as effective as UroLift
In the absence of direct comparative evidence, the company did an indirect comparison of Rezum and UroLift to relieve LUTS. This was based on the results of the Rezum II study and the Luminal Improvement Following prostatic Tissue (LIFT) study (Roehrborn et al. 2017b). Both technologies are minimally invasive procedures to treat LUTS, and the trial designs and study populations were similar. The main exception was that the Rezum II study included people with median lobe obstruction (31.1% of study participants) while the LIFT study did not. Results from the 2 trials indicated that the therapeutic effects of Rezum and UroLift in relieving LUTS were similar. Retreatment rates were different in the 2 trials: 4.4% for Rezum at year 4 and 13.6% for UroLift at year 5.
## The clinical experts consider Rezum to be a safe procedure
The Rezum II study reported 3 procedure-related serious adverse events in the 3‑month follow up, including extended urinary retention, and nausea and vomiting, which were considered to be because of the sedative medication. An additional 3 procedure-related serious adverse events were reported with Rezum during the 3‑ to 12‑month follow-up period, including bladder contracture, bladder stone and urosepsis after cystoscopy. The clinical experts did not identify any specific safety concerns with Rezum.
# Cost evidence
## The company suggests that using Rezum is cost saving compared with other treatments for BPH
The company developed a decision analytic model with a time horizon of 4 years. The model compared Rezum with 4 comparators: TURP, HoLEP, UroLift, and GreenLight laser. The model assumed that all the technologies had equal efficacy in alleviating LUTS associated with BPH. The model incorporated a cohort Markov structure. Erectile dysfunction and urinary incontinence were included as permanent adverse events that inform long-term health states. The need for surgical retreatment for recurrence of LUTS was also considered. The results of the company model indicated that Rezum was cost saving by £737, £758, £532, and £25 per person when compared with TURP, HoLEP, UroLift, and GreenLight respectively over 4 years.
## The external assessment centre's changes to the assumptions in the cost model reflect empirical evidence and expert opinion
The main parameters in the model were the technology costs, theatre time, hospital length of stay, adverse events and the need for another operation. The external assessment centre (EAC) adjusted some of the model's parameters, including the surgical retreatment rates and the adverse event rates, to reflect published empirical data and expert opinion.
## The model estimates that Rezum is cost saving compared with TURP, HoLEP and UroLift but cost neutral compared with GreenLight
The EAC base-case results showed that Rezum was cost saving by £569, £651 and £497 per person compared with TURP, HoLEP, and UroLift respectively over 4 years. Rezum remains cost saving when all parameters are subjected to a one-way deterministic sensitivity analysis. In the base case, Rezum is cost incurring by £62 per person over 4 years compared with GreenLight laser. The model assumed that GreenLight, like Rezum, was used as a day case. If, in practice, this is not the case, then Rezum is anticipated to be cost saving. Overall, the EAC considered Rezum, therefore, to be approximately cost neutral compared with GreenLight over the course of 4 years.
## Additional analysis suggests uncertainties in the cost saving when Rezum is compared with UroLift
In response to consultation comments on the draft recommendations, the EAC ran additional scenario analyses. These included different parameters relating to the current use of UroLift. The EAC also added the cost of catheter removal to the analysis to reflect that this is needed after Rezum but not after UroLift. The results showed that Rezum remains cost saving compared with UroLift when individual parameters are varied. But when all parameters are combined Rezum is cost incurring compared with UroLift. The probabilistic sensitivity analysis results indicate that there is uncertainty about whether Rezum is cost saving compared with UroLift.# Committee discussion
# Clinical-effectiveness overview
## Rezum is an effective minimally invasive procedure with clinical benefits
The committee concluded that the evidence from the Rezum II study demonstrated the effectiveness of Rezum in relieving lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) with a sustained benefit up to 4 years after the procedure. The committee noted that this is supported by the results of the observational studies. The committee noted that there are no studies that directly compare Rezum with other treatments in relieving symptoms in people with BPH, but considered an indirect comparison between Rezum and UroLift, which was drawn from analogous trial data. This suggests that Rezum is at least as effective as UroLift over 4 years. The clinical experts explained that these 2 minimally invasive procedures are used in similar cohorts of populations in clinical practice and that, in their experience, both procedures provide a similar degree of symptom relief. They also noted that Rezum is versatile in treating different shapes of prostate.
## Rezum should be used for men with moderate to severe LUTS with an estimated prostate volume of 30 cm3 to 80 cm3
The committee noted that there is 1 pivotal study that provides the evidence for the efficacy of Rezum. The clinical experts explained that Rezum II was a US study and designed to meet US Food and Drug Administration eligibility criteria. Its major inclusion criteria were: men aged 50 or over who have symptomatic BPH with an International Prostate Symptoms Score (IPSS) of 13 or greater, and with a prostate volume, measured by transrectal ultrasound, of 30 cm3 to 80 cm3. The committee concluded that there is limited evidence on the efficacy of Rezum in men outside this cohort. The clinical experts confirmed that, in their clinical practice, this cohort of patients corresponds closely to those that they treat with Rezum and that this encompasses approximately 75% to 85% of the overall population that need treatment to relieve LUTS. The clinical experts also explained that, for people with mild LUTS (IPSS less than 8), first-line treatment is medication or lifestyle change. For people with an estimated prostate volume 120 cm3 and greater, more invasive surgical interventions are recommended.
## Rezum is unlikely to damage surrounding tissue and nerves, and the risk of sexual dysfunction is low
The clinical experts explained that loss of sexual function is an important concern for people undergoing invasive treatment for LUTS because the invasive procedure is likely to damage nerves on the external surface of the prostate. They also explained that Rezum involves injecting steam into carefully directed and localised areas of the prostate from the inner, urethral surface of the prostate, and this may avoid possible damage to surrounding nerves. The committee considered that the published evidence suggests that sexual function is retained after treatment with the Rezum procedure. It did note, however, a high incidence of sexual inactivity in people included in the Rezum II study and that overall sexual function showed a tendency to decline during study follow up. The experts explained that there are different types of sexual dysfunction. They said that after treatment with Rezum erectile dysfunction is rare, but ejaculatory dysfunction has been reported. Overall, the committee concluded that the risk to sexual function is low with Rezum, and that this may be particularly important to people who are sexually active at the time of treatment. The committee was uncertain, however, about the impact of Rezum on longer-term sexual function because no data are available for longer than 4 years.
## Quality of life is an important outcome when considering patient benefit
The evidence from the Rezum II study and observational studies indicated that treatment with Rezum with significant relief of LUTS is associated with a significant improvement in quality of life, which persists for up to 4 years of follow up. The clinical experts confirmed that, in their experience, people who underwent Rezum express a high level of satisfaction after the procedure.
# Side effects and adverse events
## Urinary tract infection is a common complication after Rezum
The clinical experts advised that complications after the Rezum procedure are similar to those after other procedures for LUTS because of BPH and include urinary tract infections (UTIs), bleeding, epididymitis and abscess. The clinical experts also explained that, after the Rezum procedure, a urinary catheter is left in place for 5 to 7 days to allow the dead prostate tissue to drain away. The need for catheterisation, combined with the presence of necrotic tissue, are considered by the clinical experts to be predisposing factors for developing UTIs and, more rarely, urosepsis. This risk is higher for Rezum than UroLift, which usually does not need a post-operative urinary catheter. The clinical experts estimated that the risk of UTIs associated with a urinary catheter is around 5% to 7%, so a short course of prophylactic antibiotics may be prescribed after the procedure. The committee heard that post-procedure UTI rates associated with Rezum may be difficult to record because patients may present to their GP for treatment. It also noted that antibiotic use was not reported in the Rezum II study. The committee concluded that UTI is a common complication after Rezum but the risk of UTI can be reduced using prophylactic antibiotics.
## The rate of surgical reintervention is low with Rezum
The committee noted that the Rezum II study reported a 4.4% rate of surgical retreatment after Rezum over 4 years of follow up. The LIFT study reported a 13.6% rate of surgical retreatment after UroLift over 5 years of follow up. The clinical experts suggested that the average retreatment rate in their experience is low after Rezum, and that retreatment is most likely in the first year after the procedure. The clinical experts explained that, because there is no direct view of the prostate cavity during the Rezum procedure, additional transurethral resection of the prostate (TURP) is sometimes needed to remove residual prostate tissue after Rezum. Overall, the committee concluded that the retreatment rate with Rezum is low and compares favourably with similar treatments like UroLift.
# Relevance to the NHS
## The evidence for Rezum is broadly generalisable to the NHS
The clinical experts explained that Rezum is currently done in some NHS trusts and that there has been an increased demand by people for this procedure in some centres. The committee noted that the published evidence for Rezum is from studies that were done outside the UK. Nonetheless, the clinical experts explained that the study population included in the Rezum II study is similar to the people that they treat with Rezum in their own practices in the NHS. The committee concluded that the evidence is generalisable to UK NHS practice.
# NHS considerations overview
## Rezum is a day surgery procedure that can be done under local anaesthetic with sedation but it may not be suitable for everyone
The clinical experts said there are currently 8 different treatments, including Rezum, available in the NHS for people with significant LUTS that have not responded to conservative therapy including medication and lifestyle changes. The clinical experts considered TURP to be the standard of care for LUTS secondary to BPH, but emphasised that treatments need to be offered to people on an individual basis guided by their individual circumstances. Key factors for consideration include: the availability of procedures in their local hospitals, age, prostate gland size and characteristics, and comorbidities. Rezum's advantages over some other technologies are that it is a minimally invasive procedure that can be done under local anaesthesia with sedation, and it takes only around 20 minutes. Despite this, the clinical experts estimated that around two thirds of procedures done in the NHS are under general anaesthetic. People usually do not need an overnight stay in hospital, however. The clinical experts said that Rezum should be avoided in people with prostatitis or confirmed prostate cancer, in people for whom day case treatment is impractical or unsafe, and if there's a risk of increased bleeding, for example if they're having anticoagulant treatment.
## Rezum is used to treat patients with benign prostate enlargement but there is no consensus on how to measure prostate size
The clinical experts said that an enlarged prostate that causes LUTS as a result of prostatic obstruction is caused by prostatic hyperplasia, which is a benign histopathological diagnosis. The clinical experts explained that there is currently no consensus on how prostate size should be estimated or measured in UK clinical practice. They considered that normally imaging would be used to estimate prostate size before surgically invasive treatment. The clinical experts said that imaging modalities could complement information from rectal digital examination of the prostate. Common imaging tools include transrectal ultrasound, cystoscopy and MRI. On the basis of these measurements, the committee heard that Rezum is usually offered to people with moderate prostatic enlargement with a prostate that is typically estimated to be 30 cm3 to 80 cm3.
## The Rezum procedure is easy to learn
The clinical experts explained that urologists need specialist training to do the Rezum procedure. This training is provided by the company and includes lectures and simulation training. The clinical experts suggested that Rezum is relatively easy to learn and that the training requirement is minimal. The committee concluded that the amount of training needed to carry out the Rezum procedure is reasonable.
# Cost modelling overview
## Rezum is estimated to be cost saving compared with standard treatments for BPH but there are limitations in the cost model
The committee noted that the external assessment centre's (EAC) cost modelling results showed that Rezum is likely to be cost saving compared with TURP and holmium laser enucleation of the prostate (HoLEP) by £569 and £651 per patient respectively over 4 years. The committee noted, however, that there are some limitations in the model, including the assumption that all treatments are equally effective in relieving LUTS. Indirect comparative data from the trials suggest that the technologies may not all reduce the IPSS score to the same extent. The clinical experts confirmed that more invasive procedures such as TURP, which removes prostate tissue, would be expected to have greater IPSS improvements. It's uncertain to what extent this impacts the need for retreatment. The committee identified other limitations in the cost model, including the fact that no consideration was given to the impact of urinary catheterisation and removal, or the need for antibiotics after Rezum. The EAC said that the key drivers of the cost savings for Rezum over standard treatments such as TURP and HoLEP are the length of hospital stay and procedure time. Adding the cost of catheter removal to the modelling for Rezum does not substantially affect its cost savings compared with standard treatments. The EAC also noted that prophylactic antibiotics are likely to be common to all treatments, as well as Rezum. The committee concluded that the costs of catheter and prophylactic antibiotic use were unlikely to substantially affect Rezum's cost savings.
## The comparative costs of using Rezum compared with UroLift are uncertain
The committee noted that the base-case results, which are based on published data sources, suggested that Rezum saves £497 per person compared with UroLift over 4 years. The committee also noted, however, the results of the EAC's additional analyses, which included parameters that may better reflect current use of UroLift. The committee noted that 1 of the parameter changes was to include the cost of catheter removal for Rezum but not for UroLift. Based on the expert advice received, the committee agreed with this parameter change. The committee also noted the uncertainty about the current cost of the UroLift technology and its impact on the cost modelling results. Overall, the committee concluded that there are currently too many uncertainties to be able to draw any firm conclusions about the costs of using Rezum compared with UroLift.
# Main cost drivers
## Doing Rezum as day surgery is the main driver for cost savings
The committee heard from the clinical experts that Rezum is commonly done as day surgery and people are not usually admitted to hospital after the procedure. The EAC considered that this was a key driver in the estimated cost savings when Rezum is compared with standard treatments such as TURP. The company's model showed that the cost of consumables for Rezum such as a delivery device was estimated to be around £1,348 per person. The company provides the generator and servicing such as maintenance free of charge. The cost of consumables relative to competitor treatments also influenced the cost modelling results. The company representatives confirmed that they do not anticipate any changes to this cost model for the foreseeable future. The committee concluded that the main driver for cost savings in the model is that Rezum is done as day surgery and people do not stay overnight at hospital.
# Cost savings
## Rezum is cost saving compared with standard treatments for BPH
The EAC did deterministic sensitivity and probability sensitivity analyses that varied parameters in the cost models, and the results showed that Rezum remained cost saving compared with standard treatments such as TURP and HoLEP. The committee concluded that, based on the published evidence, cost modelling and expert opinion, using Rezum is likely to lead to a cost saving of £569 compared with TURP, and £651 compared with HoLEP, for every person treated over a 4‑year time horizon.
# Further research
## The efficacy of Rezum compared with other treatments needs research
Further evidence to address the efficacy of Rezum when directly compared with other treatments such as TURP would be welcome, including their relative impact on symptom relief, quality of life, short and long-term sexual function, and their possible benefits in people with urinary retention and with large prostate glands. More information is also needed on the number of steam injections needed with Rezum in normal clinical practice, and whether more injections are harmful.
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{'Recommendations': 'Evidence supports the case for adopting Rezum for treating lower urinary tract symptoms (LUTS) caused by benign prostatic hyperplasia (BPH) in the NHS. Rezum relieves LUTS and improves quality of life.\n\nRezum is a minimally invasive procedure. It should be considered as a treatment option for people with:\n\nmoderate to severe LUTS (International Prostate Symptoms Score [IPSS] typically 13 or over) and\n\na moderately enlarged prostate (typically between 30\xa0cm3 and 80\xa0cm3).\n\nCost modelling estimates that Rezum is cost saving compared with standard treatments such as transurethral resection of the prostate (TURP) and holmium laser enucleation of the prostate (HoLEP) by more than £550 per person over 4\xa0years. Savings compared with UroLift are uncertain. This is because of uncertainty about some of the assumptions in the cost modelling for that comparison.\n\nWhy the committee made these recommendations\n\nRezum is a minimally invasive procedure that involves injecting steam to destroy excess prostate tissue. Clinical evidence shows that using the Rezum procedure relieves LUTS caused by BPH in men with moderate to severe symptoms who have a moderately enlarged prostate. Evidence also shows that using Rezum is associated with improved quality of life and a low risk of sexual dysfunction. Cost analyses suggest that when Rezum is used as an alternative to standard treatment, such as TURP or HoLEP, it is likely to lead to cost savings because it is done as day surgery with reduced operating and recovery costs.', 'The technology': '# Technology\n\nRezum is water vapour (steam) therapy for treating lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). The technology uses water vapour to destroy excess prostate tissue with the aim of relieving symptoms.The water vapour is injected into the prostate through a single-use device attached to a urological endoscope. The process is intended to disrupt cell membranes, leading to cell death and shrinking the prostate. The intention is to relieve obstructive symptoms without interfering with surrounding tissues that might impair sexual function.The vapour is injected for 9\xa0seconds during treatment. The number of times this has to be done in each lobe of the prostate depends on the length of the prostatic urethra. It can be customised to the configuration of the gland. A maximum number of 15 full injections can be done with each delivery device although fewer injections are needed for most treatments. The procedure is usually done in the NHS under general anaesthesia or local anaesthesia with sedation, and lasts up to 20\xa0minutes.\n\n# Innovative aspects\n\nRezum differs from other prostate treatments because it uses water vapour thermal energy. It does not use a laser and can be used to treat the median or middle lobe.\n\n# Intended use\n\nRezum is intended for the treatment of prostates with volumes greater than 30\xa0cm3 (equivalent to 30\xa0g).\n\nThe instructions for use state that Rezum is contraindicated for patients:\n\nwith a urinary sphincter implant\n\nwho have a penile prosthesis.\n\n# Costs\n\nThe typical cost of consumables for the Rezum procedure is estimated at £1,348 (excluding VAT) per treatment. The company supplies the generator, which is loaned free of charge. The company also provides servicing including maintenance and other services (such as software updates) free of charge.\n\nFor more details, see the website for Rezum.', 'Evidence': "# Clinical evidence\n\n## Relevant evidence comes from 4 studies presented in 10 publications, including 1 randomised controlled trial\n\nFour studies were relevant to the decision problem in the scope:\n\nrandomised controlled trial (5 publications: McVary et al. 2019, McVary and Roehrborn 2018, Roehrborn et al. 2017, McVary et al. 2016a, McVary et al. 2016b)\n\nprospective observational study (3 publications: Mynderse et al. 2015; Dixon et al. 2015, Dixon et al. 2016)\n\nretrospective observational studies (Mollengarden et al. 2018, Darson et al. 2017).The randomised controlled trial was in 197\xa0people with an International Prostate Symptom Score (IPSS) of 13 or more and an estimated prostate volume between 30\xa0cm3 and 80\xa0cm3, who did not have urinary retention and who had no previous surgical interventions for their prostate. The observational studies included people with prostate sizes from 20\xa0cm3 to 110\xa0cm3 who had the Rezum procedure. All are non-UK studies.\n\n## The evidence suggests that Rezum is clinically effective\n\nThe Rezum\xa0II study showed that Rezum was associated with statistically significant improvements in lower urinary tract symptoms (LUTS) compared with sham at the 3‑month follow up. These improvements were maintained throughout 4\xa0years of follow up. The treatment benefits of Rezum in relieving LUTS were also seen consistently in the observational studies. The incidence of sexual dysfunction after treatment with Rezum was low, with a few people reporting a decrease in ejaculatory function but little change in erectile function. Overall, the evidence base shows that Rezum is an effective treatment for LUTS in people with benign prostatic hyperplasia (BPH). Rezum also improved quality of life (McVary et al. 2019, Darson et al. 2017; Dixon et al. 2015 and 2016).\n\n## There is no evidence that directly compares Rezum with other interventions for BPH\n\nNone of the included studies compared Rezum with other commonly used treatments for BPH. Clinical experts suggested that more invasive treatments such as transurethral resection of the prostate (TURP) were likely to be associated with a more substantial relief of urinary symptoms than Rezum. But there is currently no direct evidence to support this. Similarly, there are no direct comparisons of Rezum with UroLift, holmium laser enucleation of the prostate (HoLEP), or GreenLight laser. Expert opinion indicated that recruiting participants to clinical trials that directly compare different minimally invasive and invasive treatments is challenging because people often say they prefer to avoid more invasive treatment.\n\n## An indirect comparison suggests that Rezum is as effective as UroLift\n\nIn the absence of direct comparative evidence, the company did an indirect comparison of Rezum and UroLift to relieve LUTS. This was based on the results of the Rezum\xa0II study and the Luminal Improvement Following prostatic Tissue (LIFT) study (Roehrborn et al. 2017b). Both technologies are minimally invasive procedures to treat LUTS, and the trial designs and study populations were similar. The main exception was that the Rezum\xa0II study included people with median lobe obstruction (31.1% of study participants) while the LIFT study did not. Results from the 2 trials indicated that the therapeutic effects of Rezum and UroLift in relieving LUTS were similar. Retreatment rates were different in the 2 trials: 4.4% for Rezum at year\xa04 and 13.6% for UroLift at year\xa05.\n\n## The clinical experts consider Rezum to be a safe procedure\n\nThe Rezum\xa0II study reported 3 procedure-related serious adverse events in the 3‑month follow up, including extended urinary retention, and nausea and vomiting, which were considered to be because of the sedative medication. An additional 3 procedure-related serious adverse events were reported with Rezum during the 3‑ to 12‑month follow-up period, including bladder contracture, bladder stone and urosepsis after cystoscopy. The clinical experts did not identify any specific safety concerns with Rezum.\n\n# Cost evidence\n\n## The company suggests that using Rezum is cost saving compared with other treatments for BPH\n\nThe company developed a decision analytic model with a time horizon of 4\xa0years. The model compared Rezum with 4 comparators: TURP, HoLEP, UroLift, and GreenLight laser. The model assumed that all the technologies had equal efficacy in alleviating LUTS associated with BPH. The model incorporated a cohort Markov structure. Erectile dysfunction and urinary incontinence were included as permanent adverse events that inform long-term health states. The need for surgical retreatment for recurrence of LUTS was also considered. The results of the company model indicated that Rezum was cost saving by £737, £758, £532, and £25 per person when compared with TURP, HoLEP, UroLift, and GreenLight respectively over 4\xa0years.\n\n## The external assessment centre's changes to the assumptions in the cost model reflect empirical evidence and expert opinion\n\nThe main parameters in the model were the technology costs, theatre time, hospital length of stay, adverse events and the need for another operation. The external assessment centre (EAC) adjusted some of the model's parameters, including the surgical retreatment rates and the adverse event rates, to reflect published empirical data and expert opinion.\n\n## The model estimates that Rezum is cost saving compared with TURP, HoLEP and UroLift but cost neutral compared with GreenLight\n\nThe EAC base-case results showed that Rezum was cost saving by £569, £651 and £497 per person compared with TURP, HoLEP, and UroLift respectively over 4\xa0years. Rezum remains cost saving when all parameters are subjected to a one-way deterministic sensitivity analysis. In the base case, Rezum is cost incurring by £62 per person over 4\xa0years compared with GreenLight laser. The model assumed that GreenLight, like Rezum, was used as a day case. If, in practice, this is not the case, then Rezum is anticipated to be cost saving. Overall, the EAC considered Rezum, therefore, to be approximately cost neutral compared with GreenLight over the course of 4\xa0years.\n\n## Additional analysis suggests uncertainties in the cost saving when Rezum is compared with UroLift\n\nIn response to consultation comments on the draft recommendations, the EAC ran additional scenario analyses. These included different parameters relating to the current use of UroLift. The EAC also added the cost of catheter removal to the analysis to reflect that this is needed after Rezum but not after UroLift. The results showed that Rezum remains cost saving compared with UroLift when individual parameters are varied. But when all parameters are combined Rezum is cost incurring compared with UroLift. The probabilistic sensitivity analysis results indicate that there is uncertainty about whether Rezum is cost saving compared with UroLift.", 'Committee discussion': "# Clinical-effectiveness overview\n\n## Rezum is an effective minimally invasive procedure with clinical benefits\n\nThe committee concluded that the evidence from the Rezum\xa0II study demonstrated the effectiveness of Rezum in relieving lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) with a sustained benefit up to 4\xa0years after the procedure. The committee noted that this is supported by the results of the observational studies. The committee noted that there are no studies that directly compare Rezum with other treatments in relieving symptoms in people with BPH, but considered an indirect comparison between Rezum and UroLift, which was drawn from analogous trial data. This suggests that Rezum is at least as effective as UroLift over 4\xa0years. The clinical experts explained that these 2 minimally invasive procedures are used in similar cohorts of populations in clinical practice and that, in their experience, both procedures provide a similar degree of symptom relief. They also noted that Rezum is versatile in treating different shapes of prostate.\n\n## Rezum should be used for men with moderate to severe LUTS with an estimated prostate volume of 30\xa0cm3 to 80\xa0cm3\n\nThe committee noted that there is 1 pivotal study that provides the evidence for the efficacy of Rezum. The clinical experts explained that Rezum\xa0II was a US study and designed to meet US Food and Drug Administration eligibility criteria. Its major inclusion criteria were: men aged 50 or over who have symptomatic BPH with an International Prostate Symptoms Score (IPSS) of 13 or greater, and with a prostate volume, measured by transrectal ultrasound, of 30\xa0cm3 to 80\xa0cm3. The committee concluded that there is limited evidence on the efficacy of Rezum in men outside this cohort. The clinical experts confirmed that, in their clinical practice, this cohort of patients corresponds closely to those that they treat with Rezum and that this encompasses approximately 75% to 85% of the overall population that need treatment to relieve LUTS. The clinical experts also explained that, for people with mild LUTS (IPSS less than 8), first-line treatment is medication or lifestyle change. For people with an estimated prostate volume 120\xa0cm3 and greater, more invasive surgical interventions are recommended.\n\n## Rezum is unlikely to damage surrounding tissue and nerves, and the risk of sexual dysfunction is low\n\nThe clinical experts explained that loss of sexual function is an important concern for people undergoing invasive treatment for LUTS because the invasive procedure is likely to damage nerves on the external surface of the prostate. They also explained that Rezum involves injecting steam into carefully directed and localised areas of the prostate from the inner, urethral surface of the prostate, and this may avoid possible damage to surrounding nerves. The committee considered that the published evidence suggests that sexual function is retained after treatment with the Rezum procedure. It did note, however, a high incidence of sexual inactivity in people included in the Rezum\xa0II study and that overall sexual function showed a tendency to decline during study follow up. The experts explained that there are different types of sexual dysfunction. They said that after treatment with Rezum erectile dysfunction is rare, but ejaculatory dysfunction has been reported. Overall, the committee concluded that the risk to sexual function is low with Rezum, and that this may be particularly important to people who are sexually active at the time of treatment. The committee was uncertain, however, about the impact of Rezum on longer-term sexual function because no data are available for longer than 4\xa0years.\n\n## Quality of life is an important outcome when considering patient benefit\n\nThe evidence from the Rezum\xa0II study and observational studies indicated that treatment with Rezum with significant relief of LUTS is associated with a significant improvement in quality of life, which persists for up to 4\xa0years of follow up. The clinical experts confirmed that, in their experience, people who underwent Rezum express a high level of satisfaction after the procedure.\n\n# Side effects and adverse events\n\n## Urinary tract infection is a common complication after Rezum\n\nThe clinical experts advised that complications after the Rezum procedure are similar to those after other procedures for LUTS because of BPH and include urinary tract infections (UTIs), bleeding, epididymitis and abscess. The clinical experts also explained that, after the Rezum procedure, a urinary catheter is left in place for 5 to 7\xa0days to allow the dead prostate tissue to drain away. The need for catheterisation, combined with the presence of necrotic tissue, are considered by the clinical experts to be predisposing factors for developing UTIs and, more rarely, urosepsis. This risk is higher for Rezum than UroLift, which usually does not need a post-operative urinary catheter. The clinical experts estimated that the risk of UTIs associated with a urinary catheter is around 5% to 7%, so a short course of prophylactic antibiotics may be prescribed after the procedure. The committee heard that post-procedure UTI rates associated with Rezum may be difficult to record because patients may present to their GP for treatment. It also noted that antibiotic use was not reported in the Rezum\xa0II study. The committee concluded that UTI is a common complication after Rezum but the risk of UTI can be reduced using prophylactic antibiotics.\n\n## The rate of surgical reintervention is low with Rezum\n\nThe committee noted that the Rezum\xa0II study reported a 4.4% rate of surgical retreatment after Rezum over 4\xa0years of follow up. The LIFT study reported a 13.6% rate of surgical retreatment after UroLift over 5\xa0years of follow up. The clinical experts suggested that the average retreatment rate in their experience is low after Rezum, and that retreatment is most likely in the first year after the procedure. The clinical experts explained that, because there is no direct view of the prostate cavity during the Rezum procedure, additional transurethral resection of the prostate (TURP) is sometimes needed to remove residual prostate tissue after Rezum. Overall, the committee concluded that the retreatment rate with Rezum is low and compares favourably with similar treatments like UroLift.\n\n# Relevance to the NHS\n\n## The evidence for Rezum is broadly generalisable to the NHS\n\nThe clinical experts explained that Rezum is currently done in some NHS trusts and that there has been an increased demand by people for this procedure in some centres. The committee noted that the published evidence for Rezum is from studies that were done outside the UK. Nonetheless, the clinical experts explained that the study population included in the Rezum\xa0II study is similar to the people that they treat with Rezum in their own practices in the NHS. The committee concluded that the evidence is generalisable to UK NHS practice.\n\n# NHS considerations overview\n\n## Rezum is a day surgery procedure that can be done under local anaesthetic with sedation but it may not be suitable for everyone\n\nThe clinical experts said there are currently 8 different treatments, including Rezum, available in the NHS for people with significant LUTS that have not responded to conservative therapy including medication and lifestyle changes. The clinical experts considered TURP to be the standard of care for LUTS secondary to BPH, but emphasised that treatments need to be offered to people on an individual basis guided by their individual circumstances. Key factors for consideration include: the availability of procedures in their local hospitals, age, prostate gland size and characteristics, and comorbidities. Rezum's advantages over some other technologies are that it is a minimally invasive procedure that can be done under local anaesthesia with sedation, and it takes only around 20\xa0minutes. Despite this, the clinical experts estimated that around two thirds of procedures done in the NHS are under general anaesthetic. People usually do not need an overnight stay in hospital, however. The clinical experts said that Rezum should be avoided in people with prostatitis or confirmed prostate cancer, in people for whom day case treatment is impractical or unsafe, and if there's a risk of increased bleeding, for example if they're having anticoagulant treatment.\n\n## Rezum is used to treat patients with benign prostate enlargement but there is no consensus on how to measure prostate size\n\nThe clinical experts said that an enlarged prostate that causes LUTS as a result of prostatic obstruction is caused by prostatic hyperplasia, which is a benign histopathological diagnosis. The clinical experts explained that there is currently no consensus on how prostate size should be estimated or measured in UK clinical practice. They considered that normally imaging would be used to estimate prostate size before surgically invasive treatment. The clinical experts said that imaging modalities could complement information from rectal digital examination of the prostate. Common imaging tools include transrectal ultrasound, cystoscopy and MRI. On the basis of these measurements, the committee heard that Rezum is usually offered to people with moderate prostatic enlargement with a prostate that is typically estimated to be 30\xa0cm3 to 80\xa0cm3.\n\n## The Rezum procedure is easy to learn\n\nThe clinical experts explained that urologists need specialist training to do the Rezum procedure. This training is provided by the company and includes lectures and simulation training. The clinical experts suggested that Rezum is relatively easy to learn and that the training requirement is minimal. The committee concluded that the amount of training needed to carry out the Rezum procedure is reasonable.\n\n# Cost modelling overview\n\n## Rezum is estimated to be cost saving compared with standard treatments for BPH but there are limitations in the cost model\n\nThe committee noted that the external assessment centre's (EAC) cost modelling results showed that Rezum is likely to be cost saving compared with TURP and holmium laser enucleation of the prostate (HoLEP) by £569 and £651 per patient respectively over 4\xa0years. The committee noted, however, that there are some limitations in the model, including the assumption that all treatments are equally effective in relieving LUTS. Indirect comparative data from the trials suggest that the technologies may not all reduce the IPSS score to the same extent. The clinical experts confirmed that more invasive procedures such as TURP, which removes prostate tissue, would be expected to have greater IPSS improvements. It's uncertain to what extent this impacts the need for retreatment. The committee identified other limitations in the cost model, including the fact that no consideration was given to the impact of urinary catheterisation and removal, or the need for antibiotics after Rezum. The EAC said that the key drivers of the cost savings for Rezum over standard treatments such as TURP and HoLEP are the length of hospital stay and procedure time. Adding the cost of catheter removal to the modelling for Rezum does not substantially affect its cost savings compared with standard treatments. The EAC also noted that prophylactic antibiotics are likely to be common to all treatments, as well as Rezum. The committee concluded that the costs of catheter and prophylactic antibiotic use were unlikely to substantially affect Rezum's cost savings.\n\n## The comparative costs of using Rezum compared with UroLift are uncertain\n\nThe committee noted that the base-case results, which are based on published data sources, suggested that Rezum saves £497 per person compared with UroLift over 4\xa0years. The committee also noted, however, the results of the EAC's additional analyses, which included parameters that may better reflect current use of UroLift. The committee noted that 1 of the parameter changes was to include the cost of catheter removal for Rezum but not for UroLift. Based on the expert advice received, the committee agreed with this parameter change. The committee also noted the uncertainty about the current cost of the UroLift technology and its impact on the cost modelling results. Overall, the committee concluded that there are currently too many uncertainties to be able to draw any firm conclusions about the costs of using Rezum compared with UroLift.\n\n# Main cost drivers\n\n## Doing Rezum as day surgery is the main driver for cost savings\n\nThe committee heard from the clinical experts that Rezum is commonly done as day surgery and people are not usually admitted to hospital after the procedure. The EAC considered that this was a key driver in the estimated cost savings when Rezum is compared with standard treatments such as TURP. The company's model showed that the cost of consumables for Rezum such as a delivery device was estimated to be around £1,348 per person. The company provides the generator and servicing such as maintenance free of charge. The cost of consumables relative to competitor treatments also influenced the cost modelling results. The company representatives confirmed that they do not anticipate any changes to this cost model for the foreseeable future. The committee concluded that the main driver for cost savings in the model is that Rezum is done as day surgery and people do not stay overnight at hospital.\n\n# Cost savings\n\n## Rezum is cost saving compared with standard treatments for BPH\n\nThe EAC did deterministic sensitivity and probability sensitivity analyses that varied parameters in the cost models, and the results showed that Rezum remained cost saving compared with standard treatments such as TURP and HoLEP. The committee concluded that, based on the published evidence, cost modelling and expert opinion, using Rezum is likely to lead to a cost saving of £569 compared with TURP, and £651 compared with HoLEP, for every person treated over a 4‑year time horizon.\n\n# Further research\n\n## The efficacy of Rezum compared with other treatments needs research\n\nFurther evidence to address the efficacy of Rezum when directly compared with other treatments such as TURP would be welcome, including their relative impact on symptom relief, quality of life, short and long-term sexual function, and their possible benefits in people with urinary retention and with large prostate glands. More information is also needed on the number of steam injections needed with Rezum in normal clinical practice, and whether more injections are harmful."}
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https://www.nice.org.uk/guidance/mtg49
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Evidence-based recommendations on Rezum for treating lower urinary tract symptoms secondary to benign prostatic hyperplasia.
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a7132f50acc33706bf4451292c4eb85fbc26f8ec
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nice
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Avatrombopag for treating thrombocytopenia in people with chronic liver disease needing a planned invasive procedure
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Avatrombopag for treating thrombocytopenia in people with chronic liver disease needing a planned invasive procedure
Evidence-based recommendations on avatrombopag (Doptelet) for treating severe thrombocytopenia in adults with chronic liver disease needing a planned invasive procedure.
# Recommendations
Avatrombopag is recommended, within its marketing authorisation, as an option for treating severe thrombocytopenia (that is, a platelet count of below 50,000 platelets per microlitre of blood) in adults with chronic liver disease having a planned invasive procedure.
Why the committee made these recommendations
People with chronic liver disease may have low platelet levels. This means that they are more likely to bleed during invasive medical procedures, including surgery. Currently, they have a platelet transfusion before invasive procedures to reduce their chances of bleeding.
Avatrombopag and lusutrombopag are oral therapies that raise platelet levels to reduce the need for a platelet transfusion. Platelet transfusions rely on donors and are given intravenously, so replacing them with a treatment given by mouth is an improvement. The drugs have several other benefits, including:
fewer transfusions and a lower risk of transfusion-related complications
fewer stays in hospital.
In addition, platelets can be stored only for a short time. This may delay people getting platelets in time for their procedure. However, avatrombopag and lusutrombopag need to be taken more than a week before a procedure, so cannot be used for emergency procedures.
The economic modelling does not fully account for the benefits for patients and service delivery when using avatrombopag and lusutrombopag. It is possible that using avatrombopag would likely save the NHS money. So, avatrombopag can be recommended for treating thrombocytopenia in people with chronic liver disease who need planned invasive procedures.# Information about avatrombopag and lusutrombopag
# Marketing authorisations
Avatrombopag (Doptelet, Sobi) is recommended 'for the treatment of severe thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo an invasive procedure'.
Lusutrombopag (Mulpleo, Shionogi B.V.) is recommended 'for the treatment of severe thrombocytopenia in adult patients with chronic liver disease undergoing invasive procedures'.
# Dosages in the marketing authorisations
The recommended dosage of avatrombopag is based on the patient's platelet count:
below 40,000 platelets per microlitre of blood – 60 mg once daily
,000 to below 50,000 platelets per microlitre of blood – 40 mg once daily.Dosing should begin 10 to 13 days before the planned procedure. Patients should have their procedure 5 to 8 days after the last dose of avatrombopag. Avatrombopag is taken orally.
The recommended dosage of lusutrombopag is 3 mg once daily for 7 days. The procedure should be done from day 9 after the start of lusutrombopag treatment. Platelet count should be measured before the procedure. Lusutrombopag is taken orally.
# Price
The company has stated that the price of avatrombopag is £640 or £960 per 5‑day treatment course for the 40,000 to below 50,000 and below 40,000 platelets per microlitre of blood groups respectively.
The company has stated that the cost of lusutrombopag is £800 per 7‑day treatment course. Costs may vary in different settings because of negotiated procurement discounts.# Committee discussion
The appraisal committee (section 5) considered evidence from a number of sources. See the committee papers for full details of the evidence.
# Treatment pathway
## People with chronic liver disease and a count of below 50,000 platelets per microlitre of blood would be eligible for avatrombopag or lusutrombopag
The clinical experts explained that people with chronic liver disease and thrombocytopenia (traditionally defined as a platelet count below 150,000 platelets per microlitre of blood) are at increased risk of bleeding when having elective or urgent invasive procedures, including surgery. Planned procedures may include investigative or therapeutic procedures. To prevent or minimise bleeding, people may have a platelet transfusion before the invasive procedure. The clinical experts attending the meeting acknowledged that they were unaware of trials testing whether platelets lowered the risk of bleeding. However, they agreed that transfusing platelets was the standard of care. The clinical experts also stated that the risk of bleeding during a procedure depends on the platelet count, the procedure, other manifestations of liver disease, history of bleeding and age. NICE's guideline on blood transfusion recommends that prophylactic platelet transfusions to raise the platelet count above 50,000 platelets per microlitre of blood be considered for people having invasive procedures or surgery. The committee heard that even higher platelet counts might be needed for some invasive procedures (such as ocular surgery). It noted that avatrombopag is licensed for treating thrombocytopenia when the platelet count is below 50,000 platelets per microlitre of blood. It also noted that, although the marketing authorisation for lusutrombopag does not define severe thrombocytopenia, the company and the assessment group presented evidence (that is, clinical trial data, indirect clinical data and cost-effectiveness analyses) only for people with a platelet count below 50,000 platelets per microlitre of blood. If people bleed during or after a procedure, they may need a 'rescue therapy', including further platelet transfusions, fresh frozen plasma or tranexamic acid. The committee concluded that people with chronic liver disease having a planned invasive procedure would be eligible for treatment with avatrombopag and lusutrombopag if they had a platelet count of below 50,000 platelets per microlitre of blood. It agreed to make recommendations for this group.
## The appraisal applies to people needing planned procedures scheduled for 9 or 10 days in the future
The marketing authorisations stipulate that avatrombopag and lusutrombopag oral treatments need to be taken at least 10 days or 9 days respectively before a procedure. The clinical experts stated that it would be relatively straightforward to coordinate testing platelet concentrations and prescribing avatrombopag and lusutrombopag with a GP. Because of the time needed to increase the platelet count, the committee heard that avatrombopag and lusutrombopag would be appropriate only for planned elective procedures. However, these drugs would not have a role in planned procedures that need to be done within 9 or 10 days. The committee concluded that the appraisal applies to people with chronic liver disease and a platelet count below 50,000 platelets per microlitre of blood needing planned ('elective') invasive procedures rather than emergency procedures.
## Avatrombopag and lusutrombopag raise platelet levels for longer than a transfusion, and are taken at home so reduce wastage and hospital stays
The clinical experts explained that a platelet transfusion increases platelet levels for only a short time. This means that patients need to have their procedures soon after having a transfusion. According to the clinical experts, about 50% of patients go into hospital to have a transfusion the evening before their planned procedure and, when possible, the transfusion is given on the day of the procedure. If the 'treatment window' (that is, the time when platelet levels are raised) is missed, a patient would have another platelet transfusion before having the procedure. Avatrombopag and lusutrombopag have longer treatment windows in which to do planned invasive procedures than do platelet transfusions. Specifically, these windows are 10 to 13 days (stated in the marketing authorisation for avatrombopag) after starting avatrombopag and from day 9 (stated in the marketing authorisation for lusutrombopag) after starting lusutrombopag. The committee considered that this would ease procedure scheduling compared with platelet transfusion and may make it possible to carry out multiple procedures within a treatment window. It concluded that avatrombopag and lusutrombopag have some potential advantages over transfusing platelets. These include reducing wastage if an invasive procedure is delayed, increasing the time in which procedures can occur and reducing hospital stays.
## People would welcome an oral treatment alternative to platelet transfusions
The patient expert stated that, typically, people with chronic liver disease and thrombocytopenia are sick and have many hospital appointments. This, and the associated travel, disrupts their lives. They would value any treatment that could reduce this burden. Avatrombopag and lusutrombopag are oral treatments, and would reduce the need for a trip to hospital for a transfusion. The clinical experts acknowledged that some people who develop chronic liver disease from intravenous drug use have poor venous access. For them, transfusing platelets is difficult without central venous access, for which a procedure is also needed. The patient expert stated that the risks of adverse effects associated with platelet transfusions are low. However, people perceive oral treatments to be safer, and even just the perceived risk of platelet transfusions can cause anxiety. The committee concluded that there are benefits related to an oral treatment compared with platelet transfusions, and that people would welcome an oral treatment option.
## Reducing dependence on platelets would minimise problems associated with obtaining and transfusing platelets
Platelet transfusions, like all blood products, are a scarce resource limited by the number of donations received. The clinical experts explained that platelets also have a short shelf life (of 5 to 7 days) and need to be stored at room temperature. This means that larger hospitals store only limited amounts to avoid wastage, and that smaller hospitals do not store platelets on site. The clinical experts explained that patients can become refractory to repeated platelet transfusions. Repeated transfusions can also increase the risk of infection. Some people can react to the plasma contained in the platelets or develop antibodies against donor platelets after repeated transfusions. People who have an immune reaction to donated platelets may reduce their chance of having a successful liver transplant. The clinical experts also stated that, although donor platelets are not usually matched to the recipient, sometimes they have to be. This then makes it more difficult to find platelets, and means that no one else can use these matched platelets (for example, human leukocyte antigen matched). The committee agreed that obtaining, storing and administering platelets carries a number of practical implications for patients and for service delivery. It concluded that reducing dependence on platelets would minimise problems associated with obtaining and transfusing platelets.
# Clinical evidence
## Avatrombopag and lusutrombopag reduce the number of platelet transfusions
The avatrombopag randomised placebo-controlled trials (ADAPT 1 and ADAPT 2) assessed 2 doses of avatrombopag: 40 mg for people with a platelet count of between 40,000 and below 50,000 platelets per microlitre of blood, and 60 mg for people with a platelet count below 40,000 platelets per microlitre of blood. The lusutrombopag trials (L‑PLUS 1, L‑PLUS 2 and JapicCTI 121944) assessed 3 mg lusutrombopag in people with a platelet count below 50,000 platelets per microlitre of blood. To compare the lusutrombopag results with the avatrombopag results, the assessment group chose to separate lusutrombopag results into the same subgroups as avatrombopag. That is, it considered the lusutrombopag trial results for 2 subgroups: people with a platelet count of between 40,000 and below 50,000 platelets per microlitre of blood; and people with a platelet count below 40,000 platelets per microlitre of blood separately. However, the assessment group also presented analyses for lusutrombopag for the full population. The avatrombopag and lusutrombopag trials measured the proportion of people needing a platelet transfusion before an invasive procedure. Across all subgroups, at least 40% fewer people needed a platelet transfusion if they were randomised to avatrombopag or lusutrombopag compared with placebo. The committee concluded that the trial evidence presented was appropriate for decision making. It further concluded that the evidence showed that avatrombopag and lusutrombopag reduce the number of platelet transfusions before invasive procedures in people with chronic liver disease and thrombocytopenia when compared with placebo.
## Although both drugs' trials include people fitter than those having platelet transfusions in UK clinical practice, the results are generalisable
One way to categorise the severity of chronic liver disease is by Child–Pugh score. People in the Child–Pugh A category have less severe disease and the best prognosis; people in the Child–Pugh C category have the most severe disease and the poorest prognosis. The regulatory trials of avatrombopag included between 8.6% (40,000 to below 50,000 platelets per microlitre of blood subgroup in the avatrombopag arm of ADAPT‑1) and 15.2% (in the same subgroup of the avatrombopag arm of ADAPT‑2) of people in the Child–Pugh C category. The trials of lusutrombopag excluded people with disease scored as Child–Pugh C (although 3.6% of the pooled-trials population were in the Child–Pugh C category). The summary of product characteristics for both drugs state that they should only be used in people with Child–Pugh C liver disease if the expected benefits outweigh the expected risks. The clinical experts explained that patients with thrombocytopenia tend to have Child–Pugh B or C liver disease, and that people with Child–Pugh A liver disease rarely have thrombocytopenia. The committee agreed that this meant that the avatrombopag and lusutrombopag trials were carried out in people who were fitter than people who would have the drugs in UK clinical practice. The clinical experts explained that outcomes might be better in clinical practice than in the trials. This was because using a thrombopoietin receptor agonist such as avatrombopag or lusutrombopag in people with more severe disease and less ability to make thrombopoietin has a larger effect than in people with less severe disease. The committee agreed that this seemed a reasonable expectation, but that there was no evidence to support it. Overall, however, the committee concluded that the trial results were generalisable to NHS practice.
## There is no trial evidence to determine whether avatrombopag or lusutrombopag increase life expectancy compared with platelet transfusions
The trials of avatrombopag and lusutrombopag had a follow up of 5 weeks and did not measure survival as a clinical outcome. The committee considered that survival on avatrombopag or lusutrombopag compared with standard care may depend on:
Death rate associated with platelet transfusion: People having avatrombopag or lusutrombopag would, on average, have fewer platelet transfusions (see section 3.6). The clinical experts explained that the risk of death with a platelet transfusion was very small (see section 3.10).
Fatal bleeds: The company for lusutrombopag (Shionogi) showed data suggesting that lusutrombopag was associated with fewer severe bleeds than placebo. The committee considered it plausible that there would be fewer bleeds with a thrombopoietin receptor agonist because these drugs raise platelet levels for a longer time than a platelet transfusion. It also considered that it was difficult to use the rates of rescue therapy for bleeding (which had been measured in the avatrombopag and lusutrombopag trials) as a proxy measure for bleeding rates. This was because the definition of rescue therapy differed between the trials.
Adverse events associated with avatrombopag or lusutrombopag: The committee acknowledged that thrombopoietin receptor agonists increase the risk of thromboembolic events, but that the short-term trial results did not show a difference in thromboembolic events between placebo and avatrombopag or lusutrombopag.The committee concluded that there were no data to determine whether avatrombopag or lusutrombopag increase or decrease life expectancy compared with platelet transfusions, but that the treatments were unlikely to. It further concluded to assume no difference in death rates between people treated with or without thrombopoietin receptor agonists.
## Avatrombopag and lusutrombopag are expected to be of similar clinical effectiveness to each other
There were no head-to-head trials comparing avatrombopag with lusutrombopag, and the assessment group carried out a network meta-analysis. The committee agreed with the assessment group's concerns about comparing the clinical trials for avatrombopag and lusutrombopag. It noted that the trials defined rescue therapy differently, and had different criteria defining when platelet transfusions were indicated. The clinical experts and the company explained that they did not expect the effectiveness to differ between avatrombopag and lusutrombopag, which share the same mechanism of action. The committee agreed that this seemed plausible, and also noted that the indirect analyses mostly showed that there were no differences between drugs. The committee concluded that there was no evidence that either avatrombopag or lusutrombopag was more effective than the other.
# Cost-effectiveness evidence
## The assessment group's and Shionogi's models are structured similarly but model bleeds differently
The assessment group model was adapted from the model provided by the comparator company in this appraisal, Shionogi (the company for lusutrombopag). Shionogi's model included a short-term decision tree to model the clinical trial period (35 days). It also included a Markov model to model the life expectancy of a person with chronic liver disease over the long term (50 years). However, the models differed in how they modelled quality of life and survival related to bleeding and death associated with platelet transfusion. Shionogi modelled a risk of death associated with platelet transfusion of 0.3315%, and assumed that death happens before surgery. The assessment group's model estimated a lower (0.0005%) risk of death associated with platelet transfusion, which could occur before, during or after the procedure. The clinical experts explained that the assessment group's model was more plausible. Shionogi modelled risk of bleeding separately to risk of having rescue therapy, and assumed a lower rate of bleeds with lusutrombopag compared with established care. The assessment group did not model bleeding separately from rescue therapy. The clinical experts explained that people who bleed have rescue therapy, even after being discharged from hospital. Both Shionogi and the assessment group assumed that bleeding lowered quality of life and increased the risk of dying. The committee concluded that it was plausible that avatrombopag plus a platelet transfusion and rescue therapy would be associated with similar long-term quality of life and risk of death as a platelet transfusion and rescue therapy.
## Baseline utility values are low but appropriate for decision making
The baseline utility value, applied by the assessment group to people who did or did not have a thrombopoietin receptor agonist, was 0.544. The committee considered that this seemed low. The patient expert explained that the estimate seemed reasonable because this population is very unwell. The committee was aware that the assessment group conducted a scenario analysis using a higher baseline utility of 0.801, which minimally affected the cost-effectiveness results. The committee agreed that the baseline utility values used in the assessment group's and company's base cases were appropriate for decision making.
## Costs of platelet transfusions and delayed surgery could offset drug costs, but the models do not include all relevant costs
Shionogi modelled a higher cost for platelet transfusions than did the assessment group. It assumed a person would have an average of 3 units of platelets. The assessment group assumed an average of around 1 unit. The assessment group based its calculations on the volume of platelets transfused in the lusutrombopag trials divided by the number of platelets estimated to be in a unit of platelets obtained by apheresis. The clinical experts stated that the costs of a platelet transfusion likely fell between Shionogi's and the assessment group's estimates. The committee considered that the incremental costs for avatrombopag compared with established care modelled in the assessment group's base case may have overestimated the true costs. This was because the assessment group did not include all relevant costs. In particular, it did not include the costs of admitting patients to hospital the night before a procedure for transfusion or take into account that transfusion costs increase for patients who develop immunity. In addition, the assessment group did not model wasted surgery time for delayed or cancelled procedures. The committee did not see evidence that avatrombopag or lusutrombopag resulted in fewer cancelled or delayed procedures. However, it accepted that there would likely be fewer delays and cancellations with the drugs because of the longer treatment window in which platelet counts are expected to remain high (see section 3.2). The clinical experts explained that, when procedures are cancelled, some resources are redirected elsewhere, but the NHS likely accrues unrecoverable costs. The committee agreed that the models did not take into account all the costs that might be averted.
## Avatrombopag and lusutrombopag are innovative treatments
The patient and clinical experts explained that they considered avatrombopag and lusutrombopag to be a step change in terms of preparing people with chronic liver disease and thrombocytopenia for planned invasive procedures. This is because they are oral treatments that, on average, reduce the need for intravenous platelet transfusion. The committee agreed that benefits not captured in the quality-adjusted life year (QALY) calculation included:
lowering the risk of developing antiplatelet antibodies
increasing the availability of platelets for emergency procedures
providing an oral treatment rather than a transfusion.The committee agreed that avatrombopag and lusutrombopag are innovative, and took this into account in its decision making for avatrombopag.
## Because of costs and benefits not captured in the economic modelling, avatrombopag is highly likely to be value for money
The base case from the assessment group showed that, compared with established care without a thrombopoietin receptor agonist, avatrombopag cost £473 more for people with platelet counts of 40,000 to below 50,000 per microlitre of blood, and £801 more for people with counts below 40,000 per microlitre of blood. It was also associated with 0.0004 and 0.0001 more QALYs respectively. This resulted in an incremental cost-effectiveness ratio (ICER) of £1 million to £8 million per QALY gained. The committee noted that the ICERs were very large, and that the QALY difference was extremely small. The committee agreed that the assessment group had not modelled the following benefits:
avoiding the costs of admitting patients to hospital the night before a procedure to have a platelet transfusion
lowering the risk of developing antiplatelet antibodies and the need for matched platelets
making donated platelets more readily available for emergency procedures
increasing the 'treatment window' and available scheduling when using lusutrombopag
-ffering an oral treatment for people with poor venous access.The committee agreed that although it could not quantify the effect on the ICER of these benefits, the factors would lower the incremental costs and increase the incremental QALYs. It was aware that, because these drugs generated very small incremental QALYs, small changes to the incremental costs or QALYs would have large effects on the estimate of cost effectiveness. The committee noted its conclusion that avatrombopag and lusutrombopag represent an innovative treatment (see section 3.13). It concluded that the benefits not captured in the model made it highly likely that avatrombopag would reflect a good use of scarce NHS resources.
## Using blood products or platelets from someone of a different ethnic origin is not an equalities issue
For some people, using blood products including platelets is against their religious beliefs. The clinical experts explained that the chance of developing antiplatelet antibodies is higher if a person having platelets is of a different ethnic origin to the person donating the platelets. The committee considered that it was possible that the donating population would represent a different ethnic mix than the population with chronic liver disease and thrombocytopenia. It agreed that these were not equalities issues because they did not make it any harder for these groups to access thrombopoietin receptor agonists.
# Conclusion
## Avatrombopag would be a good use of scarce NHS resources
The committee concluded that:
avatrombopag did not improve survival compared with established care
the economic modelling had not included all the potential benefits of avatrombopag in terms of quality of life and costs
avatrombopag is innovative
including the benefits not captured in the model would make it highly likely that avatrombopag would reflect a good use of scarce NHS resources.Therefore, the committee concluded that avatrombopag could be recommended for treating thrombocytopenia in people with chronic liver disease needing planned invasive procedures.
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{'Recommendations': 'Avatrombopag is recommended, within its marketing authorisation, as an option for treating severe thrombocytopenia (that is, a platelet count of below 50,000\xa0platelets per microlitre of blood) in adults with chronic liver disease having a planned invasive procedure.\n\nWhy the committee made these recommendations\n\nPeople with chronic liver disease may have low platelet levels. This means that they are more likely to bleed during invasive medical procedures, including surgery. Currently, they have a platelet transfusion before invasive procedures to reduce their chances of bleeding.\n\nAvatrombopag and lusutrombopag are oral therapies that raise platelet levels to reduce the need for a platelet transfusion. Platelet transfusions rely on donors and are given intravenously, so replacing them with a treatment given by mouth is an improvement. The drugs have several other benefits, including:\n\nfewer transfusions and a lower risk of transfusion-related complications\n\nfewer stays in hospital.\n\nIn addition, platelets can be stored only for a short time. This may delay people getting platelets in time for their procedure. However, avatrombopag and lusutrombopag need to be taken more than a week before a procedure, so cannot be used for emergency procedures.\n\nThe economic modelling does not fully account for the benefits for patients and service delivery when using avatrombopag and lusutrombopag. It is possible that using avatrombopag would likely save the NHS money. So, avatrombopag can be recommended for treating thrombocytopenia in people with chronic liver disease who need planned invasive procedures.', 'Information about avatrombopag and lusutrombopag': "# Marketing authorisations\n\nAvatrombopag (Doptelet, Sobi) is recommended 'for the treatment of severe thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo an invasive procedure'.\n\nLusutrombopag (Mulpleo, Shionogi B.V.) is recommended 'for the treatment of severe thrombocytopenia in adult patients with chronic liver disease undergoing invasive procedures'.\n\n# Dosages in the marketing authorisations\n\nThe recommended dosage of avatrombopag is based on the patient's platelet count:\n\nbelow 40,000\xa0platelets per microlitre of blood – 60\xa0mg once daily\n\n,000\xa0to below 50,000\xa0platelets per microlitre of blood – 40\xa0mg once daily.Dosing should begin 10\xa0to\xa013\xa0days before the planned procedure. Patients should have their procedure 5\xa0to\xa08\xa0days after the last dose of avatrombopag. Avatrombopag is taken orally.\n\nThe recommended dosage of lusutrombopag is 3\xa0mg once daily for 7\xa0days. The procedure should be done from day\xa09 after the start of lusutrombopag treatment. Platelet count should be measured before the procedure. Lusutrombopag is taken orally.\n\n# Price\n\nThe company has stated that the price of avatrombopag is £640 or £960 per 5‑day treatment course for the 40,000 to below 50,000 and below 40,000\xa0platelets per microlitre of blood groups respectively.\n\nThe company has stated that the cost of lusutrombopag is £800 per 7‑day treatment course. Costs may vary in different settings because of negotiated procurement discounts.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence from a number of sources. See the committee papers for full details of the evidence.\n\n# Treatment pathway\n\n## People with chronic liver disease and a count of below 50,000\xa0platelets per microlitre of blood would be eligible for avatrombopag or lusutrombopag\n\nThe clinical experts explained that people with chronic liver disease and thrombocytopenia (traditionally defined as a platelet count below 150,000\xa0platelets per microlitre of blood) are at increased risk of bleeding when having elective or urgent invasive procedures, including surgery. Planned procedures may include investigative or therapeutic procedures. To prevent or minimise bleeding, people may have a platelet transfusion before the invasive procedure. The clinical experts attending the meeting acknowledged that they were unaware of trials testing whether platelets lowered the risk of bleeding. However, they agreed that transfusing platelets was the standard of care. The clinical experts also stated that the risk of bleeding during a procedure depends on the platelet count, the procedure, other manifestations of liver disease, history of bleeding and age. NICE's guideline on blood transfusion recommends that prophylactic platelet transfusions to raise the platelet count above 50,000\xa0platelets per microlitre of blood be considered for people having invasive procedures or surgery. The committee heard that even higher platelet counts might be needed for some invasive procedures (such as ocular surgery). It noted that avatrombopag is licensed for treating thrombocytopenia when the platelet count is below 50,000\xa0platelets per microlitre of blood. It also noted that, although the marketing authorisation for lusutrombopag does not define severe thrombocytopenia, the company and the assessment group presented evidence (that is, clinical trial data, indirect clinical data and cost-effectiveness analyses) only for people with a platelet count below 50,000\xa0platelets per microlitre of blood. If people bleed during or after a procedure, they may need a 'rescue therapy', including further platelet transfusions, fresh frozen plasma or tranexamic acid. The committee concluded that people with chronic liver disease having a planned invasive procedure would be eligible for treatment with avatrombopag and lusutrombopag if they had a platelet count of below 50,000\xa0platelets per microlitre of blood. It agreed to make recommendations for this group.\n\n## The appraisal applies to people needing planned procedures scheduled for 9\xa0or\xa010\xa0days in the future\n\nThe marketing authorisations stipulate that avatrombopag and lusutrombopag oral treatments need to be taken at least 10\xa0days or 9\xa0days respectively before a procedure. The clinical experts stated that it would be relatively straightforward to coordinate testing platelet concentrations and prescribing avatrombopag and lusutrombopag with a GP. Because of the time needed to increase the platelet count, the committee heard that avatrombopag and lusutrombopag would be appropriate only for planned elective procedures. However, these drugs would not have a role in planned procedures that need to be done within 9\xa0or\xa010\xa0days. The committee concluded that the appraisal applies to people with chronic liver disease and a platelet count below 50,000\xa0platelets per microlitre of blood needing planned ('elective') invasive procedures rather than emergency procedures.\n\n## Avatrombopag and lusutrombopag raise platelet levels for longer than a transfusion, and are taken at home so reduce wastage and hospital stays\n\nThe clinical experts explained that a platelet transfusion increases platelet levels for only a short time. This means that patients need to have their procedures soon after having a transfusion. According to the clinical experts, about 50% of patients go into hospital to have a transfusion the evening before their planned procedure and, when possible, the transfusion is given on the day of the procedure. If the 'treatment window' (that is, the time when platelet levels are raised) is missed, a patient would have another platelet transfusion before having the procedure. Avatrombopag and lusutrombopag have longer treatment windows in which to do planned invasive procedures than do platelet transfusions. Specifically, these windows are 10\xa0to\xa013\xa0days (stated in the marketing authorisation for avatrombopag) after starting avatrombopag and from day\xa09 (stated in the marketing authorisation for lusutrombopag) after starting lusutrombopag. The committee considered that this would ease procedure scheduling compared with platelet transfusion and may make it possible to carry out multiple procedures within a treatment window. It concluded that avatrombopag and lusutrombopag have some potential advantages over transfusing platelets. These include reducing wastage if an invasive procedure is delayed, increasing the time in which procedures can occur and reducing hospital stays.\n\n## People would welcome an oral treatment alternative to platelet transfusions\n\nThe patient expert stated that, typically, people with chronic liver disease and thrombocytopenia are sick and have many hospital appointments. This, and the associated travel, disrupts their lives. They would value any treatment that could reduce this burden. Avatrombopag and lusutrombopag are oral treatments, and would reduce the need for a trip to hospital for a transfusion. The clinical experts acknowledged that some people who develop chronic liver disease from intravenous drug use have poor venous access. For them, transfusing platelets is difficult without central venous access, for which a procedure is also needed. The patient expert stated that the risks of adverse effects associated with platelet transfusions are low. However, people perceive oral treatments to be safer, and even just the perceived risk of platelet transfusions can cause anxiety. The committee concluded that there are benefits related to an oral treatment compared with platelet transfusions, and that people would welcome an oral treatment option.\n\n## Reducing dependence on platelets would minimise problems associated with obtaining and transfusing platelets\n\nPlatelet transfusions, like all blood products, are a scarce resource limited by the number of donations received. The clinical experts explained that platelets also have a short shelf life (of 5\xa0to\xa07\xa0days) and need to be stored at room temperature. This means that larger hospitals store only limited amounts to avoid wastage, and that smaller hospitals do not store platelets on site. The clinical experts explained that patients can become refractory to repeated platelet transfusions. Repeated transfusions can also increase the risk of infection. Some people can react to the plasma contained in the platelets or develop antibodies against donor platelets after repeated transfusions. People who have an immune reaction to donated platelets may reduce their chance of having a successful liver transplant. The clinical experts also stated that, although donor platelets are not usually matched to the recipient, sometimes they have to be. This then makes it more difficult to find platelets, and means that no one else can use these matched platelets (for example, human leukocyte antigen matched). The committee agreed that obtaining, storing and administering platelets carries a number of practical implications for patients and for service delivery. It concluded that reducing dependence on platelets would minimise problems associated with obtaining and transfusing platelets.\n\n# Clinical evidence\n\n## Avatrombopag and lusutrombopag reduce the number of platelet transfusions\n\nThe avatrombopag randomised placebo-controlled trials (ADAPT\xa01 and ADAPT\xa02) assessed 2\xa0doses of avatrombopag: 40\xa0mg for people with a platelet count of between 40,000 and below 50,000\xa0platelets per microlitre of blood, and 60\xa0mg for people with a platelet count below 40,000\xa0platelets per microlitre of blood. The lusutrombopag trials (L‑PLUS\xa01, L‑PLUS\xa02 and JapicCTI\xa0121944) assessed 3\xa0mg lusutrombopag in people with a platelet count below 50,000\xa0platelets per microlitre of blood. To compare the lusutrombopag results with the avatrombopag results, the assessment group chose to separate lusutrombopag results into the same subgroups as avatrombopag. That is, it considered the lusutrombopag trial results for 2\xa0subgroups: people with a platelet count of between 40,000 and below 50,000\xa0platelets per microlitre of blood; and people with a platelet count below 40,000\xa0platelets per microlitre of blood separately. However, the assessment group also presented analyses for lusutrombopag for the full population. The avatrombopag and lusutrombopag trials measured the proportion of people needing a platelet transfusion before an invasive procedure. Across all subgroups, at least 40% fewer people needed a platelet transfusion if they were randomised to avatrombopag or lusutrombopag compared with placebo. The committee concluded that the trial evidence presented was appropriate for decision making. It further concluded that the evidence showed that avatrombopag and lusutrombopag reduce the number of platelet transfusions before invasive procedures in people with chronic liver disease and thrombocytopenia when compared with placebo.\n\n## Although both drugs' trials include people fitter than those having platelet transfusions in UK clinical practice, the results are generalisable\n\nOne way to categorise the severity of chronic liver disease is by Child–Pugh score. People in the Child–Pugh A\xa0category have less severe disease and the best prognosis; people in the Child–Pugh C\xa0category have the most severe disease and the poorest prognosis. The regulatory trials of avatrombopag included between 8.6% (40,000 to below 50,000\xa0platelets per microlitre of blood subgroup in the avatrombopag arm of ADAPT‑1) and 15.2% (in the same subgroup of the avatrombopag arm of ADAPT‑2) of people in the Child–Pugh C\xa0category. The trials of lusutrombopag excluded people with disease scored as Child–Pugh\xa0C (although 3.6% of the pooled-trials population were in the Child–Pugh C\xa0category). The summary of product characteristics for both drugs state that they should only be used in people with Child–Pugh C\xa0liver disease if the expected benefits outweigh the expected risks. The clinical experts explained that patients with thrombocytopenia tend to have Child–Pugh B\xa0or C\xa0liver disease, and that people with Child–Pugh A\xa0liver disease rarely have thrombocytopenia. The committee agreed that this meant that the avatrombopag and lusutrombopag trials were carried out in people who were fitter than people who would have the drugs in UK clinical practice. The clinical experts explained that outcomes might be better in clinical practice than in the trials. This was because using a thrombopoietin receptor agonist such as avatrombopag or lusutrombopag in people with more severe disease and less ability to make thrombopoietin has a larger effect than in people with less severe disease. The committee agreed that this seemed a reasonable expectation, but that there was no evidence to support it. Overall, however, the committee concluded that the trial results were generalisable to NHS practice.\n\n## There is no trial evidence to determine whether avatrombopag or lusutrombopag increase life expectancy compared with platelet transfusions\n\nThe trials of avatrombopag and lusutrombopag had a follow up of 5\xa0weeks and did not measure survival as a clinical outcome. The committee considered that survival on avatrombopag or lusutrombopag compared with standard care may depend on:\n\nDeath rate associated with platelet transfusion: People having avatrombopag or lusutrombopag would, on average, have fewer platelet transfusions (see section\xa03.6). The clinical experts explained that the risk of death with a platelet transfusion was very small (see section\xa03.10).\n\nFatal bleeds: The company for lusutrombopag (Shionogi) showed data suggesting that lusutrombopag was associated with fewer severe bleeds than placebo. The committee considered it plausible that there would be fewer bleeds with a thrombopoietin receptor agonist because these drugs raise platelet levels for a longer time than a platelet transfusion. It also considered that it was difficult to use the rates of rescue therapy for bleeding (which had been measured in the avatrombopag and lusutrombopag trials) as a proxy measure for bleeding rates. This was because the definition of rescue therapy differed between the trials.\n\nAdverse events associated with avatrombopag or lusutrombopag: The committee acknowledged that thrombopoietin receptor agonists increase the risk of thromboembolic events, but that the short-term trial results did not show a difference in thromboembolic events between placebo and avatrombopag or lusutrombopag.The committee concluded that there were no data to determine whether avatrombopag or lusutrombopag increase or decrease life expectancy compared with platelet transfusions, but that the treatments were unlikely to. It further concluded to assume no difference in death rates between people treated with or without thrombopoietin receptor agonists.\n\n## Avatrombopag and lusutrombopag are expected to be of similar clinical effectiveness to each other\n\nThere were no head-to-head trials comparing avatrombopag with lusutrombopag, and the assessment group carried out a network meta-analysis. The committee agreed with the assessment group's concerns about comparing the clinical trials for avatrombopag and lusutrombopag. It noted that the trials defined rescue therapy differently, and had different criteria defining when platelet transfusions were indicated. The clinical experts and the company explained that they did not expect the effectiveness to differ between avatrombopag and lusutrombopag, which share the same mechanism of action. The committee agreed that this seemed plausible, and also noted that the indirect analyses mostly showed that there were no differences between drugs. The committee concluded that there was no evidence that either avatrombopag or lusutrombopag was more effective than the other.\n\n# Cost-effectiveness evidence\n\n## The assessment group's and Shionogi's models are structured similarly but model bleeds differently\n\nThe assessment group model was adapted from the model provided by the comparator company in this appraisal, Shionogi (the company for lusutrombopag). Shionogi's model included a short-term decision tree to model the clinical trial period (35\xa0days). It also included a Markov model to model the life expectancy of a person with chronic liver disease over the long term (50\xa0years). However, the models differed in how they modelled quality of life and survival related to bleeding and death associated with platelet transfusion. Shionogi modelled a risk of death associated with platelet transfusion of 0.3315%, and assumed that death happens before surgery. The assessment group's model estimated a lower (0.0005%) risk of death associated with platelet transfusion, which could occur before, during or after the procedure. The clinical experts explained that the assessment group's model was more plausible. Shionogi modelled risk of bleeding separately to risk of having rescue therapy, and assumed a lower rate of bleeds with lusutrombopag compared with established care. The assessment group did not model bleeding separately from rescue therapy. The clinical experts explained that people who bleed have rescue therapy, even after being discharged from hospital. Both Shionogi and the assessment group assumed that bleeding lowered quality of life and increased the risk of dying. The committee concluded that it was plausible that avatrombopag plus a platelet transfusion and rescue therapy would be associated with similar long-term quality of life and risk of death as a platelet transfusion and rescue therapy.\n\n## Baseline utility values are low but appropriate for decision making\n\nThe baseline utility value, applied by the assessment group to people who did or did not have a thrombopoietin receptor agonist, was 0.544. The committee considered that this seemed low. The patient expert explained that the estimate seemed reasonable because this population is very unwell. The committee was aware that the assessment group conducted a scenario analysis using a higher baseline utility of 0.801, which minimally affected the cost-effectiveness results. The committee agreed that the baseline utility values used in the assessment group's and company's base cases were appropriate for decision making.\n\n## Costs of platelet transfusions and delayed surgery could offset drug costs, but the models do not include all relevant costs\n\nShionogi modelled a higher cost for platelet transfusions than did the assessment group. It assumed a person would have an average of 3\xa0units of platelets. The assessment group assumed an average of around 1\xa0unit. The assessment group based its calculations on the volume of platelets transfused in the lusutrombopag trials divided by the number of platelets estimated to be in a unit of platelets obtained by apheresis. The clinical experts stated that the costs of a platelet transfusion likely fell between Shionogi's and the assessment group's estimates. The committee considered that the incremental costs for avatrombopag compared with established care modelled in the assessment group's base case may have overestimated the true costs. This was because the assessment group did not include all relevant costs. In particular, it did not include the costs of admitting patients to hospital the night before a procedure for transfusion or take into account that transfusion costs increase for patients who develop immunity. In addition, the assessment group did not model wasted surgery time for delayed or cancelled procedures. The committee did not see evidence that avatrombopag or lusutrombopag resulted in fewer cancelled or delayed procedures. However, it accepted that there would likely be fewer delays and cancellations with the drugs because of the longer treatment window in which platelet counts are expected to remain high (see section\xa03.2). The clinical experts explained that, when procedures are cancelled, some resources are redirected elsewhere, but the NHS likely accrues unrecoverable costs. The committee agreed that the models did not take into account all the costs that might be averted.\n\n## Avatrombopag and lusutrombopag are innovative treatments\n\nThe patient and clinical experts explained that they considered avatrombopag and lusutrombopag to be a step change in terms of preparing people with chronic liver disease and thrombocytopenia for planned invasive procedures. This is because they are oral treatments that, on average, reduce the need for intravenous platelet transfusion. The committee agreed that benefits not captured in the quality-adjusted life year (QALY) calculation included:\n\nlowering the risk of developing antiplatelet antibodies\n\nincreasing the availability of platelets for emergency procedures\n\nproviding an oral treatment rather than a transfusion.The committee agreed that avatrombopag and lusutrombopag are innovative, and took this into account in its decision making for avatrombopag.\n\n## Because of costs and benefits not captured in the economic modelling, avatrombopag is highly likely to be value for money\n\nThe base case from the assessment group showed that, compared with established care without a thrombopoietin receptor agonist, avatrombopag cost £473 more for people with platelet counts of 40,000 to below 50,000\xa0per microlitre of blood, and £801 more for people with counts below 40,000\xa0per microlitre of blood. It was also associated with 0.0004 and 0.0001 more QALYs respectively. This resulted in an incremental cost-effectiveness ratio (ICER) of £1\xa0million to £8\xa0million per QALY gained. The committee noted that the ICERs were very large, and that the QALY difference was extremely small. The committee agreed that the assessment group had not modelled the following benefits:\n\navoiding the costs of admitting patients to hospital the night before a procedure to have a platelet transfusion\n\nlowering the risk of developing antiplatelet antibodies and the need for matched platelets\n\nmaking donated platelets more readily available for emergency procedures\n\nincreasing the 'treatment window' and available scheduling when using lusutrombopag\n\noffering an oral treatment for people with poor venous access.The committee agreed that although it could not quantify the effect on the ICER of these benefits, the factors would lower the incremental costs and increase the incremental QALYs. It was aware that, because these drugs generated very small incremental QALYs, small changes to the incremental costs or QALYs would have large effects on the estimate of cost effectiveness. The committee noted its conclusion that avatrombopag and lusutrombopag represent an innovative treatment (see section\xa03.13). It concluded that the benefits not captured in the model made it highly likely that avatrombopag would reflect a good use of scarce NHS resources.\n\n## Using blood products or platelets from someone of a different ethnic origin is not an equalities issue\n\nFor some people, using blood products including platelets is against their religious beliefs. The clinical experts explained that the chance of developing antiplatelet antibodies is higher if a person having platelets is of a different ethnic origin to the person donating the platelets. The committee considered that it was possible that the donating population would represent a different ethnic mix than the population with chronic liver disease and thrombocytopenia. It agreed that these were not equalities issues because they did not make it any harder for these groups to access thrombopoietin receptor agonists.\n\n# Conclusion\n\n## Avatrombopag would be a good use of scarce NHS resources\n\nThe committee concluded that:\n\navatrombopag did not improve survival compared with established care\n\nthe economic modelling had not included all the potential benefits of avatrombopag in terms of quality of life and costs\n\navatrombopag is innovative\n\nincluding the benefits not captured in the model would make it highly likely that avatrombopag would reflect a good use of scarce NHS resources.Therefore, the committee concluded that avatrombopag could be recommended for treating thrombocytopenia in people with chronic liver disease needing planned invasive procedures."}
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https://www.nice.org.uk/guidance/ta626
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Evidence-based recommendations on avatrombopag (Doptelet) for treating severe thrombocytopenia in adults with chronic liver disease needing a planned invasive procedure.
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f2227d7721937d33fac77c0aef643a8b192e4b5c
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nice
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Tests to help assess risk of acute kidney injury for people being considered for critical care admission (ARCHITECT and Alinity i Urine NGAL assays, BioPorto NGAL test and NephroCheck test)
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Tests to help assess risk of acute kidney injury for people being considered for critical care admission (ARCHITECT and Alinity i Urine NGAL assays, BioPorto NGAL test and NephroCheck test)
Evidence-based recommendations on tests to help assess risk of acute kidney injury for people being considered for critical care admission. The tests are the ARCHITECT and ALINITY i Urine NGAL assays, BioPorto NGAL test and NephroCheck test.
# Recommendations
There is not enough evidence to recommend the routine use of the ARCHITECT and Alinity i Urine neutrophil gelatinase-associated lipocalin (NGAL) assays, BioPorto NGAL test or NephroCheck test to help assess the risk of acute kidney injury for people being considered for critical care admission.
Further research is recommended to assess:
the clinical effectiveness of defined care bundles to prevent or reduce the effect of acute kidney injury in defined NHS patient populations who could benefit from preventive care for acute kidney injury (see section 5.1)
the effect on clinical outcomes of having the tests to guide care to prevent acute kidney injury (see section 5.2).
Why the committee made these recommendations
Using the tests may help to identify people with acute kidney injury earlier than monitoring serum creatinine and urine levels alone. But it is not clear how much this will benefit people being considered for admission to critical care in the NHS, for example, by reducing their hospital stay or likelihood of needing renal replacement therapy in hospital.
The cost-effectiveness estimates for the tests are very uncertain. But they are likely to be much higher than what NICE normally considers a cost-effective use of NHS resources. Therefore, these tests are not recommended for use in the NHS.
There is considerable uncertainty about which patients in the NHS could benefit from the tests. This is because preventive care for acute kidney injury may already be done (in full or in part) as standard practice, which limits the effect that the test results can have on guiding care. Further research may identify specific populations in the NHS who could benefit from the tests, and by how much.# The diagnostic tests
# Clinical need and practice
## Acute kidney injury
Acute kidney injury ranges from minor loss of kidney function to complete kidney failure. In current practice, reduced kidney function is identified, and staged, by elevated serum creatinine levels or reduced urine output, or both. There are no direct treatments for most types of acute kidney injury. Care focuses on optimising haemodynamics and fluid status, avoiding nephrotoxic treatments, and identifying and resolving the underlying cause as quickly as possible. A goal of care is to prevent further kidney injury and stop acute kidney injury progressing; in particular, to prevent it progressing to a stage when renal replacement therapy is needed.
The NephroCheck and neutrophil gelatinase-associated lipocalin (NGAL) tests could potentially detect kidney injury earlier than current methods for monitoring kidney function: serum creatinine and urine output. Serum creatinine levels are slow to rise after kidney injury. Also, using intravenous fluids and diuretics can cause issues when detecting kidney injury by measuring urine output. Earlier identification of acute kidney injury could allow earlier adoption of measures such as care bundles (a group of interventions, or processes, which when implemented together can help to reduce the severity of acute kidney injury). These could prevent the condition progressing to more severe injury and reduce the risk of adverse outcomes for patients.
The NephroCheck test is indicated for use in people who are critically ill, but the NGAL tests potentially have a broader indication. At the scoping workshop and assessment subgroup meeting, clinical experts considered the most relevant population for this assessment. They considered the different types of care for people who are critically ill to determine who could benefit from use of the tests in the NHS. People who are admitted to NHS critical care should already have a range of interventions designed to prevent acute kidney injury because they are extremely unwell. Therefore, the potential for the tests to improve outcomes in this population is limited in the NHS because the results of the tests are unlikely to change management decisions. Clinical experts highlighted that the tests could be useful for people who are being considered for admission to critical care; that is, when a decision about admission has not been made and the test results could guide the use of preventive care for acute kidney injury. The decision question for this assessment therefore focuses on this population.
# The interventions
## NephroCheck test
The NephroCheck test (Astute Medical) measures the level of 2 biomarkers (tissue inhibitor of metalloproteinase 2 and insulin-like growth factor binding protein 7 ) in urine and uses the concentrations to help assess risk of moderate to severe acute kidney injury (defined as per the Kidney Disease Improving Global Outcomes guidelines) in the subsequent 12 hours. The company states that the test result is intended to be used in conjunction with clinical evaluation as an aid in the risk assessment of acute kidney injury in the critically ill.
The concentrations of TIMP‑2 and IGFBP‑7 are used to calculate an AKIRisk score (the concentrations of each are multiplied together and divided by 1,000). A score of over 0.3 indicates a higher risk of developing moderate to severe acute kidney injury within 12 hours of assessment. The test can be run on the Astute 140 meter, the VITROS 3600 immunodiagnostic system and the VITROS 5600 and VITROS 7600 integrated system clinical chemistry analysers. The company states that the test is marketed in the UK for people over 21 years.
## ARCHITECT and Alinity i Urine NGAL assays
The ARCHITECT and Alinity i Urine NGAL assays (Abbott) are chemiluminescent microparticle immunoassays for the quantitative determination of NGAL in human urine. The company states that for diagnostic purposes, the test results should be used in conjunction with clinical assessment and the results of any other testing that has been done.
The company has no set threshold for a positive result. The ARCHITECT and Alinity i Urine NGAL assays are run on different analysers but use the same reagents. The ARCHITECT assay is run on the ARCHITECT system (i1000SR, i2000, i2000SR, ci4100, ci8200 or ci16200). The test has no age restrictions on use.
## BioPorto NGAL test
The BioPorto NGAL test (BioPorto Diagnostics) is a particle-enhanced turbidimetric immunoassay for the quantitative determination of NGAL in human urine, ethylenediaminetetraacetic acid (EDTA) plasma and heparin plasma. The company states that this is not a standalone test and clinicians should interpret the significance of any raised NGAL level alongside a person's clinical features.
The company advises that the NGAL concentration in an isolated sample of urine or EDTA plasma should exceed 250 ng/ml to indicate the presence of renal disorder, including acute kidney injury. The assay can be run on various clinical chemistry analyser systems in a laboratory. The test has no age restriction on use.
# The comparator
No additional testing to identify people at high risk of developing acute kidney injury (other than standard serum creatinine and urine output monitoring).# Evidence
The diagnostics advisory committee (section 7) considered evidence on the ARCHITECT and Alinity i Urine neutrophil gelatinase-associated lipocalin (NGAL) assays, BioPorto NGAL test and NephroCheck test for detecting emerging acute kidney injury from several sources. Full details of all the evidence are in the committee papers.
# Clinical effectiveness
The external assessment group (EAG) did a systematic review to identify evidence on the diagnostic accuracy and clinical effectiveness of the ARCHITECT and Alinity i Urine NGAL assays, BioPorto NGAL test and NephroCheck test to help assess, and reduce, the risk of acute kidney injury for critically ill patients who are being considered for critical care admission. Although the population in the scope was people being considered for critical care admission, to maximise the available data the EAG included data from studies that enrolled patients already admitted to critical care.
In total, 56 studies (reported in 71 articles) were included. Of these, 46 enrolled adults only, 8 enrolled children only and 2 enrolled both adults and children. Twenty-eight studies were done in Europe (4 in the UK), 15 in North America, 9 in Asia, 2 in North America and Europe, 1 in Australia and 1 study did not provide details of location. In most studies data were collected prospectively.
The studies either reported data on using the biomarkers to detect or predict acute kidney injury or to predict clinical outcomes (mortality or need for renal replacement therapy ) in critically ill patients admitted to hospital. No randomised controlled trials or controlled clinical trials were identified. No studies compared using the biomarkers with standard clinical care for clinical effectiveness outcomes.
The studies assessed using the tests in various clinical settings. The EAG divided the studies in adults and children into 3 groups based on clinical setting: people who had cardiac surgery, people who had major non-cardiac surgery and people admitted to critical care (including critically ill patients presenting to the emergency department, patients admitted to intensive care or patients considered for critical care for various medical conditions).
## Evidence on accuracy to detect emerging acute kidney injury
Test accuracy was determined by the ability of the tests to identify the presence of acute kidney injury according to current clinical criteria (that is, using serum creatinine and urine output). A rise in serum creatinine levels or fall in urine output, or both, occurring within a certain time after the NephroCheck or NGAL test was done (this varied between studies, from within 12 hours to within 7 days) were used to indicate if acute kidney injury occurred (reference standard). The EAG could extract or derive the necessary data for calculating sensitivity and specificity estimates from 33 of the included studies.
The QUADAS‑2 tool was used for quality assessment of the studies. The EAG commented that it was not clear in most studies if the tests were interpreted without knowledge of the reference standard (unclear risk of bias). Studies that used NephroCheck were judged at low risk of bias for interpretation of the test because they used a common threshold for a positive result. However, for the NGAL studies a common threshold was not used. The EAG also commented that in the NGAL studies the threshold was not pre-specified before data were collected. Two studies were assessed as being at high risk of bias on the patient flow domain because more than 50% of the participants were excluded from the analysis (Jaques et al. 2019) or because of poor reporting (Asada et al. 2016). The EAG considered that the applicability of the index test results to the NHS was unclear in many studies because there was wide variation in the NGAL threshold used to define a positive test result and in the timing of the test sample collection. The EAG commented that it had no major concerns that the patient population, index text and reference standard were not applicable to the review question. However, in some of the included studies people were already admitted to critical care.
Because the threshold used for a positive test result varied in the identified studies, the EAG ran meta-analyses using the hierarchical summary ROC (HSROC) model to estimate summary values for sensitivity and specificity. If multiple thresholds were used in a study, the EAG selected 1 threshold to use in its analysis. Meta-analysis was only done if data from 4 or more studies were available.
All studies assessed used the NephroCheck test on urine samples. No studies were done in the UK. Two studies assessed using NephroCheck to detect acute kidney injury after cardiac surgery and 5 studies assessed its use in hospitalised patients admitted to intensive or critical care for various clinical reasons. No studies were identified in people who had major non-cardiac surgery. The summary estimate for sensitivity was 0.75 (95% confidence interval 0.58 to 0.87) and for specificity was 0.61 (95% CI 0.49 to 0.72). The EAG commented that there was heterogeneity across studies and noted that estimates of specificity were generally low.
Two studies provided test accuracy data on using the ARCHITECT NGAL assay to detect acute kidney injury after cardiac surgery. Four studies assessed its use in hospitalised patients admitted to intensive or critical care for various clinical reasons. No studies were done in the UK or were identified in people who had major non-cardiac surgery. The summary estimate for sensitivity was 0.67 (95% CI 0.58 to 0.76) and for specificity was 0.72 (95% CI 0.64 to 0.79). The EAG commented that there was heterogeneity across studies.
Eight studies assessed using the BioPorto NGAL test with urine for detecting acute kidney injury: 1 study in people who had cardiac surgery, 1 study in people who had major non-cardiac surgery and 6 studies in hospitalised patients admitted to intensive or critical care for various clinical reasons. One study was done in the UK (Matsa et al. 2014). The summary estimate for sensitivity was 0.73 (95% CI 0.65 to 0.80) and for specificity was 0.83 (95% CI 0.64 to 0.93). The EAG commented that there was heterogeneity across studies.
The EAG only identified studies in the critical care setting for the BioPorto NGAL test used with blood plasma (4 studies). One study was done in the UK (Matsa et al. 2014). The summary estimate for sensitivity was 0.76 (95% CI 0.56 to 0.89) and for specificity was 0.67 (95% CI 0.40 to 0.86). The EAG commented that there was heterogeneity across studies.
Seven studies assessed using the NGAL assays with urine samples to detect acute kidney injury in children. No studies were done in the UK. No studies assessing the use of NephroCheck in children were identified.
Five studies assessed using the ARCHITECT Urine NGAL assay to detect acute kidney injury in children who had cardiac surgery. The summary estimate for sensitivity was 0.68 (95% CI 0.53 to 0.80) and for specificity was 0.79 (95% CI 0.63 to 0.89). The EAG commented that there was considerable heterogeneity across studies. No studies were identified in a population who had major non-cardiac surgery. One study assessed using the ARCHITECT Urine NGAL assay to detect acute kidney injury in children admitted to intensive or critical care for various clinical reasons. The sensitivity and specificity were 0.77 (95% CI 0.60 to 0.90) and 0.85 (95% CI 0.74 to 0.92), respectively.
One study assessed using the BioPorto NGAL test with urine for detecting acute kidney injury in children who had cardiac surgery. NGAL was measured using a concentration normalised by units of creatinine. The sensitivity and specificity were 0.77 (95% CI 0.69 to 0.84) and 0.47 (95% CI 0.40 to 0.54), respectively.
## Evidence on ability to predict intermediate outcomes
The EAG identified 11 studies with data on the ability of the tests to predict mortality, 4 studies with data on predicting the need for RRT and 3 studies that assessed the ability of the tests to predict worsening of acute kidney injury. All studies were in critically ill patients at risk of acute kidney injury. For predicting mortality, area under the curve (AUC) values varied from 0.55 to 0.91. For predicting the need for RRT, AUC values varied from 0.68 to 0.86. For predicting worsening of acute kidney injury, AUC values varied from 0.66 to 0.71.
The EAG commented that adding the tests to existing clinical models generally improved risk prediction of newly developed acute kidney injury, or worsening of acute kidney injury, and mortality. However, it cautioned that there were limited data available and the statistical models used varied between studies. Also, information on potential candidate variables considered in studies was often not provided.
No studies were identified that reported the effect of using the tests on clinical or patient-reported outcomes.
# Cost effectiveness
## Systematic review of cost-effectiveness evidence
The EAG did a systematic review to identify any published economic evaluations of the ARCHITECT and Alinity i Urine NGAL assays, the BioPorto NGAL test (plasma and urine) and the NephroCheck test for assessing people at risk of developing acute kidney injury. Two of the studies identified used modelling strategies that were similar, and that the EAG considered appropriate for the current decision problem. One of these (Hall et al. 2018) was done in the UK, and the EAG considered it a comprehensive and high-quality assessment. But because the setting was outside the scope of this assessment (people already admitted to intensive care units), the EAG adapted the model for critically ill patients who are at risk of acute kidney injury and being considered for admission to critical care.
## Model structure
The EAG developed a de novo economic model designed to assess the cost effectiveness of using the tests (in addition to standard clinical monitoring) to help detect the risk of developing acute kidney injury and to help start early preventive care.
This was a 2-stage model using TreeAge Pro software. Limited direct evidence was identified that showed the effect of using the tests (compared with standard monitoring alone) on health outcomes (such as acute kidney injury status; mortality; development of chronic kidney disease). So the EAG used observational associations to infer how preventing or reducing the severity of acute kidney injury may affect changes in health outcomes (a linked-evidence approach). An initial decision-tree phase modelled:
The accuracy of the tests to identify people with emerging acute kidney injury.
For people with a positive biomarker test result, the effect of preventive measures (a Kidney Disease Improving Global Outcomes care bundle) on reducing the probability that they develop acute kidney injury or reducing the severity of the condition if they develop it.
The effect of developing acute kidney injury, and its severity, on short-term outcomes (within 90 days): whether a person is admitted to intensive care, length of stay in intensive care or hospital, development of chronic kidney disease and 90‑day mortality.After this initial 90‑day period, a longer-term Markov model was used to model the effect of developing acute kidney injury while in hospital on the risk of developing chronic kidney disease, and the effect of this condition on the rest of a person's life.
The modelled population was people in hospital at risk of developing acute kidney injury, having their serum creatinine and urine output monitored. The EAG used the Grampian population register of hospitalisations to characterise this population. This dataset included 17,630 adults admitted to hospital in Grampian in 2003. It is the complete population of all patients who had an abnormal kidney function blood test on hospital admission and had at least an overnight stay in hospital, including all patients who developed acute kidney injury. The model starting base-case population was 63 years old, 54.3% women, with about 11% having chronic kidney disease (in the model, more people could develop this condition over time). The base-case prevalence of acute kidney injury (that is, people who will develop the condition while in hospital under standard monitoring) was assumed to be 9.2%.
The sensitivity and specificity of the tests to identify people who will develop acute kidney injury (as shown by a later increase in serum creatinine or drop in urine output, or both) was taken from the systematic review and meta-analysis referred to in the clinical effectiveness section. The EAG used values pooled from all studies identified for each of the tests across all clinical settings. The incidence of acute kidney injury and the effect of developing the condition on clinical outcomes (admission to intensive care, 90-day mortality) was estimated by the EAG largely using data from the Grampian observational dataset. The model could vary which clinical outcomes were affected by acute kidney injury status, and the size of this effect.
The EAG assumed that a KDIGO care bundle would be the preventive care used if the tests were positive. It did a literature search to identify studies to estimate the effectiveness of this intervention for the model. The EAG did not include the identified studies in its clinical effectiveness review because the studies did not report the direct effect of using the tests on clinical outcomes. Instead the EAG included the studies in its cost-effectiveness review (as part of the rationale for parameter values used in the model). The EAG used data from Meersch et al. (2017) for the effect of the KDIGO care bundle in the model. This was a single-centre randomised controlled trial done in Germany in people who had cardiac surgery (n=276). People who had a positive NephroCheck test (using a score of over 0.3) were randomised to either standard care (less intensive care than with the KDIGO care bundle) or standard care plus a KDIGO care bundle. People having standard care followed the recommendations of the American College of Cardiology Foundation (2011), which included keeping mean arterial pressure over 65 mmHg and central venous pressure between 8 mmHg and 10 mmHg. The KDIGO care bundles included avoiding nephrotoxic agents, discontinuing angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, close monitoring of urine output, serum creatinine, avoiding hyperglycaemia (for 72 hours), considering alternatives to radiocontrast agents, and optimising fluids. Although there was a significant reduction in occurrence of acute kidney injury by 72 hours for the KDIGO arm compared with standard care (odds ratio 0.48 ), the EAG commented that this did not appear to translate to other clinical outcomes (need for RRT in hospital, 90‑day all-cause mortality and length of stay in intensive care or hospital).
The EAG found 2 other studies reporting the effects of KDIGO care bundles; Gocze et al. (2018) and Schanz et al. (2018). Both were done in Germany and assessed the effect of NephroCheck-guided application of a KDIGO care bundle compared with standard care (no use of a care bundle). Gocze et al. was a smaller study (n=121) than Meersch et al. and reported that NephroCheck-guided care (after major non-cardiac surgery) showed a trend towards a lower probability of acute kidney injury. But the results were not statistically significant; the odds ratio for standard care compared with NephroCheck was 1.96 (95% CI 0.93 to 4.10). There was, however, a statistically significant increase in the odds of stage 2 or stage 3 acute kidney injury in the standard care group compared with NephroCheck: 3.43 (95% CI 1.04 to 11.32). Schanz et al. (n=100) compared the effect of NephroCheck-triggered implementation of KDIGO recommendations for acute kidney injury with standard care alone in an emergency department in Germany. Acute kidney injury outcomes were similar in both groups. The probability of acute kidney injury stage 2 or stage 3 was 32.1% for the intervention group and 33.3% for the control group after 1 day. After 3 days this was 38.9% for intervention group and 39.1% for the control group. The effect size from Gocze et al. was used in a scenario analysis. Data from intensive care registers, reports and studies were used for parameters in the longer-term Markov model.
Test-related costs are shown in table 1. In its base-case analysis, the EAG assumed that an Astute 140 meter would need to be purchased to use NephroCheck, so included the cost of this. The EAG assumed that the NGAL tests are run on platforms that are already available in hospital laboratories, so the cost of these analysers was assumed to be negligible and was not included in the analysis. A scenario analysis was done in which no capital costs (including an analyser) or training costs were included for the tests.
## Table 1 Test-related costs
Cost per test
NephroCheck
BioPorto NGAL test
a
Abbott ARCHITECT NGAL assay
Abbott Alinity
b
i Urine NGAL assay
Platform cost
Equipment cost
Maintenance/ consumables
Staff costs
Staff training costs
Total cost
a Costs assumed to be the same for plasma and urine samples.
b The Alinity NGAL assay was not included in the base-case analysis because of a lack of data for this assay.
Abbreviation: NGAL, neutrophil gelatinase-associated lipocalin.
The EAG assumed that the KDIGO care bundle would be applied for an additional 3 days over and above standard care for people who tested positive on the NephroCheck or NGAL tests (based on clinical opinion and consistent with the primary outcome measure from Meersch et al. 2017). Resources included in the care bundle costs included intravenous fluids (including nurse time), nephrologist and pharmacist review time and stopping blood pressure medication. The total additional cost of applying the KDIGO bundle was assumed to be £106.36 per person.
The EAG updated the searches run in Hall et al. (2018) to identify any additional source of utility data for its model for both the initial decision-tree phase and longer-term Markov model. The age- and sex-matched EQ‑5D UK population norms were calculated using an equation published by Ara and Brazier (2010). These were used to derive age- and sex-adjusted utility multipliers from the raw pooled estimates from studies, based on the age and sex distribution of the source studies.
## Base-case assumptions
The following assumptions (in addition to those described in previous sections) were applied in the base-case analyses:
Acute kidney injury, and more severe acute kidney injury, can be prevented by earlier NephroCheck or NGAL-guided use of a KDIGO care bundle (for people who would otherwise develop it with standard monitoring alone) in base case 1. In base case 2, NGAL-guided care cannot prevent acute kidney injury (but can reduce the severity of the condition).
In base case 1, the NephroCheck biomarkers and NGAL rise at similar times and the earlier identification of emerging kidney injury (relative to serum creatinine and urine output changes) is the same for both tests.
There are no adverse effects on health caused by a false-positive NephroCheck or NGAL test result.
No adaptions to standard monitoring were made for people testing negative on NephroCheck or NGAL tests (although standard monitoring done alongside would detect acute kidney injury for false-negative tests, just at a later time). This was because the EAG assumed that de-escalation of care would not occur solely because of a negative test result.
Everyone with a positive NephroCheck or NGAL test immediately had a KDIGO care bundle.
After 5 years post-transplant, mortality reverted to the general population all-cause mortality probability. The annual probability of transplant failure remained as that reported from years 3 to 5 in the UK renal registry.
The proportion of people whose transplant failed returned to dialysis. Their probability of progressing from end-stage renal disease on dialysis to a second transplant was the same as for progressing to the first transplant.
## Base-case results
No evidence for NGAL test-guided implementation of preventive care for acute kidney injury on clinical outcomes was identified. Therefore, the EAG did 2 base cases:
Base case 1: Using the NGAL test had the same effect as the NephroCheck test to prevent acute kidney injury and reduce severity of the condition if it occurred (based on Meersch et al. 2017).
Base case 2: Using the NGAL test could only reduce the severity of acute kidney injury (as for base case 1), not prevent it from occurring (NephroCheck effects were unchanged).
The results of base case 1 (probabilistic) are shown in table 2. Because of uncertainty about the extent of any effect of acute kidney injury on other clinical outcomes, the EAG did several scenario analyses (B, C and D). This was in addition to the base case varying which outcomes acute kidney injury occurrence (and severity) affected, and the size of this effect. Scenario C was the most pessimistic (no effect of preventing acute kidney injury, or reducing severity, on clinical outcomes) and scenario D was the most optimistic (full effect of preventing acute kidney injury, or reducing severity, on clinical outcomes).
## Table 2 Cost-effectiveness results (probabilistic) for base case 1
Test
Total cost
Total QALYs
Fully incremental ICER (probability cost effective at £20,000 per QALY gained)
ICER compared with standard monitoring (probability cost effective at £20,000 per QALY gained)
BioPorto NGAL test (urine)
Dominant
BioPorto NGAL test (plasma)
Dominant
Standard monitoring only
Dominated
ARCHITECT NGAL
Dominated
NephroCheck
Dominated
Abbreviations: NGAL, neutrophil gelatinase-associated lipocalin; QALYs, quality-adjusted life years; ICER, incremental cost-effectiveness ratio.
In scenario C, standard care dominated all the tests (that is, they had higher costs and lower quality-adjusted life years), with all tests having 0% probability of being cost effective at a maximum acceptable incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life year (QALY) gained. See table 3 for the results for scenario D.
## Table 3 Cost-effectiveness results (probabilistic) for scenario D (in base case 1)
Test
Total cost
Total QALYs
Fully incremental ICER (probability cost effective at £20,000 per QALY gained)
ICER compared with standard monitoring (probability cost effective at £20,000 per QALY gained)
Standard monitoring only
BioPorto NGAL test (urine)
BioPorto NGAL test (plasma)
ARCHITECT NGAL
Dominated
NephroCheck
Dominated
Abbreviations: NGAL, neutrophil gelatinase-associated lipocalin; QALYs, quality-adjusted life years; ICER, incremental cost-effectiveness ratio.
The EAG also did 16 further scenario analyses (not all are discussed in this document). Changes made to several parameters improved the cost effectiveness of the tests, so that they all dominated standard care (in a pairwise comparison):
Increasing long-term costs and risk of mortality in the Markov model (scenario G) for people who were admitted to intensive care while in hospital (in the decision-tree phase).
For people having acute kidney injury while in hospital, extending the time of increased risk of developing chronic kidney disease from 1 year to the rest of a person's life (scenario H).
Increasing the prevalence of acute kidney injury to 23% (from 9.2% in base case; scenario K).Assuming false-positive tests increased mortality (scenario M), which worsened the cost effectiveness of the tests.
In scenario Q, the EAG used alternative accuracy estimates from studies that enrolled children only. Data were only available for the ARCHITECT NGAL and the BioPorto NGAL (urine) tests. The EAG cautioned that the model was not configured for children but used parameters from an adult population. Because there were limited accuracy data for the tests in children and a lack of data for other parameters, the EAG considered the analysis to be exploratory only.
In base case 2 (probabilistic analysis), NephroCheck dominated all other tests, with an ICER of about £106,000 per QALY gained compared with standard monitoring. The probability of NephroCheck being the most cost-effective test across scenario analyses increased considerably.
In scenario T (provided in an addendum to the diagnostics assessment report), the EAG used Gocze et al. (rather than Meersch et al.) to inform estimates of the effect of a KDIGO care bundle on reducing the risk of developing acute kidney injury, or the severity of the condition if it did develop. This improved the cost-effectiveness estimates of the tests. In base case 1, all tests dominated standard monitoring. In base case 2, NephroCheck dominated all other tests and standard monitoring.# Committee discussion
# Preventing or reducing the severity of acute kidney injury could benefit patients
The patient expert explained that a diagnosis of acute kidney injury can be very unexpected and can have a substantial effect on people and their families. Acute kidney injury can mean prolonged stays in hospital, which are distressing for patients and cost family members time and money. The patient expert also suggested that earlier detection of acute kidney injury might make temporary renal replacement therapy (RRT) less likely. If this proved to be the case, it could benefit people by reducing the need for invasive RRT and would release resources. Also, developing acute kidney injury increases the risk of chronic kidney disease. The patient expert emphasised that end-stage renal disease changes people's lives (and that of their families), because it affects their lifestyle and ability to work. If the tests helped detect acute kidney injury earlier and allowed interventions to prevent or reduce the severity of the condition, this could benefit patients by improving clinical outcomes.
# There is considerable uncertainty about which patients in the NHS could benefit from the tests
The committee heard that the potential of the tests to change care and improve outcomes in NHS critical care is very limited. Clinical experts explained that the definition of critical care varied across the world. People tend to be more unwell before they are admitted to critical care in the NHS than in the US or the rest of Europe. So in the NHS they should already be having all available interventions to prevent acute kidney injury. Clinical experts also commented that it was uncertain which patients in the NHS could benefit from targeted use of preventive care bundles for acute kidney injury. They commented that care bundles (in addition to standard care) were the only option currently available to try and prevent acute kidney injury or reduce its severity. They also explained that a care bundle is a very complex intervention. It involves implementing measures (such as avoiding nephrotoxic agents, avoiding hyperglycaemia and optimising fluids) that can protect the kidneys from further damage. Many of these will already be done as part of standard care, depending on the clinical setting and the person's condition (that is, they are more likely to have been done already the more intensive the care). Care bundles can also be tailored to a person's condition, excluding some measures if they are not clinically appropriate. Therefore, the effect of the care bundles could vary between different populations. Clinical experts suggested that critical care outreach teams could potentially use the tests to guide preventive care. At consultation, a stakeholder highlighted a recent study (Kullmar et al. 2020) that showed poor adherence to Kidney Disease Improving Global Outcomes (KDIGO) recommendations after cardiac surgery. The study included patients from 2 NHS hospitals. Clinical experts acknowledged that there was likely to be variation in implementing care bundles across the NHS. The committee considered that if preventive measures for acute kidney injury were not already routinely used in a hospital, they may not be used even if there is a positive NephroCheck or neutrophil gelatinase-associated lipocalin (NGAL) test result. This would reduce any benefit of the tests in guiding preventive care. The committee concluded that there was considerable uncertainty about who in the NHS could benefit from the tests.
# Clinical effectiveness
## The accuracy of the tests to detect emerging acute kidney injury, and the clinical significance of their results, is uncertain
Most of the available data for the tests were sensitivity and specificity estimates. These measured the tests' ability to identify people who will be diagnosed with acute kidney injury using current clinical criteria (serum creatinine or urine output). The time of acute kidney injury diagnosis varied from within 12 hours to within 7 days. The external assessment group (EAG) commented that there was considerable clinical and statistical heterogeneity seen across the studies, which included very different populations, and therefore the results should be interpreted with caution. The committee also noted that even the best estimates of sensitivity and specificity showed that using the tests could result in large proportions of falsely positive or negative results. The stage of acute kidney injury detected by the tests also varied in the studies; from any stage of the condition to higher stages only. Clinical experts commented that the staging of the condition in classification systems (such as KDIGO) was developed by clinical consensus and there was uncertainty about the clinical significance of subclinical or early stage (stage 0 or stage 1) acute kidney injury and its correlation with clinical outcomes. The committee concluded that there was uncertainty about how well the tests could detect emerging acute kidney injury, and the clinical significance of what they detect in studies of test accuracy.
# Cost effectiveness
## There is considerable uncertainty about the effect of care bundles on developing acute kidney injury, and whether this would be seen in the NHS
Clinical experts commented that there was considerable uncertainty about how much benefit the care bundles used in the NHS would provide to prevent, or reduce the severity of, acute kidney injury if used earlier (when NephroCheck or NGAL tests indicate risk of acute kidney injury; see section 4.2). In its model, the EAG used data from Meersch et al. (2017) for the effect of test-guided preventive care (a KDIGO care bundle) on reducing the chance of developing acute kidney injury or reducing the severity of the condition if it developed (see section 3.23). The committee noted that people in the control arm did not have the KDIGO care bundle. This was unlikely to reflect NHS practice because although using the tests could allow earlier use of the care bundle, everyone at risk would eventually have an acute kidney injury care bundle at a later time, once serum creatine or urine levels showed acute kidney injury. The absence of the KDIGO care bundle in the control group could therefore have overestimated the treatment effect from Meersch et al. compared with NHS practice. Using the treatment effect size from Gocze et al. rather than Meersch et al. improved the cost effectiveness of the tests (see section 3.35). Clinical experts commented that standard care in Germany (the control arms of the 3 identified studies on the effectiveness of the KDIGO care bundle) may differ from standard care in the UK. Therefore, the generalisability of the results of these studies to the NHS was potentially limited. The committee concluded that there was substantial uncertainty about how much effect a KDIGO care bundle had on developing, or reducing the severity of, acute kidney injury. It also concluded that it was uncertain whether a treatment effect size determined in studies done in Germany would be seen in the NHS, and therefore if the modelled effect of the KDIGO care bundle on acute kidney injury would be seen in the NHS.
## It is not appropriate to assume that the results of the NephroCheck and NGAL tests are equivalent in the economic model
No studies were identified that showed the effect of NGAL-guided use of the KDIGO care bundle. So in base case 1, the EAG assumed that the effect of NephroCheck and NGAL-guided preventive care on acute kidney injury incidence was the same. It used data from Meersch et al. (2017), a study done in people who had a positive NephroCheck test, to estimate the effect of test-guided preventive care on acute kidney injury incidence. Clinical experts commented that the biomarkers used in the NephroCheck test (tissue inhibitor of metalloproteinase 2 and insulin-like growth factor binding protein 7 ) may perform very differently to NGAL as indicators of acute kidney injury because they are released during different physiological processes. The committee concluded that it was not appropriate to assume that the results of the NephroCheck and NGAL tests were equivalent. It also concluded that data from Meersch et al. should not be used to inform estimates of how well NGAL-guided use of the KDIGO bundle affects acute kidney injury incidence in the economic model.
## It is uncertain how much the incidence, and severity, of acute kidney injury affects clinical outcomes
In its model, the EAG used observational data to link incidence and severity of acute kidney injury to the probability of clinical outcomes, such as length of stay in hospital, 90‑day mortality and need for RRT. However, the committee noted that in Meersch et al. use of the KDIGO bundle reduced acute kidney injury incidence, but not length of stay in hospital or intensive care, need for RRT in hospital or 90‑day all-cause mortality. In Gocze et al. length of hospital and intensive care stay was significantly shorter in the KDIGO bundle study arm, but there was no significant difference in need for RRT or mortality in hospital. Clinical experts explained that how each stage of acute kidney injury affected shorter- and longer-term clinical outcomes was not clearly understood (see section 4.3). The EAG investigated how much varying the effect of having acute kidney injury, and severity, had on clinical outcomes in scenario analyses. This led to large variation in cost effectiveness (see section 4.9). The committee concluded that it was uncertain how much the incidence and severity of acute kidney injury affected clinical outcomes.
## The economic model should include the cost of analysers for the NGAL assays
The EAG did not include the cost of analysers needed to run the NGAL assays in its estimates of cost per NGAL test. This was because it assumed that the NGAL tests are run on platforms already available in hospital laboratories, so the cost of these analysers was negligible. Clinical experts commented that the analysers needed to run the different NGAL assays would not be in every hospital. The committee concluded that it would have been reasonable to include the cost of analysers needed to run the NGAL assays in the cost per test used in the model, as had been done for the NephroCheck test.
## The tests may be used very differently for children and the cost-effectiveness estimates for this group are highly uncertain
The committee discussed the lack of data available for children. It noted that the EAG did a scenario analysis that used accuracy estimates from studies that enrolled children only (scenario Q; see section 3.33). Because of a lack of data for other parameters, the EAG had to use values derived from adult populations. The EAG cautioned that this analysis should be considered as exploratory. Also, clinical experts commented that the potential use for children could be very different to that for adults in the NHS. The committee concluded that, because of a lack of data to inform model parameters and uncertainty about the intended use of the tests, the cost-effectiveness estimates of the tests for children were highly uncertain. The committee considered that future studies should consider the utility of the tests for children (see section 4.11).
## The cost-effectiveness estimates are highly uncertain and potentially much higher than what NICE normally considers cost effective
The EAG did multiple scenario analyses to reflect the uncertainty about which clinical outcomes would be affected by both the incidence and severity of acute kidney injury. It cautioned that the results of the cost-effectiveness modelling were largely speculative and should be interpreted with caution. Also, it considered it impossible to determine the best incremental cost-effectiveness ratio (ICER) given the available evidence. Incremental quality-adjusted life years (QALYs) were very low across the scenarios, with tests often having ICERs over £50,000 per QALY gained, or being dominated (that is, they had higher costs and lower QALYs) compared with standard monitoring. Varying the parameter values used in scenario analyses substantially affected the cost-effectiveness estimates for the tests. Changes to some parameters improved the cost effectiveness of the tests, to the extent that they dominated standard care (in base case 1) when compared in a pairwise manner (see section 3.30 and section 3.33). The committee further recalled that it did not consider it appropriate to use data from NephroCheck-guided use of the KDIGO care bundle to estimate the effect of NGAL-guided use of the KDIGO care bundle (see section 4.5). The committee concluded that there was substantial uncertainty about the best cost-effectiveness estimates for the tests in the defined clinical population. However, the estimates could potentially be much higher than what NICE normally considers cost effective.
## There is too much uncertainty about the cost effectiveness of the tests to recommend adoption
The committee agreed that there was substantial uncertainty about how the tests could be used in the NHS (see section 4.2) and their likely cost effectiveness. This was mainly because there was uncertainty about the effect that test-guided care could have on the incidence and progression of acute kidney injury (see section 4.4) and on other clinical outcomes (see section 4.6) in the defined NHS clinical population. Also, how clinicians would react to the test results in the NHS was unclear (that is, the changes to care they would make in response to a positive or negative result). The cost-effectiveness estimates for the tests were very uncertain and, in most scenarios, much higher than what NICE normally considers a cost-effective use of NHS resources (see section 4.9). The committee concluded that there was too much uncertainty about the cost effectiveness of the tests to recommend their adoption in the NHS. Further research could provide clarity on how the tests would affect care and outcomes in the NHS and allow their cost effectiveness to be estimated.
# Research considerations
## Consideration should be given to defining populations in the NHS who would benefit from test-guided preventive care
The committee recalled that there was uncertainty about which patient populations in the NHS could benefit from test-guided use of preventive care for acute kidney injury (see section 4.2). If care bundles were already being used, in full or in part, in a patient population this would limit the effect that the test results can have on guiding care. Clinical experts commented that the potential use for children and young people can also be very different to adults, so specific consideration is needed for this group. The costs of the NephroCheck (about £90) and of providing the KDIGO care bundle earlier (about £105) were similar. Therefore, the committee questioned whether providing the care bundle earlier to everyone (that is, without testing) could be the most cost-effective strategy for some patient populations in the NHS. The committee concluded that, before further studies are done, it was important that companies define the patient populations in the NHS who could benefit from test-guided preventive care. It noted that people who are critically unwell in the NHS would likely already be having all available care to prevent acute kidney injury.# Recommendations for further research
Companies should specify patient populations in the NHS who could benefit from test-guided preventive care for acute kidney injury. Further research is then recommended in these populations to assess the clinical effectiveness of defined care bundles designed to prevent or reduce the effect of acute kidney injury in the NHS. Research should be done in children, young people and adults, but specific considerations may be needed for children and young people when care differs from that for an adult population (see section 4.11).
Further research is recommended to assess the effect of test-guided preventive care (see section 5.1) on clinical outcomes (such as length of stay in hospital, mortality and need for renal replacement therapy and progression to chronic kidney disease). Research should be done in children, young people and adults, but specific considerations may be needed for children and young people when care differs from that for an adult population. Studies should investigate the effects of both positive and negative test results on clinical decisions and subsequent care.
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{'Recommendations': 'There is not enough evidence to recommend the routine use of the ARCHITECT and Alinity i Urine neutrophil gelatinase-associated lipocalin (NGAL) assays, BioPorto NGAL test or NephroCheck test to help assess the risk of acute kidney injury for people being considered for critical care admission.\n\nFurther research is recommended to assess:\n\nthe clinical effectiveness of defined care bundles to prevent or reduce the effect of acute kidney injury in defined NHS patient populations who could benefit from preventive care for acute kidney injury (see section\xa05.1)\n\nthe effect on clinical outcomes of having the tests to guide care to prevent acute kidney injury (see section\xa05.2).\n\nWhy the committee made these recommendations\n\nUsing the tests may help to identify people with acute kidney injury earlier than monitoring serum creatinine and urine levels alone. But it is not clear how much this will benefit people being considered for admission to critical care in the NHS, for example, by reducing their hospital stay or likelihood of needing renal replacement therapy in hospital.\n\nThe cost-effectiveness estimates for the tests are very uncertain. But they are likely to be much higher than what NICE normally considers a cost-effective use of NHS resources. Therefore, these tests are not recommended for use in the NHS.\n\nThere is considerable uncertainty about which patients in the NHS could benefit from the tests. This is because preventive care for acute kidney injury may already be done (in full or in part) as standard practice, which limits the effect that the test results can have on guiding care. Further research may identify specific populations in the NHS who could benefit from the tests, and by how much.', 'The diagnostic tests': "# Clinical need and practice\n\n## Acute kidney injury\n\nAcute kidney injury ranges from minor loss of kidney function to complete kidney failure. In current practice, reduced kidney function is identified, and staged, by elevated serum creatinine levels or reduced urine output, or both. There are no direct treatments for most types of acute kidney injury. Care focuses on optimising haemodynamics and fluid status, avoiding nephrotoxic treatments, and identifying and resolving the underlying cause as quickly as possible. A goal of care is to prevent further kidney injury and stop acute kidney injury progressing; in particular, to prevent it progressing to a stage when renal replacement therapy is needed.\n\nThe NephroCheck and neutrophil gelatinase-associated lipocalin (NGAL) tests could potentially detect kidney injury earlier than current methods for monitoring kidney function: serum creatinine and urine output. Serum creatinine levels are slow to rise after kidney injury. Also, using intravenous fluids and diuretics can cause issues when detecting kidney injury by measuring urine output. Earlier identification of acute kidney injury could allow earlier adoption of measures such as care bundles (a group of interventions, or processes, which when implemented together can help to reduce the severity of acute kidney injury). These could prevent the condition progressing to more severe injury and reduce the risk of adverse outcomes for patients.\n\nThe NephroCheck test is indicated for use in people who are critically ill, but the NGAL tests potentially have a broader indication. At the scoping workshop and assessment subgroup meeting, clinical experts considered the most relevant population for this assessment. They considered the different types of care for people who are critically ill to determine who could benefit from use of the tests in the NHS. People who are admitted to NHS critical care should already have a range of interventions designed to prevent acute kidney injury because they are extremely unwell. Therefore, the potential for the tests to improve outcomes in this population is limited in the NHS because the results of the tests are unlikely to change management decisions. Clinical experts highlighted that the tests could be useful for people who are being considered for admission to critical care; that is, when a decision about admission has not been made and the test results could guide the use of preventive care for acute kidney injury. The decision question for this assessment therefore focuses on this population.\n\n# The interventions\n\n## NephroCheck test\n\nThe NephroCheck test (Astute Medical) measures the level of 2\xa0biomarkers (tissue inhibitor of metalloproteinase\xa02 [TIMP‑2] and insulin-like growth factor binding protein\xa07 [IGFBP‑7]) in urine and uses the concentrations to help assess risk of moderate to severe acute kidney injury (defined as per the Kidney Disease Improving Global Outcomes [KDIGO] guidelines) in the subsequent 12\xa0hours. The company states that the test result is intended to be used in conjunction with clinical evaluation as an aid in the risk assessment of acute kidney injury in the critically ill.\n\nThe concentrations of TIMP‑2 and IGFBP‑7 are used to calculate an AKIRisk score (the concentrations of each [nanograms/millilitre; ng/ml] are multiplied together and divided by 1,000). A score of over 0.3 indicates a higher risk of developing moderate to severe acute kidney injury within 12\xa0hours of assessment. The test can be run on the Astute\xa0140 meter, the VITROS\xa03600 immunodiagnostic system and the VITROS\xa05600 and VITROS\xa07600 integrated system clinical chemistry analysers. The company states that the test is marketed in the UK for people over 21\xa0years.\n\n## ARCHITECT and Alinity i Urine NGAL assays\n\nThe ARCHITECT and Alinity i Urine NGAL assays (Abbott) are chemiluminescent microparticle immunoassays for the quantitative determination of NGAL in human urine. The company states that for diagnostic purposes, the test results should be used in conjunction with clinical assessment and the results of any other testing that has been done.\n\nThe company has no set threshold for a positive result. The ARCHITECT and Alinity i Urine NGAL assays are run on different analysers but use the same reagents. The ARCHITECT assay is run on the ARCHITECT system (i1000SR, i2000, i2000SR, ci4100, ci8200 or ci16200). The test has no age restrictions on use.\n\n## BioPorto NGAL test\n\nThe BioPorto NGAL test (BioPorto Diagnostics) is a particle-enhanced turbidimetric immunoassay for the quantitative determination of NGAL in human urine, ethylenediaminetetraacetic acid (EDTA) plasma and heparin plasma. The company states that this is not a standalone test and clinicians should interpret the significance of any raised NGAL level alongside a person's clinical features.\n\nThe company advises that the NGAL concentration in an isolated sample of urine or EDTA plasma should exceed 250\xa0ng/ml to indicate the presence of renal disorder, including acute kidney injury. The assay can be run on various clinical chemistry analyser systems in a laboratory. The test has no age restriction on use.\n\n# The comparator\n\nNo additional testing to identify people at high risk of developing acute kidney injury (other than standard serum creatinine and urine output monitoring).", 'Evidence': "The diagnostics advisory committee (section\xa07) considered evidence on the ARCHITECT and Alinity i Urine neutrophil gelatinase-associated lipocalin (NGAL) assays, BioPorto NGAL test and NephroCheck test for detecting emerging acute kidney injury from several sources. Full details of all the evidence are in the committee papers.\n\n# Clinical effectiveness\n\nThe external assessment group (EAG) did a systematic review to identify evidence on the diagnostic accuracy and clinical effectiveness of the ARCHITECT and Alinity i Urine NGAL assays, BioPorto NGAL test and NephroCheck test to help assess, and reduce, the risk of acute kidney injury for critically ill patients who are being considered for critical care admission. Although the population in the scope was people being considered for critical care admission, to maximise the available data the EAG included data from studies that enrolled patients already admitted to critical care.\n\nIn total, 56\xa0studies (reported in 71\xa0articles) were included. Of these, 46\xa0enrolled adults only, 8\xa0enrolled children only and 2\xa0enrolled both adults and children. Twenty-eight studies were done in Europe (4\xa0in the UK), 15\xa0in North America, 9\xa0in Asia, 2\xa0in North America and Europe, 1\xa0in Australia and 1\xa0study did not provide details of location. In most studies data were collected prospectively.\n\nThe studies either reported data on using the biomarkers to detect or predict acute kidney injury or to predict clinical outcomes (mortality or need for renal replacement therapy [RRT]) in critically ill patients admitted to hospital. No randomised controlled trials or controlled clinical trials were identified. No studies compared using the biomarkers with standard clinical care for clinical effectiveness outcomes.\n\nThe studies assessed using the tests in various clinical settings. The EAG divided the studies in adults and children into 3\xa0groups based on clinical setting: people who had cardiac surgery, people who had major non-cardiac surgery and people admitted to critical care (including critically ill patients presenting to the emergency department, patients admitted to intensive care or patients considered for critical care for various medical conditions).\n\n## Evidence on accuracy to detect emerging acute kidney injury\n\nTest accuracy was determined by the ability of the tests to identify the presence of acute kidney injury according to current clinical criteria (that is, using serum creatinine and urine output). A rise in serum creatinine levels or fall in urine output, or both, occurring within a certain time after the NephroCheck or NGAL test was done (this varied between studies, from within 12\xa0hours to within 7\xa0days) were used to indicate if acute kidney injury occurred (reference standard). The EAG could extract or derive the necessary data for calculating sensitivity and specificity estimates from 33 of the included studies.\n\nThe QUADAS‑2 tool was used for quality assessment of the studies. The EAG commented that it was not clear in most studies if the tests were interpreted without knowledge of the reference standard (unclear risk of bias). Studies that used NephroCheck were judged at low risk of bias for interpretation of the test because they used a common threshold for a positive result. However, for the NGAL studies a common threshold was not used. The EAG also commented that in the NGAL studies the threshold was not pre-specified before data were collected. Two studies were assessed as being at high risk of bias on the patient flow domain because more than 50% of the participants were excluded from the analysis (Jaques et al. 2019) or because of poor reporting (Asada et al. 2016). The EAG considered that the applicability of the index test results to the NHS was unclear in many studies because there was wide variation in the NGAL threshold used to define a positive test result and in the timing of the test sample collection. The EAG commented that it had no major concerns that the patient population, index text and reference standard were not applicable to the review question. However, in some of the included studies people were already admitted to critical care.\n\nBecause the threshold used for a positive test result varied in the identified studies, the EAG ran meta-analyses using the hierarchical summary ROC (HSROC) model to estimate summary values for sensitivity and specificity. If multiple thresholds were used in a study, the EAG selected\xa01 threshold to use in its analysis. Meta-analysis was only done if data from\xa04 or more studies were available.\n\nAll studies assessed used the NephroCheck test on urine samples. No studies were done in the UK. Two studies assessed using NephroCheck to detect acute kidney injury after cardiac surgery and 5\xa0studies assessed its use in hospitalised patients admitted to intensive or critical care for various clinical reasons. No studies were identified in people who had major non-cardiac surgery. The summary estimate for sensitivity was 0.75 (95% confidence interval [CI] 0.58\xa0to\xa00.87) and for specificity was 0.61 (95% CI 0.49\xa0to\xa00.72). The EAG commented that there was heterogeneity across studies and noted that estimates of specificity were generally low.\n\nTwo studies provided test accuracy data on using the ARCHITECT NGAL assay to detect acute kidney injury after cardiac surgery. Four studies assessed its use in hospitalised patients admitted to intensive or critical care for various clinical reasons. No studies were done in the UK or were identified in people who had major non-cardiac surgery. The summary estimate for sensitivity was 0.67 (95% CI 0.58\xa0to\xa00.76) and for specificity was 0.72 (95% CI 0.64\xa0to\xa00.79). The EAG commented that there was heterogeneity across studies.\n\nEight studies assessed using the BioPorto NGAL test with urine for detecting acute kidney injury: 1\xa0study in people who had cardiac surgery, 1\xa0study in people who had major non-cardiac surgery and 6\xa0studies in hospitalised patients admitted to intensive or critical care for various clinical reasons. One study was done in the UK (Matsa et al. 2014). The summary estimate for sensitivity was 0.73 (95% CI 0.65\xa0to\xa00.80) and for specificity was 0.83 (95% CI 0.64\xa0to\xa00.93). The EAG commented that there was heterogeneity across studies.\n\nThe EAG only identified studies in the critical care setting for the BioPorto NGAL test used with blood plasma (4\xa0studies). One study was done in the UK (Matsa et al. 2014). The summary estimate for sensitivity was 0.76 (95% CI 0.56\xa0to\xa00.89) and for specificity was 0.67 (95% CI 0.40\xa0to\xa00.86). The EAG commented that there was heterogeneity across studies.\n\nSeven studies assessed using the NGAL assays with urine samples to detect acute kidney injury in children. No studies were done in the UK. No studies assessing the use of NephroCheck in children were identified.\n\nFive studies assessed using the ARCHITECT Urine NGAL assay to detect acute kidney injury in children who had cardiac surgery. The summary estimate for sensitivity was 0.68 (95% CI 0.53\xa0to\xa00.80) and for specificity was 0.79 (95% CI 0.63\xa0to\xa00.89). The EAG commented that there was considerable heterogeneity across studies. No studies were identified in a population who had major non-cardiac surgery. One study assessed using the ARCHITECT Urine NGAL assay to detect acute kidney injury in children admitted to intensive or critical care for various clinical reasons. The sensitivity and specificity were 0.77 (95% CI 0.60\xa0to\xa00.90) and 0.85 (95% CI 0.74\xa0to\xa00.92), respectively.\n\nOne study assessed using the BioPorto NGAL test with urine for detecting acute kidney injury in children who had cardiac surgery. NGAL was measured using a concentration normalised by units of creatinine. The sensitivity and specificity were 0.77 (95% CI 0.69\xa0to\xa00.84) and 0.47 (95% CI 0.40\xa0to\xa00.54), respectively.\n\n## Evidence on ability to predict intermediate outcomes\n\nThe EAG identified 11\xa0studies with data on the ability of the tests to predict mortality, 4\xa0studies with data on predicting the need for RRT and 3\xa0studies that assessed the ability of the tests to predict worsening of acute kidney injury. All studies were in critically ill patients at risk of acute kidney injury. For predicting mortality, area under the curve (AUC) values varied from 0.55\xa0to\xa00.91. For predicting the need for RRT, AUC values varied from 0.68\xa0to\xa00.86. For predicting worsening of acute kidney injury, AUC values varied from 0.66\xa0to\xa00.71.\n\nThe EAG commented that adding the tests to existing clinical models generally improved risk prediction of newly developed acute kidney injury, or worsening of acute kidney injury, and mortality. However, it cautioned that there were limited data available and the statistical models used varied between studies. Also, information on potential candidate variables considered in studies was often not provided.\n\nNo studies were identified that reported the effect of using the tests on clinical or patient-reported outcomes.\n\n# Cost effectiveness\n\n## Systematic review of cost-effectiveness evidence\n\nThe EAG did a systematic review to identify any published economic evaluations of the ARCHITECT and Alinity i Urine NGAL assays, the BioPorto NGAL test (plasma and urine) and the NephroCheck test for assessing people at risk of developing acute kidney injury. Two of the studies identified used modelling strategies that were similar, and that the EAG considered appropriate for the current decision problem. One of these (Hall et al. 2018) was done in the UK, and the EAG considered it a comprehensive and high-quality assessment. But because the setting was outside the scope of this assessment (people already admitted to intensive care units), the EAG adapted the model for critically ill patients who are at risk of acute kidney injury and being considered for admission to critical care.\n\n## Model structure\n\nThe EAG developed a de novo economic model designed to assess the cost effectiveness of using the tests (in addition to standard clinical monitoring) to help detect the risk of developing acute kidney injury and to help start early preventive care.\n\nThis was a 2-stage model using TreeAge Pro software. Limited direct evidence was identified that showed the effect of using the tests (compared with standard monitoring alone) on health outcomes (such as acute kidney injury status; mortality; development of chronic kidney disease). So the EAG used observational associations to infer how preventing or reducing the severity of acute kidney injury may affect changes in health outcomes (a linked-evidence approach). An initial decision-tree phase modelled:\n\nThe accuracy of the tests to identify people with emerging acute kidney injury.\n\nFor people with a positive biomarker test result, the effect of preventive measures (a Kidney Disease Improving Global Outcomes [KDIGO] care bundle) on reducing the probability that they develop acute kidney injury or reducing the severity of the condition if they develop it.\n\nThe effect of developing acute kidney injury, and its severity, on short-term outcomes (within 90\xa0days): whether a person is admitted to intensive care, length of stay in intensive care or hospital, development of chronic kidney disease and 90‑day mortality.After this initial 90‑day period, a longer-term Markov model was used to model the effect of developing acute kidney injury while in hospital on the risk of developing chronic kidney disease, and the effect of this condition on the rest of a person's life.\n\nThe modelled population was people in hospital at risk of developing acute kidney injury, having their serum creatinine and urine output monitored. The EAG used the Grampian population register of hospitalisations to characterise this population. This dataset included 17,630\xa0adults admitted to hospital in Grampian in 2003. It is the complete population of all patients who had an abnormal kidney function blood test on hospital admission and had at least an overnight stay in hospital, including all patients who developed acute kidney injury. The model starting base-case population was 63\xa0years old, 54.3% women, with about 11% having chronic kidney disease (in the model, more people could develop this condition over time). The base-case prevalence of acute kidney injury (that is, people who will develop the condition while in hospital under standard monitoring) was assumed to be 9.2%.\n\nThe sensitivity and specificity of the tests to identify people who will develop acute kidney injury (as shown by a later increase in serum creatinine or drop in urine output, or both) was taken from the systematic review and meta-analysis referred to in the clinical effectiveness section. The EAG used values pooled from all studies identified for each of the tests across all clinical settings. The incidence of acute kidney injury and the effect of developing the condition on clinical outcomes (admission to intensive care, 90-day mortality) was estimated by the EAG largely using data from the Grampian observational dataset. The model could vary which clinical outcomes were affected by acute kidney injury status, and the size of this effect.\n\nThe EAG assumed that a KDIGO care bundle would be the preventive care used if the tests were positive. It did a literature search to identify studies to estimate the effectiveness of this intervention for the model. The EAG did not include the identified studies in its clinical effectiveness review because the studies did not report the direct effect of using the tests on clinical outcomes. Instead the EAG included the studies in its cost-effectiveness review (as part of the rationale for parameter values used in the model). The EAG used data from Meersch et al. (2017) for the effect of the KDIGO care bundle in the model. This was a single-centre randomised controlled trial done in Germany in people who had cardiac surgery (n=276). People who had a positive NephroCheck test (using a score of over 0.3) were randomised to either standard care (less intensive care than with the KDIGO care bundle) or standard care plus a KDIGO care bundle. People having standard care followed the recommendations of the American College of Cardiology Foundation (2011), which included keeping mean arterial pressure over 65\xa0mmHg and central venous pressure between 8 mmHg\xa0and 10\xa0mmHg. The KDIGO care bundles included avoiding nephrotoxic agents, discontinuing angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, close monitoring of urine output, serum creatinine, avoiding hyperglycaemia (for 72\xa0hours), considering alternatives to radiocontrast agents, and optimising fluids. Although there was a significant reduction in occurrence of acute kidney injury by 72\xa0hours for the KDIGO arm compared with standard care (odds ratio 0.48 [95% CI 0.29\xa0to\xa00.80]), the EAG commented that this did not appear to translate to other clinical outcomes (need for RRT in hospital, 90‑day all-cause mortality and length of stay in intensive care or hospital).\n\nThe EAG found 2\xa0other studies reporting the effects of KDIGO care bundles; Gocze et al. (2018) and Schanz et al. (2018). Both were done in Germany and assessed the effect of NephroCheck-guided application of a KDIGO care bundle compared with standard care (no use of a care bundle). Gocze et al. was a smaller study (n=121) than Meersch et al. and reported that NephroCheck-guided care (after major non-cardiac surgery) showed a trend towards a lower probability of acute kidney injury. But the results were not statistically significant; the odds ratio for standard care compared with NephroCheck was 1.96 (95% CI 0.93\xa0to\xa04.10). There was, however, a statistically significant increase in the odds of stage 2\xa0or\xa0stage 3 acute kidney injury in the standard care group compared with NephroCheck: 3.43 (95% CI 1.04\xa0to\xa011.32). Schanz et al. (n=100) compared the effect of NephroCheck-triggered implementation of KDIGO recommendations for acute kidney injury with standard care alone in an emergency department in Germany. Acute kidney injury outcomes were similar in both groups. The probability of acute kidney injury stage\xa02 or\xa0stage 3 was 32.1% for the intervention group and 33.3% for the control group after 1\xa0day. After 3\xa0days this was 38.9% for intervention group and 39.1% for the control group. The effect size from Gocze et al. was used in a scenario analysis. Data from intensive care registers, reports and studies were used for parameters in the longer-term Markov model.\n\nTest-related costs are shown in table\xa01. In its base-case analysis, the EAG assumed that an Astute\xa0140 meter would need to be purchased to use NephroCheck, so included the cost of this. The EAG assumed that the NGAL tests are run on platforms that are already available in hospital laboratories, so the cost of these analysers was assumed to be negligible and was not included in the analysis. A scenario analysis was done in which no capital costs (including an analyser) or training costs were included for the tests.\n\n## Table\xa01 Test-related costs\n\nCost per test\n\nNephroCheck\n\nBioPorto NGAL test \n \n a\n\nAbbott ARCHITECT NGAL assay\n\nAbbott Alinity \n \n b \n \n i\xa0Urine NGAL assay\n\nPlatform cost\n\n£0.53\n\n–\n\n–\n\n–\n\nEquipment cost\n\n£49.80\n\n£20.00\n\n£25.71\n\n£28.29\n\nMaintenance/ consumables\n\n£4.23\n\n£1.90\n\n£3.51\n\n£3.51\n\nStaff costs\n\n£37.62\n\n£37.62\n\n£37.62\n\n£37.62\n\nStaff training costs\n\n£0.08\n\n£0.03\n\n£0.03\n\n£0.03\n\nTotal cost\n\n£92.26\n\n£59.55\n\n£66.87\n\n£69.44\n\na Costs assumed to be the same for plasma and urine samples.\n\nb The Alinity NGAL assay was not included in the base-case analysis because of a lack of data for this assay.\n\nAbbreviation: NGAL, neutrophil gelatinase-associated lipocalin.\n\nThe EAG assumed that the KDIGO care bundle would be applied for an additional 3\xa0days over and above standard care for people who tested positive on the NephroCheck or NGAL tests (based on clinical opinion and consistent with the primary outcome measure from Meersch et al. 2017). Resources included in the care bundle costs included intravenous fluids (including nurse time), nephrologist and pharmacist review time and stopping blood pressure medication. The total additional cost of applying the KDIGO bundle was assumed to be £106.36 per person.\n\nThe EAG updated the searches run in Hall et al. (2018) to identify any additional source of utility data for its model for both the initial decision-tree phase and longer-term Markov model. The age- and sex-matched EQ‑5D UK population norms were calculated using an equation published by Ara and Brazier (2010). These were used to derive age- and sex-adjusted utility multipliers from the raw pooled estimates from studies, based on the age and sex distribution of the source studies.\n\n## Base-case assumptions\n\nThe following assumptions (in addition to those described in previous sections) were applied in the base-case analyses:\n\nAcute kidney injury, and more severe acute kidney injury, can be prevented by earlier NephroCheck or NGAL-guided use of a KDIGO care bundle (for people who would otherwise develop it with standard monitoring alone) in base case\xa01. In base case\xa02, NGAL-guided care cannot prevent acute kidney injury (but can reduce the severity of the condition).\n\nIn base case\xa01, the NephroCheck biomarkers and NGAL rise at similar times and the earlier identification of emerging kidney injury (relative to serum creatinine and urine output changes) is the same for both tests.\n\nThere are no adverse effects on health caused by a false-positive NephroCheck or NGAL test result.\n\nNo adaptions to standard monitoring were made for people testing negative on NephroCheck or NGAL tests (although standard monitoring done alongside would detect acute kidney injury for false-negative tests, just at a later time). This was because the EAG assumed that de-escalation of care would not occur solely because of a negative test result.\n\nEveryone with a positive NephroCheck or NGAL test immediately had a KDIGO care bundle.\n\nAfter 5\xa0years post-transplant, mortality reverted to the general population all-cause mortality probability. The annual probability of transplant failure remained as that reported from years 3\xa0to\xa05 in the UK renal registry.\n\nThe proportion of people whose transplant failed returned to dialysis. Their probability of progressing from end-stage renal disease on dialysis to a second transplant was the same as for progressing to the first transplant.\n\n## Base-case results\n\nNo evidence for NGAL test-guided implementation of preventive care for acute kidney injury on clinical outcomes was identified. Therefore, the EAG did 2\xa0base cases:\n\nBase case\xa01: Using the NGAL test had the same effect as the NephroCheck test to prevent acute kidney injury and reduce severity of the condition if it occurred (based on Meersch et al. 2017).\n\nBase case\xa02: Using the NGAL test could only reduce the severity of acute kidney injury (as for base case\xa01), not prevent it from occurring (NephroCheck effects were unchanged).\n\nThe results of base case\xa01 (probabilistic) are shown in table\xa02. Because of uncertainty about the extent of any effect of acute kidney injury on other clinical outcomes, the EAG did several scenario analyses (B, C and D). This was in addition to the base case varying which outcomes acute kidney injury occurrence (and severity) affected, and the size of this effect. Scenario\xa0C was the most pessimistic (no effect of preventing acute kidney injury, or reducing severity, on clinical outcomes) and scenario\xa0D was the most optimistic (full effect of preventing acute kidney injury, or reducing severity, on clinical outcomes).\n\n## Table\xa02 Cost-effectiveness results (probabilistic) for base case\xa01\n\nTest\n\nTotal cost\n\nTotal QALYs\n\nFully incremental ICER (probability cost effective at £20,000 per QALY gained)\n\nICER compared with standard monitoring (probability cost effective at £20,000 per QALY gained)\n\nBioPorto NGAL test (urine)\n\n£22,887\n\n\n\n–\n\n(43.5%)\n\nDominant\n\n(54.6%)\n\nBioPorto NGAL test (plasma)\n\n£22,900\n\n\n\n£2,694,918\n\n(11.1%)\n\nDominant\n\n(47.6%)\n\nStandard monitoring only\n\n£22,901\n\n\n\nDominated\n\n(45.1%)\n\n–\n\nARCHITECT NGAL\n\n£22,912\n\n\n\nDominated\n\n(0.1%)\n\n£32,131\n\n(41.4%)\n\nNephroCheck\n\n£22,938\n\n\n\nDominated\n\n(0.2%)\n\n£101,456\n\n(31.9%)\n\nAbbreviations: NGAL, neutrophil gelatinase-associated lipocalin; QALYs, quality-adjusted life years; ICER, incremental cost-effectiveness ratio.\n\nIn scenario\xa0C, standard care dominated all the tests (that is, they had higher costs and lower quality-adjusted life years), with all tests having 0% probability of being cost effective at a maximum acceptable incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life year (QALY) gained. See table\xa03 for the results for scenario\xa0D.\n\n## Table\xa03 Cost-effectiveness results (probabilistic) for scenario\xa0D (in base case\xa01)\n\nTest\n\nTotal cost\n\nTotal QALYs\n\nFully incremental ICER (probability cost effective at £20,000 per QALY gained)\n\nICER compared with standard monitoring (probability cost effective at £20,000 per QALY gained)\n\nStandard monitoring only\n\n£22,959\n\n\n\n–\n\n(0.7%)\n\n–\n\nBioPorto NGAL test (urine)\n\n£23,013\n\n\n\n£2,052\n\n(40.7%)\n\n£2,052\n\n(99.3%)\n\nBioPorto NGAL test (plasma)\n\n£23,028\n\n\n\n£17,702\n\n(47.5%)\n\n£2,538\n\n(99.1%)\n\nARCHITECT NGAL\n\n£23,031\n\n\n\nDominated\n\n(1.1%)\n\n£2,981\n\n(98.8%)\n\nNephroCheck\n\n£23,065\n\n\n\nDominated\n\n(10.0%)\n\n£3,955\n\n(97.7%)\n\nAbbreviations: NGAL, neutrophil gelatinase-associated lipocalin; QALYs, quality-adjusted life years; ICER, incremental cost-effectiveness ratio.\n\nThe EAG also did 16\xa0further scenario analyses (not all are discussed in this document). Changes made to several parameters improved the cost effectiveness of the tests, so that they all dominated standard care (in a pairwise comparison):\n\nIncreasing long-term costs and risk of mortality in the Markov model (scenario\xa0G) for people who were admitted to intensive care while in hospital (in the decision-tree phase).\n\nFor people having acute kidney injury while in hospital, extending the time of increased risk of developing chronic kidney disease from 1\xa0year to the rest of a person's life (scenario\xa0H).\n\nIncreasing the prevalence of acute kidney injury to 23% (from 9.2% in base case; scenario\xa0K).Assuming false-positive tests increased mortality (scenario\xa0M), which worsened the cost effectiveness of the tests.\n\nIn scenario\xa0Q, the EAG used alternative accuracy estimates from studies that enrolled children only. Data were only available for the ARCHITECT NGAL and the BioPorto NGAL (urine) tests. The EAG cautioned that the model was not configured for children but used parameters from an adult population. Because there were limited accuracy data for the tests in children and a lack of data for other parameters, the EAG considered the analysis to be exploratory only.\n\nIn base case\xa02 (probabilistic analysis), NephroCheck dominated all other tests, with an ICER of about £106,000 per QALY gained compared with standard monitoring. The probability of NephroCheck being the most cost-effective test across scenario analyses increased considerably.\n\nIn scenario\xa0T (provided in an addendum to the diagnostics assessment report), the EAG used Gocze et al. (rather than Meersch et al.) to inform estimates of the effect of a KDIGO care bundle on reducing the risk of developing acute kidney injury, or the severity of the condition if it did develop. This improved the cost-effectiveness estimates of the tests. In base case\xa01, all tests dominated standard monitoring. In base case\xa02, NephroCheck dominated all other tests and standard monitoring.", 'Committee discussion': "# Preventing or reducing the severity of acute kidney injury could benefit patients\n\nThe patient expert explained that a diagnosis of acute kidney injury can be very unexpected and can have a substantial effect on people and their families. Acute kidney injury can mean prolonged stays in hospital, which are distressing for patients and cost family members time and money. The patient expert also suggested that earlier detection of acute kidney injury might make temporary renal replacement therapy (RRT) less likely. If this proved to be the case, it could benefit people by reducing the need for invasive RRT and would release resources. Also, developing acute kidney injury increases the risk of chronic kidney disease. The patient expert emphasised that end-stage renal disease changes people's lives (and that of their families), because it affects their lifestyle and ability to work. If the tests helped detect acute kidney injury earlier and allowed interventions to prevent or reduce the severity of the condition, this could benefit patients by improving clinical outcomes.\n\n# There is considerable uncertainty about which patients in the NHS could benefit from the tests\n\nThe committee heard that the potential of the tests to change care and improve outcomes in NHS critical care is very limited. Clinical experts explained that the definition of critical care varied across the world. People tend to be more unwell before they are admitted to critical care in the NHS than in the US or the rest of Europe. So in the NHS they should already be having all available interventions to prevent acute kidney injury. Clinical experts also commented that it was uncertain which patients in the NHS could benefit from targeted use of preventive care bundles for acute kidney injury. They commented that care bundles (in addition to standard care) were the only option currently available to try and prevent acute kidney injury or reduce its severity. They also explained that a care bundle is a very complex intervention. It involves implementing measures (such as avoiding nephrotoxic agents, avoiding hyperglycaemia and optimising fluids) that can protect the kidneys from further damage. Many of these will already be done as part of standard care, depending on the clinical setting and the person's condition (that is, they are more likely to have been done already the more intensive the care). Care bundles can also be tailored to a person's condition, excluding some measures if they are not clinically appropriate. Therefore, the effect of the care bundles could vary between different populations. Clinical experts suggested that critical care outreach teams could potentially use the tests to guide preventive care. At consultation, a stakeholder highlighted a recent study (Kullmar et al. 2020) that showed poor adherence to Kidney Disease Improving Global Outcomes (KDIGO) recommendations after cardiac surgery. The study included patients from 2\xa0NHS hospitals. Clinical experts acknowledged that there was likely to be variation in implementing care bundles across the NHS. The committee considered that if preventive measures for acute kidney injury were not already routinely used in a hospital, they may not be used even if there is a positive NephroCheck or neutrophil gelatinase-associated lipocalin (NGAL) test result. This would reduce any benefit of the tests in guiding preventive care. The committee concluded that there was considerable uncertainty about who in the NHS could benefit from the tests.\n\n# Clinical effectiveness\n\n## The accuracy of the tests to detect emerging acute kidney injury, and the clinical significance of their results, is uncertain\n\nMost of the available data for the tests were sensitivity and specificity estimates. These measured the tests' ability to identify people who will be diagnosed with acute kidney injury using current clinical criteria (serum creatinine or urine output). The time of acute kidney injury diagnosis varied from within 12\xa0hours to within 7\xa0days. The external assessment group (EAG) commented that there was considerable clinical and statistical heterogeneity seen across the studies, which included very different populations, and therefore the results should be interpreted with caution. The committee also noted that even the best estimates of sensitivity and specificity showed that using the tests could result in large proportions of falsely positive or negative results. The stage of acute kidney injury detected by the tests also varied in the studies; from any stage of the condition to higher stages only. Clinical experts commented that the staging of the condition in classification systems (such as KDIGO) was developed by clinical consensus and there was uncertainty about the clinical significance of subclinical or early stage (stage\xa00 or stage\xa01) acute kidney injury and its correlation with clinical outcomes. The committee concluded that there was uncertainty about how well the tests could detect emerging acute kidney injury, and the clinical significance of what they detect in studies of test accuracy.\n\n# Cost effectiveness\n\n## There is considerable uncertainty about the effect of care bundles on developing acute kidney injury, and whether this would be seen in the NHS\n\nClinical experts commented that there was considerable uncertainty about how much benefit the care bundles used in the NHS would provide to prevent, or reduce the severity of, acute kidney injury if used earlier (when NephroCheck or NGAL tests indicate risk of acute kidney injury; see section\xa04.2). In its model, the EAG used data from Meersch et al. (2017) for the effect of test-guided preventive care (a KDIGO care bundle) on reducing the chance of developing acute kidney injury or reducing the severity of the condition if it developed (see section\xa03.23). The committee noted that people in the control arm did not have the KDIGO care bundle. This was unlikely to reflect NHS practice because although using the tests could allow earlier use of the care bundle, everyone at risk would eventually have an acute kidney injury care bundle at a later time, once serum creatine or urine levels showed acute kidney injury. The absence of the KDIGO care bundle in the control group could therefore have overestimated the treatment effect from Meersch et al. compared with NHS practice. Using the treatment effect size from Gocze et al. rather than Meersch et al. improved the cost effectiveness of the tests (see section\xa03.35). Clinical experts commented that standard care in Germany (the control arms of the 3\xa0identified studies on the effectiveness of the KDIGO care bundle) may differ from standard care in the UK. Therefore, the generalisability of the results of these studies to the NHS was potentially limited. The committee concluded that there was substantial uncertainty about how much effect a KDIGO care bundle had on developing, or reducing the severity of, acute kidney injury. It also concluded that it was uncertain whether a treatment effect size determined in studies done in Germany would be seen in the NHS, and therefore if the modelled effect of the KDIGO care bundle on acute kidney injury would be seen in the NHS.\n\n## It is not appropriate to assume that the results of the NephroCheck and NGAL tests are equivalent in the economic model\n\nNo studies were identified that showed the effect of NGAL-guided use of the KDIGO care bundle. So in base case\xa01, the EAG assumed that the effect of NephroCheck and NGAL-guided preventive care on acute kidney injury incidence was the same. It used data from Meersch et al. (2017), a study done in people who had a positive NephroCheck test, to estimate the effect of test-guided preventive care on acute kidney injury incidence. Clinical experts commented that the biomarkers used in the NephroCheck test (tissue inhibitor of metalloproteinase\xa02 [TIMP‑2] and insulin-like growth factor binding protein\xa07 [IGFBP‑7]) may perform very differently to NGAL as indicators of acute kidney injury because they are released during different physiological processes. The committee concluded that it was not appropriate to assume that the results of the NephroCheck and NGAL tests were equivalent. It also concluded that data from Meersch et al. should not be used to inform estimates of how well NGAL-guided use of the KDIGO bundle affects acute kidney injury incidence in the economic model.\n\n## It is uncertain how much the incidence, and severity, of acute kidney injury affects clinical outcomes\n\nIn its model, the EAG used observational data to link incidence and severity of acute kidney injury to the probability of clinical outcomes, such as length of stay in hospital, 90‑day mortality and need for RRT. However, the committee noted that in Meersch et al. use of the KDIGO bundle reduced acute kidney injury incidence, but not length of stay in hospital or intensive care, need for RRT in hospital or 90‑day all-cause mortality. In Gocze et al. length of hospital and intensive care stay was significantly shorter in the KDIGO bundle study arm, but there was no significant difference in need for RRT or mortality in hospital. Clinical experts explained that how each stage of acute kidney injury affected shorter- and longer-term clinical outcomes was not clearly understood (see section\xa04.3). The EAG investigated how much varying the effect of having acute kidney injury, and severity, had on clinical outcomes in scenario analyses. This led to large variation in cost effectiveness (see section\xa04.9). The committee concluded that it was uncertain how much the incidence and severity of acute kidney injury affected clinical outcomes.\n\n## The economic model should include the cost of analysers for the NGAL assays\n\nThe EAG did not include the cost of analysers needed to run the NGAL assays in its estimates of cost per NGAL test. This was because it assumed that the NGAL tests are run on platforms already available in hospital laboratories, so the cost of these analysers was negligible. Clinical experts commented that the analysers needed to run the different NGAL assays would not be in every hospital. The committee concluded that it would have been reasonable to include the cost of analysers needed to run the NGAL assays in the cost per test used in the model, as had been done for the NephroCheck test.\n\n## The tests may be used very differently for children and the cost-effectiveness estimates for this group are highly uncertain\n\nThe committee discussed the lack of data available for children. It noted that the EAG did a scenario analysis that used accuracy estimates from studies that enrolled children only (scenario\xa0Q; see section\xa03.33). Because of a lack of data for other parameters, the EAG had to use values derived from adult populations. The EAG cautioned that this analysis should be considered as exploratory. Also, clinical experts commented that the potential use for children could be very different to that for adults in the NHS. The committee concluded that, because of a lack of data to inform model parameters and uncertainty about the intended use of the tests, the cost-effectiveness estimates of the tests for children were highly uncertain. The committee considered that future studies should consider the utility of the tests for children (see section\xa04.11).\n\n## The cost-effectiveness estimates are highly uncertain and potentially much higher than what NICE normally considers cost effective\n\nThe EAG did multiple scenario analyses to reflect the uncertainty about which clinical outcomes would be affected by both the incidence and severity of acute kidney injury. It cautioned that the results of the cost-effectiveness modelling were largely speculative and should be interpreted with caution. Also, it considered it impossible to determine the best incremental cost-effectiveness ratio (ICER) given the available evidence. Incremental quality-adjusted life years (QALYs) were very low across the scenarios, with tests often having ICERs over £50,000 per QALY gained, or being dominated (that is, they had higher costs and lower QALYs) compared with standard monitoring. Varying the parameter values used in scenario analyses substantially affected the cost-effectiveness estimates for the tests. Changes to some parameters improved the cost effectiveness of the tests, to the extent that they dominated standard care (in base case\xa01) when compared in a pairwise manner (see section\xa03.30 and section\xa03.33). The committee further recalled that it did not consider it appropriate to use data from NephroCheck-guided use of the KDIGO care bundle to estimate the effect of NGAL-guided use of the KDIGO care bundle (see section\xa04.5). The committee concluded that there was substantial uncertainty about the best cost-effectiveness estimates for the tests in the defined clinical population. However, the estimates could potentially be much higher than what NICE normally considers cost effective.\n\n## There is too much uncertainty about the cost effectiveness of the tests to recommend adoption\n\nThe committee agreed that there was substantial uncertainty about how the tests could be used in the NHS (see section\xa04.2) and their likely cost effectiveness. This was mainly because there was uncertainty about the effect that test-guided care could have on the incidence and progression of acute kidney injury (see section\xa04.4) and on other clinical outcomes (see section\xa04.6) in the defined NHS clinical population. Also, how clinicians would react to the test results in the NHS was unclear (that is, the changes to care they would make in response to a positive or negative result). The cost-effectiveness estimates for the tests were very uncertain and, in most scenarios, much higher than what NICE normally considers a cost-effective use of NHS resources (see section\xa04.9). The committee concluded that there was too much uncertainty about the cost effectiveness of the tests to recommend their adoption in the NHS. Further research could provide clarity on how the tests would affect care and outcomes in the NHS and allow their cost effectiveness to be estimated.\n\n# Research considerations\n\n## Consideration should be given to defining populations in the NHS who would benefit from test-guided preventive care\n\nThe committee recalled that there was uncertainty about which patient populations in the NHS could benefit from test-guided use of preventive care for acute kidney injury (see section\xa04.2). If care bundles were already being used, in full or in part, in a patient population this would limit the effect that the test results can have on guiding care. Clinical experts commented that the potential use for children and young people can also be very different to adults, so specific consideration is needed for this group. The costs of the NephroCheck (about £90) and of providing the KDIGO care bundle earlier (about £105) were similar. Therefore, the committee questioned whether providing the care bundle earlier to everyone (that is, without testing) could be the most cost-effective strategy for some patient populations in the NHS. The committee concluded that, before further studies are done, it was important that companies define the patient populations in the NHS who could benefit from test-guided preventive care. It noted that people who are critically unwell in the NHS would likely already be having all available care to prevent acute kidney injury.", 'Recommendations for further research': 'Companies should specify patient populations in the NHS who could benefit from test-guided preventive care for acute kidney injury. Further research is then recommended in these populations to assess the clinical effectiveness of defined care bundles designed to prevent or reduce the effect of acute kidney injury in the NHS. Research should be done in children, young people and adults, but specific considerations may be needed for children and young people when care differs from that for an adult population (see section\xa04.11).\n\nFurther research is recommended to assess the effect of test-guided preventive care (see section\xa05.1) on clinical outcomes (such as length of stay in hospital, mortality and need for renal replacement therapy and progression to chronic kidney disease). Research should be done in children, young people and adults, but specific considerations may be needed for children and young people when care differs from that for an adult population. Studies should investigate the effects of both positive and negative test results on clinical decisions and subsequent care.'}
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https://www.nice.org.uk/guidance/dg39
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Evidence-based recommendations on tests to help assess risk of acute kidney injury for people being considered for critical care admission. The tests are the ARCHITECT and ALINITY i Urine NGAL assays, BioPorto NGAL test and NephroCheck test.
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e10dc7640ab829593e92d868e184b122411379a1
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nice
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Ustekinumab for treating moderately to severely active ulcerative colitis
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Ustekinumab for treating moderately to severely active ulcerative colitis
Evidence-based recommendations on ustekinumab (Stelara) for treating moderately to severely active ulcerative colitis in adults.
# Recommendations
Ustekinumab is recommended as an option for treating moderately to severely active ulcerative colitis in adults when conventional therapy or a biological agent cannot be tolerated, or the disease has responded inadequately or lost response to treatment, only if:
a tumour necrosis factor‑alpha inhibitor has failed (that is the disease has responded inadequately or has lost response to treatment) or
a tumour necrosis factor‑alpha inhibitor cannot be tolerated or is not suitable, and
the company provides ustekinumab at the same price or lower than that agreed with the Commercials Medicines Unit.
This recommendation is not intended to affect treatment with ustekinumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Tumour necrosis factor (TNF)‑alpha inhibitors are the most commonly used biological treatment option for moderately to severely active ulcerative colitis. People who cannot have TNF‑alpha inhibitors are usually offered vedolizumab, so this is the most relevant comparator for ustekinumab. Both drugs have similar safety profiles and work differently to TNF‑alpha inhibitors.
Clinical trial evidence shows that ustekinumab is more effective than placebo for treating moderately to severely active ulcerative colitis. During induction (the first 8 weeks of treatment), indirect comparisons suggest that ustekinumab may be more effective than one of the TNF‑alpha inhibitors. However, for maintenance treatment, indirect comparisons suggest there is no difference between the treatments.
The cost-effectiveness estimates for ustekinumab compared with vedolizumab are below what NICE considers a cost-effective use of NHS resources. Therefore, ustekinumab is recommended when a TNF‑alpha inhibitor is not appropriate or has not been effective.# Information about ustekinumab
# Marketing authorisation indication
Ustekinumab (Stelara, Janssen) has a marketing authorisation that includes the following indication: 'treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a biologic or have medical contraindications to such therapies'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics. Induction treatment is administered intravenously as a weight-based dose using 130 mg concentrate for solution for infusion. Maintenance treatment is administered as a subcutaneous injection using solution for injection in a vial or pre-filled syringe.
# Price
The list price of ustekinumab is £2,147 per 130‑mg vial of concentrate for solution for infusion, and £2,147 per 90‑mg solution for injection in a pre-filled syringe (excluding VAT; BNF online accessed February 2020).
The annual treatment costs are £14,482 in the induction year, and £9,304 per year for maintenance treatment (year 2 onwards).
The company has agreed a nationally available price reduction for ustekinumab with the Commercial Medicines Unit. The prices agreed through the framework are commercial in confidence.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Janssen, a review of this submission by the evidence review group (ERG), the technical report developed through engagement with stakeholders, the responses to the appraisal consultation document and the ERG's review of the company's consultation responses. See the committee papers for full details of the evidence.
The appraisal committee was aware that none of the issues raised during the technical engagement stage had been fully resolved. Therefore, it considered all the feedback received from consultees and commentators, the ERG's report on the company's response to engagement and other issues that had not been consulted on during engagement.
# Clinical need and current management
## Living with moderately to severely active disease is physically and emotionally disabling
The patient expert explained that the experience of living with moderately to severely active ulcerative colitis varies on an individual level, but in their experience it is extremely challenging. They explained that, in the 5 years between initial diagnosis and the point at which they had surgery, they had only experienced about 18 months in total when their disease was not active. During periods of active disease, they never had fewer than 4 to 5 bowel movements per day. They experienced constant pain, sleep deprivation (caused by being awake in the night to go to the toilet) and depression. They also explained that using corticosteroids is associated with side effects and contributes to low mood. They commented that the effects of the disease and side effects of medication can be moderated, to an extent, through management strategies, such as avoiding social activities and mapping local toilets. However, this is an extreme burden. They explained that feeling out of control is an important and common issue for many people with moderately to severely active ulcerative colitis. The clinical experts said that the patient expert's comments reflect the experience of patients that they see in practice, and responses received during consultation from consultees also reflected these comments. The committee took account of comments submitted in writing by patient experts and research undertaken by the company, which highlighted the effects of the disease and current treatments, including surgery, on daily activities, relationships, self-esteem and body image. It concluded that living with moderately to severely active disease is physically and emotionally disabling.
## Ustekinumab is an alternative to vedolizumab
The clinical experts recognised that NICE already recommends several treatment options for when conventional therapy or a biological agent cannot be tolerated, or the disease has responded inadequately or lost response to treatment. The clinical experts commented that all the current treatments are similarly effective, however, in current practice, most patients will be offered a tumour necrosis factor (TNF)‑alpha inhibitor first when conventional therapy has failed. This is because biosimilars are available in this class, which have a lower price. The clinical experts stated that the cheapest infliximab biosimilar is usually prescribed first. If a patient has a loss of response and has produced antibodies, they would be offered another TNF‑alpha inhibitor. If a patient has not produced antibodies and their disease has responded inadequately or lost response to treatment with 1 TNF‑alpha inhibitor, then vedolizumab or tofacitinib are considered. The clinical experts noted that a patient's choice of treatment is often influenced by the drugs' safety profiles, and that in their experience tofacitinib is sometimes more effective but associated with more severe side effects and is not often used in clinical practice. They explained that TNF‑alpha inhibitors are not appropriate for everyone. For example, people who have contraindications such as high risk of heart failure, or people who are at high risk of infection, including older people. The clinical experts explained that, for these people, vedolizumab would usually be offered instead. They stated that conventional therapy is not a suitable comparator for ustekinumab, because ustekinumab's place in the clinical pathway is likely to be the same as for vedolizumab. The committee noted that vedolizumab and ustekinumab have different mechanisms of action to TNF‑alpha inhibitors, and that ustekinumab and vedolizumab have similar adverse effect profiles. It also noted that ustekinumab may be preferred over vedolizumab because of its mode of administration (subcutaneous injection rather than intravenous injection). Also, because vedolizumab acts mainly on the gut, ustekinumab could be advantageous because it acts on other manifestations of the disease (such as in the skin and joints). The committee noted that vedolizumab and tofacitinib are recommended for people who cannot have TNF‑alpha inhibitors. However, vedolizumab is the most relevant comparator because it has a similar safety profile to ustekinumab. The committee therefore concluded it is most appropriate to consider ustekinumab at the same place in the treatment pathway as vedolizumab.
## There is an unmet need for new treatments that reduce the need for corticosteroids or surgery
The clinical and patient experts, and the consultation responses, agreed that there is an unmet need for new non-surgical treatment options because many people have an inadequate response to current therapies or they stop working. The only option for these people, other than surgery, is long-term corticosteroid use. This is associated with extreme side effects including mood changes such as irritability and depression, osteoporosis and cataracts. The patient and clinical experts, and comments from consultees, agreed that surgery can be an effective treatment for some patients, but it is avoided until this is the last available treatment option. Outcomes of surgery are variable; there can be a psychological impact, and abdominal scarring can significantly affect sexual and reproductive function. The patient expert also noted that ustekinumab's mode and frequency of administration during maintenance treatment may be more convenient than that of some other current treatments. The committee concluded that new medical treatment options would be welcome.
# Clinical evidence
## The UNIFI trial shows that ustekinumab is more effective than placebo at inducing and maintaining remission and response in all patients
UNIFI is a randomised, placebo-controlled trial of patients who had had an inadequate disease response to, or unacceptable side effects from, biological treatments (TNF‑alpha inhibitors or vedolizumab) or conventional non-biological therapy (corticosteroids or the immunomodulators azathioprine or mercaptopurine). It had an induction-phase study and a maintenance-phase study. There were 961 patients in the induction study, with outcomes measured at week 8 in the intention-to-treat (ITT) analyses and at week 16 in the non-ITT analyses. 523 patients with disease that had responded after 8 weeks of induction treatment with ustekinumab were entered into the ITT population of the maintenance study, and re-randomised to determine what maintenance treatment they would have (ustekinumab or placebo). The maintenance study also included 2 non-randomised populations: patients whose disease had responded to placebo during induction treatment (sample size and results not reported) and patients who had had more than 8 weeks of induction therapy with ustekinumab and were in response at week 16 (n=157; described by the company as 'delayed responders'). The company reported results for the ITT population for the following subgroups:
a 'biologic-failure' subgroup of people who had had at least 1 biological treatment (a TNF‑alpha inhibitor or vedolizumab) and either their disease did not respond or lost an initial response, or they could not tolerate it
a 'non-biologic failure' subgroup of people who had never had a biological treatment, but that also included some people who had had biological treatments but not had a documented 'biological failure'.At the end of induction treatment, rates of clinical remission and response were statistically significantly higher in the ustekinumab 6 mg per kg and 130 mg groups than the placebo group. This was the case for both the non-biologic failure and biologic-failure subgroups, and for the overall ITT population. At week 44 of the maintenance phase, a statistically significantly greater proportion of patients who had had ustekinumab maintenance with either dose were in clinical remission than those who had had placebo. This was the case for both the non-biologic failure and biologic-failure subgroups, and for the overall ITT population. The committee noted that these subgroups were defined differently to those in the NICE scope, and that in many trials of ulcerative colitis therapies patients are classified based on biological-treatment exposure status rather than biological-treatment failure status. The committee heard that there was considerable overlap in the definitions, however, with 94% of patients in the UNIFI non-biologic failure subgroup having had no previous exposure to biological therapy. The committee concluded that UNIFI data are generalisable to the population who would be eligible to have treatment with ustekinumab in the NHS. It also concluded that the results demonstrated that ustekinumab is more effective than placebo at inducing and maintaining remission and response in all patients covered by the marketing authorisation.
## Issues raised about UNIFI at technical engagement have been resolved and do not affect the interpretation of the trial results
The committee reviewed the following points raised in technical report issue 1:
The UNIFI clinical-response results reported in the company submission do not appear to match those in the New England Journal of Medicine (NEJM) trial report, published in September 2019.
It is not clear from the information in the company submission that blinding was maintained between induction week 8 and the maintenance phase, or that baseline characteristics of patients in the re-randomised groups were well balanced. Therefore, it is not possible to assess whether the study is at high risk of bias.
The results for placebo 'non-responders' who had 6 mg per kg ustekinumab intravenously at week 8 and were assessed at week 16 are not reported in the company submission. The committee considered a summary of the company's responses to these points, which consisted of further explanations and data. The committee agreed with the ERG that the company's response demonstrated that there are no important discrepancies between the company submission and the NEJM article, and that UNIFI is at low risk of bias. The committee considered new UNIFI data that the company provided for patients who had 6 mg per kg ustekinumab intravenously at week 8 and who were assessed at week 16. It agreed that the new data did not change the interpretation of the results for the ITT population in the induction study.
# Indirect treatment comparisons
## The exclusion of trials carried out in Asian countries from the network meta-analyses has little effect on the cost-effectiveness estimates
The company identified 5 trials from Asian countries in its systematic literature review. However, it decided to exclude these studies from the network meta analyses (NMAs) that informed its cost-effectiveness analyses. The company tested the effect of its approach by doing sensitivity NMAs that included data from the Asian trials. The ERG identified some methodological problems with these sensitivity NMAs and feedback was sought on these points during technical engagement (see technical report issue 2). The company's response to technical engagement issue 2 resolved one, but not all, of the ERG's concerns about the sensitivity NMAs. The ERG explained that some of the company's inclusion and exclusion decisions about the sensitivity NMAs remained inappropriate. The ERG did, however, note that the Asian trials were relatively small. The overall effect on the results of the sensitivity NMAs was therefore likely to be low, and the main NMAs produced similar results to the sensitivity NMAs. The ERG concluded that excluding the Asian trials from the NMAs had little effect on the cost-effectiveness estimates. The committee noted that responses to technical engagement indicated that there was no clinical rationale for excluding the Asian trials, and that it would have been more appropriate for them to be included in the analyses that informed the economic model. Overall, it agreed with the ERG that this issue has little effect on the cost-effectiveness estimates and decided to further consider the NMAs that excluded the Asian trials.
## The maintenance-phase NMAs are uncertain but provide more robust estimates of relative effectiveness than the company's unadjusted indirect treatment comparison
The committee agreed with the ERG that the company's induction-phase NMAs were methodologically robust and provided a suitable source of clinical data for the transition probabilities in the induction phase of the model. However, the committee noted that estimating the relative effectiveness of ustekinumab and its comparators in the maintenance phase by combining data from different trials was methodologically challenging, because of the lack of head-to-head trial data and differences in the trial designs. It was aware that the company had explored both the adjusted NMA and the unadjusted indirect comparison methods, and that the company's preference was to use the results of its unadjusted indirect treatment comparison (ITC) to inform the cost-effectiveness estimates. The committee was aware that the ERG considered the results of the company's unadjusted ITC to be unreliable and had therefore used results from the company's and its own NMAs to inform its exploratory analyses. The committee was aware that feedback had been sought at technical engagement (see technical report issues 4 and 5) to try to understand if any of the methods explored by the company and the ERG were more appropriate, or if other types of analyses should have been done. The committee reviewed the responses to the engagement issues 4 and 5 and noted the following:
No new data have been provided to support the assertion that heterogeneity in the placebo arms of the re-randomised maintenance-phase data is mainly caused by the continuing effects of induction treatment.
The company asserted that drug half-life is a cause of the continuing effects of induction treatment being observed during the maintenance phase. But evidence provided by a comparator company suggests there is no correlation between drug half-life and placebo-arm response rates.
The ERG and the company agreed that further analyses using existing data are unlikely to reduce the outstanding uncertainties.The clinical experts commented that multiple differences between the trials mean that they are not comparable. For example, the approaches to corticosteroid tapering varied. The committee considered the different approaches to combining the maintenance phase trial data. It agreed with the ERG that the unadjusted ITC methods preferred by the company are not recommended and the results of these analyses are not robust enough to inform decision making. At the first committee meeting the committee concluded that the company's 1‑year NMA conditional on response and the ERG's maintenance-only NMA both had limitations and the results were very uncertain. However, because no alternative data were available, the results provided the best available estimates of relative effectiveness. In response to the appraisal consultation document, the company updated its base case using its 1‑year NMA conditional on response, which the ERG had also used in its base case. The committee concluded that although the results of this NMA are highly uncertain, it was preferred to the ERG's maintenance-only NMA for providing estimates of relative effectiveness to inform the cost-effectiveness model.
## The pooling of the standard and escalated-dose effects in the maintenance phase has little effect on the results
The committee noted that the company and the ERG had not agreed a preferred approach for the pooling of standard and escalated efficacy dose effects during the maintenance phase (technical report issue 7). The committee concluded that this was a relatively minor issue compared with the other uncertainties in the maintenance analyses and did not have a major effect on decision making.
# The company's economic model
## The model is appropriate for decision making but additional health states in the model would have been preferable
The company estimated the cost effectiveness of ustekinumab using a model with a hybrid structure (the induction phase was modelled using a decision tree and the maintenance phase was modelled using a Markov structure). The company provided cost-effectiveness estimates for 2 subgroups defined by biological-treatment failure status, but not for the overall population. The committee noted that the ERG had used the same model for its base-case analyses, but with different assumptions including the proportions of patients experiencing response and remission after the failure of initial treatment. The committee considered the health state definitions, recalling the clinical experts' comments that many patients in the population of interest have chronically active disease that is controlled with the long-term use of corticosteroids. The committee noted that the company's 'active disease' health state definition (Mayo score between 6 and 12 points, 'remission or response without remission not achieved') did not necessarily apply to this group of patients. The company explained that the 'active disease' health state represents a mixed population of people with active ulcerative colitis that is controlled with corticosteroids and people with active ulcerative colitis who are experiencing an exacerbation. It is therefore difficult to identify the appropriate utility value for this health state in the model. The committee agreed that it would have preferred the inclusion of additional health states in the model to appropriately reflect the progression of the disease. The clinical experts commented that if patients taking long-term corticosteroids stop treatment, they are likely to start experiencing active disease again over time. On this basis, the committee concluded that although the model structure did not explicitly account for patients with disease that was being controlled through the long-term use of corticosteroids, and additional health states would have been more appropriate, the model could be used for decision making.
## The assumption that 30% of patients have escalated doses of maintenance treatment is acceptable
The committee noted that, in response to technical engagement issue 6, the company had adjusted its base-case assumptions about dose escalation for patients having maintenance infliximab to reflect the ERG's preference. The ERG assumed that for all drugs included in the analysis, 30% of patients would have an escalated maintenance dose, even though the escalated dose for infliximab is not licensed in the UK. The committee noted that other responses to engagement indicated that off-label use of escalated-dose infliximab is common UK practice but that escalation rates vary between biological therapies. The clinical experts agreed that infliximab dose escalation is common practice but noted that the variation in escalation rates across treatments cited in the engagement responses was not realistic. The committee recognised that there was some uncertainty about this issue. It concluded that this was not a major driver of cost effectiveness, and it was willing to accept the company's revised assumption.
## Response rates and remission rates are uncertain for patients with disease that does not respond or loses response to initial therapy
The committee noted that ulcerative colitis is not always a chronically active disease and many people with ulcerative colitis have ongoing periods of relapse and remission. The company and ERG base-case analyses used different assumptions for response rates and remission rates in patients whose disease did not respond or lost response to initial therapy. The committee noted that the responses to technical engagement issue 3 had not provided any additional clarity on this issue because the additional evidence provided by the company was of low quality. Comments from a patient organisation suggested that most patients continue to experience active disease until surgery or death, but this is not the same as assuming that no patients ever experience an improvement in symptoms. The company, the ERG and the clinical experts all acknowledged that there is limited evidence about the course of the disease after initial treatment failure. However, the clinical experts stated that for patients such as those in the UNIFI trial they would not expect many, if any, patients to experience an improvement in symptoms unless they were on corticosteroids. The committee considered that the ERG's assumption might be considered optimistic, but it agreed that there is likely to be a small number of people who improve without treatment. It concluded that it was not possible to estimate the rates of response and remission for patients with disease that did not respond or lost response to initial therapy, but it was likely to be nearer the company's assumption of a 0% response rate.
# Utility values in the economic model
## The utility values are uncertain, and the choice of inputs has a large effect on the cost-effectiveness estimates
The committee noted that the company and the ERG both used the same utility values in their base cases, but that other sources of utility data are available. Their utility data came from a publication by Woehl et al. 2008. The committee noted that other utility values for response, response without remission, and active ulcerative colitis health states based on EQ‑5D‑5L data were collected in UNIFI and therefore could have been used instead. It was also aware of other sources of utility data in this population (for example, Swinburn et al. 2012 and Vaizey et al. 2013), with values somewhere between the values from Woehl et al. and those collected in UNIFI, which had been used in scenario analyses in previous appraisals. The utility value for the 'active disease' state in Woehl et al. was considerably lower (0.41) than the equivalent value derived from the UNIFI EQ‑5D‑5L data. Because of this, the choice of utility data has a large effect on the cost-effectiveness estimates. The committee noted that the Woehl et al. 2008 data had been considered in all previous ulcerative colitis appraisals but that the reliability of the utility estimates had also been a source of controversy in all the previous appraisals. It noted that the Woehl et al. 2008 publication is only available as an abstract that includes little information about the study methodology or the characteristics of the patients it included. Therefore, it is difficult to assess whether the patients in Woehl et al. 2008 are representative of the population of interest and if the methodology is appropriate. The committee noted that the sample size of Woehl et al. 2008 is smaller than that in the UNIFI EQ‑5D analyses. It also noted that the ERG cited consistency with other appraisals as the only reason for choosing the Woehl et al. 2008 data over the UNIFI data, and that it considered the UNIFI analyses to be well conducted. The committee acknowledged that there were limitations with the trial-based utility values. It noted that the UNIFI EQ‑5D data may be subject to placebo effects and that the length of time over which the data were collected was probably inadequate for estimating the real effect of the disease on health-related quality of life. The committee recalled the patient expert's description of the disease experience and decided that it was plausible that some of the effects on health-related quality of life (such as feeling out of control) might not have been captured in either the Woehl et al. 2008 or the UNIFI analyses. It agreed that all data sources (including Woehl et al. 2008, UNIFI, Swinburn et al. 2012 and Vaizey et al. 2013) had some strengths and some limitations, and it was not possible to determine which was most robust. The ERG explained that there was no basis to distinguish between the 3 published analyses of utility values in ulcerative colitis in terms of methodological or reporting quality, generalisability of the results or applicability to the current decision problem. The committee noted that the UNIFI analyses reported similar values to some of the published utility values in ulcerative colitis. It therefore concluded that the UNIFI analyses were as appropriate as other available utility analyses and therefore considered both this and Woehl et al. 2008 in its decision making.
## The economic model is unsuitable for modelling 'stopping rules'
The company proposed that it is appropriate to consider 'stopping rules' for ustekinumab, in line with NICE's guidance on infliximab, adalimumab and golimumab for ulcerative colitis and on vedolizumab for ulcerative colitis. Based on the company's updated base case, it presented analyses of 'stopping rules' with ustekinumab discontinuation at 1, 2, 3 or 5 years. The clinical experts explained that it is usual practice to review treatment every 12 months; if a person is in sustained remission it may be appropriate to stop treatment, but this is dependent on a variety of factors such as patient choice and the person's overall fitness. The clinical experts also explained that if the person relapsed following discontinuation, treatment would be restarted with either the same, or a different, treatment. The company confirmed that when people stop treatment in the economic model, they do not restart it. The committee agreed that the model does not reflect clinical practice, because it does not account for people who stop treatment but later relapse and restart treatment. The ERG highlighted that it is difficult to model 'stopping rules' and that these have not been modelled in economic analyses in previous ulcerative colitis appraisals, but they were considered qualitatively in those appraisals. The committee concluded that the model structure did not allow 'stopping rules' to be modelled to reflect clinical practice and therefore did not consider them further.
## Cost-utility analysis should be used to determine cost effectiveness
In response to the appraisal consultation document, the company submitted an additional analysis comparing ustekinumab with vedolizumab. The ERG highlighted that this was not a full cost-comparison analysis as stated by the company. It also noted that this analysis did not account for the uncertainty in the clinical efficacy of ustekinumab compared with vedolizumab, which comes from the uncertainty in the maintenance-phase NMAs and the inability to scrutinise the methods of the trial that reports data for vedolizumab as a comparator. The committee agreed that the company's analysis was not appropriate for decision making. It concluded that it was appropriate to use a cost-utility analysis for decision making, and that irrelevant comparators should be excluded from the fully incremental analysis in order to obtain the relevant incremental cost-effectiveness ratios (ICERs).
# Cost-effectiveness estimates
## Ustekinumab is cost-effective compared with vedolizumab in the cost-utility analyses
The committee considered the ERG's cost-effectiveness estimates, which incorporated the confidential comparator discounts. The committee noted that the ERG had presented a number of scenarios, which included the confidential patient access schemes and also the Commercial Medicines Unit prices for the comparators and for ustekinumab. Following consultation the company's updated base case included the committee's preferred assumptions in the 1‑year conditional on response NMA (see section 3.7), assuming 0% response and remission rates for patients with disease that did not respond or lost response to initial therapy. The company also presented a scenario analyses using 1% response and remission rates for patients with disease that did not respond or lost response to initial therapy (see section 3.11). For both analyses the company used the Woehl et al. 2008 utility values. The ERG's analyses of the company's updated base case investigated further scenario analysis, using the various utility sources (Woehl et al. 2008, Swinburn et al. 2012, Vaizey et al. 2013 and UNIFI). The committee noted that the ICERs for ustekinumab compared with the lowest-cost TNF‑alpha inhibitor are above £30,000 per quality-adjusted life year (QALY) gained, when ustekinumab was not dominated (more expensive and less effective) or extendedly dominated (its ICER was higher than that of the next more effective option) by the other comparators for both the non-biologic failure and biologic failure groups. The committee accepted that TNF‑alpha inhibitors, conventional therapy and tofacitinib are not relevant comparators in this appraisal and agreed that vedolizumab is the only relevant comparator (see section 3.2). When ustekinumab is compared with vedolizumab, for all scenarios investigated and irrespective of the source of utilities, the ICERs are below £30,000 per QALY gained for both patient subgroups (failed conventional therapy with or without prior exposure to a biological). Therefore, despite the uncertainty around the maintenance NMA results and which utility value is most appropriate in this population, the committee agreed that ustekinumab is likely to be a cost-effective use of NHS resources in people who would otherwise have vedolizumab.
# Conclusion
## Ustekinumab is recommended for people who cannot have TNF-alpha inhibitors
The ICER for ustekinumab compared with TNF‑alpha inhibitors was higher than what is normally considered to be cost effective. Therefore, ustekinumab is not cost effective in people who have TNF‑alpha inhibitors as a treatment option. However, the committee agreed that the most appropriate comparator for ustekinumab is vedolizumab. Vedolizumab is used usually in current practice when TNF‑alpha inhibitors have been inadequately effective or response has been lost, or they have not been tolerated or are considered inappropriate. For this population, the ICERs for ustekinumab compared with vedolizumab are within the range that would be considered a cost-effective use of NHS resources. Therefore, the committee concluded that ustekinumab can be recommended as an option for treating moderately to severely active ulcerative colitis in adults when conventional therapy or a biological agent cannot be tolerated, or the disease has responded inadequately or lost response to treatment, only if a TNF‑alpha inhibitor has failed (that is the disease has responded inadequately or has lost response to treatment) or a TNF‑alpha inhibitor cannot be tolerated or is not suitable.
|
{'Recommendations': 'Ustekinumab is recommended as an option for treating moderately to severely active ulcerative colitis in adults when conventional therapy or a biological agent cannot be tolerated, or the disease has responded inadequately or lost response to treatment, only if:\n\na tumour necrosis factor‑alpha inhibitor has failed (that is the disease has responded inadequately or has lost response to treatment) or\n\na tumour necrosis factor‑alpha inhibitor cannot be tolerated or is not suitable, and\n\nthe company provides ustekinumab at the same price or lower than that agreed with the Commercials Medicines Unit.\n\nThis recommendation is not intended to affect treatment with ustekinumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nTumour necrosis factor (TNF)‑alpha inhibitors are the most commonly used biological treatment option for moderately to severely active ulcerative colitis. People who cannot have TNF‑alpha inhibitors are usually offered vedolizumab, so this is the most relevant comparator for ustekinumab. Both drugs have similar safety profiles and work differently to TNF‑alpha inhibitors.\n\nClinical trial evidence shows that ustekinumab is more effective than placebo for treating moderately to severely active ulcerative colitis. During induction (the first 8\xa0weeks of treatment), indirect comparisons suggest that ustekinumab may be more effective than one of the TNF‑alpha inhibitors. However, for maintenance treatment, indirect comparisons suggest there is no difference between the treatments.\n\nThe cost-effectiveness estimates for ustekinumab compared with vedolizumab are below what NICE considers a cost-effective use of NHS resources. Therefore, ustekinumab is recommended when a TNF‑alpha inhibitor is not appropriate or has not been effective.', 'Information about ustekinumab': "# Marketing authorisation indication\n\nUstekinumab (Stelara, Janssen) has a marketing authorisation that includes the following indication: 'treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a biologic or have medical contraindications to such therapies'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics. Induction treatment is administered intravenously as a weight-based dose using 130\xa0mg concentrate for solution for infusion. Maintenance treatment is administered as a subcutaneous injection using solution for injection in a vial or pre-filled syringe.\n\n# Price\n\nThe list price of ustekinumab is £2,147 per 130‑mg vial of concentrate for solution for infusion, and £2,147 per 90‑mg solution for injection in a pre-filled syringe (excluding VAT; BNF online accessed February\xa02020).\n\nThe annual treatment costs are £14,482 in the induction year, and £9,304 per year for maintenance treatment (year\xa02 onwards).\n\nThe company has agreed a nationally available price reduction for ustekinumab with the Commercial Medicines Unit. The prices agreed through the framework are commercial in confidence.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Janssen, a review of this submission by the evidence review group (ERG), the technical report developed through engagement with stakeholders, the responses to the appraisal consultation document and the ERG's review of the company's consultation responses. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that none of the issues raised during the technical engagement stage had been fully resolved. Therefore, it considered all the feedback received from consultees and commentators, the ERG's report on the company's response to engagement and other issues that had not been consulted on during engagement.\n\n# Clinical need and current management\n\n## Living with moderately to severely active disease is physically and emotionally disabling\n\nThe patient expert explained that the experience of living with moderately to severely active ulcerative colitis varies on an individual level, but in their experience it is extremely challenging. They explained that, in the 5\xa0years between initial diagnosis and the point at which they had surgery, they had only experienced about 18\xa0months in total when their disease was not active. During periods of active disease, they never had fewer than 4\xa0to 5\xa0bowel movements per day. They experienced constant pain, sleep deprivation (caused by being awake in the night to go to the toilet) and depression. They also explained that using corticosteroids is associated with side effects and contributes to low mood. They commented that the effects of the disease and side effects of medication can be moderated, to an extent, through management strategies, such as avoiding social activities and mapping local toilets. However, this is an extreme burden. They explained that feeling out of control is an important and common issue for many people with moderately to severely active ulcerative colitis. The clinical experts said that the patient expert's comments reflect the experience of patients that they see in practice, and responses received during consultation from consultees also reflected these comments. The committee took account of comments submitted in writing by patient experts and research undertaken by the company, which highlighted the effects of the disease and current treatments, including surgery, on daily activities, relationships, self-esteem and body image. It concluded that living with moderately to severely active disease is physically and emotionally disabling.\n\n## Ustekinumab is an alternative to vedolizumab\n\nThe clinical experts recognised that NICE already recommends several treatment options for when conventional therapy or a biological agent cannot be tolerated, or the disease has responded inadequately or lost response to treatment. The clinical experts commented that all the current treatments are similarly effective, however, in current practice, most patients will be offered a tumour necrosis factor (TNF)‑alpha inhibitor first when conventional therapy has failed. This is because biosimilars are available in this class, which have a lower price. The clinical experts stated that the cheapest infliximab biosimilar is usually prescribed first. If a patient has a loss of response and has produced antibodies, they would be offered another TNF‑alpha inhibitor. If a patient has not produced antibodies and their disease has responded inadequately or lost response to treatment with 1\xa0TNF‑alpha inhibitor, then vedolizumab or tofacitinib are considered. The clinical experts noted that a patient's choice of treatment is often influenced by the drugs' safety profiles, and that in their experience tofacitinib is sometimes more effective but associated with more severe side effects and is not often used in clinical practice. They explained that TNF‑alpha inhibitors are not appropriate for everyone. For example, people who have contraindications such as high risk of heart failure, or people who are at high risk of infection, including older people. The clinical experts explained that, for these people, vedolizumab would usually be offered instead. They stated that conventional therapy is not a suitable comparator for ustekinumab, because ustekinumab's place in the clinical pathway is likely to be the same as for vedolizumab. The committee noted that vedolizumab and ustekinumab have different mechanisms of action to TNF‑alpha inhibitors, and that ustekinumab and vedolizumab have similar adverse effect profiles. It also noted that ustekinumab may be preferred over vedolizumab because of its mode of administration (subcutaneous injection rather than intravenous injection). Also, because vedolizumab acts mainly on the gut, ustekinumab could be advantageous because it acts on other manifestations of the disease (such as in the skin and joints). The committee noted that vedolizumab and tofacitinib are recommended for people who cannot have TNF‑alpha inhibitors. However, vedolizumab is the most relevant comparator because it has a similar safety profile to ustekinumab. The committee therefore concluded it is most appropriate to consider ustekinumab at the same place in the treatment pathway as vedolizumab.\n\n## There is an unmet need for new treatments that reduce the need for corticosteroids or surgery\n\nThe clinical and patient experts, and the consultation responses, agreed that there is an unmet need for new non-surgical treatment options because many people have an inadequate response to current therapies or they stop working. The only option for these people, other than surgery, is long-term corticosteroid use. This is associated with extreme side effects including mood changes such as irritability and depression, osteoporosis and cataracts. The patient and clinical experts, and comments from consultees, agreed that surgery can be an effective treatment for some patients, but it is avoided until this is the last available treatment option. Outcomes of surgery are variable; there can be a psychological impact, and abdominal scarring can significantly affect sexual and reproductive function. The patient expert also noted that ustekinumab's mode and frequency of administration during maintenance treatment may be more convenient than that of some other current treatments. The committee concluded that new medical treatment options would be welcome.\n\n# Clinical evidence\n\n## The UNIFI trial shows that ustekinumab is more effective than placebo at inducing and maintaining remission and response in all patients\n\nUNIFI is a randomised, placebo-controlled trial of patients who had had an inadequate disease response to, or unacceptable side effects from, biological treatments (TNF‑alpha inhibitors or vedolizumab) or conventional non-biological therapy (corticosteroids or the immunomodulators azathioprine or mercaptopurine). It had an induction-phase study and a maintenance-phase study. There were 961\xa0patients in the induction study, with outcomes measured at week\xa08 in the intention-to-treat (ITT) analyses and at week\xa016 in the non-ITT analyses. 523\xa0patients with disease that had responded after 8\xa0weeks of induction treatment with ustekinumab were entered into the ITT population of the maintenance study, and re-randomised to determine what maintenance treatment they would have (ustekinumab or placebo). The maintenance study also included 2\xa0non-randomised populations: patients whose disease had responded to placebo during induction treatment (sample size and results not reported) and patients who had had more than 8\xa0weeks of induction therapy with ustekinumab and were in response at week\xa016 (n=157; described by the company as 'delayed responders'). The company reported results for the ITT population for the following subgroups:\n\na 'biologic-failure' subgroup of people who had had at least 1\xa0biological treatment (a TNF‑alpha inhibitor or vedolizumab) and either their disease did not respond or lost an initial response, or they could not tolerate it\n\na 'non-biologic failure' subgroup of people who had never had a biological treatment, but that also included some people who had had biological treatments but not had a documented 'biological failure'.At the end of induction treatment, rates of clinical remission and response were statistically significantly higher in the ustekinumab 6\xa0mg\xa0per\xa0kg and 130\xa0mg groups than the placebo group. This was the case for both the non-biologic failure and biologic-failure subgroups, and for the overall ITT population. At week\xa044 of the maintenance phase, a statistically significantly greater proportion of patients who had had ustekinumab maintenance with either dose were in clinical remission than those who had had placebo. This was the case for both the non-biologic failure and biologic-failure subgroups, and for the overall ITT population. The committee noted that these subgroups were defined differently to those in the NICE scope, and that in many trials of ulcerative colitis therapies patients are classified based on biological-treatment exposure status rather than biological-treatment failure status. The committee heard that there was considerable overlap in the definitions, however, with 94% of patients in the UNIFI non-biologic failure subgroup having had no previous exposure to biological therapy. The committee concluded that UNIFI data are generalisable to the population who would be eligible to have treatment with ustekinumab in the NHS. It also concluded that the results demonstrated that ustekinumab is more effective than placebo at inducing and maintaining remission and response in all patients covered by the marketing authorisation.\n\n## Issues raised about UNIFI at technical engagement have been resolved and do not affect the interpretation of the trial results\n\nThe committee reviewed the following points raised in technical report issue\xa01:\n\nThe UNIFI clinical-response results reported in the company submission do not appear to match those in the New England Journal of Medicine (NEJM) trial report, published in September\xa02019.\n\nIt is not clear from the information in the company submission that blinding was maintained between induction week\xa08 and the maintenance phase, or that baseline characteristics of patients in the re-randomised groups were well balanced. Therefore, it is not possible to assess whether the study is at high risk of bias.\n\nThe results for placebo 'non-responders' who had 6\xa0mg\xa0per\xa0kg ustekinumab intravenously at week\xa08 and were assessed at week\xa016 are not reported in the company submission. The committee considered a summary of the company's responses to these points, which consisted of further explanations and data. The committee agreed with the ERG that the company's response demonstrated that there are no important discrepancies between the company submission and the NEJM article, and that UNIFI is at low risk of bias. The committee considered new UNIFI data that the company provided for patients who had 6\xa0mg\xa0per\xa0kg ustekinumab intravenously at week\xa08 and who were assessed at week\xa016. It agreed that the new data did not change the interpretation of the results for the ITT population in the induction study.\n\n# Indirect treatment comparisons\n\n## The exclusion of trials carried out in Asian countries from the network meta-analyses has little effect on the cost-effectiveness estimates\n\nThe company identified 5\xa0trials from Asian countries in its systematic literature review. However, it decided to exclude these studies from the network meta analyses (NMAs) that informed its cost-effectiveness analyses. The company tested the effect of its approach by doing sensitivity NMAs that included data from the Asian trials. The ERG identified some methodological problems with these sensitivity NMAs and feedback was sought on these points during technical engagement (see technical report issue\xa02). The company's response to technical engagement issue\xa02 resolved one, but not all, of the ERG's concerns about the sensitivity NMAs. The ERG explained that some of the company's inclusion and exclusion decisions about the sensitivity NMAs remained inappropriate. The ERG did, however, note that the Asian trials were relatively small. The overall effect on the results of the sensitivity NMAs was therefore likely to be low, and the main NMAs produced similar results to the sensitivity NMAs. The ERG concluded that excluding the Asian trials from the NMAs had little effect on the cost-effectiveness estimates. The committee noted that responses to technical engagement indicated that there was no clinical rationale for excluding the Asian trials, and that it would have been more appropriate for them to be included in the analyses that informed the economic model. Overall, it agreed with the ERG that this issue has little effect on the cost-effectiveness estimates and decided to further consider the NMAs that excluded the Asian trials.\n\n## The maintenance-phase NMAs are uncertain but provide more robust estimates of relative effectiveness than the company's unadjusted indirect treatment comparison\n\nThe committee agreed with the ERG that the company's induction-phase NMAs were methodologically robust and provided a suitable source of clinical data for the transition probabilities in the induction phase of the model. However, the committee noted that estimating the relative effectiveness of ustekinumab and its comparators in the maintenance phase by combining data from different trials was methodologically challenging, because of the lack of head-to-head trial data and differences in the trial designs. It was aware that the company had explored both the adjusted NMA and the unadjusted indirect comparison methods, and that the company's preference was to use the results of its unadjusted indirect treatment comparison (ITC) to inform the cost-effectiveness estimates. The committee was aware that the ERG considered the results of the company's unadjusted ITC to be unreliable and had therefore used results from the company's and its own NMAs to inform its exploratory analyses. The committee was aware that feedback had been sought at technical engagement (see technical report issues 4\xa0and\xa05) to try to understand if any of the methods explored by the company and the ERG were more appropriate, or if other types of analyses should have been done. The committee reviewed the responses to the engagement issues 4\xa0and\xa05 and noted the following:\n\nNo new data have been provided to support the assertion that heterogeneity in the placebo arms of the re-randomised maintenance-phase data is mainly caused by the continuing effects of induction treatment.\n\nThe company asserted that drug half-life is a cause of the continuing effects of induction treatment being observed during the maintenance phase. But evidence provided by a comparator company suggests there is no correlation between drug half-life and placebo-arm response rates.\n\nThe ERG and the company agreed that further analyses using existing data are unlikely to reduce the outstanding uncertainties.The clinical experts commented that multiple differences between the trials mean that they are not comparable. For example, the approaches to corticosteroid tapering varied. The committee considered the different approaches to combining the maintenance phase trial data. It agreed with the ERG that the unadjusted ITC methods preferred by the company are not recommended and the results of these analyses are not robust enough to inform decision making. At the first committee meeting the committee concluded that the company's 1‑year NMA conditional on response and the ERG's maintenance-only NMA both had limitations and the results were very uncertain. However, because no alternative data were available, the results provided the best available estimates of relative effectiveness. In response to the appraisal consultation document, the company updated its base case using its 1‑year NMA conditional on response, which the ERG had also used in its base case. The committee concluded that although the results of this NMA are highly uncertain, it was preferred to the ERG's maintenance-only NMA for providing estimates of relative effectiveness to inform the cost-effectiveness model.\n\n## The pooling of the standard and escalated-dose effects in the maintenance phase has little effect on the results\n\nThe committee noted that the company and the ERG had not agreed a preferred approach for the pooling of standard and escalated efficacy dose effects during the maintenance phase (technical report issue\xa07). The committee concluded that this was a relatively minor issue compared with the other uncertainties in the maintenance analyses and did not have a major effect on decision making.\n\n# The company's economic model\n\n## The model is appropriate for decision making but additional health states in the model would have been preferable\n\nThe company estimated the cost effectiveness of ustekinumab using a model with a hybrid structure (the induction phase was modelled using a decision tree and the maintenance phase was modelled using a Markov structure). The company provided cost-effectiveness estimates for 2\xa0subgroups defined by biological-treatment failure status, but not for the overall population. The committee noted that the ERG had used the same model for its base-case analyses, but with different assumptions including the proportions of patients experiencing response and remission after the failure of initial treatment. The committee considered the health state definitions, recalling the clinical experts' comments that many patients in the population of interest have chronically active disease that is controlled with the long-term use of corticosteroids. The committee noted that the company's 'active disease' health state definition (Mayo score between 6\xa0and\xa012 points, 'remission or response without remission not achieved') did not necessarily apply to this group of patients. The company explained that the 'active disease' health state represents a mixed population of people with active ulcerative colitis that is controlled with corticosteroids and people with active ulcerative colitis who are experiencing an exacerbation. It is therefore difficult to identify the appropriate utility value for this health state in the model. The committee agreed that it would have preferred the inclusion of additional health states in the model to appropriately reflect the progression of the disease. The clinical experts commented that if patients taking long-term corticosteroids stop treatment, they are likely to start experiencing active disease again over time. On this basis, the committee concluded that although the model structure did not explicitly account for patients with disease that was being controlled through the long-term use of corticosteroids, and additional health states would have been more appropriate, the model could be used for decision making.\n\n## The assumption that 30%\xa0of patients have escalated doses of maintenance treatment is acceptable\n\nThe committee noted that, in response to technical engagement issue\xa06, the company had adjusted its base-case assumptions about dose escalation for patients having maintenance infliximab to reflect the ERG's preference. The ERG assumed that for all drugs included in the analysis, 30%\xa0of patients would have an escalated maintenance dose, even though the escalated dose for infliximab is not licensed in the UK. The committee noted that other responses to engagement indicated that off-label use of escalated-dose infliximab is common UK practice but that escalation rates vary between biological therapies. The clinical experts agreed that infliximab dose escalation is common practice but noted that the variation in escalation rates across treatments cited in the engagement responses was not realistic. The committee recognised that there was some uncertainty about this issue. It concluded that this was not a major driver of cost effectiveness, and it was willing to accept the company's revised assumption.\n\n## Response rates and remission rates are uncertain for patients with disease that does not respond or loses response to initial therapy\n\nThe committee noted that ulcerative colitis is not always a chronically active disease and many people with ulcerative colitis have ongoing periods of relapse and remission. The company and ERG base-case analyses used different assumptions for response rates and remission rates in patients whose disease did not respond or lost response to initial therapy. The committee noted that the responses to technical engagement issue\xa03 had not provided any additional clarity on this issue because the additional evidence provided by the company was of low quality. Comments from a patient organisation suggested that most patients continue to experience active disease until surgery or death, but this is not the same as assuming that no patients ever experience an improvement in symptoms. The company, the ERG and the clinical experts all acknowledged that there is limited evidence about the course of the disease after initial treatment failure. However, the clinical experts stated that for patients such as those in the UNIFI trial they would not expect many, if any, patients to experience an improvement in symptoms unless they were on corticosteroids. The committee considered that the ERG's assumption might be considered optimistic, but it agreed that there is likely to be a small number of people who improve without treatment. It concluded that it was not possible to estimate the rates of response and remission for patients with disease that did not respond or lost response to initial therapy, but it was likely to be nearer the company's assumption of a 0%\xa0response rate.\n\n# Utility values in the economic model\n\n## The utility values are uncertain, and the choice of inputs has a large effect on the cost-effectiveness estimates\n\nThe committee noted that the company and the ERG both used the same utility values in their base cases, but that other sources of utility data are available. Their utility data came from a publication by Woehl et al.\xa02008. The committee noted that other utility values for response, response without remission, and active ulcerative colitis health states based on EQ‑5D‑5L data were collected in UNIFI and therefore could have been used instead. It was also aware of other sources of utility data in this population (for example, Swinburn et al.\xa02012 and Vaizey et al.\xa02013), with values somewhere between the values from Woehl et al. and those collected in UNIFI, which had been used in scenario analyses in previous appraisals. The utility value for the 'active disease' state in Woehl et al. was considerably lower (0.41) than the equivalent value derived from the UNIFI EQ‑5D‑5L data. Because of this, the choice of utility data has a large effect on the cost-effectiveness estimates. The committee noted that the Woehl et al.\xa02008 data had been considered in all previous ulcerative colitis appraisals but that the reliability of the utility estimates had also been a source of controversy in all the previous appraisals. It noted that the Woehl et al.\xa02008 publication is only available as an abstract that includes little information about the study methodology or the characteristics of the patients it included. Therefore, it is difficult to assess whether the patients in Woehl et al.\xa02008 are representative of the population of interest and if the methodology is appropriate. The committee noted that the sample size of Woehl et al.\xa02008 is smaller than that in the UNIFI EQ‑5D analyses. It also noted that the ERG cited consistency with other appraisals as the only reason for choosing the Woehl et al.\xa02008 data over the UNIFI data, and that it considered the UNIFI analyses to be well conducted. The committee acknowledged that there were limitations with the trial-based utility values. It noted that the UNIFI EQ‑5D data may be subject to placebo effects and that the length of time over which the data were collected was probably inadequate for estimating the real effect of the disease on health-related quality of life. The committee recalled the patient expert's description of the disease experience and decided that it was plausible that some of the effects on health-related quality of life (such as feeling out of control) might not have been captured in either the Woehl et al.\xa02008 or the UNIFI analyses. It agreed that all data sources (including Woehl et al.\xa02008, UNIFI, Swinburn et al.\xa02012 and Vaizey et al.\xa02013) had some strengths and some limitations, and it was not possible to determine which was most robust. The ERG explained that there was no basis to distinguish between the 3\xa0published analyses of utility values in ulcerative colitis in terms of methodological or reporting quality, generalisability of the results or applicability to the current decision problem. The committee noted that the UNIFI analyses reported similar values to some of the published utility values in ulcerative colitis. It therefore concluded that the UNIFI analyses were as appropriate as other available utility analyses and therefore considered both this and Woehl et al.\xa02008 in its decision making.\n\n## The economic model is unsuitable for modelling 'stopping rules'\n\nThe company proposed that it is appropriate to consider 'stopping rules' for ustekinumab, in line with NICE's guidance on infliximab, adalimumab and golimumab for ulcerative colitis and on vedolizumab for ulcerative colitis. Based on the company's updated base case, it presented analyses of 'stopping rules' with ustekinumab discontinuation at 1,\xa02,\xa03\xa0or 5\xa0years. The clinical experts explained that it is usual practice to review treatment every 12\xa0months; if a person is in sustained remission it may be appropriate to stop treatment, but this is dependent on a variety of factors such as patient choice and the person's overall fitness. The clinical experts also explained that if the person relapsed following discontinuation, treatment would be restarted with either the same, or a different, treatment. The company confirmed that when people stop treatment in the economic model, they do not restart it. The committee agreed that the model does not reflect clinical practice, because it does not account for people who stop treatment but later relapse and restart treatment. The ERG highlighted that it is difficult to model 'stopping rules' and that these have not been modelled in economic analyses in previous ulcerative colitis appraisals, but they were considered qualitatively in those appraisals. The committee concluded that the model structure did not allow 'stopping rules' to be modelled to reflect clinical practice and therefore did not consider them further.\n\n## Cost-utility analysis should be used to determine cost effectiveness\n\nIn response to the appraisal consultation document, the company submitted an additional analysis comparing ustekinumab with vedolizumab. The ERG highlighted that this was not a full cost-comparison analysis as stated by the company. It also noted that this analysis did not account for the uncertainty in the clinical efficacy of ustekinumab compared with vedolizumab, which comes from the uncertainty in the maintenance-phase NMAs and the inability to scrutinise the methods of the trial that reports data for vedolizumab as a comparator. The committee agreed that the company's analysis was not appropriate for decision making. It concluded that it was appropriate to use a cost-utility analysis for decision making, and that irrelevant comparators should be excluded from the fully incremental analysis in order to obtain the relevant incremental cost-effectiveness ratios (ICERs).\n\n# Cost-effectiveness estimates\n\n## Ustekinumab is cost-effective compared with vedolizumab in the cost-utility analyses\n\nThe committee considered the ERG's cost-effectiveness estimates, which incorporated the confidential comparator discounts. The committee noted that the ERG had presented a number of scenarios, which included the confidential patient access schemes and also the Commercial Medicines Unit prices for the comparators and for ustekinumab. Following consultation the company's updated base case included the committee's preferred assumptions in the 1‑year conditional on response NMA (see\xa0section 3.7), assuming 0%\xa0response and remission rates for patients with disease that did not respond or lost response to initial therapy. The company also presented a scenario analyses using 1%\xa0response and remission rates for patients with disease that did not respond or lost response to initial therapy (see\xa0section 3.11). For both analyses the company used the Woehl et al.\xa02008 utility values. The ERG's analyses of the company's updated base case investigated further scenario analysis, using the various utility sources (Woehl et al.\xa02008, Swinburn et al.\xa02012, Vaizey et al.\xa02013 and UNIFI). The committee noted that the ICERs for ustekinumab compared with the lowest-cost TNF‑alpha inhibitor are above £30,000 per quality-adjusted life year (QALY) gained, when ustekinumab was not dominated (more expensive and less effective) or extendedly dominated (its ICER was higher than that of the next more effective option) by the other comparators for both the non-biologic failure and biologic failure groups. The committee accepted that TNF‑alpha inhibitors, conventional therapy and tofacitinib are not relevant comparators in this appraisal and agreed that vedolizumab is the only relevant comparator (see\xa0section 3.2). When ustekinumab is compared with vedolizumab, for all scenarios investigated and irrespective of the source of utilities, the ICERs are below £30,000 per QALY gained for both patient subgroups (failed conventional therapy with or without prior exposure to a biological). Therefore, despite the uncertainty around the maintenance NMA results and which utility value is most appropriate in this population, the committee agreed that ustekinumab is likely to be a cost-effective use of NHS resources in people who would otherwise have vedolizumab.\n\n# Conclusion\n\n## Ustekinumab is recommended for people who cannot have TNF-alpha inhibitors\n\nThe ICER for ustekinumab compared with TNF‑alpha inhibitors was higher than what is normally considered to be cost effective. Therefore, ustekinumab is not cost effective in people who have TNF‑alpha inhibitors as a treatment option. However, the committee agreed that the most appropriate comparator for ustekinumab is vedolizumab. Vedolizumab is used usually in current practice when TNF‑alpha inhibitors have been inadequately effective or response has been lost, or they have not been tolerated or are considered inappropriate. For this population, the ICERs for ustekinumab compared with vedolizumab are within the range that would be considered a cost-effective use of NHS resources. Therefore, the committee concluded that ustekinumab can be recommended as an option for treating moderately to severely active ulcerative colitis in adults when conventional therapy or a biological agent cannot be tolerated, or the disease has responded inadequately or lost response to treatment, only if a TNF‑alpha inhibitor has failed (that is the disease has responded inadequately or has lost response to treatment) or a TNF‑alpha inhibitor cannot be tolerated or is not suitable."}
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https://www.nice.org.uk/guidance/ta633
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Evidence-based recommendations on ustekinumab (Stelara) for treating moderately to severely active ulcerative colitis in adults.
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ff88df6b3fc092a5dba6b09fd13d87c6ebfdbd0c
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nice
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Generalised anxiety disorder and panic disorder in adults: management
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Generalised anxiety disorder and panic disorder in adults: management
This guideline covers the care and treatment of people aged 18 and over with generalised anxiety disorder (chronic anxiety) or panic disorder (with or without agoraphobia or panic attacks). It aims to help people achieve complete relief of symptoms (remission), which is associated with better functioning and a lower likelihood of relapse.
# Introduction
Generalised anxiety disorder (GAD) is 1 of a range of anxiety disorders that includes panic disorder (with and without agoraphobia), post-traumatic stress disorder, obsessive–compulsive disorder, social phobia, specific phobias (for example, of spiders) and acute stress disorder. Anxiety disorders can exist in isolation but more commonly occur with other anxiety and depressive disorders. This guideline covers both 'pure' GAD, in which no comorbidities are present, and the more typical presentation of GAD comorbid with other anxiety and depressive disorders in which GAD is the primary diagnosis. NICE has also developed a guideline on case identification and referral for common mental health disorders that will provide further guidance on the identification and treatment of comorbid conditions (see the NICE guideline on common mental health problems: identification and pathways to care).
GAD is a common disorder, of which the central feature is excessive worry about a number of different events associated with heightened tension. A formal diagnosis using the DSM‑IV classification system requires 2 major symptoms (excessive anxiety and worry about a number of events and activities, and difficulty controlling the worry) and 3 or more additional symptoms from a list of 6 (see the American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th edition). Symptoms should be present for at least 6 months and should cause clinically significant distress or impairment in social, occupational or other important areas of functioning.
According to the DSM‑IV‑TR, a fundamental characteristic of panic disorder is the presence of recurring, unforeseen panic attacks followed by at least 1 month of persistent worry about having another panic attack and concern about the consequences of a panic attack, or a significant change in behaviour related to the attacks (see the American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision). At least 2 unexpected panic attacks are necessary for diagnosis and the attacks should not be accounted for by the use of a substance, a general medical condition or another psychological problem. Panic disorder can be diagnosed with or without agoraphobia.
GAD and panic disorder vary in severity and complexity and this has implications for response to treatment. Therefore, it is important to consider symptom severity, duration, degree of distress, functional impairment, personal history and comorbidities when undertaking a diagnostic assessment.
GAD and panic disorder can follow both chronic and remitting courses. Where possible, the goal of an intervention should be complete relief of symptoms (remission), which is associated with better functioning and a lower likelihood of relapse.
The guideline assumes that prescribers will use a drug's summary of product characteristics (SPC) to inform their decisions made with individual service users.
This guideline recommends some drugs for indications for which they do not have a UK marketing authorisation at the date of publication, if there is good evidence to support that use. Where recommendations have been made for the use of drugs outside their licensed indications ('off-label use'), this is indicated in the recommendation.
New and updated recommendations are included on the management of generalised anxiety disorder in adults.# Recommendations
The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.
People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Principles of care for people with generalised anxiety disorder (GAD)
## Information and support for people with GAD, their families and carers
When working with people with GAD:
build a relationship and work in an open, engaging and non-judgemental manner
explore the person's worries in order to jointly understand the impact of GAD
explore treatment options collaboratively with the person, indicating that decision making is a shared process
ensure that discussion takes place in settings in which confidentiality, privacy and dignity are respected.
When working with people with GAD:
provide information appropriate to the person's level of understanding about the nature of GAD and the range of treatments available
if possible, ensure that comprehensive written information is available in the person's preferred language and in audio format
-ffer independent interpreters if needed.
When families and carers are involved in supporting a person with GAD, consider:
providing information, including contact details, about family and carer support groups and voluntary organisations, and helping families or carers to access these
negotiating between the person with GAD and their family or carers about confidentiality and the sharing of information
providing written and verbal information on GAD and its management, including how families and carers can support the person
providing contact numbers and information about what to do and who to contact in a crisis.See the NICE guideline on supporting adult carers for recommendations on identifying, assessing and meeting the caring, physical and mental health needs of families and carers.
Inform people with GAD about local and national self-help organisations and support groups, in particular where they can talk to others with similar experiences.
For people with GAD who have a mild learning disability or mild acquired cognitive impairment, offer the same interventions as for other people with GAD, adjusting the method of delivery or duration of the intervention if necessary to take account of the disability or impairment.
When assessing or offering an intervention to people with GAD and a moderate to severe learning disability or moderate to severe acquired cognitive impairment, consider consulting with a relevant specialist.
# Stepped care for people with GAD
A stepped-care model (shown below) is used to organise the provision of services and to help people with GAD, their families, carers and practitioners to choose the most effective interventions.
Follow the stepped-care model, offering the least intrusive, most effective intervention first.
Focus of the intervention
Nature of the intervention
STEP 4: Complex treatment-refractory generalised anxiety disorder (GAD) and very marked functional impairment, such as self-neglect or a high risk of self-harm
Highly specialist treatment, such as complex drug and/or psychological treatment regimens; input from multi-agency teams, crisis services, day hospitals or inpatient care
STEP 3: GAD with an inadequate response to step 2 interventions or marked functional impairment
Choice of a high-intensity psychological intervention (cognitive behavioural therapy /applied relaxation) or a drug treatment
STEP 2: Diagnosed GAD that has not improved after education and active monitoring in primary care
Low-intensity psychological interventions: individual non-facilitated self-help, individual guided self-help and psychoeducational groups
STEP 1: All known and suspected presentations of GAD
Identification and assessment; education about GAD and treatment options; active monitoring
Individual non-facilitated self-help: this is a self-administered intervention intended to treat GAD involving written or electronic self-help materials (usually a book or workbook). It is similar to individual guided self-help but usually with minimal therapist contact, for example an occasional short telephone call of no more than 5 minutes.
## Step 1: All known and suspected presentations of GAD
See also the section on identification and assessment in the NICE guideline on common mental health problems.
Identify and communicate the diagnosis of GAD as early as possible to help people understand the disorder and start effective treatment promptly.
Consider the diagnosis of GAD in people presenting with anxiety or significant worry, and in people who attend primary care frequently who:
have a chronic physical health problem or
do not have a physical health problem but are seeking reassurance about somatic symptoms (particularly older people and people from minority ethnic groups) or
are repeatedly worrying about a wide range of different issues.
When a person with known or suspected GAD attends primary care seeking reassurance about a chronic physical health problem or somatic symptoms and/or repeated worrying, consider with the person whether some of their symptoms may be due to GAD.
For people who may have GAD, conduct a comprehensive assessment that does not rely solely on the number, severity and duration of symptoms, but also considers the degree of distress and functional impairment.
As part of the comprehensive assessment, consider how the following factors might have affected the development, course and severity of the person's GAD:
any comorbid depressive disorder or other anxiety disorder
any comorbid substance misuse
any comorbid medical condition
a history of mental health disorders
past experience of, and response to, treatments. Be aware when prescribing selective serotonin reuptake inhibitors (SSRIs) of the need to ask about cocaine use when considering drug–drug interactions, and the need to avoid concurrent use of multiple serotonergic drugs. Follow the Medicines and Healthcare products Regulatory Agency (MHRA) safety advice on citalopram.
For people with GAD and a comorbid depressive or other anxiety disorder, treat the primary disorder first (that is, the 1 that is more severe and in which it is more likely that treatment will improve overall functioning).For guidance on depression, obsessive–compulsive disorder and post-traumatic stress disorder see our guidelines on mental health and behavioural conditions.
For people with GAD who misuse substances, be aware that:
substance misuse can be a complication of GAD
non-harmful substance use should not be a contraindication to the treatment of GAD
harmful and dependent substance misuse should be treated first as this may lead to significant improvement in the symptoms of GAD (see our guidelines on drug misuse and alcohol-use disorders).Be aware when prescribing SSRIs of the need to ask about cocaine use when considering drug–drug interactions, and the need to avoid concurrent use of multiple serotonergic drugs. Follow the MHRA safety advice on citalopram.
Following assessment and diagnosis of GAD:
provide education about the nature of GAD and the options for treatment, including NICE's information for the public
monitor the person's symptoms and functioning (known as active monitoring). This is because education and active monitoring may improve less severe presentations and avoid the need for further interventions.
Discuss the use of over-the-counter medications and preparations with people with GAD. Explain the potential for interactions with other prescribed and over-the-counter medications and the lack of evidence to support their safe use.
## Step 2: Diagnosed GAD that has not improved after step 1 interventions
For people with GAD whose symptoms have not improved after education and active monitoring in step 1, offer 1 or more of the following as a first-line intervention, guided by the person's preference:
individual non-facilitated self-help
individual guided self-help
psychoeducational groups.
Individual non-facilitated self-help for people with GAD should:
include written or electronic materials of a suitable reading age (or alternative media)
be based on the treatment principles of cognitive behavioural therapy (CBT)
include instructions for the person to work systematically through the materials over a period of at least 6 weeks
usually involve minimal therapist contact, for example an occasional short telephone call of no more than 5 minutes.
Individual guided self-help for people with GAD should:
be based on the treatment principles of CBT
include written or electronic materials of a suitable reading age (or alternative media)
be supported by a trained practitioner, who facilitates the self-help programme and reviews progress and outcome
usually consist of 5 to 7 weekly or fortnightly face-to-face or telephone sessions, each lasting 20 to 30 minutes.
Psychoeducational groups for people with GAD should:
be based on CBT principles, have an interactive design and encourage observational learning
include presentations and self-help manuals
be conducted by trained practitioners
have a ratio of 1 therapist to about 12 participants
usually consist of 6 weekly sessions, each lasting 2 hours.
Practitioners providing guided self-help and/or psychoeducational groups should:
receive regular high-quality supervision
use routine outcome measures and ensure that the person with GAD is involved in reviewing the efficacy of the treatment.
## Step 3: GAD with marked functional impairment or that has not improved after step 2 interventions
For people with GAD and marked functional impairment, or those whose symptoms have not responded adequately to step 2 interventions:
Offer either
an individual high-intensity psychological intervention (see recommendations 1.2.17 to 1.2.21) or
drug treatment (see recommendations 1.2.22 to 1.2.32).
Provide verbal and written information on the likely benefits and disadvantages of each mode of treatment, including the tendency of drug treatments to be associated with side effects and withdrawal syndromes.
Base the choice of treatment on the person's preference as there is no evidence that either mode of treatment (individual high-intensity psychological intervention or drug treatment) is better.
If a person with GAD chooses a high-intensity psychological intervention, offer either CBT or applied relaxation.
CBT for people with GAD should:
be based on the treatment manuals used in the clinical trials of CBT for GAD
be delivered by trained and competent practitioners
usually consist of 12 to 15 weekly sessions (fewer if the person recovers sooner; more if clinically required), each lasting 1 hour.
Applied relaxation for people with GAD should:
be based on the treatment manuals used in the clinical trials of applied relaxation for GAD
be delivered by trained and competent practitioners
usually consist of 12 to 15 weekly sessions (fewer if the person recovers sooner; more if clinically required), each lasting 1 hour.
Practitioners providing high-intensity psychological interventions for GAD should:
have regular supervision to monitor fidelity to the treatment model, using audio or video recording of treatment sessions if possible and if the person consents
use routine outcome measures and ensure that the person with GAD is involved in reviewing the efficacy of the treatment.
Consider providing all interventions in the preferred language of the person with GAD if possible.
If a person with GAD chooses drug treatment, offer a selective serotonin reuptake inhibitor (SSRI). Consider offering sertraline first because it is the most cost-effective drug, but note that at the time of publication (January 2011) sertraline did not have UK marketing authorisation for this indication. Informed consent should be obtained and documented. Monitor the person carefully for adverse reactions.Note that this is an off-label use for some SSRIs. See NICE's information on prescribing medicines.
If sertraline is ineffective, offer an alternative SSRI or a serotonin–noradrenaline reuptake inhibitor (SNRI), taking into account the following factors:
tendency to produce a withdrawal syndrome (especially with paroxetine and venlafaxine)
the side-effect profile and the potential for drug interactions
the risk of suicide and likelihood of toxicity in overdose (especially with venlafaxine)
the person's prior experience of treatment with individual drugs (particularly adherence, effectiveness, side effects, experience of withdrawal syndrome and the person's preference). Note that this is an off-label use for some SSRIs. See NICE's information on prescribing medicines.
If the person cannot tolerate SSRIs or SNRIs, consider offering pregabalin. As of 1 April 2019, pregabalin is a Class C controlled substance (under the Misuse of Drugs Act 1971) and scheduled under the Misuse of Drugs Regulations 2001 as Schedule 3. Evaluate patients carefully for a history of drug abuse before prescribing and observe patients for development of signs of abuse and dependence (MHRA, Drug Safety Update April 2019). Follow the MHRA safety advice on pregabalin in pregnancy.
Do not offer a benzodiazepine for the treatment of GAD in primary or secondary care except as a short-term measure during crises. Follow the advice in the BNF on the use of a benzodiazepine in this context.
Do not offer an antipsychotic for the treatment of GAD in primary care.
Before prescribing any medication, discuss the treatment options and any concerns the person with GAD has about taking medication. Explain fully the reasons for prescribing and provide written and verbal information on:
the likely benefits of different treatments
the different propensities of each drug for side effects, withdrawal syndromes and drug interactions (consult the interactions section of the BNF)
the risk of activation with SSRIs and SNRIs, with symptoms such as increased anxiety, agitation and problems sleeping
the gradual development, over 1 week or more, of the full anxiolytic effect
the importance of taking medication as prescribed and the need to continue treatment after remission to avoid relapse.
Take into account the increased risk of bleeding associated with SSRIs, particularly for older people or people taking other drugs that can damage the gastrointestinal mucosa or interfere with clotting (for example, non-steroidal anti-inflammatory drugs or aspirin). Consider prescribing a gastroprotective drug in these circumstances.
For people aged under 30 who are offered an SSRI or SNRI:
warn them that these drugs are associated with an increased risk of suicidal thinking and self-harm in a minority of people under 30 and
see them within 1 week of first prescribing and
monitor the risk of suicidal thinking and self-harm weekly for the first month.
For people who develop side effects soon after starting drug treatment, provide information and consider 1 of the following strategies:
monitoring the person's symptoms closely (if the side effects are mild and acceptable to the person) or
reducing the dose of the drug or
stopping the drug and, according to the person's preference, offering either
an alternative drug (see recommendations 1.2.23 to 1.2.24) or
a high-intensity psychological intervention (see recommendations 1.2.17 to 1.2.21).
Review the effectiveness and side effects of the drug every 2 to 4 weeks during the first 3 months of treatment and every 3 months thereafter.
If the drug is effective, advise the person to continue taking it for at least a year as the likelihood of relapse is high.
If a person's GAD has not responded to a full course of a high-intensity psychological intervention, offer a drug treatment (see recommendations 1.2.22 to 1.2.32).
If a person's GAD has not responded to drug treatment, offer either a high-intensity psychological intervention (see recommendations 1.2.17 to 1.2.21) or an alternative drug treatment (see recommendations 1.2.23 to 1.2.24).
If a person's GAD has partially responded to drug treatment, consider offering a high-intensity psychological intervention in addition to drug treatment.
Consider referral to step 4 if the person with GAD has severe anxiety with marked functional impairment in conjunction with:
a risk of self-harm or suicide or
significant comorbidity, such as substance misuse, personality disorder or complex physical health problems or
self-neglect or
an inadequate response to step 3 interventions.
## Step 4: Complex, treatment-refractory GAD and very marked functional impairment or high risk of self-harm
(Step 4 normally refers to community mental health teams but may include specialist services and specialist practitioners in primary care.)
For guidance on safe prescribing of antidepressants and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.
Offer the person with GAD a specialist assessment of needs and risks, including:
duration and severity of symptoms, functional impairment, comorbidities, risk to self and self-neglect
a formal review of current and past treatments, including adherence to previously prescribed drug treatments and the fidelity of prior psychological interventions, and their impact on symptoms and functional impairment
home environment
support in the community
relationships with and impact on families and carers.
Advise carers about their right to carer assessment, and assessment for respite care and other support (see the NICE guideline on supporting adult carers for recommendations on identifying, assessing and meeting the caring, physical and mental health needs of families and carers).
Develop a comprehensive care plan in collaboration with the person with GAD that addresses needs, risks and functional impairment and has a clear treatment plan.
Inform people with GAD who have not been offered or have refused the interventions in steps 1 to 3 about the potential benefits of these interventions, and offer them any they have not tried.
Consider offering combinations of psychological and drug treatments, combinations of antidepressants or augmentation of antidepressants with other drugs, but exercise caution and be aware that:
evidence for the effectiveness of combination treatments is lacking and
side effects and interactions are more likely when combining and augmenting antidepressants.
Combination treatments should be undertaken only by practitioners with expertise in the psychological and drug treatment of complex, treatment-refractory anxiety disorders and after full discussion with the person about the likely advantages and disadvantages of the treatments suggested.
When treating people with complex and treatment-refractory GAD, inform them of relevant clinical research in which they may wish to participate, working within local and national ethical guidelines at all times.
# Principles of care for people with panic disorder
## General management for panic disorder
People who have panic disorder and their families and carers need comprehensive information, presented in clear and understandable language, about the nature of their condition and the treatment options available. Such information is essential for shared decision making between people with panic disorder and healthcare professionals, particularly when making choices between broadly equivalent treatments. In addition, given the emotional, social and economic costs panic disorder usually entails, people with panic disorder and their families and carers may need help in contacting support and self-help groups. Support groups can also promote understanding and collaboration between people who have panic disorder, their families and carers, and healthcare professionals at all levels of primary and secondary care.
## Shared decision making and information provision
Shared decision making should take place as it improves concordance and clinical outcomes.
Shared decision making between the individual and healthcare professionals should take place during the process of diagnosis and in all phases of care.
People with panic disorder and, when appropriate, families and carers should be provided with information on the nature, course and treatment of panic disorder, including information on the use and likely side-effect profile of medication.
To facilitate shared decision making, evidence-based information about treatments should be available and discussion of the possible options should take place.
People's preference and the experience and outcome of previous treatment(s) should be considered in determining the choice of treatment.
Common concerns about taking medication, such as fears of addiction, should be addressed.
In addition to being provided with high-quality information, people with panic disorder and their families and carers should be informed of self-help groups and support groups and be encouraged to participate in such programmes where appropriate.
## Language
When talking to people with panic disorder and their families and carers, healthcare professionals should use everyday, jargon-free language. If technical terms are used they should be explained to the person.
Where appropriate, all services should provide written material in the language of the person, and appropriate interpreters should be sought for people whose preferred language is not English.
Where available, consideration should be given to providing psychotherapies in the person's own language if this is not English.
# Stepped care for people with panic disorder
The guideline provides recommendations for care at different stages of the person's journey, represented as different steps:
Step 1 – recognition and diagnosis
Step 2 – treatment in primary care
Step 3 – review and consideration of alternative treatments
Step 4 – review and referral to specialist mental health services
Step 5 – care in specialist mental health services.
## Step 1: Recognition and diagnosis of panic disorder
All healthcare professionals involved in diagnosis and management should have a demonstrably high standard of consultation skills so that a structured approach can be taken to the diagnosis and subsequent management plan for panic disorder. The standards required for Membership of the Royal College of General Practitioners are a good example of standards for consulting skills.
The accurate diagnosis of panic disorder is central to the effective management of this condition. It is acknowledged that frequently there are other conditions present, such as depression, that can make the presentation and diagnosis confusing.
The diagnostic process should elicit necessary relevant information such as personal history, any self-medication, and cultural or other individual characteristics that may be important considerations in subsequent care.
There is insufficient evidence on which to recommend a well-validated, self-reporting screening instrument to use in the diagnostic process, and so consultation skills should be relied upon to elicit all necessary information.
The clinician should be alert to the common clinical situation of comorbidity, in particular, panic disorder with depression and panic disorder with substance misuse. Be aware when prescribing SSRIs of the need to ask about cocaine use when considering drug–drug interactions, and the need to avoid concurrent use of multiple serotonergic drugs. Follow the MHRA safety advice on citalopram.
The main problem(s) to be treated should be identified through a process of discussion with the person. In determining the priorities of the comorbidities, the sequencing of the problems should be clarified. This can be helped by drawing up a timeline to identify when the various problems developed. By understanding when the symptoms developed, a better understanding of the relative priorities of the comorbidities can be achieved, and there is a better opportunity of developing an effective intervention that fits the needs of the individual.
It is important to remember that a panic attack does not necessarily constitute a panic disorder and appropriate treatment of a panic attack may limit the development of panic disorder. For people who present with chest pain at A&E services, there appears to be a greater likelihood of the cause being panic disorder if coronary artery disease is not present or the person is female or relatively young. Two other variables, atypical chest pain and self-reported anxiety, may also be associated with panic disorder presentations, but there is insufficient evidence to establish a relationship.
If a person presents in A&E, or other settings, with a panic attack, they should:
be asked if they are already receiving treatment for panic disorder
undergo the minimum investigations necessary to exclude acute physical problems
not usually be admitted to a medical or psychiatric bed
be referred to primary care for subsequent care, even if assessment has been undertaken in A&E
be given appropriate written information about panic attacks and why they are being referred to primary care
be offered appropriate written information about sources of support, including local and national voluntary and self-help groups.
## Panic disorder – steps 2 to 5
## Step 2 for people with panic disorder: offer treatment in primary care
The recommended treatment options have an evidence base: psychological therapy, medication and self-help have all been shown to be effective. The choice of treatment will be a consequence of the assessment process and shared decision making.
Refer to recommendations 1.4.1.1 to 1.4.1.4 in the NICE guideline on common mental health problems for guidance on identifying the correct treatment options.
The treatment option of choice should be available promptly.
There are positive advantages of services based in primary care (for example, lower rates of people who do not attend) and these services are often preferred by people.
For people with mild to moderate panic disorder, offer or refer for 1 of the following low-intensity interventions:
individual non-facilitated self-help
individual facilitated self-help.(This recommendation is taken from the NICE guideline on common mental health problems.)
Information about support groups, where they are available, should be offered. (Support groups may provide face-to-face meetings, telephone conference support groups , or additional information on all aspects of anxiety disorders plus other sources of help.)
The benefits of exercise as part of good general health should be discussed with all people with panic disorder as appropriate.
## Step 3 for people with panic disorder: review and offer alternative treatment if appropriate
For guidance on safe prescribing of antidepressants and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.
For people with moderate to severe panic disorder (with or without agoraphobia), consider referral for:
CBT or
an antidepressant if the disorder is long-standing or the person has not benefitted from or has declined psychological intervention.(This recommendation is taken from the NICE guideline on common mental health problems.)
CBT should be used.
CBT should be delivered only by suitably trained and supervised people who can demonstrate that they adhere closely to empirically grounded treatment protocols.
CBT in the optimal range of duration (7 to 14 hours in total) should be offered.
For most people, CBT should take the form of weekly sessions of 1 to 2 hours and should be completed within a maximum of 4 months of commencement.
Briefer CBT should be supplemented with appropriate focused information and tasks.
Where briefer CBT is used, it should be around 7 hours and designed to integrate with structured self-help materials.
For a few people, more intensive CBT over a very short period of time might be appropriate.
Benzodiazepines are associated with a less good outcome in the long term and should not be prescribed for the treatment of individuals with panic disorder.
Sedating antihistamines or antipsychotics should not be prescribed for the treatment of panic disorder.
Antidepressants should be the only pharmacological intervention used in the longer-term management of panic disorder. The classes of antidepressants that have an evidence base for effectiveness are the selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs). At the time of this amendment (June 2020) escitalopram, sertraline, citalopram, paroxetine and venlafaxine are licensed for the treatment of panic disorder.
The following must be taken into account when deciding which medication to offer:
the age of the person
previous treatment response
risks
the likelihood of accidental overdose by the person being treated and by other family members if appropriate
the likelihood of deliberate self-harm, by overdose or otherwise (the highest risk is with TCAs)
tolerability
the possibility of interactions with concomitant medication (consult the interactions section of the BNF)
the preference of the person being treated
cost, where equal effectiveness is demonstrated. Also see recommendation 1.2.29 on SSRIs and SNRIs.
All people who are prescribed antidepressants should be informed, at the time that treatment is initiated, of potential side effects (including transient increase in anxiety at the start of treatment) and of the risk of discontinuation/withdrawal symptoms if the treatment is stopped abruptly or in some instances if a dose is missed or, occasionally, on reducing the dose of the drug.Also see recommendation 1.2.29 on SSRIs and SNRIs.
People started on antidepressants should be informed about the delay in onset of effect, the time course of treatment, the need to take medication as prescribed, and possible discontinuation/withdrawal symptoms. Written information appropriate to the person's needs should be made available.
Unless otherwise indicated, an SSRI licensed for panic disorder should be offered.
If an SSRI is not suitable or there is no improvement after a 12‑week course and if a further medication is appropriate, imipramine or clomipramine may be considered. Note that this is an off-label use for imipramine and clomipramine. See prescribing medicines for more information.
When prescribing an antidepressant, the healthcare professional should consider the following.
Side effects on the initiation of antidepressants may be minimised by starting at a low dose and increasing the dose slowly until a satisfactory therapeutic response is achieved.
In some instances, doses at the upper end of the indicated dose range may be necessary and should be offered if needed.
Long-term treatment may be necessary for some people and should be offered if needed.
If the person is showing improvement on treatment with an antidepressant, the medication should be continued for at least 6 months after the optimal dose is reached, after which the dose can be tapered.
If there is no improvement after a 12‑week course, an antidepressant from the alternative class (if another medication is appropriate) or another form of therapy (see recommendation 1.4.9) should be offered.
People should be advised to take their medication as prescribed. This may be particularly important with short half-life medication in order to avoid discontinuation/withdrawal symptoms.
Stopping antidepressants abruptly can cause discontinuation/withdrawal symptoms. To minimise the risk of discontinuation/withdrawal symptoms when stopping antidepressants, the dose should be reduced gradually over an extended period of time.
All people prescribed antidepressants should be informed that, although the drugs are not associated with tolerance and craving, discontinuation/withdrawal symptoms may occur on stopping or missing doses or, occasionally, on reducing the dose of the drug. These symptoms are usually mild and self-limiting but occasionally can be severe, particularly if the drug is stopped abruptly.
Healthcare professionals should inform people that the most commonly experienced discontinuation/withdrawal symptoms are dizziness, numbness and tingling, gastrointestinal disturbances (particularly nausea and vomiting), headache, sweating, anxiety and sleep disturbances.
Healthcare professionals should inform people that they should seek advice from their medical practitioner if they experience significant discontinuation/withdrawal symptoms.
If discontinuation/withdrawal symptoms are mild, the practitioner should reassure the person and monitor symptoms. If severe symptoms are experienced after discontinuing an antidepressant, the practitioner should consider reintroducing it (or prescribing another from the same class that has a longer half-life) and gradually reducing the dose while monitoring symptoms.
## Step 4 for people with panic disorder: review and offer referral from primary care if appropriate
In most instances, if there have been 2 interventions provided (any combination of psychological intervention, medication, or bibliotherapy) and the person still has significant symptoms, then referral to specialist mental health services should be offered.
## Step 5 for people with panic disorder: care in specialist mental health services
Specialist mental health services should conduct a thorough, holistic reassessment of the individual, their environment and social circumstances. This reassessment should include evaluation of:
previous treatments, including effectiveness and concordance
any substance use, including nicotine, alcohol, caffeine and recreational drugs
comorbidities
day-to-day functioning
social networks
continuing chronic stressors
the role of agoraphobic and other avoidant symptoms. A comprehensive risk assessment should be undertaken and an appropriate risk management plan developed. Be aware when prescribing SSRIs of the need to ask about cocaine use when considering drug–drug interactions, and the need to avoid concurrent use of multiple serotonergic drugs. Follow the MHRA safety advice on citalopram.
To undertake these evaluations, and to develop and share a full formulation, more than 1 session may be required and should be available.
Care and management should be based on the individual's circumstances and shared decisions made. Options include:
treatment of comorbid conditions
CBT with an experienced therapist if not offered already, including home-based CBT if attendance at clinic is difficult
full exploration of pharmacotherapy
day support to relieve carers and family members
referral for advice, assessment or management to tertiary centres.
There should be accurate and effective communication between all healthcare professionals involved in the care of any person with panic disorder, and particularly between primary care clinicians (GP and teams) and secondary care clinicians (community mental health teams) if there are existing physical health conditions that also require active management.
There should be a process within each practice to assess the progress of a person undergoing CBT. The nature of that process should be determined on a case-by-case basis.
When a new medication is started, the efficacy and side-effects should be reviewed within 2 weeks of starting treatment and again at 4, 6 and 12 weeks. Follow the summary of product characteristics with respect to all other monitoring required.
At the end of 12 weeks, an assessment of the effectiveness of the treatment should be made, and a decision made as to whether to continue or consider an alternative intervention.
If medication is to be continued beyond 12 weeks, the individual should be reviewed at 8- to 12‑week intervals, depending on clinical progress and individual circumstances.
Individuals receiving self-help interventions should be offered contact with primary healthcare professionals, so that progress can be monitored and alternative interventions considered if appropriate. The frequency of such contact should be determined on a case-by-case basis, but is likely to be between every 4 and 8 weeks.
Short, self-completed questionnaires (such as the panic subscale of the agoraphobic mobility inventory for individuals with panic disorder) should be used to monitor outcomes wherever possible. # Recommendations for research
The 2011 Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. The Guideline Development Group's full set of recommendations for research is detailed in the full guideline.
# A comparison of the clinical and cost effectiveness of sertraline and CBT in people with GAD that has not responded to guided self-help and psychoeducation
What is the relative effectiveness of sertraline compared with cognitive behavioural therapy (CBT) in people with generalised anxiety disorder (GAD) that has not responded to guided self-help and psychoeducation in a stepped-care model?
This question should be addressed using a randomised controlled design in which people with GAD that has not responded to step 2 interventions are allocated openly to treatment with sertraline, CBT or waiting-list control for 12 to 16 weeks. The control group is important to demonstrate that the 2 active treatments produce effects greater than those of natural remission. The period of waiting-list control is the standard length of CBT treatment for GAD and is also commonly the length of time that it would take for specialist CBT to become available in routine practice. After 12 to 16 weeks all participants should receive further treatment chosen in collaboration with their treating clinicians.
The outcomes chosen at 12 to 16 weeks should include both observer- and participant-rated measures of clinical symptoms and functioning specific to GAD, and of quality of life. An economic analysis should also be carried out alongside the trial. The trial needs to be large enough to determine the presence or absence of clinically important effects and of any differences in costs between the treatment options using a non-inferiority design. Mediators and moderators of response should be investigated. Follow-up assessments should continue over the next 2 years to ascertain whether short-term benefits are maintained and, in particular, whether CBT produces a better long-term outcome.
## Why this is important
Both sertraline and CBT are efficacious in the treatment of GAD but their relative efficacy has not been compared. In a stepped-care model both CBT and sertraline are treatment options if step 2 interventions (guided self-help and/or psychoeducation) have not resulted in a satisfactory clinical response. At present, however, there are no randomised trial data to help prioritise next-step treatments and no information on how individuals with GAD may be matched to particular therapies. Clarification of the relative short- and longer-term benefits of sertraline and CBT would be helpful in guiding treatment.
# The clinical and cost effectiveness of 2 CBT-based low-intensity interventions (CCBT and guided bibliotherapy) compared with a waiting-list control for the treatment of GAD
In well-defined GAD, what is the clinical and cost effectiveness of 2 CBT-based low-intensity interventions (computerised cognitive behavioural therapy and guided bibliotherapy) compared with a waiting-list control?
This question should be answered using a 3‑armed randomised controlled design using both short- and medium-term outcomes (including cost-effectiveness outcomes). Particular attention should be paid to the reproducibility of the treatment model with regard to content, duration and the training and supervision of those delivering interventions to ensure that the results are both robust and generalisable. The outcomes chosen should include both observer- and participant-rated measures of clinical symptoms and functioning specific to GAD, and an assessment of the acceptability and accessibility of the treatment options.
## Why this is important
Psychological treatments are a recommended therapeutic option for people with GAD. CCBT is a promising low-intensity intervention for GAD that does not yet have a substantial evidence base. It is therefore important to establish whether CCBT is an effective and cost-effective treatment that should be provided for GAD, and how it compares with other low-intensity interventions such as guided bibliotherapy. The results of this trial will have important implications for the provision, accessibility and acceptability of psychological treatment in the NHS.
# The effectiveness of physical activity compared with waiting-list control for the treatment of GAD
For people with GAD who are ready to start a low-intensity intervention, what is the clinical effectiveness of physical activity compared with waiting-list control?
This question should be answered using a randomised controlled design for people with GAD who have been educated about the disorder (as described in step 1) and are stepping up to a low-intensity intervention. The period of waiting-list control should be 12 weeks. The outcomes chosen should include both observer- and participant-rated measures of clinical symptoms and functioning specific to GAD, and of quality of life.
## Why this is important
The evidence base for the effectiveness of physical activity in reducing anxiety symptoms is substantially smaller than that for depression. However, where evidence exists there are signs that physical activity could help to reduce anxiety. As GAD is a commonly experienced mental health disorder the results of this study will have important implications in widening the range of treatment options available in the NHS.
# The effectiveness of chamomile and ginkgo biloba in the treatment of GAD
Is chamomile/ginkgo biloba more effective than placebo in increasing response and remission rates and decreasing anxiety ratings for people with GAD?
This question should be addressed using a placebo-controlled, double-blind randomised design to compare the effects of a standardised dose of chamomile (220 mg to 1100 mg) or ginkgo biloba (30 mg to 500 mg) in a readily available form, for example a capsule, with placebo. This should assess outcomes at the end of the trial and at 12-month post-trial follow-up. The outcomes chosen should include both observer- and participant-rated measures of clinical symptoms and functioning specific to GAD, and of side effects. There should be a health economic evaluation included and an assessment of quality of life. The trial should be large enough to determine the presence or absence of clinically important effects using a non-inferiority design. Mediators and moderators of response should be investigated.
## Why this is important
GAD is a common mental health disorder and the results of this study will be generalisable to a large number of people. There is evidence for the efficacy of chamomile and ginkgo biloba in reducing anxiety in people with GAD but the evidence base is small (1 study). However, the scarce literature on the effectiveness of other herbal interventions for treating GAD points to chamomile and ginkgo biloba as 2 of the more effective herbal interventions. Moreover, both these herbal remedies are widely available and relatively inexpensive. Furthermore, at present there is no scientific evidence of side effects or drug–herbal interactions in relation to chamomile or ginkgo biloba. As both these herbal interventions are readily available and have no known side effects, they could be used at an early stage as a means of preventing progression to drug treatments, which are associated with a number of undesirable side effects and dependency.
# The clinical and cost effectiveness of a primary care-based collaborative care approach to improving the treatment of GAD compared with usual care
What are the benefits of a primary care-based collaborative care approach to improving the treatment of GAD compared with usual care?
This question should be addressed using a cluster randomised controlled design in which the clusters are GP practices and people with GAD are recruited following screening of consecutive attenders at participating GP practices. GPs in intervention practices should receive training in recognising GAD and providing both drug treatment and GP-delivered low-intensity psychological interventions (psychoeducation and non-facilitated self-help). Psychological wellbeing practitioners in intervention practices should provide these low-intensity psychological interventions and support GP-prescribed drug treatment by providing information about side effects, monitoring medication use and liaising about any changes to medication. They should also support the referral for CBT of participants whose symptoms have not improved following low-intensity interventions. Structured, practice-based protocols should define care pathways, the interventions to be provided by practitioners at each point in the care pathway and the mechanisms they should use to liaise about individual patients. In control practices, participants should receive care as usual from the GP, including referral for primary and secondary care psychological interventions or mental health services.
Outcomes should be evaluated at 6 months with follow-up assessments continuing for up to 2 years to establish whether short-term benefits are maintained in the longer term. The outcomes chosen should include both observer- and participant-rated measures of clinical symptoms and functioning specific to GAD, and of quality of life. An economic analysis should also be carried out alongside the trial. The trial needs to be large enough to determine the presence or absence of clinically important effects and of any differences in costs between collaborative care and usual care.
## Why this is important
Most people with GAD in the UK do not receive evidence-based management and poor recognition of GAD by GPs contributes to a lack of appropriate interventions being offered. There is some evidence that complex interventions involving the training of primary care practitioners, together with a collaborative care approach involving GPs, other primary care practitioners and mental health professionals, can improve the uptake of evidence-based interventions and clinical and functional outcomes for people with GAD. However, these approaches have not been evaluated in primary care in the UK. Given the differences between the organisation of primary care in different countries, such as the US, it is important to demonstrate whether these approaches can also be effective in the UK.
# The clinical and cost effectiveness of 2 CBT-based low-intensity interventions (CCBT and guided bibliotherapy) compared with a waiting-list control for the treatment of panic disorder
In well-defined panic disorder, what is the clinical and cost effectiveness of 2 CBT-based low-intensity interventions (CCBT and guided bibliotherapy) compared with a waiting-list control?
This question should be answered using a 3‑armed randomised controlled design using both short- and medium-term outcomes (including cost-effectiveness outcomes). Particular attention should be paid to the reproducibility of the treatment model with regard to content, duration and the training and supervision of those delivering interventions to ensure that the results are both robust and generalisable. The outcomes chosen should include both observer- and participant-rated measures of clinical symptoms and functioning specific to panic disorder, and an assessment of the acceptability and accessibility of the treatment options.
## Why this is important
Psychological treatments are a recommended therapeutic option for people with panic disorder. CCBT is a promising low-intensity intervention for panic disorder that does not yet have a substantial evidence base. It is therefore important to establish whether CCBT is an effective and cost-effective treatment that should be provided for panic disorder, and how it compares with other low-intensity interventions such as guided bibliotherapy. The results of this trial will have important implications for the provision, accessibility and acceptability of psychological treatment in the NHS.# Appendix: Assessing generalised anxiety disorder
As set out in the introduction to this guideline, the assessment of generalised anxiety disorder (GAD) is based on the criteria in DSM‑IV. Assessment should include the number and severity of symptoms, duration of the current episode and course of the disorder.
Key symptoms of GAD
The key symptoms of GAD are:
excessive anxiety and worry about a number of events or activities
difficulty controlling the worry.
The worry should occur on a majority of days for at least 6 months. The focus of the worry should not be confined to features of another anxiety disorder (for example, not just about having a panic attack, social embarrassment, a traumatic event, being contaminated or having a serious illness).
If the 2 key symptoms are present, ask about the following associated symptoms:
restlessness
being easily fatigued
difficulty concentrating
irritability
muscle tension
disturbed sleep.
Then ask about duration, distress, impairment of functioning and past history of anxiety and mood disorders.
Factors that favour initial education about GAD and active monitoring
only (step 1) are:
few symptoms of GAD or symptoms that are intermittent or of less than 6 months' duration (hence subclinical)
-nly mild distress and no or limited functional impairment
no comorbid anxiety or mood disorder
no past history of anxiety or mood disorders
individual not interested in any active treatment option.
Factors that favour initial active treatment with low-intensity psychological interventions, including GP-prescribed non-facilitated self-help (step 2) are:
diagnostic criteria for GAD met
clinically significant distress and/or impairment in social, occupational or other important areas of functioning
comorbid anxiety or mood disorder
individual wishes to pursue active treatment for GAD.
Factors that favour treatment with a high-intensity psychological intervention or a pharmacological intervention (step 3) are:
marked functional impairment
less marked but clinically significant functional impairment or distress and inadequate response to a step 2 intervention
past history of anxiety or mood disorders.
Factors that favour referral for specialist treatment (step 4) are:
GAD that is refractory to both cognitive behavioural therapy (CBT) and drug treatment
very severe functional impairment (such as self-neglect)
persistent suicidal thoughts
multiple psychiatric comorbidities.
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{'Introduction': "Generalised anxiety disorder (GAD) is 1\xa0of a range of anxiety disorders that includes panic disorder (with and without agoraphobia), post-traumatic stress disorder, obsessive–compulsive disorder, social phobia, specific phobias (for example, of spiders) and acute stress disorder. Anxiety disorders can exist in isolation but more commonly occur with other anxiety and depressive disorders. This guideline covers both 'pure' GAD, in which no comorbidities are present, and the more typical presentation of GAD comorbid with other anxiety and depressive disorders in which GAD is the primary diagnosis. NICE has also developed a guideline on case identification and referral for common mental health disorders that will provide further guidance on the identification and treatment of comorbid conditions (see the NICE guideline on common mental health problems: identification and pathways to care).\n\nGAD is a common disorder, of which the central feature is excessive worry about a number of different events associated with heightened tension. A formal diagnosis using the DSM‑IV classification system requires 2\xa0major symptoms (excessive anxiety and worry about a number of events and activities, and difficulty controlling the worry) and 3\xa0or more additional symptoms from a list of\xa06 (see the American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th edition). Symptoms should be present for at least 6\xa0months and should cause clinically significant distress or impairment in social, occupational or other important areas of functioning.\n\nAccording to the DSM‑IV‑TR, a fundamental characteristic of panic disorder is the presence of recurring, unforeseen panic attacks followed by at least 1\xa0month of persistent worry about having another panic attack and concern about the consequences of a panic attack, or a significant change in behaviour related to the attacks (see the American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision). At least 2\xa0unexpected panic attacks are necessary for diagnosis and the attacks should not be accounted for by the use of a substance, a general medical condition or another psychological problem. Panic disorder can be diagnosed with or without agoraphobia.\n\nGAD and panic disorder vary in severity and complexity and this has implications for response to treatment. Therefore, it is important to consider symptom severity, duration, degree of distress, functional impairment, personal history and comorbidities when undertaking a diagnostic assessment.\n\nGAD and panic disorder can follow both chronic and remitting courses. Where possible, the goal of an intervention should be complete relief of symptoms (remission), which is associated with better functioning and a lower likelihood of relapse.\n\nThe guideline assumes that prescribers will use a drug's summary of product characteristics (SPC) to inform their decisions made with individual service users.\n\nThis guideline recommends some drugs for indications for which they do not have a UK marketing authorisation at the date of publication, if there is good evidence to support that use. Where recommendations have been made for the use of drugs outside their licensed indications ('off-label use'), this is indicated in the recommendation.\n\nNew and updated recommendations are included on the management of generalised anxiety disorder in adults.", 'Recommendations': "The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.\n\nPeople have the right to be involved in discussions and make informed decisions about their care, as described in\xa0making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Principles of care for people with generalised anxiety disorder (GAD)\n\n## Information and support for people with GAD, their families and carers\n\nWhen working with people with GAD:\n\nbuild a relationship and work in an open, engaging and non-judgemental manner\n\nexplore the person's worries in order to jointly understand the impact of GAD\n\nexplore treatment options collaboratively with the person, indicating that decision making is a shared process\n\nensure that discussion takes place in settings in which confidentiality, privacy and dignity are respected. \n\nWhen working with people with GAD:\n\nprovide information appropriate to the person's level of understanding about the nature of GAD and the range of treatments available\n\nif possible, ensure that comprehensive written information is available in the person's preferred language and in audio format\n\noffer independent interpreters if needed. \n\nWhen families and carers are involved in supporting a person with GAD, consider:\n\nproviding information, including contact details, about family and carer support groups and voluntary organisations, and helping families or carers to access these\n\nnegotiating between the person with GAD and their family or carers about confidentiality and the sharing of information\n\nproviding written and verbal information on GAD and its management, including how families and carers can support the person\n\nproviding contact numbers and information about what to do and who to contact in a crisis.See the NICE guideline on supporting adult carers for recommendations on identifying, assessing and meeting the caring, physical and mental health needs of families and carers. [2011, amended 2020]\n\nInform people with GAD about local and national self-help organisations and support groups, in particular where they can talk to others with similar experiences. \n\nFor people with GAD who have a mild learning disability or mild acquired cognitive impairment, offer the same interventions as for other people with GAD, adjusting the method of delivery or duration of the intervention if necessary to take account of the disability or impairment. \n\nWhen assessing or offering an intervention to people with GAD and a moderate to severe learning disability or moderate to severe acquired cognitive impairment, consider consulting with a relevant specialist. \n\n# Stepped care for people with GAD\n\nA stepped-care model (shown below) is used to organise the provision of services and to help people with GAD, their families, carers and practitioners to choose the most effective interventions.\n\nFollow the stepped-care model, offering the least intrusive, most effective intervention first. \n\nFocus of the intervention\n\n\n\nNature of the intervention\n\n\n\nSTEP 4: Complex treatment-refractory generalised anxiety disorder (GAD) and very marked functional impairment, such as self-neglect or a high risk of self-harm\n\n\n\nHighly specialist treatment, such as complex drug and/or psychological treatment regimens; input from multi-agency teams, crisis services, day hospitals or inpatient care\n\n\n\nSTEP 3: GAD with an inadequate response to step 2 interventions or marked functional impairment\n\n\n\nChoice of a high-intensity psychological intervention (cognitive behavioural therapy [CBT]/applied relaxation) or a drug treatment\n\n\n\nSTEP 2: Diagnosed GAD that has not improved after education and active monitoring in primary care\n\n\n\nLow-intensity psychological interventions: individual non-facilitated self-help, individual guided self-help and psychoeducational groups\n\n\n\nSTEP 1: All known and suspected presentations of GAD\n\n\n\nIdentification and assessment; education about GAD and treatment options; active monitoring\n\n\n\nIndividual non-facilitated self-help: this is a self-administered intervention intended to treat GAD involving written or electronic self-help materials (usually a book or workbook). It is similar to individual guided self-help but usually with minimal therapist contact, for example an occasional short telephone call of no more than 5\xa0minutes.\n\n## Step 1: All known and suspected presentations of GAD\n\nSee also the section on identification and assessment in the NICE guideline on common mental health problems.\n\nIdentify and communicate the diagnosis of GAD as early as possible to help people understand the disorder and start effective treatment promptly. \n\nConsider the diagnosis of GAD in people presenting with anxiety or significant worry, and in people who attend primary care frequently who:\n\nhave a chronic physical health problem or\n\ndo not have a physical health problem but are seeking reassurance about somatic symptoms (particularly older people and people from minority ethnic groups) or\n\nare repeatedly worrying about a wide range of different issues. \n\nWhen a person with known or suspected GAD attends primary care seeking reassurance about a chronic physical health problem or somatic symptoms and/or repeated worrying, consider with the person whether some of their symptoms may be due to GAD. \n\nFor people who may have GAD, conduct a comprehensive assessment that does not rely solely on the number, severity and duration of symptoms, but also considers the degree of distress and functional impairment. \n\nAs part of the comprehensive assessment, consider how the following factors might have affected the development, course and severity of the person's GAD:\n\nany comorbid depressive disorder or other anxiety disorder\n\nany comorbid substance misuse\n\nany comorbid medical condition\n\na history of mental health disorders\n\npast experience of, and response to, treatments. Be aware when prescribing selective serotonin reuptake inhibitors (SSRIs) of the need to ask about cocaine use when considering drug–drug interactions, and the need to avoid concurrent use of multiple serotonergic drugs. Follow the Medicines and Healthcare products Regulatory Agency (MHRA) safety advice on citalopram. [2011, amended 2020]\n\nFor people with GAD and a comorbid depressive or other anxiety disorder, treat the primary disorder first (that is, the 1\xa0that is more severe and in which it is more likely that treatment will improve overall functioning).For guidance on depression, obsessive–compulsive disorder and post-traumatic stress disorder see our guidelines on mental health and behavioural conditions. [2011, amended 2020]\n\nFor people with GAD who misuse substances, be aware that:\n\nsubstance misuse can be a complication of GAD\n\nnon-harmful substance use should not be a contraindication to the treatment of GAD\n\nharmful and dependent substance misuse should be treated first as this may lead to significant improvement in the symptoms of GAD (see our guidelines on drug misuse and alcohol-use disorders).Be aware when prescribing SSRIs of the need to ask about cocaine use when considering drug–drug interactions, and the need to avoid concurrent use of multiple serotonergic drugs. Follow the MHRA safety advice on citalopram. [2011, amended 2020]\n\nFollowing assessment and diagnosis of GAD:\n\nprovide education about the nature of GAD and the options for treatment, including NICE's information for the public\n\nmonitor the person's symptoms and functioning (known as active monitoring). This is because education and active monitoring may improve less severe presentations and avoid the need for further interventions. \n\nDiscuss the use of over-the-counter medications and preparations with people with GAD. Explain the potential for interactions with other prescribed and over-the-counter medications and the lack of evidence to support their safe use. \n\n## Step 2: Diagnosed GAD that has not improved after step\xa01 interventions\n\nFor people with GAD whose symptoms have not improved after education and active monitoring in step\xa01, offer 1\xa0or more of the following as a first-line intervention, guided by the person's preference:\n\nindividual non-facilitated self-help\n\nindividual guided self-help\n\npsychoeducational groups. \n\nIndividual non-facilitated self-help for people with GAD should:\n\ninclude written or electronic materials of a suitable reading age (or alternative media)\n\nbe based on the treatment principles of cognitive behavioural therapy (CBT)\n\ninclude instructions for the person to work systematically through the materials over a period of at least 6\xa0weeks\n\nusually involve minimal therapist contact, for example an occasional short telephone call of no more than 5\xa0minutes. \n\nIndividual guided self-help for people with GAD should:\n\nbe based on the treatment principles of CBT\n\ninclude written or electronic materials of a suitable reading age (or alternative media)\n\nbe supported by a trained practitioner, who facilitates the self-help programme and reviews progress and outcome\n\nusually consist of 5\xa0to\xa07 weekly or fortnightly face-to-face or telephone sessions, each lasting 20\xa0to 30\xa0minutes. [2011, amended 2018]\n\nPsychoeducational groups for people with GAD should:\n\nbe based on CBT principles, have an interactive design and encourage observational learning\n\ninclude presentations and self-help manuals\n\nbe conducted by trained practitioners\n\nhave a ratio of 1\xa0therapist to about 12\xa0participants\n\nusually consist of 6\xa0weekly sessions, each lasting 2\xa0hours. \n\nPractitioners providing guided self-help and/or psychoeducational groups should:\n\nreceive regular high-quality supervision\n\nuse routine outcome measures and ensure that the person with GAD is involved in reviewing the efficacy of the treatment. \n\n## Step 3: GAD with marked functional impairment or that has not improved after step\xa02 interventions\n\nFor people with GAD and marked functional impairment, or those whose symptoms have not responded adequately to step\xa02 interventions:\n\nOffer either\n\n\n\nan individual high-intensity psychological intervention (see recommendations 1.2.17 to 1.2.21) or\n\ndrug treatment (see recommendations 1.2.22 to 1.2.32).\n\n\n\nProvide verbal and written information on the likely benefits and disadvantages of each mode of treatment, including the tendency of drug treatments to be associated with side effects and withdrawal syndromes.\n\nBase the choice of treatment on the person's preference as there is no evidence that either mode of treatment (individual high-intensity psychological intervention or drug treatment) is better. \n\nIf a person with GAD chooses a high-intensity psychological intervention, offer either CBT or applied relaxation. \n\nCBT for people with GAD should:\n\nbe based on the treatment manuals used in the clinical trials of CBT for GAD\n\nbe delivered by trained and competent practitioners\n\nusually consist of 12 to 15\xa0weekly sessions (fewer if the person recovers sooner; more if clinically required), each lasting 1\xa0hour. \n\nApplied relaxation for people with GAD should:\n\nbe based on the treatment manuals used in the clinical trials of applied relaxation for GAD\n\nbe delivered by trained and competent practitioners\n\nusually consist of 12 to 15\xa0weekly sessions (fewer if the person recovers sooner; more if clinically required), each lasting 1\xa0hour. \n\nPractitioners providing high-intensity psychological interventions for GAD should:\n\nhave regular supervision to monitor fidelity to the treatment model, using audio or video recording of treatment sessions if possible and if the person consents\n\nuse routine outcome measures and ensure that the person with GAD is involved in reviewing the efficacy of the treatment. \n\nConsider providing all interventions in the preferred language of the person with GAD if possible. \n\nIf a person with GAD chooses drug treatment, offer a selective serotonin reuptake inhibitor (SSRI). Consider offering sertraline first because it is the most cost-effective drug, but note that at the time of publication (January\xa02011) sertraline did not have UK marketing authorisation for this indication. Informed consent should be obtained and documented. Monitor the person carefully for adverse reactions.Note that this is an off-label use for some SSRIs. See\xa0NICE's information on prescribing medicines. [2011, amended 2020]\n\nIf sertraline is ineffective, offer an alternative SSRI or a serotonin–noradrenaline reuptake inhibitor (SNRI), taking into account the following factors:\n\ntendency to produce a withdrawal syndrome (especially with paroxetine and venlafaxine)\n\nthe side-effect profile and the potential for drug interactions\n\nthe risk of suicide and likelihood of toxicity in overdose (especially with venlafaxine)\n\nthe person's prior experience of treatment with individual drugs (particularly adherence, effectiveness, side effects, experience of withdrawal syndrome and the person's preference). Note that this is an off-label use for some SSRIs. See\xa0NICE's information on prescribing medicines. [2011, amended 2020]\n\nIf the person cannot tolerate SSRIs or SNRIs, consider offering pregabalin. As of 1\xa0April\xa02019, pregabalin is a Class C controlled substance (under the Misuse of Drugs Act 1971) and scheduled under the Misuse of Drugs Regulations 2001 as Schedule\xa03. Evaluate patients carefully for a history of drug abuse before prescribing and observe patients for development of signs of abuse and dependence (MHRA, Drug Safety Update April 2019). Follow the MHRA safety advice on pregabalin in pregnancy. [2011, amended 2020]\n\nDo not offer a benzodiazepine for the treatment of GAD in primary or secondary care except as a short-term measure during crises. Follow the advice in the BNF on the use of a benzodiazepine in this context. \n\nDo not offer an antipsychotic for the treatment of GAD in primary care. [2011, amended 2020]\n\nBefore prescribing any medication, discuss the treatment options and any concerns the person with GAD has about taking medication. Explain fully the reasons for prescribing and provide written and verbal information on:\n\nthe likely benefits of different treatments\n\nthe different propensities of each drug for side effects, withdrawal syndromes and drug interactions (consult the interactions section of the BNF)\n\nthe risk of activation with SSRIs and SNRIs, with symptoms such as increased anxiety, agitation and problems sleeping\n\nthe gradual development, over 1\xa0week or more, of the full anxiolytic effect\n\nthe importance of taking medication as prescribed and the need to continue treatment after remission to avoid relapse. [2011, amended 2020]\n\nTake into account the increased risk of bleeding associated with SSRIs, particularly for older people or people taking other drugs that can damage the gastrointestinal mucosa or interfere with clotting (for example, non-steroidal anti-inflammatory drugs [NSAIDS] or aspirin). Consider prescribing a gastroprotective drug in these circumstances. \n\nFor people aged under\xa030 who are offered an SSRI or SNRI:\n\nwarn them that these drugs are associated with an increased risk of suicidal thinking and self-harm in a minority of people under\xa030 and\n\nsee them within 1\xa0week of first prescribing and\n\nmonitor the risk of suicidal thinking and self-harm weekly for the first month. \n\nFor people who develop side effects soon after starting drug treatment, provide information and consider 1\xa0of the following strategies:\n\nmonitoring the person's symptoms closely (if the side effects are mild and acceptable to the person) or\n\nreducing the dose of the drug or\n\nstopping the drug and, according to the person's preference, offering either\n\n\n\nan alternative drug (see recommendations 1.2.23 to 1.2.24) or\n\na high-intensity psychological intervention (see recommendations 1.2.17 to 1.2.21). \n\n\n\nReview the effectiveness and side effects of the drug every 2 to 4\xa0weeks during the first 3\xa0months of treatment and every 3\xa0months thereafter. \n\nIf the drug is effective, advise the person to continue taking it for at least a year as the likelihood of relapse is high. \n\nIf a person's GAD has not responded to a full course of a high-intensity psychological intervention, offer a drug treatment (see recommendations 1.2.22 to 1.2.32). \n\nIf a person's GAD has not responded to drug treatment, offer either a high-intensity psychological intervention (see recommendations 1.2.17 to 1.2.21) or an alternative drug treatment (see recommendations 1.2.23 to 1.2.24). \n\nIf a person's GAD has partially responded to drug treatment, consider offering a high-intensity psychological intervention in addition to drug treatment. \n\nConsider referral to step 4 if the person with GAD has severe anxiety with marked functional impairment in conjunction with:\n\na risk of self-harm or suicide or\n\nsignificant comorbidity, such as substance misuse, personality disorder or complex physical health problems or\n\nself-neglect or\n\nan inadequate response to step\xa03 interventions. \n\n## Step 4: Complex, treatment-refractory GAD and very marked functional impairment or high risk of self-harm\n\n(Step 4 normally refers to community mental health teams but may include specialist services and specialist practitioners in primary care.)\n\nFor guidance on safe prescribing of antidepressants and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.\n\nOffer the person with GAD a specialist assessment of needs and risks, including:\n\nduration and severity of symptoms, functional impairment, comorbidities, risk to self and self-neglect\n\na formal review of current and past treatments, including adherence to previously prescribed drug treatments and the fidelity of prior psychological interventions, and their impact on symptoms and functional impairment\n\nhome environment\n\nsupport in the community\n\nrelationships with and impact on families and carers. \n\nAdvise carers about their right to carer assessment, and assessment for respite care and other support (see the NICE guideline on supporting adult carers for recommendations on identifying, assessing and meeting the caring, physical and mental health needs of families and carers). [2011, amended 2020]\n\nDevelop a comprehensive care plan in collaboration with the person with GAD that addresses needs, risks and functional impairment and has a clear treatment plan. \n\nInform people with GAD who have not been offered or have refused the interventions in steps 1 to 3 about the potential benefits of these interventions, and offer them any they have not tried. \n\nConsider offering combinations of psychological and drug treatments, combinations of antidepressants or augmentation of antidepressants with other drugs, but exercise caution and be aware that:\n\nevidence for the effectiveness of combination treatments is lacking and\n\nside effects and interactions are more likely when combining and augmenting antidepressants. \n\nCombination treatments should be undertaken only by practitioners with expertise in the psychological and drug treatment of complex, treatment-refractory anxiety disorders and after full discussion with the person about the likely advantages and disadvantages of the treatments suggested. \n\nWhen treating people with complex and treatment-refractory GAD, inform them of relevant clinical research in which they may wish to participate, working within local and national ethical guidelines at all times. \n\n# Principles of care for people with panic disorder\n\n## General management for panic disorder\n\nPeople who have panic disorder and their families and carers need comprehensive information, presented in clear and understandable language, about the nature of their condition and the treatment options available. Such information is essential for shared decision making between people with panic disorder and healthcare professionals, particularly when making choices between broadly equivalent treatments. In addition, given the emotional, social and economic costs panic disorder usually entails, people with panic disorder and their families and carers may need help in contacting support and self-help groups. Support groups can also promote understanding and collaboration between people who have panic disorder, their families and carers, and healthcare professionals at all levels of primary and secondary care.\n\n## Shared decision making and information provision\n\nShared decision making should take place as it improves concordance and clinical outcomes. \n\nShared decision making between the individual and healthcare professionals should take place during the process of diagnosis and in all phases of care. \n\nPeople with panic disorder and, when appropriate, families and carers should be provided with information on the nature, course and treatment of panic disorder, including information on the use and likely side-effect profile of medication. \n\nTo facilitate shared decision making, evidence-based information about treatments should be available and discussion of the possible options should take place. \n\nPeople's preference and the experience and outcome of previous treatment(s) should be considered in determining the choice of treatment. \n\nCommon concerns about taking medication, such as fears of addiction, should be addressed. \n\nIn addition to being provided with high-quality information, people with panic disorder and their families and carers should be informed of self-help groups and support groups and be encouraged to participate in such programmes where appropriate. \n\n## Language\n\nWhen talking to people with panic disorder and their families and carers, healthcare professionals should use everyday, jargon-free language. If technical terms are used they should be explained to the person. \n\nWhere appropriate, all services should provide written material in the language of the person, and appropriate interpreters should be sought for people whose preferred language is not English. \n\nWhere available, consideration should be given to providing psychotherapies in the person's own language if this is not English. \n\n# Stepped care for people with panic disorder\n\nThe guideline provides recommendations for care at different stages of the person's journey, represented as different steps:\n\nStep 1 – recognition and diagnosis\n\nStep 2 – treatment in primary care\n\nStep 3 – review and consideration of alternative treatments\n\nStep 4 – review and referral to specialist mental health services\n\nStep 5 – care in specialist mental health services.\n\n## Step 1: Recognition and diagnosis of panic disorder\n\nAll healthcare professionals involved in diagnosis and management should have a demonstrably high standard of consultation skills so that a structured approach can be taken to the diagnosis and subsequent management plan for panic disorder. The standards required for Membership of the Royal College of General Practitioners are a good example of standards for consulting skills. [2004, amended 2020]\n\nThe accurate diagnosis of panic disorder is central to the effective management of this condition. It is acknowledged that frequently there are other conditions present, such as depression, that can make the presentation and diagnosis confusing.\n\nThe diagnostic process should elicit necessary relevant information such as personal history, any self-medication, and cultural or other individual characteristics that may be important considerations in subsequent care. \n\nThere is insufficient evidence on which to recommend a well-validated, self-reporting screening instrument to use in the diagnostic process, and so consultation skills should be relied upon to elicit all necessary information. \n\nThe clinician should be alert to the common clinical situation of comorbidity, in particular, panic disorder with depression and panic disorder with substance misuse. Be aware when prescribing SSRIs of the need to ask about cocaine use when considering drug–drug interactions, and the need to avoid concurrent use of multiple serotonergic drugs. Follow the MHRA safety advice on citalopram. [2004, amended 2020]\n\nThe main problem(s) to be treated should be identified through a process of discussion with the person. In determining the priorities of the comorbidities, the sequencing of the problems should be clarified. This can be helped by drawing up a timeline to identify when the various problems developed. By understanding when the symptoms developed, a better understanding of the relative priorities of the comorbidities can be achieved, and there is a better opportunity of developing an effective intervention that fits the needs of the individual. \n\nIt is important to remember that a panic attack does not necessarily constitute a panic disorder and appropriate treatment of a panic attack may limit the development of panic disorder. For people who present with chest pain at A&E services, there appears to be a greater likelihood of the cause being panic disorder if coronary artery disease is not present or the person is female or relatively young. Two other variables, atypical chest pain and self-reported anxiety, may also be associated with panic disorder presentations, but there is insufficient evidence to establish a relationship.\n\nIf a person presents in A&E, or other settings, with a panic attack, they should:\n\nbe asked if they are already receiving treatment for panic disorder\n\nundergo the minimum investigations necessary to exclude acute physical problems\n\nnot usually be admitted to a medical or psychiatric bed\n\nbe referred to primary care for subsequent care, even if assessment has been undertaken in A&E\n\nbe given appropriate written information about panic attacks and why they are being referred to primary care\n\nbe offered appropriate written information about sources of support, including local and national voluntary and self-help groups. \n\n## Panic disorder – steps 2 to 5\n\n## Step 2 for people with panic disorder: offer treatment in primary care\n\nThe recommended treatment options have an evidence base: psychological therapy, medication and self-help have all been shown to be effective. The choice of treatment will be a consequence of the assessment process and shared decision making.\n\nRefer to recommendations 1.4.1.1 to 1.4.1.4 in the NICE guideline on common mental health problems for guidance on identifying the correct treatment options. \n\nThe treatment option of choice should be available promptly. \n\nThere are positive advantages of services based in primary care (for example, lower rates of people who do not attend) and these services are often preferred by people. \n\nFor people with mild to moderate panic disorder, offer or refer for 1\xa0of the following low-intensity interventions:\n\nindividual non-facilitated self-help\n\nindividual facilitated self-help.(This recommendation is taken from the NICE guideline on common mental health problems.)\n\nInformation about support groups, where they are available, should be offered. (Support groups may provide face-to-face meetings, telephone conference support groups [which can be based on CBT principles], or additional information on all aspects of anxiety disorders plus other sources of help.) \n\nThe benefits of exercise as part of good general health should be discussed with all people with panic disorder as appropriate. \n\n## Step 3 for people with panic disorder: review and offer alternative treatment if appropriate\n\nFor guidance on safe prescribing of antidepressants and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.\n\nFor people with moderate to severe panic disorder (with or without agoraphobia), consider referral for:\n\nCBT or\n\nan antidepressant if the disorder is long-standing or the person has not benefitted from or has declined psychological intervention.(This recommendation is taken from the NICE guideline on common mental health problems.)\n\nCBT should be used. \n\nCBT should be delivered only by suitably trained and supervised people who can demonstrate that they adhere closely to empirically grounded treatment protocols. \n\nCBT in the optimal range of duration (7\xa0to 14\xa0hours in total) should be offered. \n\nFor most people, CBT should take the form of weekly sessions of 1\xa0to 2\xa0hours and should be completed within a maximum of 4\xa0months of commencement. \n\nBriefer CBT should be supplemented with appropriate focused information and tasks. \n\nWhere briefer CBT is used, it should be around 7\xa0hours and designed to integrate with structured self-help materials. \n\nFor a few people, more intensive CBT over a very short period of time might be appropriate. \n\nBenzodiazepines are associated with a less good outcome in the long term and should not be prescribed for the treatment of individuals with panic disorder. \n\nSedating antihistamines or antipsychotics should not be prescribed for the treatment of panic disorder. \n\nAntidepressants should be the only pharmacological intervention used in the longer-term management of panic disorder. The classes of antidepressants that have an evidence base for effectiveness are the selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs). At the time of this amendment (June\xa02020) escitalopram, sertraline, citalopram, paroxetine and venlafaxine are licensed for the treatment of panic disorder.\n\nThe following must be taken into account when deciding which medication to offer:\n\nthe age of the person\n\nprevious treatment response\n\nrisks\n\n\n\nthe likelihood of accidental overdose by the person being treated and by other family members if appropriate\n\nthe likelihood of deliberate self-harm, by overdose or otherwise (the highest risk is with TCAs)\n\n\n\ntolerability\n\nthe possibility of interactions with concomitant medication (consult the interactions section of the BNF)\n\nthe preference of the person being treated\n\ncost, where equal effectiveness is demonstrated. Also see recommendation 1.2.29 on SSRIs and SNRIs. [2004, amended 2020]\n\nAll people who are prescribed antidepressants should be informed, at the time that treatment is initiated, of potential side effects (including transient increase in anxiety at the start of treatment) and of the risk of discontinuation/withdrawal symptoms if the treatment is stopped abruptly or in some instances if a dose is missed or, occasionally, on reducing the dose of the drug.Also see recommendation 1.2.29 on SSRIs and SNRIs. [2004, amended 2020]\n\nPeople started on antidepressants should be informed about the delay in onset of effect, the time course of treatment, the need to take medication as prescribed, and possible discontinuation/withdrawal symptoms. Written information appropriate to the person's needs should be made available. \n\nUnless otherwise indicated, an SSRI licensed for panic disorder should be offered. \n\nIf an SSRI is not suitable or there is no improvement after a 12‑week course and if a further medication is appropriate, imipramine or clomipramine may be considered. Note that this is an off-label use for imipramine and clomipramine. See prescribing medicines for more information. [2004, amended 2020]\n\nWhen prescribing an antidepressant, the healthcare professional should consider the following.\n\nSide effects on the initiation of antidepressants may be minimised by starting at a low dose and increasing the dose slowly until a satisfactory therapeutic response is achieved.\n\nIn some instances, doses at the upper end of the indicated dose range may be necessary and should be offered if needed.\n\nLong-term treatment may be necessary for some people and should be offered if needed.\n\nIf the person is showing improvement on treatment with an antidepressant, the medication should be continued for at least 6\xa0months after the optimal dose is reached, after which the dose can be tapered. \n\nIf there is no improvement after a 12‑week course, an antidepressant from the alternative class (if another medication is appropriate) or another form of therapy (see recommendation\xa01.4.9) should be offered. \n\nPeople should be advised to take their medication as prescribed. This may be particularly important with short half-life medication in order to avoid discontinuation/withdrawal symptoms. \n\nStopping antidepressants abruptly can cause discontinuation/withdrawal symptoms. To minimise the risk of discontinuation/withdrawal symptoms when stopping antidepressants, the dose should be reduced gradually over an extended period of time. \n\nAll people prescribed antidepressants should be informed that, although the drugs are not associated with tolerance and craving, discontinuation/withdrawal symptoms may occur on stopping or missing doses or, occasionally, on reducing the dose of the drug. These symptoms are usually mild and self-limiting but occasionally can be severe, particularly if the drug is stopped abruptly. \n\nHealthcare professionals should inform people that the most commonly experienced discontinuation/withdrawal symptoms are dizziness, numbness and tingling, gastrointestinal disturbances (particularly nausea and vomiting), headache, sweating, anxiety and sleep disturbances. \n\nHealthcare professionals should inform people that they should seek advice from their medical practitioner if they experience significant discontinuation/withdrawal symptoms. \n\nIf discontinuation/withdrawal symptoms are mild, the practitioner should reassure the person and monitor symptoms. If severe symptoms are experienced after discontinuing an antidepressant, the practitioner should consider reintroducing it (or prescribing another from the same class that has a longer half-life) and gradually reducing the dose while monitoring symptoms. \n\n## Step 4 for people with panic disorder: review and offer referral from primary care if appropriate\n\nIn most instances, if there have been 2\xa0interventions provided (any combination of psychological intervention, medication, or bibliotherapy) and the person still has significant symptoms, then referral to specialist mental health services should be offered. \n\n## Step 5 for people with panic disorder: care in specialist mental health services\n\nSpecialist mental health services should conduct a thorough, holistic reassessment of the individual, their environment and social circumstances. This reassessment should include evaluation of:\n\nprevious treatments, including effectiveness and concordance\n\nany substance use, including nicotine, alcohol, caffeine and recreational drugs\n\ncomorbidities\n\nday-to-day functioning\n\nsocial networks\n\ncontinuing chronic stressors\n\nthe role of agoraphobic and other avoidant symptoms. A comprehensive risk assessment should be undertaken and an appropriate risk management plan developed. Be aware when prescribing SSRIs of the need to ask about cocaine use when considering drug–drug interactions, and the need to avoid concurrent use of multiple serotonergic drugs. Follow the MHRA safety advice on citalopram. [2004, amended 2020]\n\nTo undertake these evaluations, and to develop and share a full formulation, more than 1\xa0session may be required and should be available. \n\nCare and management should be based on the individual's circumstances and shared decisions made. Options include:\n\ntreatment of comorbid conditions\n\nCBT with an experienced therapist if not offered already, including home-based CBT if attendance at clinic is difficult\n\nfull exploration of pharmacotherapy\n\nday support to relieve carers and family members\n\nreferral for advice, assessment or management to tertiary centres. \n\nThere should be accurate and effective communication between all healthcare professionals involved in the care of any person with panic disorder, and particularly between primary care clinicians (GP and teams) and secondary care clinicians (community mental health teams) if there are existing physical health conditions that also require active management. \n\nThere should be a process within each practice to assess the progress of a person undergoing CBT. The nature of that process should be determined on a case-by-case basis. \n\nWhen a new medication is started, the efficacy and side-effects should be reviewed within 2\xa0weeks of starting treatment and again at 4, 6 and 12\xa0weeks. Follow the summary of product characteristics with respect to all other monitoring required. \n\nAt the end of 12\xa0weeks, an assessment of the effectiveness of the treatment should be made, and a decision made as to whether to continue or consider an alternative intervention. \n\nIf medication is to be continued beyond 12\xa0weeks, the individual should be reviewed at 8- to 12‑week intervals, depending on clinical progress and individual circumstances. \n\nIndividuals receiving self-help interventions should be offered contact with primary healthcare professionals, so that progress can be monitored and alternative interventions considered if appropriate. The frequency of such contact should be determined on a case-by-case basis, but is likely to be between every 4 and 8\xa0weeks. \n\nShort, self-completed questionnaires (such as the panic subscale of the agoraphobic mobility inventory for individuals with panic disorder) should be used to monitor outcomes wherever possible. ", 'Recommendations for research': "The 2011 Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. The Guideline Development Group's full set of recommendations for research is detailed in the full guideline.\n\n# A comparison of the clinical and cost effectiveness of sertraline and CBT in people with GAD that has not responded to guided self-help and psychoeducation\n\nWhat is the relative effectiveness of sertraline compared with cognitive behavioural therapy (CBT) in people with generalised anxiety disorder (GAD) that has not responded to guided self-help and psychoeducation in a stepped-care model?\n\nThis question should be addressed using a randomised controlled design in which people with GAD that has not responded to step\xa02 interventions are allocated openly to treatment with sertraline, CBT or waiting-list control for 12\xa0to 16\xa0weeks. The control group is important to demonstrate that the 2\xa0active treatments produce effects greater than those of natural remission. The period of waiting-list control is the standard length of CBT treatment for GAD and is also commonly the length of time that it would take for specialist CBT to become available in routine practice. After 12\xa0to 16\xa0weeks all participants should receive further treatment chosen in collaboration with their treating clinicians.\n\nThe outcomes chosen at 12\xa0to 16\xa0weeks should include both observer- and participant-rated measures of clinical symptoms and functioning specific to GAD, and of quality of life. An economic analysis should also be carried out alongside the trial. The trial needs to be large enough to determine the presence or absence of clinically important effects and of any differences in costs between the treatment options using a non-inferiority design. Mediators and moderators of response should be investigated. Follow-up assessments should continue over the next 2\xa0years to ascertain whether short-term benefits are maintained and, in particular, whether CBT produces a better long-term outcome.\n\n## Why this is important\n\nBoth sertraline and CBT are efficacious in the treatment of GAD but their relative efficacy has not been compared. In a stepped-care model both CBT and sertraline are treatment options if step\xa02 interventions (guided self-help and/or psychoeducation) have not resulted in a satisfactory clinical response. At present, however, there are no randomised trial data to help prioritise next-step treatments and no information on how individuals with GAD may be matched to particular therapies. Clarification of the relative short- and longer-term benefits of sertraline and CBT would be helpful in guiding treatment.\n\n# The clinical and cost effectiveness of 2\xa0CBT-based low-intensity interventions (CCBT and guided bibliotherapy) compared with a waiting-list control for the treatment of GAD\n\nIn well-defined GAD, what is the clinical and cost effectiveness of 2\xa0CBT-based low-intensity interventions (computerised cognitive behavioural therapy [CCBT] and guided bibliotherapy) compared with a waiting-list control?\n\nThis question should be answered using a 3‑armed randomised controlled design using both short- and medium-term outcomes (including cost-effectiveness outcomes). Particular attention should be paid to the reproducibility of the treatment model with regard to content, duration and the training and supervision of those delivering interventions to ensure that the results are both robust and generalisable. The outcomes chosen should include both observer- and participant-rated measures of clinical symptoms and functioning specific to GAD, and an assessment of the acceptability and accessibility of the treatment options.\n\n## Why this is important\n\nPsychological treatments are a recommended therapeutic option for people with GAD. CCBT is a promising low-intensity intervention for GAD that does not yet have a substantial evidence base. It is therefore important to establish whether CCBT is an effective and cost-effective treatment that should be provided for GAD, and how it compares with other low-intensity interventions such as guided bibliotherapy. The results of this trial will have important implications for the provision, accessibility and acceptability of psychological treatment in the NHS.\n\n# The effectiveness of physical activity compared with waiting-list control for the treatment of GAD\n\nFor people with GAD who are ready to start a low-intensity intervention, what is the clinical effectiveness of physical activity compared with waiting-list control?\n\nThis question should be answered using a randomised controlled design for people with GAD who have been educated about the disorder (as described in step 1) and are stepping up to a low-intensity intervention. The period of waiting-list control should be 12 weeks. The outcomes chosen should include both observer- and participant-rated measures of clinical symptoms and functioning specific to GAD, and of quality of life.\n\n## Why this is important\n\nThe evidence base for the effectiveness of physical activity in reducing anxiety symptoms is substantially smaller than that for depression. However, where evidence exists there are signs that physical activity could help to reduce anxiety. As GAD is a commonly experienced mental health disorder the results of this study will have important implications in widening the range of treatment options available in the NHS.\n\n# The effectiveness of chamomile and ginkgo biloba in the treatment of GAD\n\nIs chamomile/ginkgo biloba more effective than placebo in increasing response and remission rates and decreasing anxiety ratings for people with GAD?\n\nThis question should be addressed using a placebo-controlled, double-blind randomised design to compare the effects of a standardised dose of chamomile (220\xa0mg to 1100\xa0mg) or ginkgo biloba (30\xa0mg to 500\xa0mg) in a readily available form, for example a capsule, with placebo. This should assess outcomes at the end of the trial and at 12-month post-trial follow-up. The outcomes chosen should include both observer- and participant-rated measures of clinical symptoms and functioning specific to GAD, and of side effects. There should be a health economic evaluation included and an assessment of quality of life. The trial should be large enough to determine the presence or absence of clinically important effects using a non-inferiority design. Mediators and moderators of response should be investigated.\n\n## Why this is important\n\nGAD is a common mental health disorder and the results of this study will be generalisable to a large number of people. There is evidence for the efficacy of chamomile and ginkgo biloba in reducing anxiety in people with GAD but the evidence base is small (1\xa0study). However, the scarce literature on the effectiveness of other herbal interventions for treating GAD points to chamomile and ginkgo biloba as 2\xa0of the more effective herbal interventions. Moreover, both these herbal remedies are widely available and relatively inexpensive. Furthermore, at present there is no scientific evidence of side effects or drug–herbal interactions in relation to chamomile or ginkgo biloba. As both these herbal interventions are readily available and have no known side effects, they could be used at an early stage as a means of preventing progression to drug treatments, which are associated with a number of undesirable side effects and dependency.\n\n# The clinical and cost effectiveness of a primary care-based collaborative care approach to improving the treatment of GAD compared with usual care\n\nWhat are the benefits of a primary care-based collaborative care approach to improving the treatment of GAD compared with usual care?\n\nThis question should be addressed using a cluster randomised controlled design in which the clusters are GP practices and people with GAD are recruited following screening of consecutive attenders at participating GP practices. GPs in intervention practices should receive training in recognising GAD and providing both drug treatment and GP-delivered low-intensity psychological interventions (psychoeducation and non-facilitated self-help). Psychological wellbeing practitioners in intervention practices should provide these low-intensity psychological interventions and support GP-prescribed drug treatment by providing information about side effects, monitoring medication use and liaising about any changes to medication. They should also support the referral for CBT of participants whose symptoms have not improved following low-intensity interventions. Structured, practice-based protocols should define care pathways, the interventions to be provided by practitioners at each point in the care pathway and the mechanisms they should use to liaise about individual patients. In control practices, participants should receive care as usual from the GP, including referral for primary and secondary care psychological interventions or mental health services.\n\nOutcomes should be evaluated at 6 months with follow-up assessments continuing for up to 2 years to establish whether short-term benefits are maintained in the longer term. The outcomes chosen should include both observer- and participant-rated measures of clinical symptoms and functioning specific to GAD, and of quality of life. An economic analysis should also be carried out alongside the trial. The trial needs to be large enough to determine the presence or absence of clinically important effects and of any differences in costs between collaborative care and usual care.\n\n## Why this is important\n\nMost people with GAD in the UK do not receive evidence-based management and poor recognition of GAD by GPs contributes to a lack of appropriate interventions being offered. There is some evidence that complex interventions involving the training of primary care practitioners, together with a collaborative care approach involving GPs, other primary care practitioners and mental health professionals, can improve the uptake of evidence-based interventions and clinical and functional outcomes for people with GAD. However, these approaches have not been evaluated in primary care in the UK. Given the differences between the organisation of primary care in different countries, such as the US, it is important to demonstrate whether these approaches can also be effective in the UK.\n\n# The clinical and cost effectiveness of 2\xa0CBT-based low-intensity interventions (CCBT and guided bibliotherapy) compared with a waiting-list control for the treatment of panic disorder\n\nIn well-defined panic disorder, what is the clinical and cost effectiveness of 2\xa0CBT-based low-intensity interventions (CCBT and guided bibliotherapy) compared with a waiting-list control?\n\nThis question should be answered using a 3‑armed randomised controlled design using both short- and medium-term outcomes (including cost-effectiveness outcomes). Particular attention should be paid to the reproducibility of the treatment model with regard to content, duration and the training and supervision of those delivering interventions to ensure that the results are both robust and generalisable. The outcomes chosen should include both observer- and participant-rated measures of clinical symptoms and functioning specific to panic disorder, and an assessment of the acceptability and accessibility of the treatment options.\n\n## Why this is important\n\nPsychological treatments are a recommended therapeutic option for people with panic disorder. CCBT is a promising low-intensity intervention for panic disorder that does not yet have a substantial evidence base. It is therefore important to establish whether CCBT is an effective and cost-effective treatment that should be provided for panic disorder, and how it compares with other low-intensity interventions such as guided bibliotherapy. The results of this trial will have important implications for the provision, accessibility and acceptability of psychological treatment in the NHS.", 'Appendix: Assessing generalised anxiety disorder': "As set out in the introduction to this guideline, the assessment of generalised anxiety disorder (GAD) is based on the criteria in DSM‑IV. Assessment should include the number and severity of symptoms, duration of the current episode and course of the disorder.\n\nKey symptoms of GAD\n\nThe key symptoms of GAD are:\n\nexcessive anxiety and worry about a number of events or activities\n\ndifficulty controlling the worry.\n\nThe worry should occur on a majority of days for at least 6\xa0months. The focus of the worry should not be confined to features of another anxiety disorder (for example, not just about having a panic attack, social embarrassment, a traumatic event, being contaminated or having a serious illness).\n\nIf the 2\xa0key symptoms are present, ask about the following associated symptoms:\n\nrestlessness\n\nbeing easily fatigued\n\ndifficulty concentrating\n\nirritability\n\nmuscle tension\n\ndisturbed sleep.\n\nThen ask about duration, distress, impairment of functioning and past history of anxiety and mood disorders.\n\nFactors that favour initial education about GAD and active monitoring\n only (step 1) are:\n\nfew symptoms of GAD or symptoms that are intermittent or of less than 6 months' duration (hence subclinical)\n\nonly mild distress and no or limited functional impairment\n\nno comorbid anxiety or mood disorder\n\nno past history of anxiety or mood disorders\n\nindividual not interested in any active treatment option.\n\nFactors that favour initial active treatment with low-intensity psychological interventions, including GP-prescribed non-facilitated self-help (step 2) are:\n\ndiagnostic criteria for GAD met\n\nclinically significant distress and/or impairment in social, occupational or other important areas of functioning\n\ncomorbid anxiety or mood disorder\n\nindividual wishes to pursue active treatment for GAD.\n\nFactors that favour treatment with a high-intensity psychological intervention or a pharmacological intervention (step 3) are:\n\nmarked functional impairment\n\nless marked but clinically significant functional impairment or distress and inadequate response to a step 2 intervention\n\npast history of anxiety or mood disorders.\n\nFactors that favour referral for specialist treatment (step 4) are:\n\nGAD that is refractory to both cognitive behavioural therapy (CBT) and drug treatment\n\nvery severe functional impairment (such as self-neglect)\n\npersistent suicidal thoughts\n\nmultiple psychiatric comorbidities."}
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https://www.nice.org.uk/guidance/cg113
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This guideline covers the care and treatment of people aged 18 and over with generalised anxiety disorder (chronic anxiety) or panic disorder (with or without agoraphobia or panic attacks). It aims to help people achieve complete relief of symptoms (remission), which is associated with better functioning and a lower likelihood of relapse.
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90c301a366b4cb797eb61db7b100d79107de7ff1
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nice
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Intravenous fluid therapy in children and young people in hospital
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Intravenous fluid therapy in children and young people in hospital
This guideline covers general principles for managing intravenous (IV) fluids for children and young people under 16 years, including assessing fluid and electrolyte status and prescribing IV fluid therapy. It applies to a range of conditions and different settings. It does not include recommendations relating to specific conditions. This guideline represents a major opportunity to improve patient safety for children and young people having IV fluid therapy in hospital.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Principles and protocols for intravenous fluid therapy
For guidance on the principles and protocols for intravenous (IV) fluid therapy, see the principles and protocols for intravenous fluid therapy section in NICE's guideline on intravenous fluid therapy in adults (recommendations 1.1.1, 1.1.2, 1.1.3, 1.1.5, 1.1.6, 1.1.7 and 1.1.8 apply to all ages).
Offer IV fluid therapy as part of a protocol (see algorithms for IV fluid therapy in children and young people in hospital):
Assess fluid and electrolyte needs following algorithm 1: Assessment and monitoring.
If term neonates, children and young people need IV fluids for fluid resuscitation, follow algorithm 2: Fluid resuscitation.
If term neonates, children and young people need IV fluids for routine maintenance, follow algorithm 3: Routine maintenance.
If term neonates, children and young people need IV fluids to address existing deficits or excesses, ongoing abnormal losses or abnormal fluid distribution, follow algorithm 4: Replacement and redistribution.
If hypernatraemia develops, follow algorithm 5: Managing hypernatraemia that develops during IV fluid therapy.
If hyponatraemia develops, follow algorithm 6: Managing hyponatraemia that develops during IV fluid therapy.
# Assessment and monitoring
Use body weight to calculate IV fluid and electrolyte needs for term neonates, children and young people.
Consider using body surface area to calculate IV fluid and electrolyte needs if accurate calculation of insensible losses is important (for example, if the weight is above the 91st centile, or with acute kidney injury, known chronic kidney disease or cancer).
In term neonates, children and young people who are receiving IV fluids, assess and document the following:
Actual or estimated daily body weight. Record the weight from the current day, the previous day, and the difference between the two. If an estimate was used, the actual weight should be measured as soon as clinically possible.
Fluid input, output and balance over the previous 24 hours.
Any special instructions for prescribing, including relevant history.
An assessment of the fluid status.
The results of laboratory and point‑of‑care assessments, including:
full blood count
urea
creatinine
plasma electrolyte concentrations (including chloride, sodium and potassium; see recommendation 1.2.4)
blood glucose (see recommendation 1.2.5)
urinary electrolyte concentrations.
Details of any ongoing losses (see recommendation 1.5.1 and the diagram of ongoing losses).
Calculations of fluid needs for routine maintenance, replacement, redistribution and resuscitation.
The fluid and electrolyte prescription (in ml per hour), with clear signatures, dates and times.
Types and volumes of fluid input and output (urine, gastric and other), recorded hourly and with running totals.
-hourly fluid balance subtotals.
-hourly fluid balance totals.
-hourly reassessments of:
the fluid prescription
current hydration status
whether oral fluids can be started
urine and other outputs.
Measure plasma electrolyte concentrations using laboratory tests when starting IV fluids, and then at least every 24 hours or more frequently if there are electrolyte disturbances.
Measure blood glucose when starting IV fluids, and then at least every 24 hours or more frequently if there is a risk of hypoglycaemia.
Consider point-of-care testing for measuring plasma electrolyte concentrations and blood glucose in time‑critical situations when IV fluids are needed (for example, during emergency situations and in A&E, theatre and critical care).
Diagnose clinical dehydration and hypovolaemic shock using the clinical features listed in table 1, but be aware that it can be difficult to identify the clinical features in term neonates.
No clinically detectable dehydration
Clinical dehydration
Hypovolaemic shock
Alert and responsive
Red flag
Altered responsiveness (for example, irritable, lethargic)
Decreased level of consciousness
Appears well
Red flag
Appears to be unwell or deteriorating
Eyes not sunken
Red flag
Sunken eyes
Moist mucous membranes (except after a drink)
Dry mucous membranes (except for 'mouth breather')
Normal blood pressure
Normal blood pressure
Hypotension (decompensated shock)
Normal breathing pattern
Red flag
Tachypnoea
Tachypnoea
Normal capillary refill time
Normal capillary refill time
Prolonged capillary refill time
Normal heart rate
Red flag
Tachycardia
Tachycardia
Normal peripheral pulses
Normal peripheral pulses
Weak peripheral pulses
Normal skin turgor
Red flag
Reduced skin turgor
Normal urine output
Decreased urine output
Skin colour unchanged
Skin colour unchanged
Pale or mottled skin
Warm extremities
Warm extremities
Cold extremities
Notes:
Within the category of 'clinical dehydration' there is a spectrum of severity indicated by increasingly numerous and more pronounced clinical features. For hypovolaemic shock, 1 or more of the clinical features listed would be expected to be present. Dashes (–) indicate that these features do not specifically indicate hypovolaemic shock. This table has been adapted from the assessing dehydration and shock section of NICE's guideline on diarrhoea and vomiting in children.
# Fluid resuscitation
If children and young people need IV fluid resuscitation, use glucose‑free crystalloids that contain sodium in the range 131–154 mmol/litre, with a bolus of 10 ml/kg over less than 10 minutes. Take into account pre‑existing conditions (for example, cardiac disease or kidney disease), as smaller fluid volumes may be needed.Note that this is an off-label use for some intravenous fluid therapy preparations in some age groups. See prescribing medicines for more information.
If term neonates need IV fluid resuscitation, use glucose‑free crystalloids that contain sodium in the range 131–154 mmol/litre, with a bolus of 10–20 ml/kg over less than 10 minutes.Note that this is an off-label use for some intravenous fluid therapy preparations in some age groups. See prescribing medicines for more information.
Do not use tetrastarch for fluid resuscitation.
For guidance on using IV fluids for fluid resuscitation in children and young people with diabetic ketoacidosis, see the diabetic ketoacidosis section of NICE's guideline on diabetes (type 1 and type 2) in children and young people.
Reassess term neonates, children and young people after completion of the IV fluid bolus, and decide whether they need more fluids.
Seek expert advice (for example, from the paediatric intensive care team) if 40–60 ml/kg of IV fluid or more is needed as part of the initial fluid resuscitation.
# Routine maintenance
Calculate routine maintenance IV fluid rates for children and young people using the Holliday–Segar formula (100 ml/kg/day for the first 10 kg of weight, 50 ml/kg/day for the next 10 kg and 20 ml/kg/day for the weight over 20 kg). Be aware that over a 24‑hour period, males rarely need more than 2,500 ml and females rarely need more than 2,000 ml of fluids.
Calculate routine maintenance IV fluid rates for term neonates according to their age, using the following as a guide:
From birth to day 1: 50 to 60 ml/kg/day.
Day 2: 70 to 80 ml/kg/day.
Day 3: 80 to 100 ml/kg/day.
Day 4: 100 to 120 ml/kg/day.
Days 5 to 28: 120 to 150 ml/kg/day.
If children and young people need IV fluids for routine maintenance, initially use isotonic crystalloids that contain sodium in the range 131 to 154 mmol/litre.Note that this is an off-label use for some intravenous fluid therapy preparations in some age groups. See prescribing medicines for more information.
Measure plasma electrolyte concentrations and blood glucose when starting IV fluids for routine maintenance (except before most elective surgery), and at least every 24 hours thereafter.
Be aware that plasma electrolyte concentrations and blood glucose are not routinely measured before elective surgery unless there is a need to do so, based on the child's medical condition or the type of surgery.
Base any subsequent IV fluid prescriptions on the plasma electrolyte concentrations and blood glucose measurements.
If term neonates aged 8 days or over need IV fluids for routine maintenance, initially use isotonic crystalloids that contain sodium in the range 131–154 mmol/litre with 5–10% glucose. For term neonates aged up to 7 days, use professional judgement, taking into account:
the individual circumstances, and
for term neonates in the first days of life, a sodium content of 131 to 154 mmol/litre may be too high (or sodium may not be needed) and a glucose content of 5% to 10% may be too low. Note that this is an off-label use for some intravenous fluid therapy preparations in some age groups. See prescribing medicines for more information.
For term neonates in critical postnatal adaptation phase (for example, term neonates with respiratory distress syndrome, meconium aspiration, hypoxic ischaemic encephalopathy), give no or minimal sodium until postnatal diuresis with weight loss occurs.
If there is a risk of water retention associated with non‑osmotic antidiuretic hormone (ADH) secretion, consider either:
restricting fluids to 50% to 80% of routine maintenance needs or
reducing fluids, calculated on the basis of insensible losses within the range 300–400 ml/m2/24 hours plus urinary output.
When using body surface area to calculate IV fluid needs for routine maintenance (see recommendation 1.2.2), estimate insensible losses within the range 300–400 ml/m2/24 hours plus urinary output.
For a short explanation of why the committee made the 2020 change to recommendation 1.4.7, see the rationale on routine maintenance .
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# Replacement and redistribution
If term neonates, children and young people need IV fluids for replacement or redistribution, adjust the IV fluid prescription (in addition to maintenance needs) to account for existing fluid and/or electrolyte deficits or excesses, ongoing losses (see the diagram of ongoing losses) or abnormal distribution, for example, tissue oedema seen in sepsis.
Consider isotonic crystalloids that contain sodium in the range 131 to 154 mmol/litre for redistribution. Note that this is an off-label use for some intravenous fluid therapy preparations in some age groups. See prescribing medicines for more information.
Use 0.9% sodium chloride containing potassium to replace ongoing losses (see the diagram of ongoing losses).
Base any subsequent fluid prescriptions on the plasma electrolyte concentrations and blood glucose measurements.
# Managing hypernatraemia that develops during intravenous fluid therapy
If hypernatraemia develops in term neonates, children and young people, review the fluid status and take action as follows:
If there is no evidence of dehydration and an isotonic fluid is being used, consider changing to a hypotonic fluid (for example, 0.45% sodium chloride with glucose). Note that this is an off-label use for some intravenous fluid therapy preparations in some age groups. See prescribing medicines for more information.
If dehydration is diagnosed, calculate the water deficit and replace it over 48 hours, initially with 0.9% sodium chloride.
If the fluid status is uncertain, measure urine sodium and osmolality.
If hypernatraemia worsens or is unchanged after replacing the deficit, review the fluid type and consider changing to a hypotonic solution (for example, 0.45% sodium chloride with glucose).
When correcting hypernatraemia, ensure that the rate of fall of plasma sodium does not exceed 12 mmol/litre in a 24‑hour period.
Measure plasma electrolyte concentrations every 4 to 6 hours for the first 24 hours, and after this base the frequency of further plasma electrolyte measurements on the treatment response.
# Managing hyponatraemia that develops during intravenous fluid therapy
If asymptomatic hyponatraemia develops in term neonates, children and young people, review the fluid status and take action as follows:
If a child is prescribed a hypotonic fluid, change to an isotonic fluid (for example, 0.9% sodium chloride).
Restrict maintenance IV fluids in children and young people who are hypervolaemic or at risk of hypervolaemia (for example, if there is a risk of increased ADH secretion) by either:
restricting maintenance fluids to 50% to 80% of routine maintenance needs or
reducing fluids, calculated on the basis of insensible losses within the range 300–400 ml/m2/24 hours plus urinary output.
Be aware that the following symptoms are associated with acute hyponatraemia during IV fluid therapy:
Headache.
Nausea and vomiting.
Confusion and disorientation.
Irritability.
Lethargy.
Reduced consciousness.
Convulsions.
Coma.
Apnoea.
If acute symptomatic hyponatraemia develops in term neonates, children and young people, review the fluid status, seek immediate expert advice (for example, from the paediatric intensive care team) and consider taking action as follows:
Use a bolus of 2 ml/kg (maximum 100 ml) of 2.7% sodium chloride over 10–15 minutes.
Use a further bolus of 2 ml/kg (maximum 100 ml) of 2.7% sodium chloride over the next 10 to 15 minutes if symptoms are still present after the initial bolus.
If symptoms are still present after the second bolus, check the plasma sodium level and consider a third bolus of 2 ml/kg (maximum 100 ml) of 2.7% sodium chloride over 10 to 15 minutes.
Measure the plasma sodium concentration at least hourly.
As symptoms resolve, decrease the frequency of plasma sodium measurements based on the response to treatment.
Do not manage acute hyponatraemic encephalopathy using fluid restriction alone.
After hyponatraemia symptoms have resolved, ensure that the rate of increase of plasma sodium does not exceed 12 mmol/litre in a 24‑hour period.
# Training and education
For guidance on training and education for healthcare professionals involved in prescribing and delivering IV fluid therapy, see the training and education section of NICE's guideline on intravenous fluid therapy in adults.
## Algorithms for IV fluid therapy in children and young people in hospital
There is a PDF containing 6 algorithms for IV fluid therapy in children and young people in hospital.
## Diagram of ongoing losses for children and young people
There is a PDF diagram of ongoing losses for children and young people.
## Intravenous fluid types for children and young people
Note that fluids given are examples of appropriate fluids; for further details, see the BNFc information on fluids and electrolytes.
Fluid type
Osmolality (compared with plasma)
Tonicity (with reference to cell membrane)
Sodium content (mmol/litre)
Potassium content (mmol/litre)
% sodium chloride
Isosmolar
Isotonic
Hartmann's solution
Isosmolar
Isotonic
Fluid type
Osmolality (compared with plasma)
Tonicity (with reference to cell membrane)
Sodium content (mmol/litre)
Potassium content (mmol/litre)
% sodium chloride with 5% glucose
Hyperosmolar
Isotonic
Fluid type
Osmolality (compared with plasma)
Tonicity (with reference to cell membrane)
Sodium content (mmol/litre)
Potassium content (mmol/litre)
% sodium chloride with 5% glucose
Hyperosmolar
Hypotonic
% sodium chloride with 2.5% glucose
Isosmolar
Hypotonic
% sodium chloride
Hyposmolar
Hypotonic
% glucose
Isosmolar
Hypotonic
% glucose
Hyperosmolar
Hypotonic
# Terms used in this guideline
## Neonates, children and young people are defined as follows:
neonates: infants aged 28 days and under (born at term; or born prematurely who have a corrected age of term or more)
children: 29 days to under 12 years
young people: 12 to under 16 years.# Rationale
# Routine maintenance
Recommendation 1.4.7
In 2020 NICE checked whether the guideline needed updating and decided that it did not. When we consulted on this decision, concerns were raised about recommendation 1.4.7 on IV fluids for routine maintenance in term neonates. Specifically, that for term neonates in the first days of life, the sodium content may be too high and the glucose content too low. Evidence in this area was very limited when the guideline committee made the original recommendation in 2015, with no evidence at all in term neonates aged 0 to 48 hours. The committee therefore made a recommendation based on consensus.
We found no further evidence in this area in 2020. After discussion with topic experts, the recommendation has been revised to reduce the potential for incorrect use of isotonic crystalloids in the youngest neonates. We may revisit this area if we become aware of any relevant new evidence in future.
Return to recommendations# Context
Correct fluid and electrolyte balance is essential to maintain physiological function. Normally, children and young people get the fluid they need by drinking. Many children and young people admitted to hospital may be too ill to drink so may need intravenous (IV) fluid therapy to correct or maintain their fluid and electrolyte balance.
Children and young people may need IV fluids to account for losses of red blood cells, plasma, water or electrolytes beyond the usual losses in urine, stools and sweat. These losses can come from burns, diarrhoea, vomiting or leakage of fluid into the interstitial space. In these cases the aim is to replace any depleted fluids and restore electrolyte balance. Conditions such as cardiac dysfunction, liver disease, inappropriate antidiuretic hormone secretion and nephrotic syndrome can result in an excess of fluids in the body, known as fluid overload. If this happens, the aim is to rebalance and redistribute fluids and ensure the correct levels of electrolytes.
Whether IV fluid therapy is needed for fluid resuscitation, routine maintenance, replacement or redistribution, it is vital that the correct composition, volume and timing of IV fluid therapy is used. IV fluid types include colloids, crystalloids and combinations of fluids, and different types of fluids are appropriate for different situations (see the MHRA Drug Safety Alert for hydroxyethyl starch intravenous infusions). Errors in prescribing or administering IV fluids can result in inadequate or excessive provision, leading to hypovolaemia and poor organ perfusion, or hypervolaemia, oedema and heart failure. Failing to correct imbalances in electrolytes can lead to disturbances in intracellular or extracellular electrolyte balance, particularly in children and young people with reduced liver or kidney function. Failing to deliver correct fluids can therefore have a significant impact on morbidity and mortality.
Surveys have shown that many staff who prescribe IV fluids know neither the likely fluid and electrolyte needs of individual patients, nor the specific composition of the many choices of IV fluids available to them. There is little formal training and education in IV fluid management to support correct prescribing.
There is also a wide variation in the charts used to prescribe fluids and to record fluid and electrolyte status. Monitoring children and young people is often challenging: it may be difficult to assess urine output accurately, and blood tests can be painful, distressing and difficult to repeat. Assessment and monitoring is often suboptimal, and fluid and electrolyte status may not be recorded accurately. Changes in patients' fluid needs may not be reassessed appropriately or at the correct intervals, which can lead to fluids being prescribed incorrectly. Clinical staff need to ensure that appropriate identification, treatment and monitoring of changes in fluid and electrolyte status is maintained and documented. There is a need for a standardised approach to assessing patients' fluid and electrolyte status and prescribing IV fluid therapy in the NHS. This guidance represents a major opportunity to improve patient safety for children and young people having IV fluid therapy in hospital.# Recommendations for research
The guideline committee has made the following recommendations for research. The committee's full set of research recommendations is detailed in the full guideline.
# Complications of IV fluid therapy
What is the incidence of complications during, and as a consequence of, IV fluid therapy in children and young people?
## Why this is important
Every day, children and young people are prescribed IV fluid therapy for a variety of reasons. However, there is little evidence on IV fluids in children and young people, and the limited evidence available is of very poor quality.
Complications of IV fluid therapy can lead to mortality and significant morbidity for the patient. This, in turn, represents a cost burden for the NHS in terms of critical care admissions, prolonged inpatient stays or the potential need for long‑term follow‑up and care by medical and allied healthcare professionals.
# Glucose concentration
What is the most appropriate glucose concentration in IV fluids for children and young people of different ages?
## Why this is important
In recent years, the use of glucose‑containing hypotonic IV fluids in children and young people has been questioned, because of the risk of hyponatraemia. Many children and young people are now prescribed non‑glucose‑containing isotonic IV fluids for maintenance. However, there are several groups of children and young people, in particular, neonates and some children in the perioperative period (for example, those who underwent prolonged fasting preoperatively, and those who had central blocks during anaesthesia), who may benefit from glucose‑containing IV solutions to prevent hypoglycaemia. A blanket prescription of 5 or 10% glucose solution for all may result in hyperglycaemia in some children and young people. However, the use of IV fluids containing lower concentrations of glucose may be sufficient to prevent hypoglycaemia and also avoid unnecessary hyperglycaemia. This may have a clinical application across all age groups, including neonates.
# Fluid balance charts
For children and young people receiving IV fluids, does the use of a standardised national fluid balance chart reduce the rate of complications arising as a result of prescription and/or administration errors?
## Why this is important
The National Confidential Enquiry into Perioperative Deaths reports in 1999 and 2009 identified problems in fluid management in patients in the UK. A lack of consistency in prescribing and recording IV fluids may contribute to this. A lack of familiarity of 'mobile' medical and nursing staff with fluid balance charts in different hospital settings may further increase the likelihood of prescription and administration errors.
A prospective cohort of children and young people receiving IV fluids, prescribed and documented on a standardised national fluid balance chart, or a case–control study comparing the use of a standardised national fluid balance chart with non‑standard 'local' fluid balance charts is needed to assess the clinical and cost effectiveness of using a standardised national fluid balance chart. Outcomes should include complications of IV fluid therapy (hypovolaemia, hypervolaemia, electrolyte abnormalities, neurological complications and hypoglycaemia) and incidence of prescription errors. If using a standardised national fluid balance chart resulted in better fluid prescription and clinical outcomes in children and young people, this could potentially lead to significant cost savings for the NHS.
# Training and education of healthcare professionals
Does ensuring that all hospital healthcare professionals involved in prescribing and delivering IV fluids for children and young people are appropriately trained in the principles of fluid prescribing and IV fluid therapy‑related complications lead to a reduction in IV fluid‑related complications and associated healthcare costs?
## Why this is important
Assessing patients' IV fluid needs, as well as prescribing and delivering IV fluids, are essential daily tasks on most paediatric wards. These are complex responsibilities that entail careful clinical assessment, good understanding of the physiology of fluid homeostasis both in health and disease, and appropriate supervision and training. There is currently no standard training provided for healthcare professionals working in the UK. Any teaching at both undergraduate and postgraduate level is currently delivered ad hoc, and in many cases may be limited. If fluid management in hospitalised children and young people is to improve, standardised training is likely to be needed. Any educational interventions made would need to be evaluated to assess whether practice had subsequently improved.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Principles and protocols for intravenous fluid therapy\n\nFor guidance on the principles and protocols for intravenous (IV) fluid therapy, see the principles and protocols for intravenous fluid therapy section in NICE's guideline on intravenous fluid therapy in adults (recommendations\xa01.1.1, 1.1.2, 1.1.3,\xa01.1.5, 1.1.6, 1.1.7 and 1.1.8 apply to all ages).\n\nOffer IV fluid therapy as part of a protocol (see algorithms for IV fluid therapy in children and young people in hospital):\n\nAssess fluid and electrolyte needs following algorithm\xa01: Assessment and monitoring.\n\nIf term neonates, children and young people need IV fluids for fluid resuscitation, follow algorithm\xa02: Fluid resuscitation.\n\nIf term neonates, children and young people need IV fluids for routine maintenance, follow algorithm\xa03: Routine maintenance.\n\nIf term neonates, children and young people need IV fluids to address existing deficits or excesses, ongoing abnormal losses or abnormal fluid distribution, follow algorithm\xa04: Replacement and redistribution.\n\nIf hypernatraemia develops, follow algorithm\xa05: Managing hypernatraemia that develops during IV fluid therapy.\n\nIf hyponatraemia develops, follow algorithm\xa06: Managing hyponatraemia that develops during IV fluid therapy.\n\n# Assessment and monitoring\n\nUse body weight to calculate IV fluid and electrolyte needs for term neonates, children and young people.\n\nConsider using body surface area to calculate IV fluid and electrolyte needs if accurate calculation of insensible losses is important (for example, if the weight is above the 91st\xa0centile, or with acute kidney injury, known chronic kidney disease or cancer).\n\nIn term neonates, children and young people who are receiving IV fluids, assess and document the following:\n\nActual or estimated daily body weight. Record the weight from the current day, the previous day, and the difference between the two. If an estimate was used, the actual weight should be measured as soon as clinically possible.\n\nFluid input, output and balance over the previous 24\xa0hours.\n\nAny special instructions for prescribing, including relevant history.\n\nAn assessment of the fluid status.\n\nThe results of laboratory and point‑of‑care assessments, including:\n\n\n\nfull blood count\n\nurea\n\ncreatinine\n\nplasma electrolyte concentrations (including chloride, sodium and potassium; see recommendation\xa01.2.4)\n\nblood glucose (see recommendation\xa01.2.5)\n\nurinary electrolyte concentrations.\n\n\n\nDetails of any ongoing losses (see recommendation\xa01.5.1 and the diagram of ongoing losses).\n\nCalculations of fluid needs for routine maintenance, replacement, redistribution and resuscitation.\n\nThe fluid and electrolyte prescription (in ml per hour), with clear signatures, dates and times.\n\nTypes and volumes of fluid input and output (urine, gastric and other), recorded hourly and with running totals.\n\n-hourly fluid balance subtotals.\n\n-hourly fluid balance totals.\n\n-hourly reassessments of:\n\n\n\nthe fluid prescription\n\ncurrent hydration status\n\nwhether oral fluids can be started\n\nurine and other outputs.\n\n\n\nMeasure plasma electrolyte concentrations using laboratory tests when starting IV fluids, and then at least every 24\xa0hours or more frequently if there are electrolyte disturbances.\n\nMeasure blood glucose when starting IV fluids, and then at least every 24\xa0hours or more frequently if there is a risk of hypoglycaemia.\n\nConsider point-of-care testing for measuring plasma electrolyte concentrations and blood glucose in time‑critical situations when IV fluids are needed (for example, during emergency situations and in A&E, theatre and critical care).\n\nDiagnose clinical dehydration and hypovolaemic shock using the clinical features listed in table\xa01, but be aware that it can be difficult to identify the clinical features in term neonates.\n\nNo clinically detectable dehydration\n\nClinical dehydration\n\nHypovolaemic shock\n\nAlert and responsive\n\nRed flag\n\nAltered responsiveness (for example, irritable, lethargic)\n\nDecreased level of consciousness\n\nAppears well\n\nRed flag\n\nAppears to be unwell or deteriorating\n\n–\n\nEyes not sunken\n\nRed flag\n\nSunken eyes\n\n–\n\nMoist mucous membranes (except after a drink)\n\nDry mucous membranes (except for 'mouth breather')\n\n–\n\nNormal blood pressure\n\nNormal blood pressure\n\nHypotension (decompensated shock)\n\nNormal breathing pattern\n\nRed flag\n\nTachypnoea\n\nTachypnoea\n\nNormal capillary refill time\n\nNormal capillary refill time\n\nProlonged capillary refill time\n\nNormal heart rate\n\nRed flag\n\nTachycardia\n\nTachycardia\n\nNormal peripheral pulses\n\nNormal peripheral pulses\n\nWeak peripheral pulses\n\nNormal skin turgor\n\nRed flag\n\nReduced skin turgor\n\n–\n\nNormal urine output\n\nDecreased urine output\n\n–\n\nSkin colour unchanged\n\nSkin colour unchanged\n\nPale or mottled skin\n\nWarm extremities\n\nWarm extremities\n\nCold extremities\n\nNotes:\n\nWithin the category of 'clinical dehydration' there is a spectrum of severity indicated by increasingly numerous and more pronounced clinical features. For hypovolaemic shock, 1 or more of the clinical features listed would be expected to be present. Dashes (–) indicate that these features do not specifically indicate hypovolaemic shock. This table has been adapted from the assessing dehydration and shock section of NICE's guideline on diarrhoea and vomiting in children.\n\n# Fluid resuscitation\n\nIf children and young people need IV fluid resuscitation, use glucose‑free crystalloids that contain sodium in the range 131–154\xa0mmol/litre, with a bolus of 10\xa0ml/kg over less than 10\xa0minutes. Take into account pre‑existing conditions (for example, cardiac disease or kidney disease), as smaller fluid volumes may be needed.Note that this is an off-label use for some intravenous fluid therapy preparations in some age groups. See prescribing medicines for more information.\n\nIf term neonates need IV fluid resuscitation, use glucose‑free crystalloids that contain sodium in the range 131–154\xa0mmol/litre, with a bolus of 10–20\xa0ml/kg over less than\xa010\xa0minutes.Note that this is an off-label use for some intravenous fluid therapy preparations in some age groups. See prescribing medicines for more information.\n\nDo not use tetrastarch for fluid resuscitation.\n\nFor guidance on using IV fluids for fluid resuscitation in children and young people with diabetic ketoacidosis, see the diabetic ketoacidosis section of NICE's guideline on diabetes (type\xa01 and type\xa02) in children and young people.\n\nReassess term neonates, children and young people after completion of the IV fluid bolus, and decide whether they need more fluids.\n\nSeek expert advice (for example, from the paediatric intensive care team) if 40–60\xa0ml/kg of IV fluid or more is needed as part of the initial fluid resuscitation.\n\n# Routine maintenance\n\nCalculate routine maintenance IV fluid rates for children and young people using the Holliday–Segar formula (100\xa0ml/kg/day for the first 10\xa0kg of weight, 50\xa0ml/kg/day for the next 10\xa0kg and 20\xa0ml/kg/day for the weight over 20\xa0kg). Be aware that over a 24‑hour period, males rarely need more than 2,500\xa0ml and females rarely need more than 2,000\xa0ml of fluids.\n\nCalculate routine maintenance IV fluid rates for term neonates according to their age, using the following as a guide:\n\nFrom birth to day\xa01: 50\xa0to\xa060\xa0ml/kg/day.\n\nDay\xa02: 70 \xa0to\xa080\xa0ml/kg/day.\n\nDay\xa03: 80\xa0to\xa0100\xa0ml/kg/day.\n\nDay\xa04: 100\xa0to\xa0120\xa0ml/kg/day.\n\nDays\xa05 to 28: 120\xa0to\xa0150\xa0ml/kg/day.\n\nIf children and young people need IV fluids for routine maintenance, initially use isotonic crystalloids that contain sodium in the range 131\xa0to\xa0154\xa0mmol/litre.Note that this is an off-label use for some intravenous fluid therapy preparations in some age groups. See prescribing medicines for more information.\n\nMeasure plasma electrolyte concentrations and blood glucose when starting IV fluids for routine maintenance (except before most elective surgery), and at least every 24\xa0hours thereafter.\n\nBe aware that plasma electrolyte concentrations and blood glucose are not routinely measured before elective surgery unless there is a need to do so, based on the child's medical condition or the type of surgery.\n\nBase any subsequent IV fluid prescriptions on the plasma electrolyte concentrations and blood glucose measurements.\n\nIf term neonates aged 8\xa0days or over need IV fluids for routine maintenance, initially use isotonic crystalloids that contain sodium in the range 131–154\xa0mmol/litre with 5–10% glucose. For term neonates aged up to 7 days, use professional judgement, taking into account:\n\nthe individual circumstances, and\n\nfor term neonates in the first days of life, a sodium content of 131 to 154 mmol/litre may be too high (or sodium may not be needed) and a glucose content of 5% to 10% may be too low. Note that this is an off-label use for some intravenous fluid therapy preparations in some age groups. See prescribing medicines for more information. [amended 2020]\n\nFor term neonates in critical postnatal adaptation phase (for example, term neonates with respiratory distress syndrome, meconium aspiration, hypoxic ischaemic encephalopathy), give no or minimal sodium until postnatal diuresis with weight loss occurs.\n\nIf there is a risk of water retention associated with non‑osmotic antidiuretic hormone (ADH) secretion, consider either:\n\nrestricting fluids to 50% to 80% of routine maintenance needs or\n\nreducing fluids, calculated on the basis of insensible losses within the range 300–400\xa0ml/m2/24\xa0hours plus urinary output.\n\nWhen using body surface area to calculate IV fluid needs for routine maintenance (see recommendation\xa01.2.2), estimate insensible losses within the range 300–400\xa0ml/m2/24\xa0hours plus urinary output.\n\nFor a short explanation of why the committee made the 2020 change to recommendation 1.4.7, see the rationale on routine maintenance\xa0.\n\nLoading. Please wait.\n\n# Replacement and redistribution\n\nIf term neonates, children and young people need IV fluids for replacement or redistribution, adjust the IV fluid prescription (in addition to maintenance needs) to account for existing fluid and/or electrolyte deficits or excesses, ongoing losses (see the diagram of ongoing losses) or abnormal distribution, for example, tissue oedema seen in sepsis.\n\nConsider isotonic crystalloids that contain sodium in the range 131 to 154\xa0mmol/litre for redistribution. Note that this is an off-label use for some intravenous fluid therapy preparations in some age groups. See prescribing medicines for more information.\n\nUse 0.9% sodium chloride containing potassium to replace ongoing losses (see the diagram of ongoing losses).\n\nBase any subsequent fluid prescriptions on the plasma electrolyte concentrations and blood glucose measurements.\n\n# Managing hypernatraemia that develops during intravenous fluid therapy\n\nIf hypernatraemia develops in term neonates, children and young people, review the fluid status and take action as follows:\n\nIf there is no evidence of dehydration and an isotonic fluid is being used, consider changing to a hypotonic fluid (for example, 0.45% sodium chloride with glucose). Note that this is an off-label use for some intravenous fluid therapy preparations in some age groups. See prescribing medicines for more information.\n\nIf dehydration is diagnosed, calculate the water deficit and replace it over 48\xa0hours, initially with 0.9% sodium chloride.\n\nIf the fluid status is uncertain, measure urine sodium and osmolality.\n\nIf hypernatraemia worsens or is unchanged after replacing the deficit, review the fluid type and consider changing to a hypotonic solution (for example, 0.45% sodium chloride with glucose).\n\nWhen correcting hypernatraemia, ensure that the rate of fall of plasma sodium does not exceed 12\xa0mmol/litre in a 24‑hour period.\n\nMeasure plasma electrolyte concentrations every 4 to 6\xa0hours for the first 24\xa0hours, and after this base the frequency of further plasma electrolyte measurements on the treatment response.\n\n# Managing hyponatraemia that develops during intravenous fluid therapy\n\nIf asymptomatic hyponatraemia develops in term neonates, children and young people, review the fluid status and take action as follows:\n\nIf a child is prescribed a hypotonic fluid, change to an isotonic fluid (for example, 0.9% sodium chloride).\n\nRestrict maintenance IV fluids in children and young people who are hypervolaemic or at risk of hypervolaemia (for example, if there is a risk of increased ADH secretion) by either:\n\n\n\nrestricting maintenance fluids to 50% to 80% of routine maintenance needs or\n\n\n\nreducing fluids, calculated on the basis of insensible losses within the range 300–400\xa0ml/m2/24\xa0hours plus urinary output.\n\nBe aware that the following symptoms are associated with acute hyponatraemia during IV fluid therapy:\n\nHeadache.\n\nNausea and vomiting.\n\nConfusion and disorientation.\n\nIrritability.\n\nLethargy.\n\nReduced consciousness.\n\nConvulsions.\n\nComa.\n\nApnoea.\n\nIf acute symptomatic hyponatraemia develops in term neonates, children and young people, review the fluid status, seek immediate expert advice (for example, from the paediatric intensive care team) and consider taking action as follows:\n\nUse a bolus of 2\xa0ml/kg (maximum 100\xa0ml) of 2.7% sodium chloride over 10–15\xa0minutes.\n\nUse a further bolus of 2\xa0ml/kg (maximum 100\xa0ml) of 2.7% sodium chloride over the next 10 to 15\xa0minutes if symptoms are still present after the initial bolus.\n\nIf symptoms are still present after the second bolus, check the plasma sodium level and consider a third bolus of 2\xa0ml/kg (maximum 100\xa0ml) of 2.7% sodium chloride over 10\xa0to\xa015\xa0minutes.\n\nMeasure the plasma sodium concentration at least hourly.\n\nAs symptoms resolve, decrease the frequency of plasma sodium measurements based on the response to treatment.\n\nDo not manage acute hyponatraemic encephalopathy using fluid restriction alone.\n\nAfter hyponatraemia symptoms have resolved, ensure that the rate of increase of plasma sodium does not exceed 12\xa0mmol/litre in a 24‑hour period.\n\n# Training and education\n\nFor guidance on training and education for healthcare professionals involved in prescribing and delivering IV fluid therapy, see the training and education section of NICE's guideline on intravenous fluid therapy in adults.\n\n## Algorithms for IV fluid therapy in children and young people in hospital\n\nThere is a PDF containing 6 algorithms for IV fluid therapy in children and young people in hospital.\n\n## Diagram of ongoing losses for children and young people\n\nThere is a PDF diagram of ongoing losses for children and young people.\n\n## Intravenous fluid types for children and young people\n\nNote that fluids given are examples of appropriate fluids; for further details, see the BNFc information on fluids and electrolytes.\n\nFluid type\n\nOsmolality (compared with plasma)\n\nTonicity (with reference to cell membrane)\n\nSodium content (mmol/litre)\n\nPotassium content (mmol/litre)\n\n% sodium chloride\n\nIsosmolar\n\nIsotonic\n\n\n\n\n\nHartmann's solution\n\nIsosmolar\n\nIsotonic\n\n\n\n\n\nFluid type\n\nOsmolality (compared with plasma)\n\nTonicity (with reference to cell membrane)\n\nSodium content (mmol/litre)\n\nPotassium content (mmol/litre)\n\n% sodium chloride with 5% glucose\n\nHyperosmolar\n\nIsotonic\n\n\n\n\n\nFluid type\n\nOsmolality (compared with plasma)\n\nTonicity (with reference to cell membrane)\n\nSodium content (mmol/litre)\n\nPotassium content (mmol/litre)\n\n% sodium chloride with 5% glucose\n\nHyperosmolar\n\nHypotonic\n\n\n\n\n\n% sodium chloride with 2.5% glucose\n\nIsosmolar\n\nHypotonic\n\n\n\n\n\n% sodium chloride\n\nHyposmolar\n\nHypotonic\n\n\n\n\n\n% glucose\n\nIsosmolar\n\nHypotonic\n\n\n\n\n\n% glucose\n\nHyperosmolar\n\nHypotonic\n\n\n\n\n\n# Terms used in this guideline\n\n## Neonates, children and young people are defined as follows:\n\nneonates: infants aged 28\xa0days and under (born at term; or born prematurely who have a corrected age of term or more)\n\nchildren: 29\xa0days to under 12\xa0years\n\nyoung people: 12 to under 16\xa0years.", 'Rationale': '# Routine maintenance\n\nRecommendation 1.4.7\n\nIn 2020 NICE checked whether the guideline needed updating and decided that it did not. When we consulted on this decision, concerns were raised about recommendation 1.4.7 on IV fluids for routine maintenance in term neonates. Specifically, that for term neonates in the first days of life, the sodium content may be too high and the glucose content too low. Evidence in this area was very limited when the guideline committee made the original recommendation in 2015, with no evidence at all in term neonates aged 0 to 48\xa0hours. The committee therefore made a recommendation based on consensus.\n\nWe found no further evidence in this area in 2020. After discussion with topic experts, the recommendation has been revised to reduce the potential for incorrect use of isotonic crystalloids in the youngest neonates. We may revisit this area if we become aware of any relevant new evidence in future.\n\nReturn to recommendations', 'Context': "Correct fluid and electrolyte balance is essential to maintain physiological function. Normally, children and young people get the fluid they need by drinking. Many children and young people admitted to hospital may be too ill to drink so may need intravenous (IV) fluid therapy to correct or maintain their fluid and electrolyte balance.\n\nChildren and young people may need IV fluids to account for losses of red blood cells, plasma, water or electrolytes beyond the usual losses in urine, stools and sweat. These losses can come from burns, diarrhoea, vomiting or leakage of fluid into the interstitial space. In these cases the aim is to replace any depleted fluids and restore electrolyte balance. Conditions such as cardiac dysfunction, liver disease, inappropriate antidiuretic hormone secretion and nephrotic syndrome can result in an excess of fluids in the body, known as fluid overload. If this happens, the aim is to rebalance and redistribute fluids and ensure the correct levels of electrolytes.\n\nWhether IV fluid therapy is needed for fluid resuscitation, routine maintenance, replacement or redistribution, it is vital that the correct composition, volume and timing of IV fluid therapy is used. IV fluid types include colloids, crystalloids and combinations of fluids, and different types of fluids are appropriate for different situations (see the MHRA Drug Safety Alert for hydroxyethyl starch intravenous infusions). Errors in prescribing or administering IV fluids can result in inadequate or excessive provision, leading to hypovolaemia and poor organ perfusion, or hypervolaemia, oedema and heart failure. Failing to correct imbalances in electrolytes can lead to disturbances in intracellular or extracellular electrolyte balance, particularly in children and young people with reduced liver or kidney function. Failing to deliver correct fluids can therefore have a significant impact on morbidity and mortality.\n\nSurveys have shown that many staff who prescribe IV fluids know neither the likely fluid and electrolyte needs of individual patients, nor the specific composition of the many choices of IV fluids available to them. There is little formal training and education in IV fluid management to support correct prescribing.\n\nThere is also a wide variation in the charts used to prescribe fluids and to record fluid and electrolyte status. Monitoring children and young people is often challenging: it may be difficult to assess urine output accurately, and blood tests can be painful, distressing and difficult to repeat. Assessment and monitoring is often suboptimal, and fluid and electrolyte status may not be recorded accurately. Changes in patients' fluid needs may not be reassessed appropriately or at the correct intervals, which can lead to fluids being prescribed incorrectly. Clinical staff need to ensure that appropriate identification, treatment and monitoring of changes in fluid and electrolyte status is maintained and documented. There is a need for a standardised approach to assessing patients' fluid and electrolyte status and prescribing IV fluid therapy in the NHS. This guidance represents a major opportunity to improve patient safety for children and young people having IV fluid therapy in hospital.", 'Recommendations for research': "The guideline committee has made the following recommendations for research. The committee's full set of research recommendations is detailed in the full guideline.\n\n# Complications of IV fluid therapy\n\nWhat is the incidence of complications during, and as a consequence of, IV fluid therapy in children and young people?\n\n## Why this is important\n\nEvery day, children and young people are prescribed IV fluid therapy for a variety of reasons. However, there is little evidence on IV fluids in children and young people, and the limited evidence available is of very poor quality.\n\nComplications of IV fluid therapy can lead to mortality and significant morbidity for the patient. This, in turn, represents a cost burden for the NHS in terms of critical care admissions, prolonged inpatient stays or the potential need for long‑term follow‑up and care by medical and allied healthcare professionals.\n\n# Glucose concentration\n\nWhat is the most appropriate glucose concentration in IV fluids for children and young people of different ages?\n\n## Why this is important\n\nIn recent years, the use of glucose‑containing hypotonic IV fluids in children and young people has been questioned, because of the risk of hyponatraemia. Many children and young people are now prescribed non‑glucose‑containing isotonic IV fluids for maintenance. However, there are several groups of children and young people, in particular, neonates and some children in the perioperative period (for example, those who underwent prolonged fasting preoperatively, and those who had central blocks during anaesthesia), who may benefit from glucose‑containing IV solutions to prevent hypoglycaemia. A blanket prescription of 5 or 10% glucose solution for all may result in hyperglycaemia in some children and young people. However, the use of IV fluids containing lower concentrations of glucose may be sufficient to prevent hypoglycaemia and also avoid unnecessary hyperglycaemia. This may have a clinical application across all age groups, including neonates.\n\n# Fluid balance charts\n\nFor children and young people receiving IV fluids, does the use of a standardised national fluid balance chart reduce the rate of complications arising as a result of prescription and/or administration errors?\n\n## Why this is important\n\nThe National Confidential Enquiry into Perioperative Deaths reports in 1999 and 2009 identified problems in fluid management in patients in the UK. A lack of consistency in prescribing and recording IV fluids may contribute to this. A lack of familiarity of 'mobile' medical and nursing staff with fluid balance charts in different hospital settings may further increase the likelihood of prescription and administration errors.\n\nA prospective cohort of children and young people receiving IV fluids, prescribed and documented on a standardised national fluid balance chart, or a case–control study comparing the use of a standardised national fluid balance chart with non‑standard 'local' fluid balance charts is needed to assess the clinical and cost effectiveness of using a standardised national fluid balance chart. Outcomes should include complications of IV fluid therapy (hypovolaemia, hypervolaemia, electrolyte abnormalities, neurological complications and hypoglycaemia) and incidence of prescription errors. If using a standardised national fluid balance chart resulted in better fluid prescription and clinical outcomes in children and young people, this could potentially lead to significant cost savings for the NHS.\n\n# Training and education of healthcare professionals\n\nDoes ensuring that all hospital healthcare professionals involved in prescribing and delivering IV fluids for children and young people are appropriately trained in the principles of fluid prescribing and IV fluid therapy‑related complications lead to a reduction in IV fluid‑related complications and associated healthcare costs?\n\n## Why this is important\n\nAssessing patients' IV fluid needs, as well as prescribing and delivering IV fluids, are essential daily tasks on most paediatric wards. These are complex responsibilities that entail careful clinical assessment, good understanding of the physiology of fluid homeostasis both in health and disease, and appropriate supervision and training. There is currently no standard training provided for healthcare professionals working in the UK. Any teaching at both undergraduate and postgraduate level is currently delivered ad hoc, and in many cases may be limited. If fluid management in hospitalised children and young people is to improve, standardised training is likely to be needed. Any educational interventions made would need to be evaluated to assess whether practice had subsequently improved."}
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https://www.nice.org.uk/guidance/ng29
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This guideline covers general principles for managing intravenous (IV) fluids for children and young people under 16 years, including assessing fluid and electrolyte status and prescribing IV fluid therapy. It applies to a range of conditions and different settings. It does not include recommendations relating to specific conditions. This guideline represents a major opportunity to improve patient safety for children and young people having IV fluid therapy in hospital.
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df0703144d6dd72f5bcf6fd5aa8e111055ed66b4
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nice
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Trastuzumab emtansine for adjuvant treatment of HER2-positive early breast cancer
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Trastuzumab emtansine for adjuvant treatment of HER2-positive early breast cancer
Evidence-based recommendations on trastuzumab emtansine (Kadcyla) for human epidermal growth factor receptor 2 (HER2)‑positive early breast cancer in adults who have residual invasive disease in the breast or lymph nodes after neoadjuvant taxane-based and HER2‑targeted therapy.
# Recommendations
Trastuzumab emtansine is recommended, within its marketing authorisation, as an option for the adjuvant treatment of human epidermal growth factor receptor 2 (HER2)‑positive early breast cancer in adults who have residual invasive disease in the breast or lymph nodes after neoadjuvant taxane-based and HER2‑targeted therapy. It is recommended only if the company provides trastuzumab emtansine according to the commercial arrangement.
Why the committee made these recommendations
Neoadjuvant therapy aims to reduce the size of the tumour before surgery. It sometimes shrinks completely, but people may still have cancer remaining when they have their surgery (residual invasive disease). The cancer may have spread to lymph nodes in the armpit (node-positive disease).
Adjuvant treatment aims to reduce the risk of cancer returning after surgery. Trastuzumab is an adjuvant treatment for people with node-negative or node-positive disease. Pertuzumab plus trastuzumab with chemotherapy is an adjuvant treatment for node-positive disease but not for node-negative disease. Trastuzumab emtansine would be an alternative adjuvant treatment for people with node-negative or node-positive disease.
Clinical trial evidence shows that in people with residual invasive disease after neoadjuvant therapy and surgery, trastuzumab emtansine increases the time people remain free of disease compared with trastuzumab alone. We do not know if trastuzumab emtansine increases the length of time people live because the final trial results are not yet available. An indirect comparison in people with node-positive disease suggests that trastuzumab emtansine increases the time until cancer progresses compared with pertuzumab plus trastuzumab with chemotherapy, but this is uncertain because there are differences between people in the 2 trials.
The cost-effectiveness estimates are within what NICE considers an acceptable use of NHS resources. Therefore, trastuzumab emtansine is recommended.# Information about trastuzumab emtansine
# Marketing authorisation indication
Trastuzumab emtansine (Kadcyla, Roche), as a single agent, is indicated for 'the adjuvant treatment of adult patients with HER2‑positive early breast cancer who have residual invasive disease, in the breast and/or lymph nodes, after neoadjuvant taxane-based and HER2‑targeted therapy'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
Trastuzumab emtansine costs £1,641.01 per 100‑mg vial and £2,625.62 per 160‑mg vial (powder for solution for infusion; excluding VAT; British national formulary online, accessed March 2020). The company has a commercial arrangement. This makes trastuzumab emtansine available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Roche, a review of this submission by the evidence review group (ERG), the technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed:
Invasive disease-free survival extrapolation: The company's original approach overestimated invasive disease-free survival for trastuzumab during the observed period of the KATHERINE trial. The ERG suggested that using the Kaplan–Meier data plus extrapolation is more appropriate. The company adopted the ERG's approach after technical engagement in its base case (issue 3, see technical report pages 18 to 25).
Drug costs and modelling assumptions: The company's assumptions in its original submission followed those used in NICE's guidance on adjuvant treatment with pertuzumab. These were validated during technical engagement. No changes were made after technical engagement (issue 6, see technical report pages 31 to 33).
Modelling the intention-to-treat (ITT) population: The company updated the ITT population model after technical engagement and provided supportive results for a comparison of trastuzumab emtansine against pertuzumab plus trastuzumab with chemotherapy, and against trastuzumab-based therapy using the ITT population (issue 7, see technical report page 34).
Modelling the lymph node positive population: The company updated the lymph node positive population model with population-specific data after technical engagement (issue 8, see technical report pages 34 to 37).The committee recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, table 2, page 42), and took these into account in its decision making. It discussed the following issues (issues 1, 2, 4 and 5), which were outstanding after the technical engagement stage.
# Treatment pathway
## Trastuzumab emtansine is a new adjuvant treatment for people with residual invasive disease after neoadjuvant therapy
Human epidermal growth factor receptor 2 (HER2)‑positive breast cancer has a considerable effect on patients and their families. In early HER2‑positive breast cancer, neoadjuvant treatment may be used to eradicate or reduce tumour size before surgery. NICE recommends pertuzumab for the neoadjuvant treatment of HER2-positive breast cancer, with trastuzumab and chemotherapy, for locally advanced, inflammatory or early breast cancer at high risk of recurrence. The patient expert explained that when residual disease is found during surgery this is a disappointing outcome, and preventing the cancer returning is very important to patients. After surgery, adjuvant treatment is used to reduce the risk of recurrence. NICE recommends pertuzumab for adjuvant treatment of HER2-positive early stage breast cancer, with trastuzumab and chemotherapy, in adults who have lymph node positive disease. People with lymph node negative disease are offered adjuvant trastuzumab, in line with NICE's guideline on early breast cancer. Trastuzumab emtansine is a new adjuvant treatment for HER2‑positive early breast cancer for people who have residual invasive disease after neoadjuvant therapy. It can be offered to people with node-positive or node-negative disease.
## There is a clinical need for an additional treatment for people who have residual disease after neoadjuvant therapy
The clinical experts explained that people who have residual invasive disease after neoadjuvant therapy are considered to be at higher risk of disease recurrence than those who have a pathological complete response (that is, no residual invasive disease was found during surgery). Most people with HER2‑positive early breast cancer have pertuzumab with trastuzumab and chemotherapy as neoadjuvant treatment. The clinical experts explained that a complete pathological response after neoadjuvant pertuzumab and trastuzumab is considered to show that the disease is sensitive to this combination, and the patient would benefit from having it again in the adjuvant setting. However, residual invasive disease after neoadjuvant treatment with pertuzumab and trastuzumab is considered to show that the disease is resistant to this treatment, and the patient would benefit from an alternative treatment such as trastuzumab emtansine. The committee concluded that there is an unmet clinical need for an additional adjuvant therapy for people who have residual disease after neoadjuvant therapy.
# Clinical evidence
## Trastuzumab emtansine improves invasive disease-free survival compared with trastuzumab
KATHERINE (n=1,486) is an open-label, randomised, multicentre trial of adjuvant trastuzumab emtansine compared with adjuvant trastuzumab, in people with HER2‑positive early breast cancer who had residual invasive disease after trastuzumab-based neoadjuvant therapy with chemotherapy. Invasive disease-free survival was the primary outcome. In the trial, about 20% of people had neoadjuvant pertuzumab plus trastuzumab and 80% had neoadjuvant trastuzumab. The clinical experts considered that the trial results are generalisable to clinical practice, although in clinical practice most people would have pertuzumab plus trastuzumab as neoadjuvant therapy. They also noted that the hazard ratios for invasive disease-free survival were very similar for people who had had trastuzumab previously and those who had pertuzumab plus trastuzumab. The hazard ratio for invasive disease-free survival for the ITT population was 0.50 (95% confidence interval 0.39 to 0.62). The hazard ratio for invasive disease-free survival for the lymph node negative population (n=689), who would have trastuzumab in clinical practice, was 0.44 (95% CI 0.28 to 0.68). For node-positive disease (n=797), the hazard ratio was 0.52 (95% CI 0.38 to 0.71). Interim overall-survival results are available, however the data are immature. The committee concluded that trastuzumab emtansine improves invasive disease-free survival compared with trastuzumab. However, it is not known whether trastuzumab emtansine increases the length of time people live because the data are immature.
# Indirect comparison of trastuzumab emtansine against pertuzumab plus trastuzumab and chemotherapy
## The estimates are uncertain but appropriate for decision making
No study directly compared trastuzumab emtansine with pertuzumab plus trastuzumab with chemotherapy. The company therefore did an indirect comparison using data from KATHERINE and the APHINITY trial. APHINITY (n=4,804) is a double-blind, randomised, multicentre trial of adjuvant pertuzumab plus trastuzumab and chemotherapy compared with adjuvant placebo with trastuzumab and chemotherapy, in people with HER2‑positive early breast cancer who had not had neoadjuvant therapy. Because adjuvant treatment with pertuzumab plus trastuzumab and chemotherapy is only recommended for people who have lymph node positive disease, a subgroup of people with lymph node positive disease from KATHERINE (n=689) and APHINITY (n=3,006) was used for the comparison. The indirect comparison hazard ratio for invasive disease-free survival in the node-positive subgroup was 0.722 (95% CI 0.50 to 1.04). Both the company and the ERG considered the results uncertain because all patients in KATHERINE had residual invasive disease after neoadjuvant therapy, whereas patients in APHINITY had not had neoadjuvant therapy before surgery. However, they agreed that the results represented the best available evidence for trastuzumab emtansine compared with pertuzumab plus trastuzumab and chemotherapy. The clinical experts considered that the indirect comparison results may be a conservative estimate because in KATHERINE people had already had a suboptimal response to neoadjuvant therapy and were therefore preselected to be at higher risk. The committee concluded that the results of the indirect comparison for trastuzumab emtansine compared with pertuzumab plus trastuzumab and chemotherapy are uncertain, but they are suitable for decision making.
# Treatment-waning effect of trastuzumab emtansine
## The ERG's approach is uncertain but appropriate for decision making
Before technical engagement the company assumed that trastuzumab emtansine's treatment effect is maintained for 7 years, then gradually decreases to no treatment effect at 10 years. The ERG agreed with the company that the treatment effect lasts beyond the KATHERINE follow-up time. However, it used annualised hazard ratios from KATHERINE to estimate the start and end of treatment waning. In the ERG's approach, the trastuzumab emtansine treatment effect is maintained for 3 years, then gradually decreases to no treatment effect at 8 years. The company considered the ERG's approach to be conservative because updated data from APHINITY suggest that benefit from adjuvant pertuzumab is still present at 6 years. However, it adopted the ERG's approach after technical engagement. The company noted that all its exploratory analyses, with varied assumptions about the duration of treatment effect, resulted in cost-effectiveness estimates within the acceptable range. The committee accepted the ERG's approach of using KATHERINE data and was reassured by the company's exploratory analyses. It concluded that although the duration of the treatment effect is currently unknown, the ERG's approach is suitable for decision making.
# Utilities
## The utilities are appropriate for decision making
The company used utility values from KATHERINE for invasive disease-free survival. No significant difference was found between the results for trastuzumab emtansine and for trastuzumab, therefore the values were pooled. This assumes that people having either treatment have the same health-related quality of life. KATHERINE did not collect utilities for people who had metastatic recurrence, so the company used Lloyd et al. (2006) utilities for progressed disease because this study has been used in previous appraisals. The ERG noted that the model did not include any disutilities for adverse effects. It preferred to use individual treatment utilities for invasive disease-free survival to capture any differences between the 2 treatments. Also, it preferred to use Lidgren et al. (2007) for metastatic states, because these correspond more closely to the NICE reference case than Lloyd et al. After technical engagement, the company adopted the ERG's approach. The committee noted that both Lloyd et al. and Lidgren et al. have been used in previous NICE appraisals. However, it favoured the ERG's approach. It concluded that the utilities from KATHERINE, calculated per treatment for invasive disease-free survival, and the Lidgren et al. utilities for metastatic states were suitable for decision making.
# Cost-effectiveness estimates
## The ICERs for trastuzumab emtansine compared with trastuzumab are within what NICE considers acceptable
After technical engagement, the company's preferred incremental cost-effectiveness ratio (ICER) for trastuzumab emtansine compared with trastuzumab in the node-negative population was £8,829 per quality-adjusted life year (QALY) gained. The ERG agreed with the company's revised base case in this population. The company provided supportive data from the ITT population of KATHERINE. The ICER in the ITT population was £5,985 per QALY gained. The ERG preferred extrapolating invasive disease-free survival using Kaplan–Meier data and a generalised gamma curve, instead of the company's preference of Kaplan–Meier data and an exponential curve. The ERG's preferred ICER for the ITT population was £7,213 per QALY gained. These estimates include commercial arrangements for trastuzumab emtansine, trastuzumab and an assumed discount for trastuzumab biosimilars of 70%. Estimates that include all commercial arrangements remained within the range NICE normally considers an acceptable use of NHS resources.
## The ICERs for trastuzumab emtansine compared with pertuzumab plus trastuzumab with chemotherapy are within what NICE considers acceptable
After technical engagement, the company's preferred ICER for trastuzumab emtansine compared with pertuzumab plus trastuzumab and chemotherapy in the node-positive population was £4,955 per QALY gained. The model assumed that chemotherapy would have been given in the neoadjuvant setting and therefore no chemotherapy cost was included as part of the adjuvant pertuzumab plus trastuzumab treatment. The ERG agreed with the company's revised base case in this population. The company provided supportive data from the KATHERINE and APHINITY ITT populations, and it used the hazard ratio from the indirect comparison using the node-positive populations (see section 3.4). The company's ICER in the ITT population was £8,203 per QALY gained. The ERG preferred to extrapolate invasive disease-free survival using Kaplan–Meier data and a generalised gamma curve, rather than the company's method of Kaplan–Meier data and an exponential curve. The ERG's preferred ICER for the ITT population was £6,388 per QALY gained. These estimates include commercial arrangements for trastuzumab emtansine, pertuzumab, trastuzumab and an assumed discount for trastuzumab biosimilars of 70%. Estimates that include all commercial arrangements remained within the range NICE normally considers an acceptable use of NHS resources.
## The cost-effectiveness estimates are uncertain but trastuzumab emtansine is recommended
Both the company's and the ERG's preferred ICERs were within the range NICE normally considers an acceptable use of NHS resources (see section 3.7 and section 3.8). The committee was aware of the uncertainty associated with the indirect comparison estimate (see section 3.4) and treatment effect (see section 3.5), and the effect of the additional uncertainties as summarised in the technical report (see table 2 on pages 41 to 42, and table 3 on pages 43 to 44). It considered that the most plausible ICER was unknown and could be higher or lower than the company's and the ERG's preferred ICERs. However, it agreed that the most plausible ICER was unlikely to be above what NICE normally considers an acceptable use of NHS resources. It therefore recommended trastuzumab emtansine as an option for the adjuvant treatment of HER2‑positive early breast cancer in adults who have residual invasive disease after neoadjuvant therapy.
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{'Recommendations': 'Trastuzumab emtansine is recommended, within its marketing authorisation, as an option for the adjuvant treatment of human epidermal growth factor receptor\xa02 (HER2)‑positive early breast cancer in adults who have residual invasive disease in the breast or lymph nodes after neoadjuvant taxane-based and HER2‑targeted therapy. It is recommended only if the company provides trastuzumab emtansine according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nNeoadjuvant therapy aims to reduce the size of the tumour before surgery. It sometimes shrinks completely, but people may still have cancer remaining when they have their surgery (residual invasive disease). The cancer may have spread to lymph nodes in the armpit (node-positive disease).\n\nAdjuvant treatment aims to reduce the risk of cancer returning after surgery. Trastuzumab is an adjuvant treatment for people with node-negative or node-positive disease. Pertuzumab plus trastuzumab with chemotherapy is an adjuvant treatment for node-positive disease but not for node-negative disease. Trastuzumab emtansine would be an alternative adjuvant treatment for people with node-negative or node-positive disease.\n\nClinical trial evidence shows that in people with residual invasive disease after neoadjuvant therapy and surgery, trastuzumab emtansine increases the time people remain free of disease compared with trastuzumab alone. We do not know if trastuzumab emtansine increases the length of time people live because the final trial results are not yet available. An indirect comparison in people with node-positive disease suggests that trastuzumab emtansine increases the time until cancer progresses compared with pertuzumab plus trastuzumab with chemotherapy, but this is uncertain because there are differences between people in the 2\xa0trials.\n\nThe cost-effectiveness estimates are within what NICE considers an acceptable use of NHS resources. Therefore, trastuzumab emtansine is recommended.', 'Information about trastuzumab emtansine': "# Marketing authorisation indication\n\nTrastuzumab emtansine (Kadcyla, Roche), as a single agent, is indicated for 'the adjuvant treatment of adult patients with HER2‑positive early breast cancer who have residual invasive disease, in the breast and/or lymph nodes, after neoadjuvant taxane-based and HER2‑targeted therapy'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nTrastuzumab emtansine costs £1,641.01 per 100‑mg vial and £2,625.62 per 160‑mg vial (powder for solution for infusion; excluding VAT; British national formulary online, accessed March\xa02020). The company has a commercial arrangement. This makes trastuzumab emtansine available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee (section 5) considered evidence submitted by Roche, a review of this submission by the evidence review group (ERG), the technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed:\n\nInvasive disease-free survival extrapolation: The company's original approach overestimated invasive disease-free survival for trastuzumab during the observed period of the KATHERINE trial. The ERG suggested that using the Kaplan–Meier data plus extrapolation is more appropriate. The company adopted the ERG's approach after technical engagement in its base case (issue\xa03, see technical report pages 18\xa0to\xa025).\n\nDrug costs and modelling assumptions: The company's assumptions in its original submission followed those used in NICE's guidance on adjuvant treatment with pertuzumab. These were validated during technical engagement. No changes were made after technical engagement (issue\xa06, see technical report pages 31\xa0to\xa033).\n\nModelling the intention-to-treat (ITT) population: The company updated the ITT population model after technical engagement and provided supportive results for a comparison of trastuzumab emtansine against pertuzumab plus trastuzumab with chemotherapy, and against trastuzumab-based therapy using the ITT population (issue\xa07, see technical report page\xa034).\n\nModelling the lymph node positive population: The company updated the lymph node positive population model with population-specific data after technical engagement (issue\xa08, see technical report pages 34\xa0to\xa037).The committee recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, table\xa02, page\xa042), and took these into account in its decision making. It discussed the following issues (issues 1,\xa02,\xa04\xa0and\xa05), which were outstanding after the technical engagement stage.\n\n# Treatment pathway\n\n## Trastuzumab emtansine is a new adjuvant treatment for people with residual invasive disease after neoadjuvant therapy\n\nHuman epidermal growth factor receptor\xa02 (HER2)‑positive breast cancer has a considerable effect on patients and their families. In early HER2‑positive breast cancer, neoadjuvant treatment may be used to eradicate or reduce tumour size before surgery. NICE recommends pertuzumab for the neoadjuvant treatment of HER2-positive breast cancer, with trastuzumab and chemotherapy, for locally advanced, inflammatory or early breast cancer at high risk of recurrence. The patient expert explained that when residual disease is found during surgery this is a disappointing outcome, and preventing the cancer returning is very important to patients. After surgery, adjuvant treatment is used to reduce the risk of recurrence. NICE recommends pertuzumab for adjuvant treatment of HER2-positive early stage breast cancer, with trastuzumab and chemotherapy, in adults who have lymph node positive disease. People with lymph node negative disease are offered adjuvant trastuzumab, in line with NICE's guideline on early breast cancer. Trastuzumab emtansine is a new adjuvant treatment for HER2‑positive early breast cancer for people who have residual invasive disease after neoadjuvant therapy. It can be offered to people with node-positive or node-negative disease.\n\n## There is a clinical need for an additional treatment for people who have residual disease after neoadjuvant therapy\n\nThe clinical experts explained that people who have residual invasive disease after neoadjuvant therapy are considered to be at higher risk of disease recurrence than those who have a pathological complete response (that is, no residual invasive disease was found during surgery). Most people with HER2‑positive early breast cancer have pertuzumab with trastuzumab and chemotherapy as neoadjuvant treatment. The clinical experts explained that a complete pathological response after neoadjuvant pertuzumab and trastuzumab is considered to show that the disease is sensitive to this combination, and the patient would benefit from having it again in the adjuvant setting. However, residual invasive disease after neoadjuvant treatment with pertuzumab and trastuzumab is considered to show that the disease is resistant to this treatment, and the patient would benefit from an alternative treatment such as trastuzumab emtansine. The committee concluded that there is an unmet clinical need for an additional adjuvant therapy for people who have residual disease after neoadjuvant therapy.\n\n# Clinical evidence\n\n## Trastuzumab emtansine improves invasive disease-free survival compared with trastuzumab\n\nKATHERINE (n=1,486) is an open-label, randomised, multicentre trial of adjuvant trastuzumab emtansine compared with adjuvant trastuzumab, in people with HER2‑positive early breast cancer who had residual invasive disease after trastuzumab-based neoadjuvant therapy with chemotherapy. Invasive disease-free survival was the primary outcome. In the trial, about 20% of people had neoadjuvant pertuzumab plus trastuzumab and 80% had neoadjuvant trastuzumab. The clinical experts considered that the trial results are generalisable to clinical practice, although in clinical practice most people would have pertuzumab plus trastuzumab as neoadjuvant therapy. They also noted that the hazard ratios for invasive disease-free survival were very similar for people who had had trastuzumab previously and those who had pertuzumab plus trastuzumab. The hazard ratio for invasive disease-free survival for the ITT population was 0.50 (95%\xa0confidence interval [CI] 0.39\xa0to\xa00.62). The hazard ratio for invasive disease-free survival for the lymph node negative population (n=689), who would have trastuzumab in clinical practice, was 0.44 (95%\xa0CI 0.28\xa0to\xa00.68). For node-positive disease (n=797), the hazard ratio was 0.52 (95%\xa0CI 0.38\xa0to\xa00.71). Interim overall-survival results are available, however the data are immature. The committee concluded that trastuzumab emtansine improves invasive disease-free survival compared with trastuzumab. However, it is not known whether trastuzumab emtansine increases the length of time people live because the data are immature.\n\n# Indirect comparison of trastuzumab emtansine against pertuzumab plus trastuzumab and chemotherapy\n\n## The estimates are uncertain but appropriate for decision making\n\nNo study directly compared trastuzumab emtansine with pertuzumab plus trastuzumab with chemotherapy. The company therefore did an indirect comparison using data from KATHERINE and the APHINITY trial. APHINITY (n=4,804) is a double-blind, randomised, multicentre trial of adjuvant pertuzumab plus trastuzumab and chemotherapy compared with adjuvant placebo with trastuzumab and chemotherapy, in people with HER2‑positive early breast cancer who had not had neoadjuvant therapy. Because adjuvant treatment with pertuzumab plus trastuzumab and chemotherapy is only recommended for people who have lymph node positive disease, a subgroup of people with lymph node positive disease from KATHERINE (n=689) and APHINITY (n=3,006) was used for the comparison. The indirect comparison hazard ratio for invasive disease-free survival in the node-positive subgroup was 0.722 (95%\xa0CI 0.50\xa0to\xa01.04). Both the company and the ERG considered the results uncertain because all patients in KATHERINE had residual invasive disease after neoadjuvant therapy, whereas patients in APHINITY had not had neoadjuvant therapy before surgery. However, they agreed that the results represented the best available evidence for trastuzumab emtansine compared with pertuzumab plus trastuzumab and chemotherapy. The clinical experts considered that the indirect comparison results may be a conservative estimate because in KATHERINE people had already had a suboptimal response to neoadjuvant therapy and were therefore preselected to be at higher risk. The committee concluded that the results of the indirect comparison for trastuzumab emtansine compared with pertuzumab plus trastuzumab and chemotherapy are uncertain, but they are suitable for decision making.\n\n# Treatment-waning effect of trastuzumab emtansine\n\n## The ERG's approach is uncertain but appropriate for decision making\n\nBefore technical engagement the company assumed that trastuzumab emtansine's treatment effect is maintained for 7\xa0years, then gradually decreases to no treatment effect at 10\xa0years. The ERG agreed with the company that the treatment effect lasts beyond the KATHERINE follow-up time. However, it used annualised hazard ratios from KATHERINE to estimate the start and end of treatment waning. In the ERG's approach, the trastuzumab emtansine treatment effect is maintained for 3\xa0years, then gradually decreases to no treatment effect at 8\xa0years. The company considered the ERG's approach to be conservative because updated data from APHINITY suggest that benefit from adjuvant pertuzumab is still present at 6\xa0years. However, it adopted the ERG's approach after technical engagement. The company noted that all its exploratory analyses, with varied assumptions about the duration of treatment effect, resulted in cost-effectiveness estimates within the acceptable range. The committee accepted the ERG's approach of using KATHERINE data and was reassured by the company's exploratory analyses. It concluded that although the duration of the treatment effect is currently unknown, the ERG's approach is suitable for decision making.\n\n# Utilities\n\n## The utilities are appropriate for decision making\n\nThe company used utility values from KATHERINE for invasive disease-free survival. No significant difference was found between the results for trastuzumab emtansine and for trastuzumab, therefore the values were pooled. This assumes that people having either treatment have the same health-related quality of life. KATHERINE did not collect utilities for people who had metastatic recurrence, so the company used Lloyd et al.\xa0(2006) utilities for progressed disease because this study has been used in previous appraisals. The ERG noted that the model did not include any disutilities for adverse effects. It preferred to use individual treatment utilities for invasive disease-free survival to capture any differences between the 2\xa0treatments. Also, it preferred to use Lidgren et al.\xa0(2007) for metastatic states, because these correspond more closely to the NICE reference case than Lloyd et al. After technical engagement, the company adopted the ERG's approach. The committee noted that both Lloyd et al. and Lidgren et al. have been used in previous NICE appraisals. However, it favoured the ERG's approach. It concluded that the utilities from KATHERINE, calculated per treatment for invasive disease-free survival, and the Lidgren et al. utilities for metastatic states were suitable for decision making.\n\n# Cost-effectiveness estimates\n\n## The ICERs for trastuzumab emtansine compared with trastuzumab are within what NICE considers acceptable\n\nAfter technical engagement, the company's preferred incremental cost-effectiveness ratio (ICER) for trastuzumab emtansine compared with trastuzumab in the node-negative population was £8,829 per quality-adjusted life year (QALY) gained. The ERG agreed with the company's revised base case in this population. The company provided supportive data from the ITT population of KATHERINE. The ICER in the ITT population was £5,985 per QALY gained. The ERG preferred extrapolating invasive disease-free survival using Kaplan–Meier data and a generalised gamma curve, instead of the company's preference of Kaplan–Meier data and an exponential curve. The ERG's preferred ICER for the ITT population was £7,213 per QALY gained. These estimates include commercial arrangements for trastuzumab emtansine, trastuzumab and an assumed discount for trastuzumab biosimilars of 70%. Estimates that include all commercial arrangements remained within the range NICE normally considers an acceptable use of NHS resources.\n\n## The ICERs for trastuzumab emtansine compared with pertuzumab plus trastuzumab with chemotherapy are within what NICE considers acceptable\n\nAfter technical engagement, the company's preferred ICER for trastuzumab emtansine compared with pertuzumab plus trastuzumab and chemotherapy in the node-positive population was £4,955 per QALY gained. The model assumed that chemotherapy would have been given in the neoadjuvant setting and therefore no chemotherapy cost was included as part of the adjuvant pertuzumab plus trastuzumab treatment. The ERG agreed with the company's revised base case in this population. The company provided supportive data from the KATHERINE and APHINITY ITT populations, and it used the hazard ratio from the indirect comparison using the node-positive populations (see section 3.4). The company's ICER in the ITT population was £8,203 per QALY gained. The ERG preferred to extrapolate invasive disease-free survival using Kaplan–Meier data and a generalised gamma curve, rather than the company's method of Kaplan–Meier data and an exponential curve. The ERG's preferred ICER for the ITT population was £6,388 per QALY gained. These estimates include commercial arrangements for trastuzumab emtansine, pertuzumab, trastuzumab and an assumed discount for trastuzumab biosimilars of 70%. Estimates that include all commercial arrangements remained within the range NICE normally considers an acceptable use of NHS resources.\n\n## The cost-effectiveness estimates are uncertain but trastuzumab emtansine is recommended\n\nBoth the company's and the ERG's preferred ICERs were within the range NICE normally considers an acceptable use of NHS resources (see section 3.7 and section 3.8). The committee was aware of the uncertainty associated with the indirect comparison estimate (see section 3.4) and treatment effect (see section 3.5), and the effect of the additional uncertainties as summarised in the technical report (see table\xa02 on pages 41\xa0to\xa042, and table\xa03 on pages 43\xa0to\xa044). It considered that the most plausible ICER was unknown and could be higher or lower than the company's and the ERG's preferred ICERs. However, it agreed that the most plausible ICER was unlikely to be above what NICE normally considers an acceptable use of NHS resources. It therefore recommended trastuzumab emtansine as an option for the adjuvant treatment of HER2‑positive early breast cancer in adults who have residual invasive disease after neoadjuvant therapy."}
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https://www.nice.org.uk/guidance/ta632
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Evidence-based recommendations on trastuzumab emtansine (Kadcyla) for human epidermal growth factor receptor 2 (HER2)‑positive early breast cancer in adults who have residual invasive disease in the breast or lymph nodes after neoadjuvant taxane-based and HER2‑targeted therapy.
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a0e396b0e239a24829cef93ca78f52d4825cd2ab
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nice
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Joint replacement (primary): hip, knee and shoulder
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Joint replacement (primary): hip, knee and shoulder
This guideline covers care before, during and after a planned knee, hip or shoulder replacement. It includes recommendations to ensure that people are given full information about their options for surgery, including anaesthesia. It offers advice for healthcare professionals on surgical procedures and ensuring safety during operations. It also offers guidance on providing support and rehabilitation before and after surgery.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Shared decision making and information for people offered hip, knee or shoulder replacement
Follow the recommendations on communication, information and shared decision making in the NICE guidelines on patient experience in adult NHS services and shared decision making when discussing treatment with people offered primary elective hip, knee or shoulder replacement.
Support shared decision making by discussing treatment options with people offered primary elective hip, knee or shoulder replacement and their families or carers (as appropriate). Include in the discussions:
the alternatives to joint replacement
the potential benefits and risks of the available procedures and types of implant for joint replacement, including the possible need for more surgery in the future
the options for anaesthesia and analgesia, and the potential benefits and risks of each option (see section on anaesthesia and analgesia).
Give people offered primary elective hip, knee or shoulder replacement and their family members or carers (as appropriate) information that is:
specific to the procedure they are being offered
in a format they can easily understand
provided starting at the first appointment, then whenever needed throughout their care.
Give information on primary elective hip, knee or shoulder replacement that includes:
what to expect before, during and after surgery, including length of hospital stay, recovery and rehabilitation
who to contact if they have questions or concerns before or after surgery
preparing for surgery, including steps they can take to optimise their recovery (see section on preoperative rehabilitation)
pain after surgery and how it can be managed
wound care
returning to work
returning to usual activities, for example playing sports, driving and sexual activity.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on shared decision making and information for people offered hip, knee or shoulder replacement .
Full details of the evidence and the committee's discussion are in evidence review A: information needs.
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## Decision aids for elective joint replacement
The committee did not make recommendations for specific decision aids for elective joint replacement but recognised that they could have value in shared decision making. They made a recommendation for research on the components of a decision aid.
For a short explanation of why the committee did not make a recommendation, see the rationale on decision aids for elective joint replacement .
Full details of the evidence and the committee's discussion are in evidence review B: decision aids.
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# Preoperative rehabilitation
## Preoperative rehabilitation for hip or knee replacement
Give people having hip or knee replacement advice on preoperative rehabilitation. Include advice on:
exercises to do before and after surgery that will aid recovery
lifestyle, including weight management, diet and smoking cessation (see NICE's guidance on lifestyle and wellbeing)
maximising functional independence and quality of life before and after surgery.
## Preoperative rehabilitation for shoulder replacement
The committee were unable to make recommendations for practice in this area. They included preoperative rehabilitation for shoulder replacement in their recommendation for research on preoperative rehabilitation.
For a short explanation of why the committee made the recommendation on preoperative rehabilitation for hip or knee replacement and how it might affect practice, and why they were unable to make recommendations on preoperative rehabilitation for shoulder replacement, see the rationale and impact section on preoperative rehabilitation .
Full details of the evidence and the committee's discussion are in evidence review C: preoperative rehabilitation.
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# Anaesthesia and analgesia
## Anaesthesia and analgesia for hip replacement
Offer people having primary elective hip replacement a choice of:
regional anaesthesia in combination with local infiltration analgesia (LIA) or
general anaesthesia in combination with LIA.Consider a nerve block that does not impair motor function as an alternative to LIA in either of the options above, provided it does not delay surgery significantly.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on anaesthesia and analgesia for hip replacement .
Full details of the evidence and the committee's discussion are in evidence review D: anaesthesia for hip replacement.
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## Anaesthesia and analgesia for knee replacement
Offer people having primary elective knee replacement a choice of:
regional anaesthesia in combination with LIA or
general anaesthesia in combination with LIA.Consider adding a nerve block that does not impair motor function to either of the options above, provided it does not delay surgery significantly.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on anaesthesia and analgesia for knee replacement .
Full details of the evidence and the committee's discussion are in evidence review E: anaesthesia for knee replacement
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## Anaesthesia and analgesia for shoulder replacement
Discuss the options for anaesthesia and analgesia with people having primary elective shoulder replacement, including general anaesthesia, regional anaesthesia, local infiltration analgesia and nerve blocks.
The committee were unable to recommend specific options for anaesthesia and analgesia for shoulder replacement. They made recommendations for research on supplementary anaesthesia, and on regional compared with general anaesthesia or a combination in elective shoulder replacement.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on anaesthesia and analgesia for shoulder replacement .
Full details of the evidence and the committee's discussion are in evidence review F: anaesthesia for shoulder replacement.
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# Tranexamic acid to minimise blood loss
In June 2020, tranexamic acid solution for injection was off label for topical (intra-articular) use. See NICE's information on prescribing medicines.
In these recommendations 'renal impairment' refers to mild to moderate renal impairment. See the summary of product characteristics for dosage reductions according to serum creatinine level. Tranexamic acid is contraindicated for people with severe renal impairment.
For primary elective hip or knee replacement:
Give intravenous tranexamic acid.
If there is no renal impairment, also apply 1 g to 2 g of topical (intra-articular) tranexamic acid diluted in saline after the final wash-out and before wound closure. Ensure that the total combined dose of tranexamic acid does not exceed 3 g.
If there is renal impairment, give a reduced dose of intravenous tranexamic acid on its own.For primary elective shoulder replacement:
Consider intravenous tranexamic acid.
If there is no renal impairment, consider 1 g to 2 g of topical (intra-articular) tranexamic acid diluted in saline applied after the final wash-out and before wound closure. Ensure that the total combined dose of tranexamic acid does not exceed 3 g.
If there is renal impairment and tranexamic acid is used, give a reduced dose of intravenous tranexamic acid on its own.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on tranexamic acid to minimise blood loss .
Full details of the evidence and the committee's discussion are in evidence review G: tranexamic acid to minimise blood loss.
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# Preventing infections
## Antibiotic or antiseptic agents in wound wash-out solutions
Follow the recommendations on antibiotic prophylaxis, wound irrigation and intracavity lavage, and antiseptics and antibiotics before wound closure in the NICE guideline on surgical site infections, for people having primary elective hip, knee or shoulder replacement.
## Ultra-clean air ventilation in operating theatres
Use ultra-clean air ventilation in operating theatres for primary hip, knee or shoulder elective joint replacement.
For a short explanation of why the committee made these recommendations see and how they might affect practice, see the rationale and impact section on preventing infections .
Full details of the evidence and the committee's discussion are in evidence review H: wound lavage and evidence review I: ultra-clean air.
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# Avoiding implant selection errors
Use 2 intraoperative 'stop moments', 1 before implantation and 1 before wound closure, to check all implant details and ensure compatibility of each component.
Consider intraoperative real-time data entry before implantation using a system that provides an alert of mismatched implant components, such as the National Joint Registry database.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on avoiding implant selection errors .
Full details of the evidence and the committee's discussion are in evidence review J: wrong implant selection.
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# Procedures for primary elective knee replacement
## Partial and total knee replacement
Offer a choice of partial or total knee replacement to people with isolated medial compartmental osteoarthritis. Discuss the potential benefits and risks of each option with the person.
For a short explanation of why the committee made the recommendation and how it might affect practice, see the rationale and impact section on partial and total knee replacement .
Full details of the evidence and the committee's discussion are in evidence review K: total knee replacement.
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## Patella resurfacing
Offer resurfacing of the patella to people having primary elective total knee replacement.
For a short explanation of why the committee made the recommendation and how it might affect practice, see the rationale and impact section on patella resurfacing .
Full details of the evidence and the committee's discussion are in evidence review L: patella resurfacing.
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# Surgical approaches and implants for primary elective hip replacement
## Surgical approaches for primary elective hip replacement
Consider a posterior or anterolateral approach for primary elective hip replacement.
The committee were unable to make recommendations on the direct anterior, direct superior and supercapsular percutaneously assisted (SuperPATH) surgical approaches. They made a recommendation for research on surgical approaches in primary elective hip replacement.
For a short explanation of why the committee made the recommendation on surgical approaches for primary elective hip replacement and how it might affect practice and why they were unable to make recommendations on the direct anterior, direct superior and SuperPATH approaches, see the rationale and impact section on surgical approaches for primary elective hip replacement .
Full details of the evidence and the committee's discussion are in evidence review M: hip replacement approach
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## Implants for primary elective hip replacement
For NICE technology appraisal guidance on implants for primary elective hip replacement see the NICE topic page on joint replacement.
# Procedures for primary elective shoulder replacement
## Shoulder replacement for osteoarthritis with no rotator cuff tear
If glenoid bone is adequate, offer conventional total shoulder replacement to people having primary elective shoulder replacement for osteoarthritis with no rotator cuff tear.
For a short explanation of why the committee made the recommendation and how it might affect practice, see the rationale and impact section on shoulder replacement for osteoarthritis with no rotator cuff tear .
Full details of the evidence and the committee's discussion are in evidence review N: shoulder replacement – intact rotator cuff.
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## Shoulder replacement for pain and functional loss for people with a previous proximal humeral fracture
The committee were unable to make recommendations for practice in this area. They made a recommendation for research on procedures for shoulder replacement for people with a previous proximal humeral fracture.
For a short explanation of why the committee did not make a recommendation, see the rationale on shoulder replacement for pain and functional loss for people with a previous proximal humeral fracture .
Full details of the evidence and the committee's discussion are in evidence review O: hemiarthroplasty – proximal humeral fracture.
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# Postoperative rehabilitation
## Inpatient rehabilitation
A physiotherapist or occupational therapist should offer rehabilitation, on the day of surgery if possible and no more than 24 hours after surgery, to people who have had a primary elective hip, knee or shoulder replacement. Rehabilitation should include:
advice on managing activities of daily living and
home exercise programmes and
mobilisation for people who have had knee or hip replacement or
ambulation for people who have had shoulder replacement.
For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on inpatient rehabilitation .
Full details of the evidence and the committee's discussion are in evidence review P: inpatient hip and knee postoperative rehabilitation and evidence review Q: inpatient shoulder postoperative rehabilitation.
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## Outpatient rehabilitation
For people who have had primary elective hip or knee replacement:
a member of the physiotherapy or occupational therapy team should give advice on self-directed rehabilitation
the advice should be given before the person leaves hospital
the advice should be adjusted in line with recommendations 1.10.5 and 1.10.6 if needed.
For people who have had primary elective shoulder replacement:
a member of the physiotherapy or occupational therapy team should give advice on:
self-directed rehabilitation or
supervised group rehabilitation or
individual rehabilitation
the advice should be given before the person leaves hospital
the advice should be adjusted in line with recommendations 1.10.5 and 1.10.6 if needed.
Ensure that people who are undertaking self-directed rehabilitation have:
a clear understanding of their rehabilitation goals and the importance of doing the exercises prescribed to achieve these goals
a point of contact for advice and support.
Offer supervised group or individual outpatient rehabilitation to people who:
have difficulties managing activities of daily living or
have ongoing functional impairment leading to specific rehabilitation needs or
find that self-directed rehabilitation is not meeting their rehabilitation goals.
Consider supervised group or individual outpatient rehabilitation for people with cognitive impairment.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on outpatient rehabilitation .
Full details of the evidence and the committee's discussion are in evidence review R: outpatient hip and knee postoperative rehabilitation and evidence review S: outpatient rehabilitation after shoulder replacement.
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# Long-term care
## Follow-up and monitoring
The committee were unable to make recommendations for practice in this area. They made a recommendation for research on follow-up.
## Referral from primary care
Primary care practitioners should refer people who develop new or worsening pain, limp or loss of function related to their joint replacement to an orthopaedic surgical service.
For a short explanation of why the committee did not make a recommendation, see the rationale on follow-up and monitoring in secondary care .
Full details of the evidence and the committee's discussion are in evidence review T: long-term follow-up and monitoring
Loading. Please wait.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Key recommendations for research
## Preoperative rehabilitation
What is the clinical and cost effectiveness of preoperative rehabilitation given at least 2 months before hip, knee or shoulder replacement?
For a short explanation of why the committee made the recommendation for research, see the rationale on preoperative rehabilitation .
Full details of the research recommendation are in evidence review C: preoperative rehabilitation.
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## Information for people having a joint replacement
How should information for people having joint replacement surgery be delivered?
For a short explanation of why the committee made the recommendation for research, see the rationale on information for people having a joint replacement .
Full details of the research recommendation are in evidence review A: information needs.
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## Early mobilisation of the shoulder
Is early mobilisation of the shoulder after primary elective shoulder replacement more effective than delayed mobilisation in restoring rapid return of function and relieving pain?
For a short explanation of why the committee made the recommendation for research, see the rationale on inpatient rehabilitation .
Full details of the research recommendation are in evidence review Q: inpatient shoulder postoperative rehabilitation.
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## Conventional compared with reverse total shoulder arthroplasty
What is the clinical and cost effectiveness of conventional compared with reverse total shoulder arthroplasty for adults having primary elective shoulder replacement for osteoarthritis with no rotator cuff tear?
For a short explanation of why the committee made the recommendation for research, see the rationale on shoulder arthroplasty .
Full details of the research recommendation are in evidence review N: shoulder replacement – intact rotator cuff.
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## Analgesia for knee replacement
What is the clinical and cost effectiveness of adding a nerve block to regional or general anaesthesia, in combination with local infiltration analgesia, for primary elective knee replacements?
For a short explanation of why the committee made the research recommendation, see the rationale on analgesia for knee replacement .
Full details of the research recommendation are in evidence review E: anaesthesia for knee replacement.
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## Selective resurfacing in knee replacement
In adults having elective knee replacement, what is the clinical and cost effectiveness of total knee replacement with patella resurfacing compared with selective resurfacing?
For a short explanation of why the committee made the research recommendation, see the rationale on resurfacing in knee replacement .
Full details of the research recommendation are in evidence review L: patella resurfacing.
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# Other recommendations for research
## Decision aids
What are the components of a decision aid to support people referred for elective joint replacement in making decisions about their treatment (for example, the type of procedure, timing and implant choice)?
For a short explanation of why the committee made the research recommendation, see the rationale on decision aids .
Full details of the research recommendation are in evidence review B: decision aids.
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## Supplementary analgesia or anaesthesia in elective shoulder replacement
In adults having elective shoulder joint replacement with general anaesthesia, what is the clinical and cost effectiveness of supplementary local infiltration analgesia, a nerve block or regional anaesthesia?
For a short explanation of why the committee made the research recommendation, see the rationale on supplementary analgesia or anaesthesia in elective shoulder replacement .
Full details of the research recommendation are in evidence review F: anaesthesia for shoulder replacement.
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## Regional compared with general anaesthesia or a combination in elective shoulder replacement
In adults having elective shoulder joint replacement, what is the relative clinical and cost effectiveness of general anaesthesia, regional anaesthesia, and general combined with regional anaesthesia?
For a short explanation of why the committee made the research recommendation, on, see the rationale on regional compared with general anaesthesia, or a combination, in elective shoulder replacement .
Full details of the research recommendation are in evidence review F: anaesthesia for shoulder replacement.
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## Avoiding implant selection errors
What is the most effective technological solution for minimising wrong implant selection during joint replacement surgery?
For a short explanation of why the committee made the research recommendation, see the rationale on avoiding implant selection errors .
Full details of the research recommendation are in evidence review J: wrong implant selection.
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## Surgical approaches in primary elective hip replacement
Do the direct anterior, direct superior and supercapsular percutaneously assisted (SuperPATH) approaches to hip replacement improve patient-recorded outcome measures and reduce length of hospital stays, revision rates, neurological complications and surgical site infections compared with the posterior and anterolateral approaches?
For a short explanation of why the committee made the research recommendation, see the rationale on surgical approaches in primary elective hip replacement .
Full details of the research recommendation are in evidence review M: hip replacement approach.
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## Conventional total shoulder replacement compared with humeral hemiarthroplasty for people aged under 60
What is the clinical and cost effectiveness of humeral hemiarthroplasty compared with conventional total shoulder replacement for adults aged under 60 having primary elective shoulder replacement for osteoarthritis with no rotator cuff tear?
For a short explanation of why the committee made the research recommendation, see the rationale on conventional total shoulder replacement compared with humeral hemiarthroplasty for people aged under 60 .
Full details of the research recommendation are in evidence review N: shoulder replacement – intact rotator cuff.
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## Procedures for shoulder replacement for people with a previous proximal humeral fracture
In adults having primary elective shoulder replacement for pain and functional loss after a previous proximal humeral fracture (not acute trauma), what is the clinical and cost effectiveness of reverse total shoulder replacement compared with humeral hemiarthroplasty?
For a short explanation of why the committee made the research recommendation, see the rationale on procedures for shoulder replacement for people with a previous proximal humeral fracture .
Full details of the research recommendation are in evidence review O: hemiarthroplasty – proximal humeral fracture.
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## Supporting rehabilitation after hip, knee or shoulder replacement for people with additional needs
What are the best ways to support rehabilitation after hip knee or shoulder replacement for people with additional needs (such as people with dementia, a learning difficulty or multiple disabling medical comorbidities)?
For a short explanation of why the committee made the research recommendation, see the rationale on supporting rehabilitation after hip, knee or shoulder replacement for people with additional needs .
Full details of the research recommendation are in evidence review R: outpatient hip and knee postoperative rehabilitation.
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## Outpatient rehabilitation after shoulder replacement
For people who have had primary elective shoulder replacement, does self-directed, supervised group or supervised individual rehabilitation produce the most improvement in health-related quality of life 2 years after surgery?
For a short explanation of why the committee made the research recommendation, see the rationale on postoperative rehabilitation after shoulder replacement .
Full details of the research recommendation are in evidence review S: outpatient rehabilitation after shoulder replacement.
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## Follow-up after shoulder replacement
What is the optimum time between follow‑up appointments for people who have had shoulder replacement, who should lead follow‑up and how this should be organised between hospital and community care?
For a short explanation of why the committee made the research recommendation, see the rationale on follow up after shoulder replacement .
Full details of the research recommendation are in evidence review T: long-term follow-up and monitoring.
Loading. Please wait.# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.
# Shared decision making and information for people offered hip, knee or shoulder replacement
Recommendations 1.1.1 to 1.1.4
## Why the committee made the recommendations
The NICE guideline on patient experience in adult NHS services describes shared decision making as part of enabling patients to actively participate in their care. It includes recommendations on giving information, encouraging discussion and supporting people to use the information to make choices about their care. The committee agreed, based on their experience, that people offered hip, knee or shoulder replacement need specific information on the treatment options that are available for them, given from their first appointment and whenever needed throughout their care, to enable them to express their needs and preferences.
The committee's experience reflected evidence from studies using interviews and focus groups that highlighted the importance of ensuring that the information given to people is clear and easily understandable to them. The studies showed that specific areas of patient concern included preparing for surgery, managing postoperative pain and aftercare at home, expected recovery time and returning to work. The committee also drew on their own experience of the information that people offered hip, knee or shoulder replacement need.
The committee noted uncertainty about the best way to deliver information and made a recommendation for research on information for people having a joint replacement.
## How the recommendations might affect practice
Discussions with people having elective joint replacement are current practice, although different members of the orthopaedic multidisciplinary team may be involved, depending on local arrangements and the person's specific needs. The recommendations are not expected to result in substantial changes to this.
Return to recommendations
# Decision aids for elective joint replacement
## Why the committee were unable to make recommendations for practice
The committee agreed that decision aids can be a useful way of helping people offered joint replacement surgery understand their options and make decisions about their care. Evidence from studies of decision aids for joint replacement showed that their content varied widely, and this led the committee to question what the components of a decision aid should be. Their view is that a decision aid should not simply be a means of providing information but should actively help people to participate in making decisions about their care. Because of the wide variation in the decision aids used in the studies, it was not possible to compare them with each other. The committee were therefore unable to recommend any particular decision aid for joint replacement. To investigate the question of what defines a decision aid for elective joint replacement, the committee made a recommendation for research on decision aids.
Return to recommendations
# Preoperative rehabilitation
Recommendation 1.2.1
## Why the committee made the recommendation
The committee agreed, based on their experience, that preoperative rehabilitation helps to prepare people for surgery, increases their ability to manage any complications of surgery, promotes understanding and engagement with postoperative rehabilitation and prepares people for life with a joint replacement.
Evidence showed that preoperative rehabilitation reduces the length of hospital stays for people having a hip or knee replacement, although this was for intensive rehabilitation programmes and was from settings where hospital stays are usually longer than in the NHS.
Based on the evidence and their own experience, the committee agreed that preoperative rehabilitation for people having hip or knee replacement should include advice on exercises before and after surgery, lifestyle and ways to maximise independence and quality of life.
There was no evidence on preoperative rehabilitation for people having shoulder replacement. The committee noted that preoperative exercises to improve muscle function in the affected limb are often severely limited by pain for people having shoulder replacement, and agreed that the benefits seen in people having hip and knee replacement might not apply to those having shoulder replacement. They included shoulder replacement in their recommendation for research on preoperative rehabilitation.
## How the recommendation might affect practice
Current practice varies widely, ranging from no preoperative rehabilitation to comprehensive individualised preoperative rehabilitation programmes. However, most services offer preoperative rehabilitation advice to everyone having hip or knee replacement, so this recommendation is not expected to lead to a substantial change in practice. For some services, providing information, exercise and lifestyle advice may increase the time needed from the orthopaedic multidisciplinary team. However, this cost can be expected to be offset by reductions in the length of hospital stays.
Return to recommendations
# Anaesthesia and analgesia for hip replacement
Recommendation 1.3.1
## Why the committee made the recommendation
Evidence showed that regional and general anaesthesia are equally effective for people having hip replacement surgery, so the committee recommended that a choice should be offered. There was no evidence to support a combination of regional and general anaesthesia.
Based on their experience, the committee agreed that using local or regional analgesic techniques in combination with regional or general anaesthesia reduces postoperative pain. Clinical evidence showed that, when used with general or regional anaesthesia, both local infiltration analgesia (LIA) and nerve blocks are beneficial and there was no clinical evidence to suggest that either is more beneficial than the other. However, the committee noted that some nerve blocks impair motor function and agreed that these should be avoided in hip replacement because they can delay mobilisation.
Economic evidence showed that LIA is cost effective. For nerve blocks, the evidence on costs suggested that they are cost effective if they do not delay surgery by more than 5 minutes.
## How the recommendation might affect practice
All orthopaedic units currently offer a choice of general or regional anaesthesia. Most augment this with either LIA or a nerve block. Although the cost of nerve blocks varies, it is not expected that services currently offering LIA will change to nerve blocks. This recommendation is unlikely to lead to significant changes in practice.
Return to recommendations
# Anaesthesia and analgesia for knee replacement
Recommendation 1.3.2
## Why the committee made the recommendation
Evidence showed that regional and general anaesthesia are equally effective for people having knee replacement surgery, so the committee recommended that a choice should be offered. There was no evidence to support a combination of regional and general anaesthesia.
Evidence also showed that adding local infiltration analgesia (LIA) or a nerve block to regional or general anaesthesia is beneficial, and that adding both LIA and a nerve block to regional anaesthesia is more beneficial than adding either on its own, although this benefit was less pronounced with general anaesthesia.
The committee noted that some nerve blocks impair motor function and agreed that these should be avoided because they can delay mobilisation. Adductor canal nerve blocks allow for a better range of movement sooner after surgery and are now more commonly used than femoral blocks, but the evidence on them was limited.
Economic evidence showed that LIA is cost effective. For nerve blocks, the evidence on costs suggested that they are cost effective if they do not delay surgery by more than 5 minutes. Because of the uncertainty about the cost effectiveness of nerve blocks added to LIA to augment anaesthesia in knee replacement, the committee made a recommendation for research on analgesia for knee replacement.
## How the recommendation might affect practice
In current practice, regional anaesthesia for knee replacement surgery is usually augmented with LIA, a nerve block, or both. The recommendation might lead services that currently augment anaesthesia with nerve blocks, either together with LIA or on their own, to change to augmenting with LIA only or to arrange services so that administering the nerve block does not delay surgery. Services that currently augment anaesthesia with an LIA only are not expected to see a substantial change in practice.
Return to recommendations
# Anaesthesia and analgesia for shoulder replacement
Recommendation 1.3.3
## Why the committee made the recommendation
There was not enough evidence to support recommendations on specific types of anaesthesia for shoulder replacement. Because of this uncertainty, the committee stressed the importance of discussing the options with people having this type of joint replacement. Although small benefits were seen in studies combining general anaesthesia with LIA and regional anaesthesia with LIA, they were offset by phrenic nerve palsy events. The committee made recommendations for research on supplementary analgesia or anaesthesia in elective shoulder replacement and regional, general, or regional with general anaesthesia in elective shoulder replacement. They noted that using regional anaesthesia alone has the potential to increase day-case shoulder replacement surgery.
## How the recommendation might affect practice
This recommendation is not expected to change current practice.
Return to recommendations
# Tranexamic acid to minimise blood loss
Recommendations 1.4.1 and 1.4.2
## Why the committee made the recommendations
Good evidence showed that, in people having primary elective hip or knee replacement, topical (intra-articular) tranexamic acid in combination with intravenous tranexamic acid reduces the number of blood transfusions needed when compared with topical or intravenous tranexamic acid alone. Although 1 study suggested that combining topical with oral tranexamic acid is the most clinically and cost-effective administration method, this evidence was not strong enough to support a recommendation for this combination.
Evidence in people having primary elective shoulder replacement also showed a benefit from tranexamic acid but did not address combined administration. However, the committee reasoned that the benefits seen in hip and knee replacement could also apply in shoulder replacement. They agreed that, although there may not be the same benefits in terms of reduced blood transfusions in shoulder replacement surgery, tranexamic acid reduces bleeding, which lessens fatigue and nausea. The committee noted that tranexamic acid is an inexpensive treatment.
The BNF advises a reduced dose of intravenous tranexamic acid for people with renal impairment. Because the absorption is uncertain when tranexamic acid is administered topically, the committee agreed that it should be given only intravenously to people with renal impairment.
## How the recommendations might affect practice
Although the use of tranexamic acid is widespread in current practice, the method of administration varies. In the committee's experience, topical (intra-articular) tranexamic acid is commonly used in combination with intravenous tranexamic acid in hip and knee replacements, but not in shoulder replacements. Increased use of this combination in shoulder replacements might increase doses and the use of disposables. However, the associated costs are expected to be more than offset by the savings produced by a reduced need for blood transfusions in hip and knee replacements and reduced bleeding in shoulder replacements.
Return to recommendations
# Preventing infections
Recommendations 1.5.1 and 1.5.2
## Why the committee made the recommendations
No evidence was found on adding antibiotic or antiseptic agents to saline wound wash-out solution to reduce surgical site infections in people having primary elective joint replacement. The committee acknowledged that washing the wound with saline is common practice and is used to improve visibility of the operative site for the surgeon. They noted that the use of antibiotic and antiseptic agents in wash-out solutions varies across the NHS. They were concerned about the risk of increasing antimicrobial resistance through the use of these agents. They agreed that, because of this risk, other means of preventing infection in joint replacement surgery, such as prophylactic antibiotics and ultra-clean air ventilation in operating theatres, should be used, and included a cross reference to the NICE guideline on surgical site infections.
There was little good evidence on the use of ultra-clean air ventilation in operating theatres. Evidence from randomised controlled trials supported ultra-clean air ventilation, but these trials may not fully reflect current practice. Evidence from observational studies supported conventional air ventilation systems, but it was unclear whether these studies followed up participants for more than 2 years, which the committee agreed is the minimum follow‑up period needed to produce an accurate picture of infection rates. It was also unclear whether the registry data used in the studies produced an accurate record of the number of infections over the longer term, and whether prophylactic antibiotics were used in all of the observational studies.
Although the committee noted the limitations in the evidence, they agreed that ultra-clean air ventilation is likely to be more effective at reducing surgical site infections than conventional turbulent air ventilation. They agreed that patient safety is the primary consideration and that infection after a joint replacement is a serious complication. Because of this, and given the uncertainty of the evidence, the committee agreed to recommend that current practice be maintained.
## How the recommendations might affect practice
These recommendations are expected to reduce the routine use of antibiotic or antiseptic agents in wash-out solutions. They are not expected to affect the use of prophylactic antibiotics and ultra-clean air ventilation in operating theatres, which are current practice.
Return to recommendations
# Avoiding implant selection errors
Recommendations 1.6.1 and 1.6.2
## Why the committee made the recommendations
The committee's recommendations were based on their experience and expertise. They reasoned that 2 'stop moments', when theatre staff stop other activity and formally inspect each implant component, would ensure that all components are compatible. The second stop moment provides an extra opportunity to correct an implant selection error before closure. The committee agreed that intraoperative real-time data entry could be considered as a further means of ensuring that mismatched components are identified before implantation. They also agreed that technological solutions might help and made a recommendation for research on avoiding implant selection errors.
## How the recommendations might affect practice
Intraoperative 'stop moments' to check implant components before implantation are common and are not expected to change current practice. Intraoperative real-time data entry is not current practice and, if implemented, is likely to increase theatre time.
Return to recommendations
# Partial and total knee replacement
Recommendation 1.7.1
## Why the committee made the recommendation
One large trial showed no difference between partial and total knee replacement in quality of life, patient-reported outcome measures or revision surgery at 5 years. Partial knee replacement was shown to be more cost effective. However, the trial only reported outcomes after 5 years and the committee were aware that the benefits of total knee replacement may be seen after this. Two studies that compared partial with total knee replacement had limited relevance because they looked at implants that are no longer in use or were restricted to people who had both knees replaced.
The committee agreed that there are advantages and disadvantages to both procedures and this was broadly supported by the evidence. The outcomes for each type of surgery are thought to be similar although recovery after partial knee replacement tends to be faster, with a shorter stay in hospital and less pain during the recovery period. Complications such as infections, blood clots, heart attacks or stroke are rare for both procedures, but are thought to be rarer after partial than total knee replacement. Partial knee replacement leaves more of the original knee intact, but the remaining parts of the knee could develop arthritis and may need to be replaced in the future. The committee were aware that National Joint Registry data indicate a greater likelihood of revision surgery within 10 years after partial knee replacement.
The committee agreed, based on their experience, that different people weigh these relative risks or benefits differently, depending on their personal circumstances and preferences. They therefore recommended that people should be offered a choice of partial or total knee replacement after a discussion of the benefits and risks of each.
## How the recommendation might affect practice
This recommendation may result in an increase in the number of partial knee replacements undertaken. It is expected that all orthopaedic services will need to provide both partial and total knee replacement surgery. The committee noted that total and partial knee replacement are very different types of procedure, and surgeons need to ensure they perform a sufficient number of each procedure every year to ensure good surgical outcomes.
Total knee replacements make up the majority of current practice, so offering a choice of partial or total knee replacement is likely to increase the number of partial knee replacements. The economic evidence largely suggested that partial knee replacements are cost effective compared with total knee replacements. Therefore, increasing the proportion of partial knee replacements is likely to be cost saving.
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# Patella resurfacing
Recommendation 1.7.2
## Why the committee made the recommendation
The committee looked at 3 options: resurfacing, no resurfacing and selective resurfacing. There was not enough clinical evidence to indicate whether any of the options was more beneficial than the others. However, strong economic evidence showed that resurfacing is cost effective compared with no resurfacing over a 10‑year time horizon because of reduced hospital readmissions. Because of the lack of clinical evidence, the committee also made a recommendation for research on selective resurfacing in knee replacement.
## How the recommendation might affect practice
Current practice varies, with resurfacing carried out in around 35% to 40% of knee replacements. This recommendation can be expected to increase the number of knee replacement operations with patella resurfacing. There may be an initial increase in costs because of more costly hospital stays for resurfacing, but this is expected to be more than offset by reduced numbers of hospital readmissions in the long term.
Return to recommendations
# Surgical approaches for primary elective hip replacement
Recommendation 1.8.1
## Why the committee made the recommendation
The committee looked at evidence on 5 surgical approaches for hip replacement: posterior, anterolateral, direct anterior, direct superior and supercapsular percutaneously assisted (SuperPATH). The evidence did not indicate that any of these approaches was more beneficial than any other. The National Joint Registry for 2017 reported that 97% of hip replacements were done using the posterior or anterolateral approach. They concluded that either of these 2 established approaches could be considered, with the choice of approach based on the knowledge and experience of the surgeon and individual patient characteristics.
There was limited evidence on the newer approaches (direct anterior, direct superior and SuperPATH) and the committee made a recommendation for research to investigate surgical approaches in primary elective hip replacement.
## How the recommendation might affect practice
The recommendation reflects most current practice and is not expected to lead to substantial changes.
Return to recommendations
# Shoulder replacement for osteoarthritis with no rotator cuff tear
Recommendation 1.9.1
## Why the committee made the recommendation
Evidence showed that conventional total shoulder replacement provides more overall benefit than humeral hemiarthroplasty. The recommendation is limited to people with adequate glenoid bone because this is necessary for conventional total shoulder replacement to be considered. For people without adequate glenoid bone, another solution, such as reverse shoulder replacement or other surgery, is needed.
The committee agreed that the type of implant should not be specified in the recommendation but should be part of shared decision making between the person having surgery and the surgeon.
Conventional total shoulder replacement is increasingly being offered to people aged under 60 as confidence grows in its long-term durability. There is a lack of evidence in this age group, so the committee made a recommendation for research to compare conventional total shoulder replacement with humeral hemiarthroplasty.
The committee were unable to make a recommendation for practice on reverse total shoulder replacement in this context because of the lack of evidence and their uncertainty about its effectiveness compared with other procedures. The committee noted that although reverse total shoulder replacement was originally designed for people with a rotator cuff tear, it is being used more widely for people with no rotator cuff tear to obviate the need for early revision surgery after rotator cuff failure. The committee made a recommendation for research to compare reverse total shoulder replacement with conventional total shoulder replacement.
## How the recommendation might affect practice
The recommendation reflects most current practice and is not expected to lead to substantial changes.
Return to recommendations
# Shoulder replacement for pain and functional loss for people with a previous proximal humeral fracture
## Why the committee were unable to make recommendations for practice
The committee looked at 3 types of procedures for people with a previous proximal humeral fracture: reverse total shoulder replacement, humeral hemiarthroplasty and conventional total shoulder replacement. They were unable to make recommendations for practice because of a lack of evidence. They made a recommendation for research on procedures for shoulder replacement for people with a previous proximal humeral fracture.
Return to recommendations
# Inpatient rehabilitation
Recommendation 1.10.1
## Why the committee made the recommendation
Evidence in people who have had primary elective hip or knee replacement showed that rehabilitation within 24 hours of surgery, including mobilisation, reduces length of hospital stays. The committee agreed that early discharge improves quality of life and is likely to be cost saving. They acknowledged concern about increased pain from early mobilisation, but noted the evidence showing that, for most people, the benefits outweigh any adverse effects.
The committee agreed that the first contact with the person should be made or led by a physiotherapist or occupational therapist who can assess whether the person is medically unwell or has specific needs. They may delay rehabilitation if clinically necessary. The committee agreed that some aspects of rehabilitation can be provided by a member of the physiotherapy or occupational therapy team with suitable training and support.
In the committee's experience, rehabilitation, including mobilisation, is best started on the day of surgery, but they acknowledged that this is not always possible if the operation is finished late in the day.
There was no evidence on inpatient rehabilitation after shoulder replacement. However, in the committee's experience, the benefits are similar to those seen after hip or knee replacement. They agreed that people who have had shoulder replacement should ambulate within 24 hours of surgery, but mobilisation of the shoulder depends on the orthopaedic team's clinical assessment. The committee noted that the timing of shoulder mobilisation varies widely in practice, with some services advising use of a sling for 10 days and others advising it for 6 weeks. There was no evidence available on when the shoulder should be mobilised so the committee made a recommendation for research on early mobilisation of the shoulder.
## How the recommendation might affect practice
The recommendation largely reflects current practice and is not expected to result in substantial changes. Starting inpatient rehabilitation within 24 hours of surgery might mean that some hospitals will need to reorganise or increase physiotherapy and occupational therapy services to ensure they are available throughout weekends for people who have surgery on a Friday or Saturday. Most hospitals will already have physiotherapy or occupational therapy staff present at weekends; however, in some hospitals they may not be seeing elective hip and knee replacement patients as part of current practice. For those hospitals that do need to take on additional staff, these costs are expected to be offset by a reduction in the length of hospital stays.
Return to recommendations
# Outpatient rehabilitation
Recommendations 1.10.2 to 1.10.6
## Why the committee made the recommendations
The committee agreed that outpatient rehabilitation after hip, knee or shoulder replacement is essential. Evidence suggested that, for people who have had hip or knee replacement, self-directed rehabilitation and supervised rehabilitation are similarly effective. Compared with self-directed rehabilitation, supervised rehabilitation is very costly. The committee agreed that, in their experience, self-directed rehabilitation is effective for most people after hip or knee replacement if undertaken with advice, and ongoing support if needed, from the physiotherapy or occupational therapy team.
There was no evidence to enable the committee to compare self-directed with supervised outpatient rehabilitation for people who have had shoulder replacement, so they recommended that advice may be given on either self-directed or supervised rehabilitation. They also made a recommendation for research on outpatient rehabilitation after shoulder replacement.
The committee agreed, based on their experience, that provision needs to be made for people with additional needs that make self-directed outpatient rehabilitation difficult or who find that it is not meeting their rehabilitation goals, and who would benefit from supervised group or individual rehabilitation. They noted the lack of evidence in this area and made a recommendation for research on supporting rehabilitation for people with additional needs.
## How the recommendations might affect practice
Although the proportions of people having self-directed or supervised rehabilitation after elective joint replacement are not known, it is likely that the recommendations will increase the proportion having self-directed rehabilitation and decrease rehabilitation costs.
Return to recommendations
# Long-term care
Recommendation 1.11.1
## Why the committee were unable to make recommendations on follow-up and monitoring
There was no evidence available to inform recommendations on long-term follow‑up and monitoring after joint replacement surgery. The committee were aware of an ongoing study to investigate follow‑up after hip and knee replacement surgery. That study does not include people who have had shoulder replacement, so the committee made a recommendation for research on follow-up after shoulder replacement.
## Why the committee made the recommendation on referral from primary care
The committee agreed that, in the absence of recommendations on follow‑up and monitoring after hip, knee or shoulder replacement surgery, a recommendation is needed to ensure that people who have problems with their joint replacement are referred to an orthopaedic surgical service. Primary care practitioners are expected to use their clinical judgement to determine the urgency of the referral.
## How the recommendation might affect practice
The recommendation reflects current practice and is not expected to result in changes.
Return to recommendations# Context
Hip, knee and shoulder joint replacements are among the most common orthopaedic operations performed in the UK. Around 90% of joint replacements are done to reduce pain and restore function in joints affected by osteoarthritis.
Surgical procedures for joint replacement vary. In addition, a wide range of joint implants are used. They can be made of metal, plastic or ceramic, and can be fixed into place using a variety of methods. These factors can all affect the longevity of the implant. They also have an effect on short-term outcomes such as postoperative pain and complications.
There are wide variations in the care provided before, during and after joint replacement surgery, particularly the provision of rehabilitation. This care is a vital factor in the success of this surgery.
The guideline aims to ensure that people having joint replacement surgery understand the various options and are offered the best possible care before, during and after their surgery.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Shared decision making and information for people offered hip, knee or shoulder replacement\n\nFollow the recommendations on communication, information and shared decision making in the NICE guidelines on patient experience in adult NHS services and shared decision making when discussing treatment with people offered primary elective hip, knee or shoulder replacement.\n\nSupport shared decision making by discussing treatment options with people offered primary elective hip, knee or shoulder replacement and their families or carers (as appropriate). Include in the discussions:\n\nthe alternatives to joint replacement\n\nthe potential benefits and risks of the available procedures and types of implant for joint replacement, including the possible need for more surgery in the future\n\nthe options for anaesthesia and analgesia, and the potential benefits and risks of each option (see section on anaesthesia and analgesia).\n\nGive people offered primary elective hip, knee or shoulder replacement and their family members or carers (as appropriate) information that is:\n\nspecific to the procedure they are being offered\n\nin a format they can easily understand\n\nprovided starting at the first appointment, then whenever needed throughout their care.\n\nGive information on primary elective hip, knee or shoulder replacement that includes:\n\nwhat to expect before, during and after surgery, including length of hospital stay, recovery and rehabilitation\n\nwho to contact if they have questions or concerns before or after surgery\n\npreparing for surgery, including steps they can take to optimise their recovery (see section on preoperative rehabilitation)\n\npain after surgery and how it can be managed\n\nwound care\n\nreturning to work\n\nreturning to usual activities, for example playing sports, driving and sexual activity.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on shared decision making and information for people offered hip, knee or shoulder replacement\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: information needs.\n\nLoading. Please wait.\n\n## Decision aids for elective joint replacement\n\nThe committee did not make recommendations for specific decision aids for elective joint replacement but recognised that they could have value in shared decision making. They made a recommendation for research on the components of a decision aid.\n\nFor a short explanation of why the committee did not make a recommendation, see the rationale on decision aids for elective joint replacement\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: decision aids.\n\nLoading. Please wait.\n\n# Preoperative rehabilitation\n\n## Preoperative rehabilitation for hip or knee replacement\n\nGive people having hip or knee replacement advice on preoperative rehabilitation. Include advice on:\n\nexercises to do before and after surgery that will aid recovery\n\nlifestyle, including weight management, diet and smoking cessation (see NICE's guidance on lifestyle and wellbeing)\n\nmaximising functional independence and quality of life before and after surgery.\n\n## Preoperative rehabilitation for shoulder replacement\n\nThe committee were unable to make recommendations for practice in this area. They included preoperative rehabilitation for shoulder replacement in their recommendation for research on preoperative rehabilitation.\n\nFor a short explanation of why the committee made the recommendation on preoperative rehabilitation for hip or knee replacement and how it might affect practice, and why they were unable to make recommendations on preoperative rehabilitation for shoulder replacement, see the rationale and impact section on preoperative rehabilitation \xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: preoperative rehabilitation.\n\nLoading. Please wait.\n\n# Anaesthesia and analgesia\n\n## Anaesthesia and analgesia for hip replacement\n\nOffer people having primary elective hip replacement a choice of:\n\nregional anaesthesia in combination with local infiltration analgesia (LIA) or\n\ngeneral anaesthesia in combination with LIA.Consider a nerve block that does not impair motor function as an alternative to LIA in either of the options above, provided it does not delay surgery significantly.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on anaesthesia and analgesia for hip replacement\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: anaesthesia for hip replacement.\n\nLoading. Please wait.\n\n## Anaesthesia and analgesia for knee replacement\n\nOffer people having primary elective knee replacement a choice of:\n\nregional anaesthesia in combination with LIA or\n\ngeneral anaesthesia in combination with LIA.Consider adding a nerve block that does not impair motor function to either of the options above, provided it does not delay surgery significantly.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on anaesthesia and analgesia for knee replacement\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: anaesthesia for knee replacement\n\nLoading. Please wait.\n\n## Anaesthesia and analgesia for shoulder replacement\n\nDiscuss the options for anaesthesia and analgesia with people having primary elective shoulder replacement, including general anaesthesia, regional anaesthesia, local infiltration analgesia and nerve blocks.\n\nThe committee were unable to recommend specific options for anaesthesia and analgesia for shoulder replacement. They made recommendations for research on supplementary anaesthesia, and on regional compared with general anaesthesia or a combination in elective shoulder replacement.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on anaesthesia and analgesia for shoulder replacement\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: anaesthesia for shoulder replacement.\n\nLoading. Please wait.\n\n# Tranexamic acid to minimise blood loss\n\nIn June 2020, tranexamic acid solution for injection was off label for topical (intra-articular) use. See NICE's information on prescribing medicines.\n\nIn these recommendations 'renal impairment' refers to mild to moderate renal impairment. See the summary of product characteristics for dosage reductions according to serum creatinine level. Tranexamic acid is contraindicated for people with severe renal impairment.\n\nFor primary elective hip or knee replacement:\n\nGive intravenous tranexamic acid.\n\nIf there is no renal impairment, also apply 1\xa0g to\xa02\xa0g of topical (intra-articular) tranexamic acid diluted in saline after the final wash-out and before wound closure. Ensure that the total combined dose of tranexamic acid does not exceed 3\xa0g.\n\nIf there is renal impairment, give a reduced dose of intravenous tranexamic acid on its own.For primary elective shoulder replacement:\n\nConsider intravenous tranexamic acid.\n\nIf there is no renal impairment, consider 1\xa0g\xa0to\xa02\xa0g of topical (intra-articular) tranexamic acid diluted in saline applied after the final wash-out and before wound closure. Ensure that the total combined dose of tranexamic acid does not exceed 3\xa0g.\n\nIf there is renal impairment and tranexamic acid is used, give a reduced dose of intravenous tranexamic acid on its own.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on tranexamic acid to minimise blood loss\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: tranexamic acid to minimise blood loss.\n\nLoading. Please wait.\n\n# Preventing infections\n\n## Antibiotic or antiseptic agents in wound wash-out solutions\n\nFollow the recommendations on antibiotic prophylaxis, wound irrigation and intracavity lavage, and antiseptics and antibiotics before wound closure in the NICE guideline on surgical site infections, for people having primary elective hip, knee or shoulder replacement.\n\n## Ultra-clean air ventilation in operating theatres\n\nUse ultra-clean air ventilation in operating theatres for primary hip, knee or shoulder elective joint replacement.\n\nFor a short explanation of why the committee made these recommendations see and how they might affect practice, see the rationale and impact section on preventing infections\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: wound lavage and evidence review\xa0I: ultra-clean air.\n\nLoading. Please wait.\n\n# Avoiding implant selection errors\n\nUse 2 intraoperative 'stop moments', 1\xa0before implantation and 1\xa0before wound closure, to check all implant details and ensure compatibility of each component.\n\nConsider intraoperative real-time data entry before implantation using a system that provides an alert of mismatched implant components, such as the National Joint Registry database.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on avoiding implant selection errors\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0J: wrong implant selection.\n\nLoading. Please wait.\n\n# Procedures for primary elective knee replacement\n\n## Partial and total knee replacement\n\nOffer a choice of partial or total knee replacement to people with isolated medial compartmental osteoarthritis. Discuss the potential benefits and risks of each option with the person.\n\nFor a short explanation of why the committee made the recommendation and how it might affect practice, see the rationale and impact section on partial and total knee replacement\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0K: total knee replacement.\n\nLoading. Please wait.\n\n## Patella resurfacing\n\nOffer resurfacing of the patella to people having primary elective total knee replacement.\n\nFor a short explanation of why the committee made the recommendation and how it might affect practice, see the rationale and impact section on patella resurfacing\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0L: patella resurfacing.\n\nLoading. Please wait.\n\n# Surgical approaches and implants for primary elective hip replacement\n\n## Surgical approaches for primary elective hip replacement\n\nConsider a posterior or anterolateral approach for primary elective hip replacement.\n\nThe committee were unable to make recommendations on the direct anterior, direct superior and supercapsular percutaneously assisted (SuperPATH) surgical approaches. They made a recommendation for research on surgical approaches in primary elective hip replacement.\n\nFor a short explanation of why the committee made the recommendation on surgical approaches for primary elective hip replacement and how it might affect practice and why they were unable to make recommendations on the direct anterior, direct superior and SuperPATH approaches, see the rationale and impact section on surgical approaches for primary elective hip replacement\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0M: hip replacement approach\n\nLoading. Please wait.\n\n## Implants for primary elective hip replacement\n\nFor NICE technology appraisal guidance on implants for primary elective hip replacement see the NICE topic page on joint replacement.\n\n# Procedures for primary elective shoulder replacement\n\n## Shoulder replacement for osteoarthritis with no rotator cuff tear\n\nIf glenoid bone is adequate, offer conventional total shoulder replacement to people having primary elective shoulder replacement for osteoarthritis with no rotator cuff tear.\n\nFor a short explanation of why the committee made the recommendation and how it might affect practice, see the rationale and impact section on shoulder replacement for osteoarthritis with no rotator cuff tear\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0N: shoulder replacement – intact rotator cuff.\n\nLoading. Please wait.\n\n## Shoulder replacement for pain and functional loss for people with a previous proximal humeral fracture\n\nThe committee were unable to make recommendations for practice in this area. They made a recommendation for research on procedures for shoulder replacement for people with a previous proximal humeral fracture.\n\nFor a short explanation of why the committee did not make a recommendation, see the rationale on shoulder replacement for pain and functional loss for people with a previous proximal humeral fracture\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0O: hemiarthroplasty – proximal humeral fracture.\n\nLoading. Please wait.\n\n# Postoperative rehabilitation\n\n## Inpatient rehabilitation\n\nA physiotherapist or occupational therapist should offer rehabilitation, on the day of surgery if possible and no more than 24\xa0hours after surgery, to people who have had a primary elective hip, knee or shoulder replacement. Rehabilitation should include:\n\nadvice on managing activities of daily living and\n\nhome exercise programmes and\n\nmobilisation for people who have had knee or hip replacement or\n\nambulation for people who have had shoulder replacement.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on inpatient rehabilitation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0P: inpatient hip and knee postoperative rehabilitation and evidence review\xa0Q: inpatient shoulder postoperative rehabilitation.\n\nLoading. Please wait.\n\n## Outpatient rehabilitation\n\nFor people who have had primary elective hip or knee replacement:\n\na member of the physiotherapy or occupational therapy team should give advice on self-directed rehabilitation\n\nthe advice should be given before the person leaves hospital\n\nthe advice should be adjusted in line with recommendations\xa01.10.5 and 1.10.6 if needed.\n\nFor people who have had primary elective shoulder replacement:\n\na member of the physiotherapy or occupational therapy team should give advice on:\n\n\n\nself-directed rehabilitation or\n\nsupervised group rehabilitation or\n\nindividual rehabilitation\n\n\n\nthe advice should be given before the person leaves hospital\n\nthe advice should be adjusted in line with recommendations\xa01.10.5 and 1.10.6 if needed.\n\nEnsure that people who are undertaking self-directed rehabilitation have:\n\na clear understanding of their rehabilitation goals and the importance of doing the exercises prescribed to achieve these goals\n\na point of contact for advice and support.\n\nOffer supervised group or individual outpatient rehabilitation to people who:\n\nhave difficulties managing activities of daily living or\n\nhave ongoing functional impairment leading to specific rehabilitation needs or\n\nfind that self-directed rehabilitation is not meeting their rehabilitation goals.\n\nConsider supervised group or individual outpatient rehabilitation for people with cognitive impairment.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on outpatient rehabilitation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0R: outpatient hip and knee postoperative rehabilitation and evidence review\xa0S: outpatient rehabilitation after shoulder replacement.\n\nLoading. Please wait.\n\n# Long-term care\n\n## Follow-up and monitoring\n\nThe committee were unable to make recommendations for practice in this area. They made a recommendation for research on follow-up.\n\n## Referral from primary care\n\nPrimary care practitioners should refer people who develop new or worsening pain, limp or loss of function related to their joint replacement to an orthopaedic surgical service.\n\nFor a short explanation of why the committee did not make a recommendation, see the rationale on follow-up and monitoring in secondary care\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0T: long-term follow-up and monitoring\n\nLoading. Please wait.", 'Recommendations for research': 'The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Preoperative rehabilitation\n\nWhat is the clinical and cost effectiveness of preoperative rehabilitation given at least 2\xa0months before hip, knee or shoulder replacement?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on preoperative rehabilitation\xa0.\n\nFull details of the research recommendation are in evidence review\xa0C: preoperative rehabilitation.\n\nLoading. Please wait.\n\n## Information for people having a joint replacement\n\nHow should information for people having joint replacement surgery be delivered?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on information for people having a joint replacement\xa0.\n\nFull details of the research recommendation are in evidence review\xa0A: information needs.\n\nLoading. Please wait.\n\n## Early mobilisation of the shoulder\n\nIs early mobilisation of the shoulder after primary elective shoulder replacement more effective than delayed mobilisation in restoring rapid return of function and relieving pain?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on inpatient rehabilitation\xa0.\n\nFull details of the research recommendation are in evidence review\xa0Q: inpatient shoulder postoperative rehabilitation.\n\nLoading. Please wait.\n\n## Conventional compared with reverse total shoulder arthroplasty\n\nWhat is the clinical and cost effectiveness of conventional compared with reverse total shoulder arthroplasty for adults having primary elective shoulder replacement for osteoarthritis with no rotator cuff tear?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on shoulder arthroplasty\xa0.\n\nFull details of the research recommendation are in evidence review\xa0N: shoulder replacement – intact rotator cuff.\n\nLoading. Please wait.\n\n## Analgesia for knee replacement\n\nWhat is the clinical and cost effectiveness of adding a nerve block to regional or general anaesthesia, in combination with local infiltration analgesia, for primary elective knee replacements?\n\nFor a short explanation of why the committee made the research recommendation, see the rationale on analgesia for knee replacement\xa0.\n\nFull details of the research recommendation are in evidence review\xa0E: anaesthesia for knee replacement.\n\nLoading. Please wait.\n\n## Selective resurfacing in knee replacement\n\nIn adults having elective knee replacement, what is the clinical and cost effectiveness of total knee replacement with patella resurfacing compared with selective resurfacing?\n\nFor a short explanation of why the committee made the research recommendation, see the rationale on resurfacing in knee replacement\xa0.\n\nFull details of the research recommendation are in evidence review\xa0L: patella resurfacing.\n\nLoading. Please wait.\n\n# Other recommendations for research\n\n## Decision aids\n\nWhat are the components of a decision aid to support people referred for elective joint replacement in making decisions about their treatment (for example, the type of procedure, timing and implant choice)?\n\nFor a short explanation of why the committee made the research recommendation, see the rationale on decision aids\xa0.\n\nFull details of the research recommendation are in evidence review\xa0B: decision aids.\n\nLoading. Please wait.\n\n## Supplementary analgesia or anaesthesia in elective shoulder replacement\n\nIn adults having elective shoulder joint replacement with general anaesthesia, what is the clinical and cost effectiveness of supplementary local infiltration analgesia, a nerve block or regional anaesthesia?\n\nFor a short explanation of why the committee made the research recommendation, see the rationale on supplementary analgesia or anaesthesia in elective shoulder replacement\xa0.\n\nFull details of the research recommendation are in evidence review\xa0F: anaesthesia for shoulder replacement.\n\nLoading. Please wait.\n\n## Regional compared with general anaesthesia or a combination in elective shoulder replacement\n\nIn adults having elective shoulder joint replacement, what is the relative clinical and cost effectiveness of general anaesthesia, regional anaesthesia, and general combined with regional anaesthesia?\n\nFor a short explanation of why the committee made the research recommendation, on, see the rationale on regional compared with general anaesthesia, or a combination, in elective shoulder replacement\xa0.\n\nFull details of the research recommendation are in evidence review\xa0F: anaesthesia for shoulder replacement.\n\nLoading. Please wait.\n\n## Avoiding implant selection errors\n\nWhat is the most effective technological solution for minimising wrong implant selection during joint replacement surgery?\n\nFor a short explanation of why the committee made the research recommendation, see the rationale on avoiding implant selection errors\xa0.\n\nFull details of the research recommendation are in evidence review\xa0J: wrong implant selection.\n\nLoading. Please wait.\n\n## Surgical approaches in primary elective hip replacement\n\nDo the direct anterior, direct superior and supercapsular percutaneously assisted (SuperPATH) approaches to hip replacement improve patient-recorded outcome measures and reduce length of hospital stays, revision rates, neurological complications and surgical site infections compared with the posterior and anterolateral approaches?\n\nFor a short explanation of why the committee made the research recommendation, see the rationale on surgical approaches in primary elective hip replacement\xa0.\n\nFull details of the research recommendation are in evidence review\xa0M: hip replacement approach.\n\nLoading. Please wait.\n\n## Conventional total shoulder replacement compared with humeral hemiarthroplasty for people aged under\xa060\n\nWhat is the clinical and cost effectiveness of humeral hemiarthroplasty compared with conventional total shoulder replacement for adults aged under\xa060 having primary elective shoulder replacement for osteoarthritis with no rotator cuff tear?\n\nFor a short explanation of why the committee made the research recommendation, see the rationale on conventional total shoulder replacement compared with humeral hemiarthroplasty for people aged under 60\xa0.\n\nFull details of the research recommendation are in evidence review\xa0N: shoulder replacement – intact rotator cuff.\n\nLoading. Please wait.\n\n## Procedures for shoulder replacement for people with a previous proximal humeral fracture\n\nIn adults having primary elective shoulder replacement for pain and functional loss after a previous proximal humeral fracture (not acute trauma), what is the clinical and cost effectiveness of reverse total shoulder replacement compared with humeral hemiarthroplasty?\n\nFor a short explanation of why the committee made the research recommendation, see the rationale on procedures for shoulder replacement for people with a previous proximal humeral fracture\xa0.\n\nFull details of the research recommendation are in evidence review\xa0O: hemiarthroplasty – proximal humeral fracture.\n\nLoading. Please wait.\n\n## Supporting rehabilitation after hip, knee or shoulder replacement for people with additional needs\n\nWhat are the best ways to support rehabilitation after hip knee or shoulder replacement for people with additional needs (such as people with dementia, a learning difficulty or multiple disabling medical comorbidities)?\n\nFor a short explanation of why the committee made the research recommendation, see the rationale on supporting rehabilitation after hip, knee or shoulder replacement for people with additional needs\xa0.\n\nFull details of the research recommendation are in evidence review\xa0R: outpatient hip and knee postoperative rehabilitation.\n\nLoading. Please wait.\n\n## Outpatient rehabilitation after shoulder replacement\n\nFor people who have had primary elective shoulder replacement, does self-directed, supervised group or supervised individual rehabilitation produce the most improvement in health-related quality of life 2\xa0years after surgery?\n\nFor a short explanation of why the committee made the research recommendation, see the rationale on postoperative rehabilitation after shoulder replacement\xa0.\n\nFull details of the research recommendation are in evidence review\xa0S: outpatient rehabilitation after shoulder replacement.\n\nLoading. Please wait.\n\n## Follow-up after shoulder replacement\n\nWhat is the optimum time between follow‑up appointments for people who have had shoulder replacement, who should lead follow‑up and how this should be organised between hospital and community care?\n\nFor a short explanation of why the committee made the research recommendation, see the rationale on follow up after shoulder replacement\xa0.\n\nFull details of the research recommendation are in evidence review\xa0T: long-term follow-up and monitoring.\n\nLoading. Please wait.', 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.\n\n# Shared decision making and information for people offered hip, knee or shoulder replacement\n\nRecommendations\xa01.1.1 to\xa01.1.4\n\n## Why the committee made the recommendations\n\nThe NICE guideline on patient experience in adult NHS services describes shared decision making as part of enabling patients to actively participate in their care. It includes recommendations on giving information, encouraging discussion and supporting people to use the information to make choices about their care. The committee agreed, based on their experience, that people offered hip, knee or shoulder replacement need specific information on the treatment options that are available for them, given from their first appointment and whenever needed throughout their care, to enable them to express their needs and preferences.\n\nThe committee's experience reflected evidence from studies using interviews and focus groups that highlighted the importance of ensuring that the information given to people is clear and easily understandable to them. The studies showed that specific areas of patient concern included preparing for surgery, managing postoperative pain and aftercare at home, expected recovery time and returning to work. The committee also drew on their own experience of the information that people offered hip, knee or shoulder replacement need.\n\nThe committee noted uncertainty about the best way to deliver information and made a recommendation for research on information for people having a joint replacement.\n\n## How the recommendations might affect practice\n\nDiscussions with people having elective joint replacement are current practice, although different members of the orthopaedic multidisciplinary team may be involved, depending on local arrangements and the person's specific needs. The recommendations are not expected to result in substantial changes to this.\n\nReturn to recommendations\n\n# Decision aids for elective joint replacement\n\n## Why the committee were unable to make recommendations for practice\n\nThe committee agreed that decision aids can be a useful way of helping people offered joint replacement surgery understand their options and make decisions about their care. Evidence from studies of decision aids for joint replacement showed that their content varied widely, and this led the committee to question what the components of a decision aid should be. Their view is that a decision aid should not simply be a means of providing information but should actively help people to participate in making decisions about their care. Because of the wide variation in the decision aids used in the studies, it was not possible to compare them with each other. The committee were therefore unable to recommend any particular decision aid for joint replacement. To investigate the question of what defines a decision aid for elective joint replacement, the committee made a recommendation for research on decision aids.\n\nReturn to recommendations\n\n# Preoperative rehabilitation\n\nRecommendation\xa01.2.1\n\n## Why the committee made the recommendation\n\nThe committee agreed, based on their experience, that preoperative rehabilitation helps to prepare people for surgery, increases their ability to manage any complications of surgery, promotes understanding and engagement with postoperative rehabilitation and prepares people for life with a joint replacement.\n\nEvidence showed that preoperative rehabilitation reduces the length of hospital stays for people having a hip or knee replacement, although this was for intensive rehabilitation programmes and was from settings where hospital stays are usually longer than in the NHS.\n\nBased on the evidence and their own experience, the committee agreed that preoperative rehabilitation for people having hip or knee replacement should include advice on exercises before and after surgery, lifestyle and ways to maximise independence and quality of life.\n\nThere was no evidence on preoperative rehabilitation for people having shoulder replacement. The committee noted that preoperative exercises to improve muscle function in the affected limb are often severely limited by pain for people having shoulder replacement, and agreed that the benefits seen in people having hip and knee replacement might not apply to those having shoulder replacement. They included shoulder replacement in their recommendation for research on preoperative rehabilitation.\n\n## How the recommendation might affect practice\n\nCurrent practice varies widely, ranging from no preoperative rehabilitation to comprehensive individualised preoperative rehabilitation programmes. However, most services offer preoperative rehabilitation advice to everyone having hip or knee replacement, so this recommendation is not expected to lead to a substantial change in practice. For some services, providing information, exercise and lifestyle advice may increase the time needed from the orthopaedic multidisciplinary team. However, this cost can be expected to be offset by reductions in the length of hospital stays.\n\nReturn to recommendations\n\n# Anaesthesia and analgesia for hip replacement\n\nRecommendation 1.3.1\n\n## Why the committee made the recommendation\n\nEvidence showed that regional and general anaesthesia are equally effective for people having hip replacement surgery, so the committee recommended that a choice should be offered. There was no evidence to support a combination of regional and general anaesthesia.\n\nBased on their experience, the committee agreed that using local or regional analgesic techniques in combination with regional or general anaesthesia reduces postoperative pain. Clinical evidence showed that, when used with general or regional anaesthesia, both local infiltration analgesia (LIA) and nerve blocks are beneficial and there was no clinical evidence to suggest that either is more beneficial than the other. However, the committee noted that some nerve blocks impair motor function and agreed that these should be avoided in hip replacement because they can delay mobilisation.\n\nEconomic evidence showed that LIA is cost effective. For nerve blocks, the evidence on costs suggested that they are cost effective if they do not delay surgery by more than 5\xa0minutes.\n\n## How the recommendation might affect practice\n\nAll orthopaedic units currently offer a choice of general or regional anaesthesia. Most augment this with either LIA or a nerve block. Although the cost of nerve blocks varies, it is not expected that services currently offering LIA will change to nerve blocks. This recommendation is unlikely to lead to significant changes in practice.\n\nReturn to recommendations\n\n# Anaesthesia and analgesia for knee replacement\n\nRecommendation\xa01.3.2\n\n## Why the committee made the recommendation\n\nEvidence showed that regional and general anaesthesia are equally effective for people having knee replacement surgery, so the committee recommended that a choice should be offered. There was no evidence to support a combination of regional and general anaesthesia.\n\nEvidence also showed that adding local infiltration analgesia (LIA) or a nerve block to regional or general anaesthesia is beneficial, and that adding both LIA and a nerve block to regional anaesthesia is more beneficial than adding either on its own, although this benefit was less pronounced with general anaesthesia.\n\nThe committee noted that some nerve blocks impair motor function and agreed that these should be avoided because they can delay mobilisation. Adductor canal nerve blocks allow for a better range of movement sooner after surgery and are now more commonly used than femoral blocks, but the evidence on them was limited.\n\nEconomic evidence showed that LIA is cost effective. For nerve blocks, the evidence on costs suggested that they are cost effective if they do not delay surgery by more than 5\xa0minutes. Because of the uncertainty about the cost effectiveness of nerve blocks added to LIA to augment anaesthesia in knee replacement, the committee made a recommendation for research on analgesia for knee replacement.\n\n## How the recommendation might affect practice\n\nIn current practice, regional anaesthesia for knee replacement surgery is usually augmented with LIA, a nerve block, or both. The recommendation might lead services that currently augment anaesthesia with nerve blocks, either together with LIA or on their own, to change to augmenting with LIA only or to arrange services so that administering the nerve block does not delay surgery. Services that currently augment anaesthesia with an LIA only are not expected to see a substantial change in practice.\n\nReturn to recommendations\n\n# Anaesthesia and analgesia for shoulder replacement\n\nRecommendation\xa01.3.3\n\n## Why the committee made the recommendation\n\nThere was not enough evidence to support recommendations on specific types of anaesthesia for shoulder replacement. Because of this uncertainty, the committee stressed the importance of discussing the options with people having this type of joint replacement. Although small benefits were seen in studies combining general anaesthesia with LIA and regional anaesthesia with LIA, they were offset by phrenic nerve palsy events. The committee made recommendations for research on supplementary analgesia or anaesthesia in elective shoulder replacement and regional, general, or regional with general anaesthesia in elective shoulder replacement. They noted that using regional anaesthesia alone has the potential to increase day-case shoulder replacement surgery.\n\n## How the recommendation might affect practice\n\nThis recommendation is not expected to change current practice.\n\nReturn to recommendations\n\n# Tranexamic acid to minimise blood loss\n\nRecommendations\xa01.4.1 and\xa01.4.2\n\n## Why the committee made the recommendations\n\nGood evidence showed that, in people having primary elective hip or knee replacement, topical (intra-articular) tranexamic acid in combination with intravenous tranexamic acid reduces the number of blood transfusions needed when compared with topical or intravenous tranexamic acid alone. Although 1\xa0study suggested that combining topical with oral tranexamic acid is the most clinically and cost-effective administration method, this evidence was not strong enough to support a recommendation for this combination.\n\nEvidence in people having primary elective shoulder replacement also showed a benefit from tranexamic acid but did not address combined administration. However, the committee reasoned that the benefits seen in hip and knee replacement could also apply in shoulder replacement. They agreed that, although there may not be the same benefits in terms of reduced blood transfusions in shoulder replacement surgery, tranexamic acid reduces bleeding, which lessens fatigue and nausea. The committee noted that tranexamic acid is an inexpensive treatment.\n\nThe BNF advises a reduced dose of intravenous tranexamic acid for people with renal impairment. Because the absorption is uncertain when tranexamic acid is administered topically, the committee agreed that it should be given only intravenously to people with renal impairment.\n\n## How the recommendations might affect practice\n\nAlthough the use of tranexamic acid is widespread in current practice, the method of administration varies. In the committee's experience, topical (intra-articular) tranexamic acid is commonly used in combination with intravenous tranexamic acid in hip and knee replacements, but not in shoulder replacements. Increased use of this combination in shoulder replacements might increase doses and the use of disposables. However, the associated costs are expected to be more than offset by the savings produced by a reduced need for blood transfusions in hip and knee replacements and reduced bleeding in shoulder replacements.\n\nReturn to recommendations\n\n# Preventing infections\n\nRecommendations 1.5.1 and 1.5.2\n\n## Why the committee made the recommendations\n\nNo evidence was found on adding antibiotic or antiseptic agents to saline wound wash-out solution to reduce surgical site infections in people having primary elective joint replacement. The committee acknowledged that washing the wound with saline is common practice and is used to improve visibility of the operative site for the surgeon. They noted that the use of antibiotic and antiseptic agents in wash-out solutions varies across the NHS. They were concerned about the risk of increasing antimicrobial resistance through the use of these agents. They agreed that, because of this risk, other means of preventing infection in joint replacement surgery, such as prophylactic antibiotics and ultra-clean air ventilation in operating theatres, should be used, and included a cross reference to the NICE guideline on surgical site infections.\n\nThere was little good evidence on the use of ultra-clean air ventilation in operating theatres. Evidence from randomised controlled trials supported ultra-clean air ventilation, but these trials may not fully reflect current practice. Evidence from observational studies supported conventional air ventilation systems, but it was unclear whether these studies followed up participants for more than 2\xa0years, which the committee agreed is the minimum follow‑up period needed to produce an accurate picture of infection rates. It was also unclear whether the registry data used in the studies produced an accurate record of the number of infections over the longer term, and whether prophylactic antibiotics were used in all of the observational studies.\n\nAlthough the committee noted the limitations in the evidence, they agreed that ultra-clean air ventilation is likely to be more effective at reducing surgical site infections than conventional turbulent air ventilation. They agreed that patient safety is the primary consideration and that infection after a joint replacement is a serious complication. Because of this, and given the uncertainty of the evidence, the committee agreed to recommend that current practice be maintained.\n\n## How the recommendations might affect practice\n\nThese recommendations are expected to reduce the routine use of antibiotic or antiseptic agents in wash-out solutions. They are not expected to affect the use of prophylactic antibiotics and ultra-clean air ventilation in operating theatres, which are current practice.\n\nReturn to recommendations\n\n# Avoiding implant selection errors\n\nRecommendations\xa01.6.1 and\xa01.6.2\n\n## Why the committee made the recommendations\n\nThe committee's recommendations were based on their experience and expertise. They reasoned that 2\xa0'stop moments', when theatre staff stop other activity and formally inspect each implant component, would ensure that all components are compatible. The second stop moment provides an extra opportunity to correct an implant selection error before closure. The committee agreed that intraoperative real-time data entry could be considered as a further means of ensuring that mismatched components are identified before implantation. They also agreed that technological solutions might help and made a recommendation for research on avoiding implant selection errors.\n\n## How the recommendations might affect practice\n\nIntraoperative 'stop moments' to check implant components before implantation are common and are not expected to change current practice. Intraoperative real-time data entry is not current practice and, if implemented, is likely to increase theatre time.\n\nReturn to recommendations\n\n# Partial and total knee replacement\n\nRecommendation 1.7.1\n\n## Why the committee made the recommendation\n\nOne large trial showed no difference between partial and total knee replacement in quality of life, patient-reported outcome measures or revision surgery at 5\xa0years. Partial knee replacement was shown to be more cost effective. However, the trial only reported outcomes after 5\xa0years and the committee were aware that the benefits of total knee replacement may be seen after this. Two studies that compared partial with total knee replacement had limited relevance because they looked at implants that are no longer in use or were restricted to people who had both knees replaced.\n\nThe committee agreed that there are advantages and disadvantages to both procedures and this was broadly supported by the evidence. The outcomes for each type of surgery are thought to be similar although recovery after partial knee replacement tends to be faster, with a shorter stay in hospital and less pain during the recovery period. Complications such as infections, blood clots, heart attacks or stroke are rare for both procedures, but are thought to be rarer after partial than total knee replacement. Partial knee replacement leaves more of the original knee intact, but the remaining parts of the knee could develop arthritis and may need to be replaced in the future. The committee were aware that National Joint Registry data indicate a greater likelihood of revision surgery within 10\xa0years after partial knee replacement.\n\nThe committee agreed, based on their experience, that different people weigh these relative risks or benefits differently, depending on their personal circumstances and preferences. They therefore recommended that people should be offered a choice of partial or total knee replacement after a discussion of the benefits and risks of each.\n\n## How the recommendation might affect practice\n\nThis recommendation may result in an increase in the number of partial knee replacements undertaken. It is expected that all orthopaedic services will need to provide both partial and total knee replacement surgery. The committee noted that total and partial knee replacement are very different types of procedure, and surgeons need to ensure they perform a sufficient number of each procedure every year to ensure good surgical outcomes.\n\nTotal knee replacements make up the majority of current practice, so offering a choice of partial or total knee replacement is likely to increase the number of partial knee replacements. The economic evidence largely suggested that partial knee replacements are cost effective compared with total knee replacements. Therefore, increasing the proportion of partial knee replacements is likely to be cost saving.\n\nReturn to recommendations\n\n# Patella resurfacing\n\nRecommendation 1.7.2\n\n## Why the committee made the recommendation\n\nThe committee looked at 3\xa0options: resurfacing, no resurfacing and selective resurfacing. There was not enough clinical evidence to indicate whether any of the options was more beneficial than the others. However, strong economic evidence showed that resurfacing is cost effective compared with no resurfacing over a 10‑year time horizon because of reduced hospital readmissions. Because of the lack of clinical evidence, the committee also made a recommendation for research on selective resurfacing in knee replacement.\n\n## How the recommendation might affect practice\n\nCurrent practice varies, with resurfacing carried out in around 35% to 40% of knee replacements. This recommendation can be expected to increase the number of knee replacement operations with patella resurfacing. There may be an initial increase in costs because of more costly hospital stays for resurfacing, but this is expected to be more than offset by reduced numbers of hospital readmissions in the long term.\n\nReturn to recommendations\n\n# Surgical approaches for primary elective hip replacement\n\nRecommendation 1.8.1\n\n## Why the committee made the recommendation\n\nThe committee looked at evidence on 5\xa0surgical approaches for hip replacement: posterior, anterolateral, direct anterior, direct superior and supercapsular percutaneously assisted (SuperPATH). The evidence did not indicate that any of these approaches was more beneficial than any other. The National Joint Registry for 2017 reported that 97% of hip replacements were done using the posterior or anterolateral approach. They concluded that either of these 2\xa0established approaches could be considered, with the choice of approach based on the knowledge and experience of the surgeon and individual patient characteristics.\n\nThere was limited evidence on the newer approaches (direct anterior, direct superior and SuperPATH) and the committee made a recommendation for research to investigate surgical approaches in primary elective hip replacement.\n\n## How the recommendation might affect practice\n\nThe recommendation reflects most current practice and is not expected to lead to substantial changes.\n\nReturn to recommendations\n\n# Shoulder replacement for osteoarthritis with no rotator cuff tear\n\nRecommendation\xa01.9.1\n\n## Why the committee made the recommendation\n\nEvidence showed that conventional total shoulder replacement provides more overall benefit than humeral hemiarthroplasty. The recommendation is limited to people with adequate glenoid bone because this is necessary for conventional total shoulder replacement to be considered. For people without adequate glenoid bone, another solution, such as reverse shoulder replacement or other surgery, is needed.\n\nThe committee agreed that the type of implant should not be specified in the recommendation but should be part of shared decision making between the person having surgery and the surgeon.\n\nConventional total shoulder replacement is increasingly being offered to people aged under\xa060 as confidence grows in its long-term durability. There is a lack of evidence in this age group, so the committee made a recommendation for research to compare conventional total shoulder replacement with humeral hemiarthroplasty.\n\nThe committee were unable to make a recommendation for practice on reverse total shoulder replacement in this context because of the lack of evidence and their uncertainty about its effectiveness compared with other procedures. The committee noted that although reverse total shoulder replacement was originally designed for people with a rotator cuff tear, it is being used more widely for people with no rotator cuff tear to obviate the need for early revision surgery after rotator cuff failure. The committee made a recommendation for research to compare reverse total shoulder replacement with conventional total shoulder replacement.\n\n## How the recommendation might affect practice\n\nThe recommendation reflects most current practice and is not expected to lead to substantial changes.\n\nReturn to recommendations\n\n# Shoulder replacement for pain and functional loss for people with a previous proximal humeral fracture\n\n## Why the committee were unable to make recommendations for practice\n\nThe committee looked at 3\xa0types of procedures for people with a previous proximal humeral fracture: reverse total shoulder replacement, humeral hemiarthroplasty and conventional total shoulder replacement. They were unable to make recommendations for practice because of a lack of evidence. They made a recommendation for research on procedures for shoulder replacement for people with a previous proximal humeral fracture.\n\nReturn to recommendations\n\n# Inpatient rehabilitation\n\nRecommendation\xa01.10.1\n\n## Why the committee made the recommendation\n\nEvidence in people who have had primary elective hip or knee replacement showed that rehabilitation within 24\xa0hours of surgery, including mobilisation, reduces length of hospital stays. The committee agreed that early discharge improves quality of life and is likely to be cost saving. They acknowledged concern about increased pain from early mobilisation, but noted the evidence showing that, for most people, the benefits outweigh any adverse effects.\n\nThe committee agreed that the first contact with the person should be made or led by a physiotherapist or occupational therapist who can assess whether the person is medically unwell or has specific needs. They may delay rehabilitation if clinically necessary. The committee agreed that some aspects of rehabilitation can be provided by a member of the physiotherapy or occupational therapy team with suitable training and support.\n\nIn the committee's experience, rehabilitation, including mobilisation, is best started on the day of surgery, but they acknowledged that this is not always possible if the operation is finished late in the day.\n\nThere was no evidence on inpatient rehabilitation after shoulder replacement. However, in the committee's experience, the benefits are similar to those seen after hip or knee replacement. They agreed that people who have had shoulder replacement should ambulate within 24\xa0hours of surgery, but mobilisation of the shoulder depends on the orthopaedic team's clinical assessment. The committee noted that the timing of shoulder mobilisation varies widely in practice, with some services advising use of a sling for 10\xa0days and others advising it for 6\xa0weeks. There was no evidence available on when the shoulder should be mobilised so the committee made a recommendation for research on early mobilisation of the shoulder.\n\n## How the recommendation might affect practice\n\nThe recommendation largely reflects current practice and is not expected to result in substantial changes. Starting inpatient rehabilitation within 24\xa0hours of surgery might mean that some hospitals will need to reorganise or increase physiotherapy and occupational therapy services to ensure they are available throughout weekends for people who have surgery on a Friday or Saturday. Most hospitals will already have physiotherapy or occupational therapy staff present at weekends; however, in some hospitals they may not be seeing elective hip and knee replacement patients as part of current practice. For those hospitals that do need to take on additional staff, these costs are expected to be offset by a reduction in the length of hospital stays.\n\nReturn to recommendations\n\n# Outpatient rehabilitation\n\nRecommendations\xa01.10.2 to\xa01.10.6\n\n## Why the committee made the recommendations\n\nThe committee agreed that outpatient rehabilitation after hip, knee or shoulder replacement is essential. Evidence suggested that, for people who have had hip or knee replacement, self-directed rehabilitation and supervised rehabilitation are similarly effective. Compared with self-directed rehabilitation, supervised rehabilitation is very costly. The committee agreed that, in their experience, self-directed rehabilitation is effective for most people after hip or knee replacement if undertaken with advice, and ongoing support if needed, from the physiotherapy or occupational therapy team.\n\nThere was no evidence to enable the committee to compare self-directed with supervised outpatient rehabilitation for people who have had shoulder replacement, so they recommended that advice may be given on either self-directed or supervised rehabilitation. They also made a recommendation for research on outpatient rehabilitation after shoulder replacement.\n\nThe committee agreed, based on their experience, that provision needs to be made for people with additional needs that make self-directed outpatient rehabilitation difficult or who find that it is not meeting their rehabilitation goals, and who would benefit from supervised group or individual rehabilitation. They noted the lack of evidence in this area and made a recommendation for research on supporting rehabilitation for people with additional needs.\n\n## How the recommendations might affect practice\n\nAlthough the proportions of people having self-directed or supervised rehabilitation after elective joint replacement are not known, it is likely that the recommendations will increase the proportion having self-directed rehabilitation and decrease rehabilitation costs.\n\nReturn to recommendations\n\n# Long-term care\n\nRecommendation 1.11.1\n\n## Why the committee were unable to make recommendations on follow-up and monitoring\n\nThere was no evidence available to inform recommendations on long-term follow‑up and monitoring after joint replacement surgery. The committee were aware of an ongoing study to investigate follow‑up after hip and knee replacement surgery. That study does not include people who have had shoulder replacement, so the committee made a recommendation for research on follow-up after shoulder replacement.\n\n## Why the committee made the recommendation on referral from primary care\n\nThe committee agreed that, in the absence of recommendations on follow‑up and monitoring after hip, knee or shoulder replacement surgery, a recommendation is needed to ensure that people who have problems with their joint replacement are referred to an orthopaedic surgical service. Primary care practitioners are expected to use their clinical judgement to determine the urgency of the referral.\n\n## How the recommendation might affect practice\n\nThe recommendation reflects current practice and is not expected to result in changes.\n\nReturn to recommendations", 'Context': 'Hip, knee and shoulder joint replacements are among the most common orthopaedic operations performed in the UK. Around 90% of joint replacements are done to reduce pain and restore function in joints affected by osteoarthritis.\n\nSurgical procedures for joint replacement vary. In addition, a wide range of joint implants are used. They can be made of metal, plastic or ceramic, and can be fixed into place using a variety of methods. These factors can all affect the longevity of the implant. They also have an effect on short-term outcomes such as postoperative pain and complications.\n\nThere are wide variations in the care provided before, during and after joint replacement surgery, particularly the provision of rehabilitation. This care is a vital factor in the success of this surgery.\n\nThe guideline aims to ensure that people having joint replacement surgery understand the various options and are offered the best possible care before, during and after their surgery.'}
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https://www.nice.org.uk/guidance/ng157
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This guideline covers care before, during and after a planned knee, hip or shoulder replacement. It includes recommendations to ensure that people are given full information about their options for surgery, including anaesthesia. It offers advice for healthcare professionals on surgical procedures and ensuring safety during operations. It also offers guidance on providing support and rehabilitation before and after surgery.
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3118e7a3dcec65d434315efa6e7c64bc8c209ac7
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nice
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Larotrectinib for treating NTRK fusion-positive solid tumours
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Larotrectinib for treating NTRK fusion-positive solid tumours
Evidence-based recommendations on larotrectinib (Vitrakvi) for treating neurotrophic tyrosine receptor kinase (NTRK) fusion-positive solid tumours in adults and children.
# Recommendations
Larotrectinib is recommended for use within the Cancer Drugs Fund as an option for treating neurotrophic tyrosine receptor kinase (NTRK) fusion-positive solid tumours in adults and children if:
the disease is locally advanced or metastatic or surgery could cause severe health problems and
they have no satisfactory treatment options.It is recommended only if the conditions in the managed access agreement for larotrectinib are followed.
This recommendation is not intended to affect treatment with larotrectinib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. For children and young people, this decision should be made jointly by the clinician and the child or young person or their parents or carers.
Why the committee made these recommendations
There is no standard treatment for NTRK fusion-positive solid tumours, so current treatment is based on where in the body the cancer starts. Larotrectinib is a histology-independent treatment. This means that it targets a genetic alteration, NTRK gene fusion, that is found in many different tumour types irrespective of where the cancer starts.
Evidence from trials suggests that tumours with NTRK gene fusions shrink in response to larotrectinib. But it is difficult to know how well larotrectinib works because it is not compared with other treatments in the trials. Also, there is evidence that larotrectinib works well for some types of NTRK fusion-positive tumour, but little or no evidence for other types.
The cost-effectiveness estimates for larotrectinib are very uncertain because:
they are based on data from a population that is different to that seen in NHS clinical practice and
there is substantial uncertainty about how long people would live after their disease gets worse.
Collecting more data would help to address some of the uncertainties in the clinical evidence. Larotrectinib has the potential to be a cost-effective use of NHS resources at its current price so it is recommended through the Cancer Drugs Fund while these data are collected.# Information about larotrectinib
# Marketing authorisation indication
Larotrectinib (Vitrakvi, Bayer) has a conditional marketing authorisation for 'the treatment of adult and paediatric patients with solid tumours that display a neurotrophic tyrosine receptor kinase (NTRK) gene fusion:
who have a disease that is locally advanced, metastatic or where surgical resection is likely to result in severe morbidity and
who have no satisfactory treatment options'.
# Dosage in the marketing authorisation
Adults: The recommended dose in adults is 100 mg larotrectinib twice daily, until disease progression or until unacceptable toxicity occurs. Children: Dosing in children is based on body surface area. The recommended dose is 100 mg/m2 larotrectinib twice daily with a maximum of 100 mg per dose until disease progression or until unacceptable toxicity occurs.
# Price
The cost of larotrectinib is £5,000 per 100‑ml vial of 20 mg per ml oral solution (excluding VAT; BNF online, accessed January 2020; £15,000 per 30‑day supply). Larotrectinib will be available as hard capsules (25 mg and 100 mg) to be taken orally twice daily (company submission). The company has a commercial arrangement. This makes larotrectinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Bayer and a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.
The appraisal committee discussed the following issues (see issues 1 to 19 of the technical report, pages 11 to 30), which were outstanding after the technical engagement stage.
# NTRK gene fusions
## Larotrectinib targets a genetic mutation rather than a tumour type and there are challenges in appraising it
Traditional oncology approaches treat tumours based on their type. More recently, targeted therapies based on the tumour's genetic information have been used for some indications. Larotrectinib is indicated for any solid tumour with a neurotrophic tyrosine receptor kinase (NTRK) gene fusion. Because many tumour types respond to it, the company considers larotrectinib to be 'tumour-agnostic' or 'histology-independent'. NTRK gene fusions may be able to drive tumour growth, so targeting treatment to the cause of the disease could mean higher rates of response to therapy and potentially better outcomes. The committee accepted that it was expected to appraise larotrectinib within its conditional marketing authorisation using NICE's single technology appraisal process. But it recognised the challenges of appraising a histology-independent treatment within this process.
## Solid tumours with NTRK gene fusions are rare and better characterisation is needed
NTRK gene fusions occur rarely (less than 1%) in common tumours such as lung, colorectal and breast cancers. Some rare tumour types have more than 90% NTRK fusion prevalence (for example, mammary analogue secretory carcinoma and infantile fibrosarcoma). There are many tumour types with known NTRK gene fusions and all solid tumour types are included in larotrectinib's marketing authorisation. NTRK fusions can involve portions of the NTRK1, NTRK2 and NTRK3 genes with another unrelated gene partner (over 80 different partner genes identified). The European public assessment report (EPAR) for larotrectinib notes there is evidence that the most frequent fusions found in high NTRK-prevalent tumours, ETV6‑NTRK3 fusions, drive tumour growth regardless of other characteristics. The EPAR also states that larotrectinib has shown activity in gastrointestinal stromal tumours with NTRK gene fusions and this likely reflects a similar role of NTRK gene fusions in driving tumour growth. For all other NTRK fusions, their role in driving cancer growth has not been properly studied. It is not known if there are tissue-specific mechanisms for bypassing response to drugs for NTRK fusions or effects from other drivers of tumour growth. The committee concluded that better characterisation of NTRK gene fusions was needed to fully support the histology-independent approach.
## Further data are needed on whether NTRK gene fusions affect prognosis
It is not known whether patients with tumours that have NTRK gene fusions have a different prognosis to those who do not have them. Evidence of an association between NTRK gene fusions and different disease presentation is weak and based on data from very few patients. The company assumed there was no prognostic effect of NTRK gene fusions in its base-case analysis. The ERG considered that it was unclear whether NTRK fusions affect prognosis directly or whether they are associated with other factors that affect prognosis such as age and Eastern Cooperative Oncology Group (ECOG) status. Prognosis could also vary by tumour type and NTRK gene fusion type. The committee concluded that further data would be needed to establish whether NTRK gene fusions affect prognosis.
# Treatment pathway and comparator
## People with NTRK fusion-positive solid tumours would value new treatment options
There is no defined clinical pathway for people with solid tumours with NTRK gene fusions. Treatment currently follows care guidelines for specific tumour types, with surgery, targeted therapy, immunotherapy and chemotherapy for the more common cancers. Treatment for rarer cancers is generally limited to surgery, radiotherapy and chemotherapy. The patient experts explained that people who have a solid tumour with a gene alteration would want treatment with a targeted therapy because longer survival and a better side effect profile are likely. The aim of treatment for some inoperable tumours is to shrink the solid tumour so that surgery might be a treatment option. The committee concluded that people with NTRK fusion-positive solid tumours would value new treatment options.
## Larotrectinib's position in the treatment pathway is a major uncertainty and further data are needed
Larotrectinib is indicated for 'the treatment of adult and paediatric patients with tumours that display a NTRK gene fusion and who have disease that is locally advanced, metastatic or where surgical resection is likely to result in severe morbidity, and no satisfactory treatment options'. The ERG considered that the positioning of larotrectinib would depend on which treatments clinicians consider unsatisfactory. This would vary because it involves assessing response rates and adverse events and discussing options with patients. The clinical evidence for larotrectinib comes from a population with different tumour types who have had different previous treatments. Most patients had previous systemic therapies but a proportion had no previous treatments. The patient experts considered that any targeted therapy should be used as early in the treatment pathway as possible to maximise patient access. The clinical expert stated that for some sarcomas there are very few treatment options. In larotrectinib's summary of product characteristics, it states that it should only be used if there are no treatment options with established clinical benefit, or when such treatment options have been exhausted. This is because the regulatory authority considered that larotrectinib's benefit had been established in single-arm trials in a relatively small sample of patients. But it also considered that its effect may differ depending on tumour type and other possible gene alterations, so it should not displace any effective therapies. The company therefore positioned larotrectinib as a last-line treatment, after all other treatments have been tried, by choosing the comparators: best supportive care for common cancers and chemotherapy for rarer cancers. The committee considered this positioning appropriate and in line with the marketing authorisation. However, it recognised that if larotrectinib's efficacy was further established, it was possible that clinicians would want to use it earlier in the pathway. This would displace other potentially effective therapies and is outside larotrectinib's current marketing authorisation. Further evidence about this is being collected as part of larotrectinib's conditional marketing authorisation. The committee concluded that larotrectinib's positioning was a major uncertainty and collecting further data would determine how larotrectinib would be used in clinical practice.
# Diagnosis
## The diagnostic pathway for NTRK fusions has implications for identifying patients and on diagnosis costs
All solid tumour types could potentially have NTRK gene fusions although they are rare in common tumour types (see section 3.2). Therefore, many people would need screening to identify who would benefit from larotrectinib. Currently, NTRK testing is not routinely done in the NHS for all solid tumours. However, it is available for mammary analogue secretory carcinoma and secretory breast carcinoma with immunohistochemistry techniques (a method that uses antibodies to detect the gene fusion protein). Whole genome sequencing (a method of determining the whole DNA sequence of a cancer, used for discovering mutations) can also identify NTRK gene fusions. It is available for children's cancers and sarcomas, although confirmation of the results with another targeted DNA or RNA test is needed (for example next generation sequencing, which is a faster method of sequencing targeted regions of the cancer's DNA). The committee concluded that the diagnostic pathway for NTRK gene fusions was important, with implications for identifying patients and on costs of diagnosis.
## The diagnostic pathway is uncertain until NHS England establishes a national service for genomic testing of all advanced solid tumours
The Cancer Drugs Fund clinical lead explained that NHS England is currently establishing a national service for cancer genomic testing, to replace all local testing. It involves setting up 7 laboratory hubs across England to do genomic testing by next generation sequencing and interpret all results. The committee understood that until the laboratory hubs are fully established, next generation sequencing will be done after all NHS-commissioned treatment options have been tried. When the hubs are fully established, next generation sequencing to identify gene alterations, including NTRK gene fusions, will be done when locally advanced or metastatic solid tumours are first diagnosed. The Cancer Drugs Fund clinical lead estimated that 100,000 solid tumours will be tested per year once the service is fully established. He noted that other targeted therapies will likely become available soon for different diseases and genomic testing will also be needed before these treatments are used. The committee acknowledged the ongoing developments in genomic testing practice to identify NTRK fusion-positive solid tumours. It considered that the rapid change to the diagnostic testing pathway being led by NHS England was a unique situation. The committee concluded that the diagnostic testing pathway was uncertain until NHS England establishes a national service for cancer genomic testing.
## Diagnostic techniques will improve as the genomic laboratory hubs validate their techniques and NTRK gene fusions are better characterised
The diagnostic specificity of any test needs to be very high to exclude patients who do not have an NTRK gene fusion and so would not benefit from larotrectinib. This particularly affects common tumour types with low NTRK prevalence (for example, lung, colorectal and breast tumours) in which the number of false-positive results could outnumber true-positive results if the test is not specific enough. The committee was aware that currently, DNA-based next generation sequencing and whole genome sequencing were not sensitive enough to screen for NTRK gene fusions. Clinical experts considered that DNA- and RNA-based next generation sequencing with a confirmatory targeted DNA, RNA or immunohistochemistry test when a positive result is obtained would be appropriate and minimise the number of false-positive results. Some factors may reduce the specificity of these tests, such as tissue degradation and human error. The committee noted that the last-line positioning of larotrectinib reduced the risk of displacing active treatments for patients with false-positive results for NTRK gene fusions, whose tumours would not respond to larotrectinib. However, there were concerns about the ethics of treatment for any patients with false-positive results because of adverse events. The committee concluded that diagnostic techniques would improve as the genomic laboratory hubs validate their techniques and NTRK gene fusions are better characterised (see section 3.2).
# Clinical evidence
## The key clinical evidence comes from a pooled analysis of 3 single-arm clinical trials and is appropriate for decision making
The company presented a pooled analysis of 102 patients from 3 trials:
NAVIGATE is an ongoing trial for patients of 12 years and over with locally advanced or metastatic tumours with NTRK gene fusions who have had prior therapy or who would be unlikely to clinically benefit from standard care. NAVIGATE contributed 62 patients to the pooled analysis.
SCOUT is an ongoing trial for children with locally advanced or metastatic solid tumours or primary central nervous system (CNS) tumours. SCOUT contributed 32 patients to the pooled analysis.
LOXO‑TRK‑14001 was a dose-finding study in patients with solid tumours with NTRK gene fusions, which contributed 8 patients to the pooled analysis. The group analysed for efficacy was further split by patients with primary CNS tumours (n=9) and all other patients (n=93). The committee noted the small patient numbers from each of the trials making up the pooled analysis. Also, it noted that the trials were single arm and did not include a control group. Given the rarity of the gene fusion, the committee concluded that the evidence was appropriate for decision making.
## The key clinical evidence is not generalisable to NHS clinical practice and further data are needed
The company considered the results to be generalisable to NHS clinical practice and did not do any adjustments for baseline characteristics. The ERG noted that patients in each trial were recruited by convenience sampling and there was no systematic attempt to represent the distribution of tumour types in NHS clinical practice. Therefore, a substantial number of patients in the trials had high NTRK-prevalent tumour types because these patients were easier to recruit. The over-representation of high NTRK-prevalent tumour types meant that:
response rate estimates (see section 3.13) could have included a higher proportion of children with potential to be cured (see section 3.20) and
there was likely to be fewer false-positive results in the trial population (see section 3.8) compared with NHS clinical practice.Rare tumour types were also over-represented, which meant that more people had active chemotherapy options compared with best supportive care (see section 3.4). In addition to under-represented tumour types, there were tumour types that were not represented at all in the clinical evidence. So the committee would need to accept that unrepresented solid tumours (for which there were no data) would respond to larotrectinib. The ERG also thought that not enough information was provided to explore patient characteristics in the trial and whether these were generalisable to the population who would have treatment in NHS clinical practice. The committee noted that the diversity of tumour types would make adjusting for patient characteristics by tumour type very difficult, but this was not explored. The ERG considered that it was unclear whether patients had exhausted their treatment options; the trial inclusion criteria may be different to the marketing authorisation because the definition of satisfactory is open to interpretation (see section 3.5). This could have led to considerable bias. The committee concluded that the key clinical evidence was not generalisable to NHS clinical practice because of the distribution of tumour types, including potentially unrepresented tumour types, and the unknown effect of patient characteristics. Further data are needed to explore the types of tumour and distribution of patients, which were major uncertainties.
## The size of larotrectinib's benefit on long-term survival cannot be reliably estimated because the data are immature
The primary outcome measure of the 2 larger trials was overall response rate. The committee considered that the evidence showed a clinically relevant overall response rate of 72% across multiple tumour types. But it noted that this may not be generalisable to the broader range of tumour types expected in NHS clinical practice (see section 3.10). Also, it was aware of considerable uncertainty about the extent to which the response translated into clinically meaningful survival benefits. The progression-free survival data were immature, with only 37% of patients having progressed disease (excluding primary CNS tumours). Also, overall survival data were very immature with only 14 of 102 patients dying in the trials. The immaturity of the data meant that the extrapolation of survival estimates was very uncertain (see section 3.21). The committee concluded that the immaturity of the survival data meant that the size of larotrectinib's benefit on long-term survival could not be reliably estimated.
# Heterogeneity in response
## The trials are not designed to assess heterogeneity in response
The committee was aware of several biological reasons why heterogeneity, or a difference, in response to larotrectinib might be seen. For example, response might be different by histology, by NTRK gene fusion or fusion partner, by the presence of co‑drivers of the disease and by age (for example for children's indications). None of the statistical protocols of the trials included in the pooled analysis were designed to test heterogeneity in response by any factor. NAVIGATE was a 'basket' trial (that is, a trial that included patients who had different types of cancer but the same gene mutation) which involved many small groups of patients stratified by tumour type. If a response was seen in one of these groups, a response to larotrectinib for that tumour type was assumed and the basket was further expanded to increase the sample size. However, the company later pooled all the analyses from the 3 studies of all patients in whom efficacy could be evaluated (see section 3.9). The EPAR states that selection bias on pooling the data is possible and there may be some tumour types that do not respond (type 1 error). The ERG explained that the company assumed an equal response to larotrectinib independent of tumour type and response was not formally assessed by tumour type. The committee concluded that the trials were not designed to assess heterogeneity in response.
## Assuming equal response to larotrectinib across tumour types and fusion types is inappropriate
The committee noted the challenges of assessing response because the individual subgroups were too small for meaningful analysis. For example, some tumour types with few patients in the trials, such as pancreatic tumours (n=1) and congenital mesoblastic nephroma (n=1), had 0% response or 100% response respectively. This may be because of chance findings or because of biological differences in the tumour type. For example, as noted in the EPAR, tissue-specific mechanisms for bypassing response to drugs have been seen when targeting other gene mutations (such as colorectal cancer not responding to BRAF mutation inhibitors). Tumour tissue can also affect type of NTRK gene fusion, gene fusion partners and presence of other mutations. The response to larotrectinib by NTRK gene fusion showed heterogeneity, with low response in NTRK2 and high response in NTRK3 (82%). There was also heterogeneity in response to larotrectinib by gene fusion partner. The most common fusion partner, ETV6‑NTRK3, had an overall response of 84%, higher than all other fusion partners combined. The Cancer Drugs Fund clinical lead commented that it is biologically plausible that for people with high NTRK-prevalent tumours, such as those with ETV6‑NTRK3 (see section 3.2), there would be a higher response to larotrectinib and greater benefits. The clinical experts could not comment on whether heterogeneity in the response to larotrectinib would be expected across different tumour types. The company's model assumed equal response for all tumour types and fusion types, based on the overall response from the trial population (see section 3.9) and did not explore any other assumption. The committee concluded that given the observed differences in response and the poor characterisation of NTRK gene fusions and fusion partners, assuming equal response was inappropriate. Adjustment should be made for potential differences by subgroup.
## Bayesian hierarchical modelling is a useful way to consider the heterogeneity in response to larotrectinib
The ERG presented the Bayesian hierarchical model (BHM) framework as an approach to characterise heterogeneity. The BHM framework was developed specifically for basket trials and is useful when there is limited information. This method allows for analysis of a pooled overall response rate, adjusting for the observed heterogeneity and borrowing strength across different tumour types to avoid extreme results. Extreme results may be seen because of limited patient numbers in trials; even small changes in the absolute number of people whose disease responds can considerably affect the response rate (see section 3.13). The ERG noted that because the tumour types with more response events also had high response rates, the low response rates seen in tumour types with fewer response events reduced the overall response in the pooled analysis from 72% to 57% (including primary CNS tumours, see section 3.15). The committee acknowledged that the results of the ERG's BHM approach were substantially different to the company's approach, which assumed that the response was the same across the different tumour types. The committee considered the reduced overall response output of the BHM, with wide credibility intervals, to be more appropriate for decision making because it incorporated some adjustment for heterogeneity. The ERG noted that the BHM approach could also be used for survival outcomes because response was not explicitly modelled in the company's base case. However, the company did not provide the data needed to do this analysis and the survival results were likely to be too immature for meaningful interpretation of the results. The committee concluded that the BHM was a useful tool for exploring heterogeneity in response to larotrectinib and, based on the current limited dataset, should be considered as part of its decision making.
## Patients with primary CNS tumours should be included in the response analysis
There were 9 out of 102 patients with primary CNS tumours and these tumours had a much lower response to larotrectinib than other types. Although the results for this group were analysed separately from the main efficacy analysis, they were included in the economic analysis. The company explained that tumour response to larotrectinib in patients with primary CNS tumours was assessed by investigators using the response assessment in neuro-oncology (RANO) criteria, instead of the independent review committee assessed response evaluation criteria in solid tumours (RECIST) v1.1. Surgery and radiotherapy for CNS tumours can lead to varying amounts of scarring and inflammation, which makes it difficult to assess response using RANO criteria. The company considered that this explained the lower response compared with other tumour types. However, in the EPAR it states that larotrectinib is a substrate of P‑glycoprotein, a key constituent of the blood–brain barrier. This may mean that the dose of larotrectinib reaching the brain is reduced. The ERG considered that primary CNS tumours may have a lower response to larotrectinib or that the high proportion of NTRK2 gene fusions within primary CNS tumours may explain the low response. The ERG noted that including the primary CNS data in the BHM reduced the estimated overall response rate. But the ERG did not state a preference for including or excluding primary CNS data from the BHM. The committee concluded that there was uncertainty about whether primary CNS tumours respond to larotrectinib. However, it considered that the primary CNS data should be included in the BHM until more is known about larotrectinib's efficacy in the brain and NTRK2 gene fusions are better characterised. This is so the results are more generalisable to the population covered in the marketing authorisation.
# Indirect treatment comparisons
## The naive indirect comparison with a pooled comparator arm is biased
To establish relative clinical effectiveness compared with current clinical practice, larotrectinib was compared with multiple comparators by tumour site-specific pathway. The company's base-case analysis created a pooled comparator arm by using data from last-line treatment arms in published NICE appraisals and in the literature to represent best supportive care. Survival estimates were weighted by the distribution of the efficacy population to allow a naive indirect comparison with an estimate of survival expectancy for this population. The ERG considered this method could introduce bias in many ways, including generalisability of the trial population (see section 3.10) and uncertainty over the potential prognostic importance of NTRK (see section 3.3). This method also limited the ability to adjust for any heterogeneity (see section 3.13). This was because it assumed that survival was independent of tumour type and other factors, therefore assuming a common natural history for all tumour types in the analysis. The ERG explained that the size and direction of bias was impossible to establish. The committee appreciated the difficulty in estimating a comparator population for rare tumours across multiple tumour types. But it concluded that the company's method had unadjusted bias that did not account for significant heterogeneity and could not adjust for important prognostic factors and baseline characteristics.
## The 2 confirmatory analyses also have biases, but will be considered in decision making
The company presented 2 further indirect treatment comparisons, as confirmatory analyses, to approximate the comparator arm. A response-based analysis assumed patients whose tumours did not respond to larotrectinib were equivalent to those who had best supportive care and were assumed to represent the comparator arm. The advantages of the response-based analysis were that the eligibility criteria of the trial were considered, and the ERG's adaptation of this model allowed for exploration of heterogeneity (see section 3.13). However, this method assumed that response was a surrogate outcome for survival, which may differ significantly by tumour type and have known biases. A previous line of treatment analysis compared the time to progression on the previous line of treatment with the time in progression-free survival on larotrectinib for each patient. This ratio was used as a hazard ratio to approximate a comparator arm for progression-free survival and it was assumed that overall survival behaved the same. The advantage of this analysis was that each patient acted as their own control, which was particularly beneficial for a histology-independent population. However, the ERG had concerns with how this analysis was implemented. It considered that a patient's previous unsuccessful line of therapy may not represent best supportive care and it noted that the method was uninformative for overall survival, which was a major uncertainty of the base-case analysis. The committee noted that both confirmatory analyses also had substantial biases and that all the indirect treatment comparisons had structural uncertainty. Therefore, it concluded that it would consider the outputs of all indirect treatment comparisons in its decision making.
# The company's economic models
## The most appropriate model structure for decision making is uncertain
The company's economic models were based on the indirect treatment comparisons (see section 3.16 and section 3.17). The company's base-case structure was a 3‑state partitioned survival model (progression-free, progressed and death). Survival estimates were extrapolated from the larotrectinib efficacy population and comparator arm survival estimates calculated using the method in section 3.16. Other model parameters such as utility, time on treatment and adverse events were also included to create part-models (termed 'engines' in the company submission) for each tumour type comparator. The company also provided economic models based on the confirmatory analyses in section 3.17. The ERG adapted the response-based model to a dual-partitioned survival model with the larotrectinib arm response defined by output from the BHM (see section 3.14). This allowed for some exploration of uncertainty from heterogeneity in response. The ERG also considered that this would account for issues with post-progression treatments (see section 3.22) because these would be the same in both treatment arms. The ERG considered the previous line of treatment analysis was not implemented appropriately and was uninformative for overall survival, so did not consider this model structure further. The committee recognised the difficulty in modelling treatments for single-arm data, and that the unique challenges of histology-independent treatments further complicated the modelling issues. The committee understood that there were limitations and uncertainties with each of the modelling approaches. It considered that when more data were available, the different model structures could be explored more fully. The committee concluded that the most appropriate model structure for decision making was uncertain.
## None of the models use a population that is generalisable to NHS clinical practice
The company's base-case model used the full efficacy evaluable population from the pooled analysis, which the committee considered was not generalisable to NHS clinical practice (see section 3.10). The company did not provide any information for the effectiveness of larotrectinib by individual tumour type, so it was not possible to remove patients who were over-represented from the economic model or to adjust the population to make it more generalisable. The over-representation of rare and high NTRK-prevalent tumour types introduced several issues, including:
A higher response rate from tumour types with NTRK as the known driver of the disease (see section 3.13).
The potential that an unknown number of patients would be cured in both treatment arms (see section 3.20).
Survival estimates included in the analysis were for tumour types with a higher response rate (see section 3.21).
Some tumour sites were over-represented in the utility value calculations (see section 3.23 and section 3.24).Without evidence from a more generalisable population, the committee considered that it would be most appropriate to model survival in the trial population as a proxy. However, this would add considerable additional uncertainty to any cost-effectiveness estimates from the economic model. The committee concluded that all models used the unadjusted pooled analysis so could not model a population that would be generalisable to NHS clinical practice.
## A different model structure is needed to explore the effect of a cure
The committee was aware that only a small number of patients in clinical practice would have tumour types that could potentially be cured because locally advanced and metastatic cancer is generally incurable. However, children with tumour types that could potentially be cured were included in the SCOUT trial in much greater proportions than would be seen in clinical practice (see section 3.10 and section 3.19). Most children in the evaluable population from SCOUT had no other curative options besides amputation or disfiguring surgery. The company considered that some of these patients would be cured without larotrectinib, with lifelong morbidity from amputation or disfigurement. Therefore, it considered that a cure model could be appropriate. But cure could not be determined because of short follow up, limited numbers of patients and high censoring of data. The committee noted considerable uncertainty around the potential for a cure and that the curative role of surgery had not been explored in either treatment arm. It also noted that the comparator part-model for these patients (grouped as paediatric sarcomas) did not model lifelong survival over the full-time horizon. Therefore, the current model structure captured the benefit of a cure in the Kaplan–Meier survival analysis in the larotrectinib arm but did not model the possibility of cure in the comparator arm. The committee concluded that this issue strongly biased the modelled cost-effectiveness results in favour of larotrectinib. The committee was aware that the modelled cure rates were speculative because the cure rate in the trial population was unknown and likely to be negligible for a generalisable population. The potential for a cure in the trial population supported why the model structures proposed were not appropriate for a heterogeneous non-generalisable population. The committee concluded that a different model structure should be used to explore the effect of a cure. Also, further information was needed on how larotrectinib would be used in clinical practice.
# Modelled survival outputs
## Survival extrapolation is highly uncertain and a key driver of the model
Data on overall survival and progression-free survival were incomplete and the clinical trials are ongoing. To extrapolate progression-free survival and overall survival for larotrectinib, the company fitted standard distributions to the data (the exact distributions chosen are confidential and cannot be reported here). For the pooled comparator arm, the curve accepted by the committee in previous NICE guidance was used when available and assumptions used when no NICE guidance was available. The ERG noted the considerable uncertainty in extrapolating data that are immature (see section 3.11). The overall survival extrapolation showed substantial separation from the progression-free survival extrapolation, which contributed to an implausible post-progression survival estimate (see section 3.22). During the technical engagement stage, the company provided overall survival data from an updated data-cut. The ERG considered that there were no clear differences in survival characteristics in these updated data. But it noted that a few events at the extreme end of the curve dramatically affected the survival extrapolation and modelled survival gain. The committee considered that this could be a result of uncertain extrapolation and may not suggest a true decline in survival. This was compounded by uncertainty about the possibility of including patients whose disease was cured in the larotrectinib Kaplan–Meier curves (see section 3.20). The committee concluded that the extreme sensitivity of the model output to the survival extrapolations meant that extrapolation did not provide results that the committee could trust, but that data on longer-term extrapolation could be collected in the Cancer Drugs Fund.
## The modelled post-progression survival outputs are implausible
The ERG noted that the life years gained after progression were greater than both the progression-free life years gained and overall survival in the comparator arm, which it considered implausible. The ERG considered this could be a result of the highly uncertain extrapolation or because of the high proportion of patients who had post-progression treatments, such as further larotrectinib or an experimental treatment (LOXO‑195) for people whose disease was resistant to TRK-inhibitors. The ERG considered that LOXO‑195 would not be used in clinical practice because the tumour would need to be TRK-inhibitor resistant before people could have this treatment. The committee considered it appropriate to adjust for the benefits of these treatments. However, it noted the difficulty of using adjustment techniques for an unknown treatment effect in immature survival data. The clinical expert stated that a high depth of response (prolonged benefit from shrinking the tumour) to larotrectinib might explain why post-progression survival could be higher than progression-free survival. Having a smaller tumour could mean longer survival even after developing resistance to larotrectinib. The committee considered this concept to be possible but highly speculative because the current evidence base was very immature. It also noted that TRK-inhibitor resistance mechanisms were not well characterised and would not explain the size of the discrepancy in life years gained. The ERG provided 2 scenarios based on crude adjustment of larotrectinib post-progression survival to match post-progression survival in the comparator arm (no comparative effect of larotrectinib after progression) or overall survival in the comparator arm. The committee considered these scenarios to be more plausible than the company's base case and appropriate for showing the upper limit of plausible cost-effectiveness estimates. However, it considered that the survival estimates, both progression-free and post-progression, were likely to be affected by immature extrapolation (see section 3.21) and including survival data from patients whose disease was cured (see section 3.19). The committee concluded that the post-progression survival estimates were implausible and that the ERG scenarios did not fully capture the issues with modelling survival.
# Utility values in the economic models
## Assuming equal post-progression utility values in the larotrectinib and pooled comparator arms is appropriate
The company provided utility values derived from health-related quality-of-life data collected in the SCOUT and NAVIGATE trials, mapped to EQ‑5D‑3L utility values for the pre-progression and progressed health states. For the comparator arm utility values, a similar approach to that used for estimating survival was used (see section 3.16). Utility values from published NICE guidance were pooled and weighted by the distribution of the efficacy population. The ERG considered that there was considerable uncertainty in the utility value estimate of the post-progression health state for larotrectinib because it was based on few assessments of patients, most of whom were children. The committee noted that some patients could potentially be cured (see section 3.19). It considered that the evidence for the post-progression utility values for larotrectinib was weak and there was no plausible reason why post-progression utility would be so much higher for larotrectinib than for the comparator arm for the entire population. The ERG provided a scenario with equal post-progression utility values for larotrectinib and the pooled comparator. The committee agreed that this scenario was more appropriate.
## Sensitivity analysis to see the effect of reducing utility values for larotrectinib is needed
The company's utility values suggested a difference in pre-progression utility between larotrectinib and the pooled comparator. The Cancer Drugs Fund clinical lead considered this to be implausible because the modelled comparator in NHS clinical practice was likely to be best supportive care. Therefore, any difference in utility values between arms would represent positive effects from reduced tumour size in the pre-progression state for larotrectinib and the difference in adverse effects between treatments not captured by the adverse event modelling. The committee considered that the high number of patients having chemotherapy rather than best supportive care (see section 3.10) would bias this difference in favour of larotrectinib. The committee concluded that it was appropriate to do a sensitivity analysis to see the effect of reducing larotrectinib pre-progression utility values on this bias. The committee considered this scenario to be more plausible for a population that was generalisable to NHS clinical practice.
# Resource use and costs
## It is appropriate to include diagnostic testing costs in the economic model
The committee understood that the NICE methods guide was not designed to address a system-wide change in diagnostic techniques and the cost of testing would depend on NHS England's testing strategy. The company considered that the planned changes in genomic testing (see section 3.7) would mean that none of the testing costs would be borne by larotrectinib in the economic model. This was because the system would be independent of testing for NTRK gene fusions and would not be used solely for identifying NTRK gene fusions for a particular drug. The ERG's interpretation of the methods guide was that associated costs of the diagnostic test should be incorporated into the clinical- and cost-effectiveness assessments. The committee agreed that the ERG's interpretation, which included assessment of the cost of larotrectinib in current NHS clinical practice, most closely matched the methods guide. The ERG proposed a pragmatic screening pathway for each tumour type, based on adapting current testing provisions for some tumour types that already have some genomic testing. For tumour types that are not currently tested for any genetic mutations, the ERG assumed that immunohistochemistry would be followed by confirmatory next generation sequencing if there was a positive result. This technique provided an average cost of screening for a single patient with an NTRK gene fusion, which was included in the cost-effectiveness estimates. The committee considered this analysis was reasonable because it reflected current clinical practice, but recognised that NHS England is rapidly moving towards a national service for cancer genomic testing. Therefore, the proposal from NHS England to implement next generation sequencing at diagnosis of locally advanced or metastatic disease was likely to reflect the near future once the changes to the diagnostic pathway have been established. NHS England proposed a cost per patient with an identified NTRK fusion-positive tumour to be included in the model. The committee noted that this cost was substantially less than in the ERG's scenario. The committee concluded that it was appropriate to include diagnostic testing costs in the model.
## The adjustments to the children's dose and including drug wastage costs in the economic model are appropriate
The company used the average adult and children's doses used for the efficacy population to calculate the dose of larotrectinib applied in the model. The ERG considered this to be inappropriate because some children had a lower dose in SCOUT because it was a phase 1 dose-finding study. The ERG provided a scenario in which the full children's dose was adjusted using the percentage of adults adhering to treatment. The committee agreed that the ERG's adjustments were appropriate to better generalise the dose in SCOUT to NHS clinical practice, but it noted that this did not account for potential differences in clinical effect. Additionally, the company supplied scenarios considering larotrectinib wastage after stopping treatment for 2- and 4‑week treatment supplies. The committee noted that these scenarios had little effect on the cost-effectiveness estimates but considered it appropriate to include the 4‑week treatment drug wastage scenario in the model. The committee also noted that these assumptions relied on using hard capsules, which are not yet available, so an additional scenario using the oral solution should have been provided.
## Including a scenario with the costs of oral chemotherapy administration in the economic model is appropriate
The company considered that administration costs and resource use should be applied in the model by the distribution of patients in the efficacy analysis. The committee considered this inappropriate because the over-representation of rare tumours that were modelled as having chemotherapy (see section 3.10) may have resulted in bias in favour of larotrectinib. However, it considered that the true distribution could not be calculated. The Cancer Drugs Fund clinical lead commented that the administration costs for oral chemotherapy were not included for larotrectinib. At the technical engagement stage, the company provided a scenario with these administration costs. The committee concluded that this scenario was appropriate for including in the economic model.
## The model should include the costs of post-progression treatments
The company modelled the costs of larotrectinib treatment until progression, but some patients continued to have larotrectinib after progression (see section 3.22). The company provided a scenario using the time to treatment discontinuation seen in the trial to model larotrectinib costs. The committee considered this to be more appropriate because the modelled costs of larotrectinib should match the modelled benefits. However, it noted there would be further uncertainty with extrapolation of time to treatment discontinuation, and that other methods of including these costs may be more appropriate because of the number of patients who had post-progression treatment with larotrectinib and the immaturity of the data. The committee did not see evidence for how long patients had treatment with larotrectinib after disease progression and could not comment on whether this was generalisable to NHS clinical practice. The committee concluded that the costs of post-progression larotrectinib should be included, but this issue had not been fully explored. Further data collection within the Cancer Drugs Fund could reduce this uncertainty.
# End of life
## Larotrectinib has plausible potential to meet the end-of-life criteria but there is uncertainty
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The company proposed that larotrectinib met the criteria for life-extending treatments for people with a short life expectancy (normally less than 24 months). The committee understood that the end-of-life criteria were not designed for histology-independent treatments and it was not presented with the data needed to assess the criteria for people with NTRK gene fusions specifically. Instead, it was presented with life expectancy data for people with the relevant tumour type irrespective of NTRK gene fusion status and life extension data estimated from the model. It acknowledged the challenges with the data available, for example:
the distribution of tumour types in the trials and unrepresented tumour types not included in the clinical evidence (see section 3.10)
uncertainty around larotrectinib's position in the treatment pathway (see section 3.5)
the limited survival data available (see section 3.11)
the prognostic importance of NTRK gene fusions (see section 3.3) and the uncertainty around the extrapolation of the survival data (see section 3.20).The committee considered that most tumour types represented in the trials had overall survival estimates that would meet the short life expectancy criterion. But it considered that the overall survival estimates for people with thyroid cancers were likely to exceed the short life expectancy criterion and this could also be true for some of the rarer tumour types. It considered that the extension to life criterion of greater than 3 months would likely be met for most patients whose tumours responded to larotrectinib, although the size of the benefit and the distribution of these tumour types was highly uncertain. The committee concluded that larotrectinib had plausible potential to meet NICE's criteria to be considered a life-extending treatment at the end of life. But it acknowledged that there was uncertainty in determining both the life expectancy and the exact extension to life given the immaturity of the data and potential for heterogeneity across all the different tumour types. Further data collection could resolve this uncertainty and the distribution of tumour types likely to meet the life expectancy criterion.
# Cost-effectiveness estimates
## Larotrectinib is not recommended for routine commissioning
The company's base-case model gave a deterministic incremental cost-effectiveness ratio (ICER) of £16,155 per quality-adjusted life year (QALY) gained for larotrectinib compared with current clinical management. This included an updated simple discount patient access scheme for larotrectinib after consultation. The committee considered that the base case should also include the following committee preferences:
utility values equal between post-progression treatment arms (see section 3.23)
including the oral chemotherapy administration cost for larotrectinib (see section 3.27)
including drug wastage costs based on 4‑weekly prescription (see section 3.26)
adjusting the children's dose to account for inclusion of the dose-finding study (see section 3.26)
response rate using the more generalisable response rate from the BHM (see section 3.14)
including the costs of diagnostic testing as proposed by NHS England (see section 3.25).After the committee meeting, the ERG provided analyses including these assumptions that increased the ICER to £30,888 per QALY gained. But this did not include many of the scenarios the committee considered key uncertainties of the appraisal:
including the costs of larotrectinib after progression (see section 3.28)
adjusting for the implausible post-progression survival (see section 3.22), which the committee considered would increase the ICER, based on the ERG's 2 scenarios (ICERs of £40,342 and £48,161 per QALY gained for each of the scenarios in section 3.22)
reducing pre-progression utility values for the larotrectinib arm (see section 3.24), which the committee considered would be likely to modestly increase the ICER
exploring assumptions around a potential cure affecting survival estimates (see section 3.20), which the committee considered would be likely to greatly increase the ICER.The committee considered that the ICER ranges had plausible potential to be a cost-effective use of NHS resources if larotrectinib met the end-of-life criteria. However, the committee considered that there was substantial uncertainty in the survival estimates, with ICER ranges that were likely to be higher than what is considered a cost-effective use of NHS resources. Also, much uncertainty remained from modelling a population that was not generalisable to NHS clinical practice. Therefore, the committee concluded that it could not recommend larotrectinib for routine commissioning.
# Cancer Drugs Fund
## Collecting more data could address the uncertainty in the evidence
Having concluded that larotrectinib could not be recommended for routine use, the committee then considered if it could be recommended for treating NTRK fusion-positive solid tumours within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum). It considered that some of the inherent uncertainty in appraising a histology-independent treatment could be resolved through further data collection. The committee was aware that the company expressed a preference for larotrectinib being available in the Cancer Drugs Fund because of the uncertainty in the appraisal and while data mature. The committee was aware that more larotrectinib clinical trial data are expected. Also, the company has some data collection ongoing as part of the regulatory commitments required by the conditions of the marketing authorisation. The committee concluded that some of the uncertainty associated with larotrectinib's use could be addressed through collecting more data. It noted that:
The ongoing larotrectinib clinical trials will provide more mature survival data for people already enrolled in the trials. They may recruit additional patients with solid tumours at sites not already included in the clinical trials, which will provide further data to explore the heterogeneity in response to treatment.
Real-world evidence collected in the Cancer Drugs Fund through Blueteq, SACT and the molecular dataset should provide further information on the generalisability of the clinical trials to NHS clinical practice, the prevalence of NTRK gene fusions, the distribution of tumour types in England and the screening and treatment pathway.
A non-interventional study (ON‑TRK) will collect safety and efficacy data on larotrectinib and may provide further information on heterogeneity in response.
A non-interventional study, in partnership with Genomics England, to collect NTRK gene fusion data should provide further information on whether NTRK gene fusions affect prognosis.
## Larotrectinib meets the criteria to be included in the Cancer Drugs Fund
The committee noted that it had not seen evidence that was likely to be generalisable to clinical practice, or about how larotrectinib was likely to be used in clinical practice. It acknowledged that there was substantial clinical uncertainty about the population, modelling of comparator treatments, survival estimates and utility values. However, it considered that the data from larotrectinib trials were promising, because tumour response rates were good, and it showed that larotrectinib was likely to improve overall and progression-free survival. The committee noted that many of the key clinical uncertainties could be addressed by collecting data in the Cancer Drugs Fund (see section 3.31). The committee then considered if larotrectinib showed plausible potential to be cost effective at the end of the managed access agreement. It noted that the range of ICERs from the available analyses, which included most of the committee's preferred assumptions for the population from the trials compared with established practice, were within what is usually considered a cost-effective use of NHS resources, if larotrectinib meets the end-of-life criteria. However, the committee considered that, because of the many underlying clinical uncertainties, the ICERs were not reliable, and that cost-effectiveness estimates could be improved by collecting data in the Cancer Drugs Fund. The committee recalled, from NHS England's Appraisal and funding of cancer drugs from July 2016 (including the new Cancer Drugs Fund) – a new deal for patients, taxpayers and industry, that the Cancer Drugs Fund is designed 'to offer pharmaceutical companies that are willing to price their products responsibly with a new fast-track route to NHS funding for the best and most promising drugs'. The committee concluded that larotrectinib met the criteria to be included in the Cancer Drugs Fund as an option for people with NTRK fusion-positive solid tumours, if the conditions in the managed access agreement are followed.
# Innovation
## Larotrectinib is innovative and there are wider benefits to the NHS not captured in the analysis
The company considered larotrectinib to be innovative because it targets a gene fusion instead of a tumour type. The patient and clinical experts agreed. The committee considered larotrectinib to be innovative because it represents a major change in the treatment of NTRK fusion-positive solid tumours. The committee understood that important innovations were already underway as part of the NHS long-term plan to improve genomic testing in clinical practice. These advances will likely help the uptake of treatments targeted to a gene alteration. The Cancer Drugs Fund clinical lead explained that histology-independent treatments entering the market are accelerating the advances in genomic testing in the NHS. It is estimated that 100,000 solid tumours will be tested per year once the genomic medicine service is fully established, thought to be in the next 2 years. The committee acknowledged that the improvements in genomic testing would bring wider benefits to the NHS and that these benefits have not been captured in the QALY calculation. The committee concluded that larotrectinib would be beneficial for patients, but it had not been presented with evidence of any additional benefits specific to larotrectinib that were not captured in the measurement of the QALY.
# Equality considerations
## There are no equality issues relevant to the recommendations
The company did not consider there to be any equality issues. However, it considered that the uncertainty inherent in this appraisal may pose an equity issue. There is no precedent for appraising technologies when their clinical trials have a basket trial design and a high number of comparators across multiple tumour types. The company considered that patients should have equity of access while health technology assessment methods adapt to these challenges. The committee considered that NICE's single technology appraisal process was appropriate for appraising larotrectinib. It concluded that the uncertainties associated with the trial design (see section 3.14) and multiple comparators (see section 3.17) had been appropriately accounted for in its decision making. The Cancer Drugs Fund clinical lead also noted that there may be issues with accessing larotrectinib because the genomic testing needed to identify NTRK fusion-positive solid tumours is still being established as a national service (see section 3.7). The committee understood that any variation in access to genomic testing will be resolved in the next 1 to 2 years.
|
{'Recommendations': 'Larotrectinib is recommended for use within the Cancer Drugs Fund as an option for treating neurotrophic tyrosine receptor kinase (NTRK) fusion-positive solid tumours in adults and children if:\n\nthe disease is locally advanced or metastatic or surgery could cause severe health problems and\n\nthey have no satisfactory treatment options.It is recommended only if the conditions in the managed access agreement for larotrectinib are followed.\n\nThis recommendation is not intended to affect treatment with larotrectinib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. For children and young people, this decision should be made jointly by the clinician and the child or young person or their parents or carers.\n\nWhy the committee made these recommendations\n\nThere is no standard treatment for NTRK fusion-positive solid tumours, so current treatment is based on where in the body the cancer starts. Larotrectinib is a histology-independent treatment. This means that it targets a genetic alteration, NTRK gene fusion, that is found in many different tumour types irrespective of where the cancer starts.\n\nEvidence from trials suggests that tumours with NTRK gene fusions shrink in response to larotrectinib. But it is difficult to know how well larotrectinib works because it is not compared with other treatments in the trials. Also, there is evidence that larotrectinib works well for some types of NTRK fusion-positive tumour, but little or no evidence for other types.\n\nThe cost-effectiveness estimates for larotrectinib are very uncertain because:\n\nthey are based on data from a population that is different to that seen in NHS clinical practice and\n\nthere is substantial uncertainty about how long people would live after their disease gets worse.\n\nCollecting more data would help to address some of the uncertainties in the clinical evidence. Larotrectinib has the potential to be a cost-effective use of NHS resources at its current price so it is recommended through the Cancer Drugs Fund while these data are collected.', 'Information about larotrectinib': "# Marketing authorisation indication\n\nLarotrectinib (Vitrakvi, Bayer) has a conditional marketing authorisation for 'the treatment of adult and paediatric patients with solid tumours that display a neurotrophic tyrosine receptor kinase (NTRK) gene fusion:\n\nwho have a disease that is locally advanced, metastatic or where surgical resection is likely to result in severe morbidity and\n\nwho have no satisfactory treatment options'.\n\n# Dosage in the marketing authorisation\n\nAdults: The recommended dose in adults is 100\xa0mg larotrectinib twice daily, until disease progression or until unacceptable toxicity occurs. Children: Dosing in children is based on body surface area. The recommended dose is 100\xa0mg/m2 larotrectinib twice daily with a maximum of 100\xa0mg per dose until disease progression or until unacceptable toxicity occurs.\n\n# Price\n\nThe cost of larotrectinib is £5,000 per 100‑ml vial of 20\xa0mg per ml oral solution (excluding VAT; BNF online, accessed January 2020; £15,000 per 30‑day supply). Larotrectinib will be available as hard capsules (25\xa0mg and 100\xa0mg) to be taken orally twice daily (company submission). The company has a commercial arrangement. This makes larotrectinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Bayer and a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee discussed the following issues (see issues 1\xa0to\xa019 of the technical report, pages 11\xa0to\xa030), which were outstanding after the technical engagement stage.\n\n# NTRK gene fusions\n\n## Larotrectinib targets a genetic mutation rather than a tumour type and there are challenges in appraising it\n\nTraditional oncology approaches treat tumours based on their type. More recently, targeted therapies based on the tumour's genetic information have been used for some indications. Larotrectinib is indicated for any solid tumour with a neurotrophic tyrosine receptor kinase (NTRK) gene fusion. Because many tumour types respond to it, the company considers larotrectinib to be 'tumour-agnostic' or 'histology-independent'. NTRK gene fusions may be able to drive tumour growth, so targeting treatment to the cause of the disease could mean higher rates of response to therapy and potentially better outcomes. The committee accepted that it was expected to appraise larotrectinib within its conditional marketing authorisation using NICE's single technology appraisal process. But it recognised the challenges of appraising a histology-independent treatment within this process.\n\n## Solid tumours with NTRK gene fusions are rare and better characterisation is needed\n\nNTRK gene fusions occur rarely (less than 1%) in common tumours such as lung, colorectal and breast cancers. Some rare tumour types have more than 90% NTRK fusion prevalence (for example, mammary analogue secretory carcinoma and infantile fibrosarcoma). There are many tumour types with known NTRK gene fusions and all solid tumour types are included in larotrectinib's marketing authorisation. NTRK fusions can involve portions of the NTRK1, NTRK2 and NTRK3 genes with another unrelated gene partner (over 80\xa0different partner genes identified). The European public assessment report (EPAR) for larotrectinib notes there is evidence that the most frequent fusions found in high NTRK-prevalent tumours, ETV6‑NTRK3 fusions, drive tumour growth regardless of other characteristics. The EPAR also states that larotrectinib has shown activity in gastrointestinal stromal tumours with NTRK gene fusions and this likely reflects a similar role of NTRK gene fusions in driving tumour growth. For all other NTRK fusions, their role in driving cancer growth has not been properly studied. It is not known if there are tissue-specific mechanisms for bypassing response to drugs for NTRK fusions or effects from other drivers of tumour growth. The committee concluded that better characterisation of NTRK gene fusions was needed to fully support the histology-independent approach.\n\n## Further data are needed on whether NTRK gene fusions affect prognosis\n\nIt is not known whether patients with tumours that have NTRK gene fusions have a different prognosis to those who do not have them. Evidence of an association between NTRK gene fusions and different disease presentation is weak and based on data from very few patients. The company assumed there was no prognostic effect of NTRK gene fusions in its base-case analysis. The ERG considered that it was unclear whether NTRK fusions affect prognosis directly or whether they are associated with other factors that affect prognosis such as age and Eastern Cooperative Oncology Group (ECOG) status. Prognosis could also vary by tumour type and NTRK gene fusion type. The committee concluded that further data would be needed to establish whether NTRK gene fusions affect prognosis.\n\n# Treatment pathway and comparator\n\n## People with NTRK fusion-positive solid tumours would value new treatment options\n\nThere is no defined clinical pathway for people with solid tumours with NTRK gene fusions. Treatment currently follows care guidelines for specific tumour types, with surgery, targeted therapy, immunotherapy and chemotherapy for the more common cancers. Treatment for rarer cancers is generally limited to surgery, radiotherapy and chemotherapy. The patient experts explained that people who have a solid tumour with a gene alteration would want treatment with a targeted therapy because longer survival and a better side effect profile are likely. The aim of treatment for some inoperable tumours is to shrink the solid tumour so that surgery might be a treatment option. The committee concluded that people with NTRK fusion-positive solid tumours would value new treatment options.\n\n## Larotrectinib's position in the treatment pathway is a major uncertainty and further data are needed\n\nLarotrectinib is indicated for 'the treatment of adult and paediatric patients with tumours that display a NTRK gene fusion and who have disease that is locally advanced, metastatic or where surgical resection is likely to result in severe morbidity, and no satisfactory treatment options'. The ERG considered that the positioning of larotrectinib would depend on which treatments clinicians consider unsatisfactory. This would vary because it involves assessing response rates and adverse events and discussing options with patients. The clinical evidence for larotrectinib comes from a population with different tumour types who have had different previous treatments. Most patients had previous systemic therapies but a proportion had no previous treatments. The patient experts considered that any targeted therapy should be used as early in the treatment pathway as possible to maximise patient access. The clinical expert stated that for some sarcomas there are very few treatment options. In larotrectinib's summary of product characteristics, it states that it should only be used if there are no treatment options with established clinical benefit, or when such treatment options have been exhausted. This is because the regulatory authority considered that larotrectinib's benefit had been established in single-arm trials in a relatively small sample of patients. But it also considered that its effect may differ depending on tumour type and other possible gene alterations, so it should not displace any effective therapies. The company therefore positioned larotrectinib as a last-line treatment, after all other treatments have been tried, by choosing the comparators: best supportive care for common cancers and chemotherapy for rarer cancers. The committee considered this positioning appropriate and in line with the marketing authorisation. However, it recognised that if larotrectinib's efficacy was further established, it was possible that clinicians would want to use it earlier in the pathway. This would displace other potentially effective therapies and is outside larotrectinib's current marketing authorisation. Further evidence about this is being collected as part of larotrectinib's conditional marketing authorisation. The committee concluded that larotrectinib's positioning was a major uncertainty and collecting further data would determine how larotrectinib would be used in clinical practice.\n\n# Diagnosis\n\n## The diagnostic pathway for NTRK fusions has implications for identifying patients and on diagnosis costs\n\nAll solid tumour types could potentially have NTRK gene fusions although they are rare in common tumour types (see section\xa03.2). Therefore, many people would need screening to identify who would benefit from larotrectinib. Currently, NTRK testing is not routinely done in the NHS for all solid tumours. However, it is available for mammary analogue secretory carcinoma and secretory breast carcinoma with immunohistochemistry techniques (a method that uses antibodies to detect the gene fusion protein). Whole genome sequencing (a method of determining the whole DNA sequence of a cancer, used for discovering mutations) can also identify NTRK gene fusions. It is available for children's cancers and sarcomas, although confirmation of the results with another targeted DNA or RNA test is needed (for example next generation sequencing, which is a faster method of sequencing targeted regions of the cancer's DNA). The committee concluded that the diagnostic pathway for NTRK gene fusions was important, with implications for identifying patients and on costs of diagnosis.\n\n## The diagnostic pathway is uncertain until NHS England establishes a national service for genomic testing of all advanced solid tumours\n\nThe Cancer Drugs Fund clinical lead explained that NHS England is currently establishing a national service for cancer genomic testing, to replace all local testing. It involves setting up 7\xa0laboratory hubs across England to do genomic testing by next generation sequencing and interpret all results. The committee understood that until the laboratory hubs are fully established, next generation sequencing will be done after all NHS-commissioned treatment options have been tried. When the hubs are fully established, next generation sequencing to identify gene alterations, including NTRK gene fusions, will be done when locally advanced or metastatic solid tumours are first diagnosed. The Cancer Drugs Fund clinical lead estimated that 100,000\xa0solid tumours will be tested per year once the service is fully established. He noted that other targeted therapies will likely become available soon for different diseases and genomic testing will also be needed before these treatments are used. The committee acknowledged the ongoing developments in genomic testing practice to identify NTRK fusion-positive solid tumours. It considered that the rapid change to the diagnostic testing pathway being led by NHS England was a unique situation. The committee concluded that the diagnostic testing pathway was uncertain until NHS England establishes a national service for cancer genomic testing.\n\n## Diagnostic techniques will improve as the genomic laboratory hubs validate their techniques and NTRK gene fusions are better characterised\n\nThe diagnostic specificity of any test needs to be very high to exclude patients who do not have an NTRK gene fusion and so would not benefit from larotrectinib. This particularly affects common tumour types with low NTRK prevalence (for example, lung, colorectal and breast tumours) in which the number of false-positive results could outnumber true-positive results if the test is not specific enough. The committee was aware that currently, DNA-based next generation sequencing and whole genome sequencing were not sensitive enough to screen for NTRK gene fusions. Clinical experts considered that DNA- and RNA-based next generation sequencing with a confirmatory targeted DNA, RNA or immunohistochemistry test when a positive result is obtained would be appropriate and minimise the number of false-positive results. Some factors may reduce the specificity of these tests, such as tissue degradation and human error. The committee noted that the last-line positioning of larotrectinib reduced the risk of displacing active treatments for patients with false-positive results for NTRK gene fusions, whose tumours would not respond to larotrectinib. However, there were concerns about the ethics of treatment for any patients with false-positive results because of adverse events. The committee concluded that diagnostic techniques would improve as the genomic laboratory hubs validate their techniques and NTRK gene fusions are better characterised (see section\xa03.2).\n\n# Clinical evidence\n\n## The key clinical evidence comes from a pooled analysis of 3\xa0single-arm clinical trials and is appropriate for decision making\n\nThe company presented a pooled analysis of 102\xa0patients from 3\xa0trials:\n\nNAVIGATE is an ongoing trial for patients of 12\xa0years and over with locally advanced or metastatic tumours with NTRK gene fusions who have had prior therapy or who would be unlikely to clinically benefit from standard care. NAVIGATE contributed 62\xa0patients to the pooled analysis.\n\nSCOUT is an ongoing trial for children with locally advanced or metastatic solid tumours or primary central nervous system (CNS) tumours. SCOUT contributed 32\xa0patients to the pooled analysis.\n\nLOXO‑TRK‑14001 was a dose-finding study in patients with solid tumours with NTRK gene fusions, which contributed 8\xa0patients to the pooled analysis. The group analysed for efficacy was further split by patients with primary CNS tumours (n=9) and all other patients (n=93). The committee noted the small patient numbers from each of the trials making up the pooled analysis. Also, it noted that the trials were single arm and did not include a control group. Given the rarity of the gene fusion, the committee concluded that the evidence was appropriate for decision making.\n\n## The key clinical evidence is not generalisable to NHS clinical practice and further data are needed\n\nThe company considered the results to be generalisable to NHS clinical practice and did not do any adjustments for baseline characteristics. The ERG noted that patients in each trial were recruited by convenience sampling and there was no systematic attempt to represent the distribution of tumour types in NHS clinical practice. Therefore, a substantial number of patients in the trials had high NTRK-prevalent tumour types because these patients were easier to recruit. The over-representation of high NTRK-prevalent tumour types meant that:\n\nresponse rate estimates (see section\xa03.13) could have included a higher proportion of children with potential to be cured (see section\xa03.20) and\n\nthere was likely to be fewer false-positive results in the trial population (see section\xa03.8) compared with NHS clinical practice.Rare tumour types were also over-represented, which meant that more people had active chemotherapy options compared with best supportive care (see section\xa03.4). In addition to under-represented tumour types, there were tumour types that were not represented at all in the clinical evidence. So the committee would need to accept that unrepresented solid tumours (for which there were no data) would respond to larotrectinib. The ERG also thought that not enough information was provided to explore patient characteristics in the trial and whether these were generalisable to the population who would have treatment in NHS clinical practice. The committee noted that the diversity of tumour types would make adjusting for patient characteristics by tumour type very difficult, but this was not explored. The ERG considered that it was unclear whether patients had exhausted their treatment options; the trial inclusion criteria may be different to the marketing authorisation because the definition of satisfactory is open to interpretation (see section\xa03.5). This could have led to considerable bias. The committee concluded that the key clinical evidence was not generalisable to NHS clinical practice because of the distribution of tumour types, including potentially unrepresented tumour types, and the unknown effect of patient characteristics. Further data are needed to explore the types of tumour and distribution of patients, which were major uncertainties.\n\n## The size of larotrectinib's benefit on long-term survival cannot be reliably estimated because the data are immature\n\nThe primary outcome measure of the 2\xa0larger trials was overall response rate. The committee considered that the evidence showed a clinically relevant overall response rate of 72% across multiple tumour types. But it noted that this may not be generalisable to the broader range of tumour types expected in NHS clinical practice (see section\xa03.10). Also, it was aware of considerable uncertainty about the extent to which the response translated into clinically meaningful survival benefits. The progression-free survival data were immature, with only 37% of patients having progressed disease (excluding primary CNS tumours). Also, overall survival data were very immature with only 14\xa0of 102\xa0patients dying in the trials. The immaturity of the data meant that the extrapolation of survival estimates was very uncertain (see section\xa03.21). The committee concluded that the immaturity of the survival data meant that the size of larotrectinib's benefit on long-term survival could not be reliably estimated.\n\n# Heterogeneity in response\n\n## The trials are not designed to assess heterogeneity in response\n\nThe committee was aware of several biological reasons why heterogeneity, or a difference, in response to larotrectinib might be seen. For example, response might be different by histology, by NTRK gene fusion or fusion partner, by the presence of co‑drivers of the disease and by age (for example for children's indications). None of the statistical protocols of the trials included in the pooled analysis were designed to test heterogeneity in response by any factor. NAVIGATE was a 'basket' trial (that is, a trial that included patients who had different types of cancer but the same gene mutation) which involved many small groups of patients stratified by tumour type. If a response was seen in one of these groups, a response to larotrectinib for that tumour type was assumed and the basket was further expanded to increase the sample size. However, the company later pooled all the analyses from the 3\xa0studies of all patients in whom efficacy could be evaluated (see section\xa03.9). The EPAR states that selection bias on pooling the data is possible and there may be some tumour types that do not respond (type\xa01 error). The ERG explained that the company assumed an equal response to larotrectinib independent of tumour type and response was not formally assessed by tumour type. The committee concluded that the trials were not designed to assess heterogeneity in response.\n\n## Assuming equal response to larotrectinib across tumour types and fusion types is inappropriate\n\nThe committee noted the challenges of assessing response because the individual subgroups were too small for meaningful analysis. For example, some tumour types with few patients in the trials, such as pancreatic tumours (n=1) and congenital mesoblastic nephroma (n=1), had 0% response or 100% response respectively. This may be because of chance findings or because of biological differences in the tumour type. For example, as noted in the EPAR, tissue-specific mechanisms for bypassing response to drugs have been seen when targeting other gene mutations (such as colorectal cancer not responding to BRAF mutation inhibitors). Tumour tissue can also affect type of NTRK gene fusion, gene fusion partners and presence of other mutations. The response to larotrectinib by NTRK gene fusion showed heterogeneity, with low response in NTRK2 and high response in NTRK3 (82%). There was also heterogeneity in response to larotrectinib by gene fusion partner. The most common fusion partner, ETV6‑NTRK3, had an overall response of 84%, higher than all other fusion partners combined. The Cancer Drugs Fund clinical lead commented that it is biologically plausible that for people with high NTRK-prevalent tumours, such as those with ETV6‑NTRK3 (see section\xa03.2), there would be a higher response to larotrectinib and greater benefits. The clinical experts could not comment on whether heterogeneity in the response to larotrectinib would be expected across different tumour types. The company's model assumed equal response for all tumour types and fusion types, based on the overall response from the trial population (see section\xa03.9) and did not explore any other assumption. The committee concluded that given the observed differences in response and the poor characterisation of NTRK gene fusions and fusion partners, assuming equal response was inappropriate. Adjustment should be made for potential differences by subgroup.\n\n## Bayesian hierarchical modelling is a useful way to consider the heterogeneity in response to larotrectinib\n\nThe ERG presented the Bayesian hierarchical model (BHM) framework as an approach to characterise heterogeneity. The BHM framework was developed specifically for basket trials and is useful when there is limited information. This method allows for analysis of a pooled overall response rate, adjusting for the observed heterogeneity and borrowing strength across different tumour types to avoid extreme results. Extreme results may be seen because of limited patient numbers in trials; even small changes in the absolute number of people whose disease responds can considerably affect the response rate (see section\xa03.13). The ERG noted that because the tumour types with more response events also had high response rates, the low response rates seen in tumour types with fewer response events reduced the overall response in the pooled analysis from 72% to 57% (including primary CNS tumours, see section\xa03.15). The committee acknowledged that the results of the ERG's BHM approach were substantially different to the company's approach, which assumed that the response was the same across the different tumour types. The committee considered the reduced overall response output of the BHM, with wide credibility intervals, to be more appropriate for decision making because it incorporated some adjustment for heterogeneity. The ERG noted that the BHM approach could also be used for survival outcomes because response was not explicitly modelled in the company's base case. However, the company did not provide the data needed to do this analysis and the survival results were likely to be too immature for meaningful interpretation of the results. The committee concluded that the BHM was a useful tool for exploring heterogeneity in response to larotrectinib and, based on the current limited dataset, should be considered as part of its decision making.\n\n## Patients with primary CNS tumours should be included in the response analysis\n\nThere were 9\xa0out of 102\xa0patients with primary CNS tumours and these tumours had a much lower response to larotrectinib than other types. Although the results for this group were analysed separately from the main efficacy analysis, they were included in the economic analysis. The company explained that tumour response to larotrectinib in patients with primary CNS tumours was assessed by investigators using the response assessment in neuro-oncology (RANO) criteria, instead of the independent review committee assessed response evaluation criteria in solid tumours (RECIST)\xa0v1.1. Surgery and radiotherapy for CNS tumours can lead to varying amounts of scarring and inflammation, which makes it difficult to assess response using RANO criteria. The company considered that this explained the lower response compared with other tumour types. However, in the EPAR it states that larotrectinib is a substrate of P‑glycoprotein, a key constituent of the blood–brain barrier. This may mean that the dose of larotrectinib reaching the brain is reduced. The ERG considered that primary CNS tumours may have a lower response to larotrectinib or that the high proportion of NTRK2 gene fusions within primary CNS tumours may explain the low response. The ERG noted that including the primary CNS data in the BHM reduced the estimated overall response rate. But the ERG did not state a preference for including or excluding primary CNS data from the BHM. The committee concluded that there was uncertainty about whether primary CNS tumours respond to larotrectinib. However, it considered that the primary CNS data should be included in the BHM until more is known about larotrectinib's efficacy in the brain and NTRK2 gene fusions are better characterised. This is so the results are more generalisable to the population covered in the marketing authorisation.\n\n# Indirect treatment comparisons\n\n## The naive indirect comparison with a pooled comparator arm is biased\n\nTo establish relative clinical effectiveness compared with current clinical practice, larotrectinib was compared with multiple comparators by tumour site-specific pathway. The company's base-case analysis created a pooled comparator arm by using data from last-line treatment arms in published NICE appraisals and in the literature to represent best supportive care. Survival estimates were weighted by the distribution of the efficacy population to allow a naive indirect comparison with an estimate of survival expectancy for this population. The ERG considered this method could introduce bias in many ways, including generalisability of the trial population (see section\xa03.10) and uncertainty over the potential prognostic importance of NTRK (see section\xa03.3). This method also limited the ability to adjust for any heterogeneity (see section\xa03.13). This was because it assumed that survival was independent of tumour type and other factors, therefore assuming a common natural history for all tumour types in the analysis. The ERG explained that the size and direction of bias was impossible to establish. The committee appreciated the difficulty in estimating a comparator population for rare tumours across multiple tumour types. But it concluded that the company's method had unadjusted bias that did not account for significant heterogeneity and could not adjust for important prognostic factors and baseline characteristics.\n\n## The 2\xa0confirmatory analyses also have biases, but will be considered in decision making\n\nThe company presented 2\xa0further indirect treatment comparisons, as confirmatory analyses, to approximate the comparator arm. A response-based analysis assumed patients whose tumours did not respond to larotrectinib were equivalent to those who had best supportive care and were assumed to represent the comparator arm. The advantages of the response-based analysis were that the eligibility criteria of the trial were considered, and the ERG's adaptation of this model allowed for exploration of heterogeneity (see section\xa03.13). However, this method assumed that response was a surrogate outcome for survival, which may differ significantly by tumour type and have known biases. A previous line of treatment analysis compared the time to progression on the previous line of treatment with the time in progression-free survival on larotrectinib for each patient. This ratio was used as a hazard ratio to approximate a comparator arm for progression-free survival and it was assumed that overall survival behaved the same. The advantage of this analysis was that each patient acted as their own control, which was particularly beneficial for a histology-independent population. However, the ERG had concerns with how this analysis was implemented. It considered that a patient's previous unsuccessful line of therapy may not represent best supportive care and it noted that the method was uninformative for overall survival, which was a major uncertainty of the base-case analysis. The committee noted that both confirmatory analyses also had substantial biases and that all the indirect treatment comparisons had structural uncertainty. Therefore, it concluded that it would consider the outputs of all indirect treatment comparisons in its decision making.\n\n# The company's economic models\n\n## The most appropriate model structure for decision making is uncertain\n\nThe company's economic models were based on the indirect treatment comparisons (see section\xa03.16 and section\xa03.17). The company's base-case structure was a 3‑state partitioned survival model (progression-free, progressed and death). Survival estimates were extrapolated from the larotrectinib efficacy population and comparator arm survival estimates calculated using the method in section\xa03.16. Other model parameters such as utility, time on treatment and adverse events were also included to create part-models (termed 'engines' in the company submission) for each tumour type comparator. The company also provided economic models based on the confirmatory analyses in section\xa03.17. The ERG adapted the response-based model to a dual-partitioned survival model with the larotrectinib arm response defined by output from the BHM (see section\xa03.14). This allowed for some exploration of uncertainty from heterogeneity in response. The ERG also considered that this would account for issues with post-progression treatments (see section\xa03.22) because these would be the same in both treatment arms. The ERG considered the previous line of treatment analysis was not implemented appropriately and was uninformative for overall survival, so did not consider this model structure further. The committee recognised the difficulty in modelling treatments for single-arm data, and that the unique challenges of histology-independent treatments further complicated the modelling issues. The committee understood that there were limitations and uncertainties with each of the modelling approaches. It considered that when more data were available, the different model structures could be explored more fully. The committee concluded that the most appropriate model structure for decision making was uncertain.\n\n## None of the models use a population that is generalisable to NHS clinical practice\n\nThe company's base-case model used the full efficacy evaluable population from the pooled analysis, which the committee considered was not generalisable to NHS clinical practice (see section\xa03.10). The company did not provide any information for the effectiveness of larotrectinib by individual tumour type, so it was not possible to remove patients who were over-represented from the economic model or to adjust the population to make it more generalisable. The over-representation of rare and high NTRK-prevalent tumour types introduced several issues, including:\n\nA higher response rate from tumour types with NTRK as the known driver of the disease (see section\xa03.13).\n\nThe potential that an unknown number of patients would be cured in both treatment arms (see section\xa03.20).\n\nSurvival estimates included in the analysis were for tumour types with a higher response rate (see section\xa03.21).\n\nSome tumour sites were over-represented in the utility value calculations (see section\xa03.23 and section\xa03.24).Without evidence from a more generalisable population, the committee considered that it would be most appropriate to model survival in the trial population as a proxy. However, this would add considerable additional uncertainty to any cost-effectiveness estimates from the economic model. The committee concluded that all models used the unadjusted pooled analysis so could not model a population that would be generalisable to NHS clinical practice.\n\n## A different model structure is needed to explore the effect of a cure\n\nThe committee was aware that only a small number of patients in clinical practice would have tumour types that could potentially be cured because locally advanced and metastatic cancer is generally incurable. However, children with tumour types that could potentially be cured were included in the SCOUT trial in much greater proportions than would be seen in clinical practice (see section\xa03.10 and section\xa03.19). Most children in the evaluable population from SCOUT had no other curative options besides amputation or disfiguring surgery. The company considered that some of these patients would be cured without larotrectinib, with lifelong morbidity from amputation or disfigurement. Therefore, it considered that a cure model could be appropriate. But cure could not be determined because of short follow up, limited numbers of patients and high censoring of data. The committee noted considerable uncertainty around the potential for a cure and that the curative role of surgery had not been explored in either treatment arm. It also noted that the comparator part-model for these patients (grouped as paediatric sarcomas) did not model lifelong survival over the full-time horizon. Therefore, the current model structure captured the benefit of a cure in the Kaplan–Meier survival analysis in the larotrectinib arm but did not model the possibility of cure in the comparator arm. The committee concluded that this issue strongly biased the modelled cost-effectiveness results in favour of larotrectinib. The committee was aware that the modelled cure rates were speculative because the cure rate in the trial population was unknown and likely to be negligible for a generalisable population. The potential for a cure in the trial population supported why the model structures proposed were not appropriate for a heterogeneous non-generalisable population. The committee concluded that a different model structure should be used to explore the effect of a cure. Also, further information was needed on how larotrectinib would be used in clinical practice.\n\n# Modelled survival outputs\n\n## Survival extrapolation is highly uncertain and a key driver of the model\n\nData on overall survival and progression-free survival were incomplete and the clinical trials are ongoing. To extrapolate progression-free survival and overall survival for larotrectinib, the company fitted standard distributions to the data (the exact distributions chosen are confidential and cannot be reported here). For the pooled comparator arm, the curve accepted by the committee in previous NICE guidance was used when available and assumptions used when no NICE guidance was available. The ERG noted the considerable uncertainty in extrapolating data that are immature (see section\xa03.11). The overall survival extrapolation showed substantial separation from the progression-free survival extrapolation, which contributed to an implausible post-progression survival estimate (see section\xa03.22). During the technical engagement stage, the company provided overall survival data from an updated data-cut. The ERG considered that there were no clear differences in survival characteristics in these updated data. But it noted that a few events at the extreme end of the curve dramatically affected the survival extrapolation and modelled survival gain. The committee considered that this could be a result of uncertain extrapolation and may not suggest a true decline in survival. This was compounded by uncertainty about the possibility of including patients whose disease was cured in the larotrectinib Kaplan–Meier curves (see section\xa03.20). The committee concluded that the extreme sensitivity of the model output to the survival extrapolations meant that extrapolation did not provide results that the committee could trust, but that data on longer-term extrapolation could be collected in the Cancer Drugs Fund.\n\n## The modelled post-progression survival outputs are implausible\n\nThe ERG noted that the life years gained after progression were greater than both the progression-free life years gained and overall survival in the comparator arm, which it considered implausible. The ERG considered this could be a result of the highly uncertain extrapolation or because of the high proportion of patients who had post-progression treatments, such as further larotrectinib or an experimental treatment (LOXO‑195) for people whose disease was resistant to TRK-inhibitors. The ERG considered that LOXO‑195 would not be used in clinical practice because the tumour would need to be TRK-inhibitor resistant before people could have this treatment. The committee considered it appropriate to adjust for the benefits of these treatments. However, it noted the difficulty of using adjustment techniques for an unknown treatment effect in immature survival data. The clinical expert stated that a high depth of response (prolonged benefit from shrinking the tumour) to larotrectinib might explain why post-progression survival could be higher than progression-free survival. Having a smaller tumour could mean longer survival even after developing resistance to larotrectinib. The committee considered this concept to be possible but highly speculative because the current evidence base was very immature. It also noted that TRK-inhibitor resistance mechanisms were not well characterised and would not explain the size of the discrepancy in life years gained. The ERG provided 2\xa0scenarios based on crude adjustment of larotrectinib post-progression survival to match post-progression survival in the comparator arm (no comparative effect of larotrectinib after progression) or overall survival in the comparator arm. The committee considered these scenarios to be more plausible than the company's base case and appropriate for showing the upper limit of plausible cost-effectiveness estimates. However, it considered that the survival estimates, both progression-free and post-progression, were likely to be affected by immature extrapolation (see section\xa03.21) and including survival data from patients whose disease was cured (see section\xa03.19). The committee concluded that the post-progression survival estimates were implausible and that the ERG scenarios did not fully capture the issues with modelling survival.\n\n# Utility values in the economic models\n\n## Assuming equal post-progression utility values in the larotrectinib and pooled comparator arms is appropriate\n\nThe company provided utility values derived from health-related quality-of-life data collected in the SCOUT and NAVIGATE trials, mapped to EQ‑5D‑3L utility values for the pre-progression and progressed health states. For the comparator arm utility values, a similar approach to that used for estimating survival was used (see section\xa03.16). Utility values from published NICE guidance were pooled and weighted by the distribution of the efficacy population. The ERG considered that there was considerable uncertainty in the utility value estimate of the post-progression health state for larotrectinib because it was based on few assessments of patients, most of whom were children. The committee noted that some patients could potentially be cured (see section\xa03.19). It considered that the evidence for the post-progression utility values for larotrectinib was weak and there was no plausible reason why post-progression utility would be so much higher for larotrectinib than for the comparator arm for the entire population. The ERG provided a scenario with equal post-progression utility values for larotrectinib and the pooled comparator. The committee agreed that this scenario was more appropriate.\n\n## Sensitivity analysis to see the effect of reducing utility values for larotrectinib is needed\n\nThe company's utility values suggested a difference in pre-progression utility between larotrectinib and the pooled comparator. The Cancer Drugs Fund clinical lead considered this to be implausible because the modelled comparator in NHS clinical practice was likely to be best supportive care. Therefore, any difference in utility values between arms would represent positive effects from reduced tumour size in the pre-progression state for larotrectinib and the difference in adverse effects between treatments not captured by the adverse event modelling. The committee considered that the high number of patients having chemotherapy rather than best supportive care (see section\xa03.10) would bias this difference in favour of larotrectinib. The committee concluded that it was appropriate to do a sensitivity analysis to see the effect of reducing larotrectinib pre-progression utility values on this bias. The committee considered this scenario to be more plausible for a population that was generalisable to NHS clinical practice.\n\n# Resource use and costs\n\n## It is appropriate to include diagnostic testing costs in the economic model\n\nThe committee understood that the NICE methods guide was not designed to address a system-wide change in diagnostic techniques and the cost of testing would depend on NHS England's testing strategy. The company considered that the planned changes in genomic testing (see section\xa03.7) would mean that none of the testing costs would be borne by larotrectinib in the economic model. This was because the system would be independent of testing for NTRK gene fusions and would not be used solely for identifying NTRK gene fusions for a particular drug. The ERG's interpretation of the methods guide was that associated costs of the diagnostic test should be incorporated into the clinical- and cost-effectiveness assessments. The committee agreed that the ERG's interpretation, which included assessment of the cost of larotrectinib in current NHS clinical practice, most closely matched the methods guide. The ERG proposed a pragmatic screening pathway for each tumour type, based on adapting current testing provisions for some tumour types that already have some genomic testing. For tumour types that are not currently tested for any genetic mutations, the ERG assumed that immunohistochemistry would be followed by confirmatory next generation sequencing if there was a positive result. This technique provided an average cost of screening for a single patient with an NTRK gene fusion, which was included in the cost-effectiveness estimates. The committee considered this analysis was reasonable because it reflected current clinical practice, but recognised that NHS England is rapidly moving towards a national service for cancer genomic testing. Therefore, the proposal from NHS England to implement next generation sequencing at diagnosis of locally advanced or metastatic disease was likely to reflect the near future once the changes to the diagnostic pathway have been established. NHS England proposed a cost per patient with an identified NTRK fusion-positive tumour to be included in the model. The committee noted that this cost was substantially less than in the ERG's scenario. The committee concluded that it was appropriate to include diagnostic testing costs in the model.\n\n## The adjustments to the children's dose and including drug wastage costs in the economic model are appropriate\n\nThe company used the average adult and children's doses used for the efficacy population to calculate the dose of larotrectinib applied in the model. The ERG considered this to be inappropriate because some children had a lower dose in SCOUT because it was a phase\xa01 dose-finding study. The ERG provided a scenario in which the full children's dose was adjusted using the percentage of adults adhering to treatment. The committee agreed that the ERG's adjustments were appropriate to better generalise the dose in SCOUT to NHS clinical practice, but it noted that this did not account for potential differences in clinical effect. Additionally, the company supplied scenarios considering larotrectinib wastage after stopping treatment for 2- and 4‑week treatment supplies. The committee noted that these scenarios had little effect on the cost-effectiveness estimates but considered it appropriate to include the 4‑week treatment drug wastage scenario in the model. The committee also noted that these assumptions relied on using hard capsules, which are not yet available, so an additional scenario using the oral solution should have been provided.\n\n## Including a scenario with the costs of oral chemotherapy administration in the economic model is appropriate\n\nThe company considered that administration costs and resource use should be applied in the model by the distribution of patients in the efficacy analysis. The committee considered this inappropriate because the over-representation of rare tumours that were modelled as having chemotherapy (see section\xa03.10) may have resulted in bias in favour of larotrectinib. However, it considered that the true distribution could not be calculated. The Cancer Drugs Fund clinical lead commented that the administration costs for oral chemotherapy were not included for larotrectinib. At the technical engagement stage, the company provided a scenario with these administration costs. The committee concluded that this scenario was appropriate for including in the economic model.\n\n## The model should include the costs of post-progression treatments\n\nThe company modelled the costs of larotrectinib treatment until progression, but some patients continued to have larotrectinib after progression (see section\xa03.22). The company provided a scenario using the time to treatment discontinuation seen in the trial to model larotrectinib costs. The committee considered this to be more appropriate because the modelled costs of larotrectinib should match the modelled benefits. However, it noted there would be further uncertainty with extrapolation of time to treatment discontinuation, and that other methods of including these costs may be more appropriate because of the number of patients who had post-progression treatment with larotrectinib and the immaturity of the data. The committee did not see evidence for how long patients had treatment with larotrectinib after disease progression and could not comment on whether this was generalisable to NHS clinical practice. The committee concluded that the costs of post-progression larotrectinib should be included, but this issue had not been fully explored. Further data collection within the Cancer Drugs Fund could reduce this uncertainty.\n\n# End of life\n\n## Larotrectinib has plausible potential to meet the end-of-life criteria but there is uncertainty\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The company proposed that larotrectinib met the criteria for life-extending treatments for people with a short life expectancy (normally less than 24\xa0months). The committee understood that the end-of-life criteria were not designed for histology-independent treatments and it was not presented with the data needed to assess the criteria for people with NTRK gene fusions specifically. Instead, it was presented with life expectancy data for people with the relevant tumour type irrespective of NTRK gene fusion status and life extension data estimated from the model. It acknowledged the challenges with the data available, for example:\n\nthe distribution of tumour types in the trials and unrepresented tumour types not included in the clinical evidence (see section\xa03.10)\n\nuncertainty around larotrectinib's position in the treatment pathway (see section\xa03.5)\n\nthe limited survival data available (see section\xa03.11)\n\nthe prognostic importance of NTRK gene fusions (see section\xa03.3) and the uncertainty around the extrapolation of the survival data (see section\xa03.20).The committee considered that most tumour types represented in the trials had overall survival estimates that would meet the short life expectancy criterion. But it considered that the overall survival estimates for people with thyroid cancers were likely to exceed the short life expectancy criterion and this could also be true for some of the rarer tumour types. It considered that the extension to life criterion of greater than 3\xa0months would likely be met for most patients whose tumours responded to larotrectinib, although the size of the benefit and the distribution of these tumour types was highly uncertain. The committee concluded that larotrectinib had plausible potential to meet NICE's criteria to be considered a life-extending treatment at the end of life. But it acknowledged that there was uncertainty in determining both the life expectancy and the exact extension to life given the immaturity of the data and potential for heterogeneity across all the different tumour types. Further data collection could resolve this uncertainty and the distribution of tumour types likely to meet the life expectancy criterion.\n\n# Cost-effectiveness estimates\n\n## Larotrectinib is not recommended for routine commissioning\n\nThe company's base-case model gave a deterministic incremental cost-effectiveness ratio (ICER) of £16,155 per quality-adjusted life year (QALY) gained for larotrectinib compared with current clinical management. This included an updated simple discount patient access scheme for larotrectinib after consultation. The committee considered that the base case should also include the following committee preferences:\n\nutility values equal between post-progression treatment arms (see section\xa03.23)\n\nincluding the oral chemotherapy administration cost for larotrectinib (see section\xa03.27)\n\nincluding drug wastage costs based on 4‑weekly prescription (see section\xa03.26)\n\nadjusting the children's dose to account for inclusion of the dose-finding study (see section\xa03.26)\n\nresponse rate using the more generalisable response rate from the BHM (see section\xa03.14)\n\nincluding the costs of diagnostic testing as proposed by NHS England (see section\xa03.25).After the committee meeting, the ERG provided analyses including these assumptions that increased the ICER to £30,888 per QALY gained. But this did not include many of the scenarios the committee considered key uncertainties of the appraisal:\n\nincluding the costs of larotrectinib after progression (see section\xa03.28)\n\nadjusting for the implausible post-progression survival (see section\xa03.22), which the committee considered would increase the ICER, based on the ERG's 2\xa0scenarios (ICERs of £40,342 and £48,161 per QALY gained for each of the scenarios in section\xa03.22)\n\nreducing pre-progression utility values for the larotrectinib arm (see section\xa03.24), which the committee considered would be likely to modestly increase the ICER\n\nexploring assumptions around a potential cure affecting survival estimates (see section\xa03.20), which the committee considered would be likely to greatly increase the ICER.The committee considered that the ICER ranges had plausible potential to be a cost-effective use of NHS resources if larotrectinib met the end-of-life criteria. However, the committee considered that there was substantial uncertainty in the survival estimates, with ICER ranges that were likely to be higher than what is considered a cost-effective use of NHS resources. Also, much uncertainty remained from modelling a population that was not generalisable to NHS clinical practice. Therefore, the committee concluded that it could not recommend larotrectinib for routine commissioning.\n\n# Cancer Drugs Fund\n\n## Collecting more data could address the uncertainty in the evidence\n\nHaving concluded that larotrectinib could not be recommended for routine use, the committee then considered if it could be recommended for treating NTRK fusion-positive solid tumours within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum). It considered that some of the inherent uncertainty in appraising a histology-independent treatment could be resolved through further data collection. The committee was aware that the company expressed a preference for larotrectinib being available in the Cancer Drugs Fund because of the uncertainty in the appraisal and while data mature. The committee was aware that more larotrectinib clinical trial data are expected. Also, the company has some data collection ongoing as part of the regulatory commitments required by the conditions of the marketing authorisation. The committee concluded that some of the uncertainty associated with larotrectinib's use could be addressed through collecting more data. It noted that:\n\nThe ongoing larotrectinib clinical trials will provide more mature survival data for people already enrolled in the trials. They may recruit additional patients with solid tumours at sites not already included in the clinical trials, which will provide further data to explore the heterogeneity in response to treatment.\n\nReal-world evidence collected in the Cancer Drugs Fund through Blueteq, SACT and the molecular dataset should provide further information on the generalisability of the clinical trials to NHS clinical practice, the prevalence of NTRK gene fusions, the distribution of tumour types in England and the screening and treatment pathway.\n\nA non-interventional study (ON‑TRK) will collect safety and efficacy data on larotrectinib and may provide further information on heterogeneity in response.\n\nA non-interventional study, in partnership with Genomics England, to collect NTRK gene fusion data should provide further information on whether NTRK gene fusions affect prognosis.\n\n## Larotrectinib meets the criteria to be included in the Cancer Drugs Fund\n\nThe committee noted that it had not seen evidence that was likely to be generalisable to clinical practice, or about how larotrectinib was likely to be used in clinical practice. It acknowledged that there was substantial clinical uncertainty about the population, modelling of comparator treatments, survival estimates and utility values. However, it considered that the data from larotrectinib trials were promising, because tumour response rates were good, and it showed that larotrectinib was likely to improve overall and progression-free survival. The committee noted that many of the key clinical uncertainties could be addressed by collecting data in the Cancer Drugs Fund (see section\xa03.31). The committee then considered if larotrectinib showed plausible potential to be cost effective at the end of the managed access agreement. It noted that the range of ICERs from the available analyses, which included most of the committee's preferred assumptions for the population from the trials compared with established practice, were within what is usually considered a cost-effective use of NHS resources, if larotrectinib meets the end-of-life criteria. However, the committee considered that, because of the many underlying clinical uncertainties, the ICERs were not reliable, and that cost-effectiveness estimates could be improved by collecting data in the Cancer Drugs Fund. The committee recalled, from NHS England's Appraisal and funding of cancer drugs from July 2016 (including the new Cancer Drugs Fund) – a new deal for patients, taxpayers and industry, that the Cancer Drugs Fund is designed 'to offer pharmaceutical companies that are willing to price their products responsibly with a new fast-track route to NHS funding for the best and most promising drugs'. The committee concluded that larotrectinib met the criteria to be included in the Cancer Drugs Fund as an option for people with NTRK fusion-positive solid tumours, if the conditions in the managed access agreement are followed.\n\n# Innovation\n\n## Larotrectinib is innovative and there are wider benefits to the NHS not captured in the analysis\n\nThe company considered larotrectinib to be innovative because it targets a gene fusion instead of a tumour type. The patient and clinical experts agreed. The committee considered larotrectinib to be innovative because it represents a major change in the treatment of NTRK fusion-positive solid tumours. The committee understood that important innovations were already underway as part of the NHS long-term plan to improve genomic testing in clinical practice. These advances will likely help the uptake of treatments targeted to a gene alteration. The Cancer Drugs Fund clinical lead explained that histology-independent treatments entering the market are accelerating the advances in genomic testing in the NHS. It is estimated that 100,000\xa0solid tumours will be tested per year once the genomic medicine service is fully established, thought to be in the next 2\xa0years. The committee acknowledged that the improvements in genomic testing would bring wider benefits to the NHS and that these benefits have not been captured in the QALY calculation. The committee concluded that larotrectinib would be beneficial for patients, but it had not been presented with evidence of any additional benefits specific to larotrectinib that were not captured in the measurement of the QALY.\n\n# Equality considerations\n\n## There are no equality issues relevant to the recommendations\n\nThe company did not consider there to be any equality issues. However, it considered that the uncertainty inherent in this appraisal may pose an equity issue. There is no precedent for appraising technologies when their clinical trials have a basket trial design and a high number of comparators across multiple tumour types. The company considered that patients should have equity of access while health technology assessment methods adapt to these challenges. The committee considered that NICE's single technology appraisal process was appropriate for appraising larotrectinib. It concluded that the uncertainties associated with the trial design (see section\xa03.14) and multiple comparators (see section\xa03.17) had been appropriately accounted for in its decision making. The Cancer Drugs Fund clinical lead also noted that there may be issues with accessing larotrectinib because the genomic testing needed to identify NTRK fusion-positive solid tumours is still being established as a national service (see section\xa03.7). The committee understood that any variation in access to genomic testing will be resolved in the next 1\xa0to\xa02\xa0years."}
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https://www.nice.org.uk/guidance/ta630
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Evidence-based recommendations on larotrectinib (Vitrakvi) for treating neurotrophic tyrosine receptor kinase (NTRK) fusion-positive solid tumours in adults and children.
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7787ed702fc4e23b088e04388d29b24f211bf342
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nice
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Lorlatinib for previously treated ALK-positive advanced non-small-cell lung cancer
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Lorlatinib for previously treated ALK-positive advanced non-small-cell lung cancer
Evidence-based recommendations on lorlatinib (Lorviqua) for previously treated ALK-positive advanced non-small-cell lung cancer in adults.
# Recommendations
Lorlatinib is recommended, within its marketing authorisation, as an option for treating anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer (NSCLC) in adults whose disease has progressed after:
alectinib or ceritinib as the first ALK tyrosine kinase inhibitor or
crizotinib and at least 1 other ALK tyrosine kinase inhibitor.It is recommended only if the company provides lorlatinib according to the commercial arrangement.
Why the committee made these recommendations
Advanced ALK-positive NSCLC is usually first treated with an ALK tyrosine kinase inhibitor (alectinib or ceritinib, or crizotinib followed by either brigatinib or ceritinib). People then have either platinum doublet chemotherapy (PDC) or atezolizumab with bevacizumab, carboplatin and paclitaxel (ABCP).
Lorlatinib, another ALK tyrosine kinase inhibitor, has not been compared directly with other drugs. But analyses indirectly comparing lorlatinib with PDC and ABCP suggest that people who take lorlatinib:
have longer before their disease progresses and may live longer than people who take PDC
have longer before their disease progresses and may live longer than people who take ABCP.
Lorlatinib meets NICE's criteria to be considered a life-extending treatment at the end of life. Although the methods and results of the cost-effectiveness modelling are uncertain, the most likely cost-effectiveness estimates are within what NICE normally considers an acceptable use of NHS resources. Therefore, lorlatinib is recommended.# Information about lorlatinib
# Marketing authorisation indication
Lorlatinib (Lorviqua, Pfizer) as monotherapy is indicated for 'the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) whose disease has progressed after:
alectinib or ceritinib as the first ALK tyrosine kinase inhibitor (TKI) therapy; or
crizotinib and at least one other ALK TKI'.
# Dosage in the marketing authorisation
The recommended dose is 100 mg lorlatinib taken orally once daily. Treatment with lorlatinib is recommended as long as the patient is benefitting from therapy without unacceptable toxicity.
# Price
The list price of lorlatinib is £7,044.00 per 120-tablet pack of 25-mg tablets, and £5,283.00 per 30-tablet pack of 100-mg tablets (excluding VAT; BNF online accessed January 2020). The company has a commercial arrangement. This makes lorlatinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Pfizer, a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:
Including atezolizumab with bevacizumab, carboplatin and paclitaxel (ABCP) as a comparator in the appraisal was appropriate (issue 1, see technical report page 16).
A hazard ratio of 0.8 was a reasonable estimate of the comparative efficacy between platinum doublet chemotherapy (PDC) and singlet chemotherapy (issue 2, see technical report page 18).
Of the 6 proposed methods for indirect comparison with PDC, methods 3, 4 and 6 were dismissed by the company and ERG, leaving methods 1, 2 and 5 for committee consideration (issue 3, see technical report page 22).
The generalised gamma curve was the most appropriate for measuring overall survival on lorlatinib (issue 4, see technical report page 26).
Lorlatinib treatment for 3.5 months after progression was appropriate (issue 6, see technical report page 33).
The revised assumptions for subsequent treatment discussed at the technical engagement stage were appropriate:
After lorlatinib: 45% of patients have subsequent treatments and the remaining 55% have best supportive care. Of the 45%, 66% have ABCP and 33% have PDC.
After PDC: 45% of patients have subsequent treatments and the remaining 55% have best supportive care. The 45% have immunotherapies in the proportions in the original company submission (69% atezolizumab, 31% bevacizumab based on NICE's technology appraisal guidance on atezolizumab in combination).
After ABCP: 75% of patients have docetaxel and 25% have best supportive care (issue 7, see technical report page 35).
The company was not making a case for lorlatinib as a candidate for the Cancer Drugs Fund. This was appropriate because the ongoing lorlatinib clinical trials would not provide the evidence needed to resolve the uncertainties in this appraisal (issue 8, see technical report page 37).
The committee recognised that there were remaining areas of uncertainty associated with the analyses presented and took these into account in its decision making. It discussed the following issues (issues 3 and 5; see technical report, pages 19 and 27), which were outstanding after the technical engagement stage.
# Clinical need
## A third-generation ALK TKI would offer significant benefit to patients
The patient expert explained that there was a significant unmet need for patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC), even though 4 ALK tyrosine kinase inhibitor (TKI) treatments are available. The committee noted that neither crizotinib nor ceritinib are preferred for untreated disease since the availability of alectinib. Brigatinib has been approved for previously treated disease only after crizotinib. If alectinib's treatment effect wanes the only current option is chemotherapy. ALK TKI treatments are a significant improvement over chemotherapy. People can live relatively normally and do not need to go to hospital for treatment. They do not have distressing symptoms associated with chemotherapy such as hair loss. The patient expert explained that lorlatinib may be better tolerated than other ALK TKIs, appearing to cause less fatigue and fewer sun sensitivity and gastrointestinal problems. The clinical experts confirmed that there was a high unmet need for patients with ALK-positive NSCLC, because there is no cure for metastatic disease. Also, more than 50% of patients with ALK-positive NSCLC develop brain metastases, associated with high morbidity and mortality. Lorlatinib's ability to reach the brain means that patients whose brain tumours respond to treatment may have improved quality of life, allowing them to return to their usual activities. First and second-generation ALK TKIs (alectinib, ceritinib, crizotinib and brigatinib) are associated with the development of drug resistant mutations, leading to disease progression. Brain metastases and drug resistant mutations limit the duration of disease control and benefit from current ALK TKIs. For patients to survive for longer, and to avoid the devastating consequences of brain metastases, effective treatment that can penetrate the brain and overcome ALK-resistance mutations is needed. The committee noted that lorlatinib would be another line of ALK TKI treatment before a patient has chemotherapy or chemoimmunotherapy. The committee agreed that there was an unmet clinical need in ALK-positive NSCLC and that a third-generation ALK TKI, such as lorlatinib, would significantly benefit patients.
# Clinical management
## Current treatments after ALK TKIs are not effective for brain metastases
Current treatment options after ALK TKIs are standard care PDC, ABCP or best supportive care. The clinical experts explained that there was weak evidence for PDC-based regimens for this patient population, with a relative lack of efficacy in patients with brain metastases. The clinical experts explained that ABCP also has poor brain penetration and was not available to patients in the NHS in England with symptomatically active brain or leptomeningeal (central nervous system) metastases, which are common in ALK-positive NSCLC. In the absence of a third-generation ALK TKI such as lorlatinib, ABCP is expected to be used more in people without symptomatically active central nervous system metastases. The committee agreed that the evidence for the efficacy of current treatments after ALK TKIs was weak in ALK-positive NSCLC and it was unclear how much benefit they had in people with brain metastases.
# Clinical evidence
## The main clinical evidence comes from a single-arm study
The main clinical evidence for lorlatinib came from study 1001, a single-arm, open-label, multicentre phase 1 to 2 trial, done in 13 countries but not in the UK. This study investigated the effect of lorlatinib in adults with metastatic (stage 4) ALK-positive NSCLC. It comprised 7 cohorts with 5 (EXP‑2, EXP‑3A, EXP‑3B, EXP‑4, EXP‑5) representing populations having a mix of ALK TKIs and chemotherapy regimens. The company presented evidence for the combined cohort EXP‑3B:5 of 139 patients. This was the pooled cohort of patients from cohorts EXP‑3B, EXP‑4 and EXP‑5 whose treatment history most closely resembled that of the patient population covered by the marketing authorisation. Cohort EXP‑3B was made up of 28 patients who had had first-line treatment with alectinib or ceritinib, with or without prior chemotherapy. The clinical experts explained that most patients would have alectinib as first-line treatment in the NHS, meaning that this cohort was the closest match to the NHS population. Cohort EXP‑4 was made up of 65 patients who had previous treatment with 2 ALK TKIs, with or without prior chemotherapy. Cohort EXP‑5 consisted of 46 patients who had previous treatment with 3 or more ALK TKIs, with or without prior chemotherapy. The primary outcome of study 1001 was objective response rate. Secondary outcomes included overall survival and progression‑free survival. The results showed an objective response rate of 40.3% (95% confidence interval 32.1 to 48.9) with lorlatinib. The results also showed a progression-free survival of 6.9 months (95% CI 5.4 to 8.2) and a median overall survival of 20.4 months (95% CI 16.1 to not reached).
# Indirect treatment comparisons
## The results of the indirect treatment comparisons are uncertain
The company did an unanchored matching-adjusted indirect comparison (MAIC; as recommended in the NICE Decision Support Unit's technical support document 18), to compare the single-arm trial data for lorlatinib with trial data for PDC. The company chose 4 variables for matching:
Eastern Cooperative Oncology Group performance status (0 and 1 or more than 1)
brain metastases (yes or no)
family origin (Asian or non-Asian)
sex (male or female).The PDC data in the indirect comparisons were from the ALUR and ASCEND-5 trials (for progression-free survival) and the PROFILE 1001 and PROFILE 1005 trials (for overall survival). In the trials everyone had advanced or metastatic ALK-positive NSCLC:
ALUR compared alectinib with chemotherapy after previous treatment with PDC and crizotinib.
ASCEND‑5 compared ceritinib with chemotherapy after previous treatment with PDC and crizotinib.
PROFILE 1001 was a single-arm phase 1 trial of crizotinib.
PROFILE 1005 was a single-arm phase 2 trial of crizotinib after failure of 1 or more lines of systemic treatment for locally advanced or metastatic disease.The company explained that in addition to the MAIC it used 2 further approaches for the indirect treatment comparison, giving 6 methods in total:
hazard ratios estimated using a MAIC with EXP‑2:3A (method 1) and EXP‑3B:5 (method 2)
hazard ratios estimated using an unadjusted indirect comparison with EXP‑2:3A (method 3) and EXP‑3B:5 (method 4)
direct estimation of progression-free and overall survival by fitting parametric curves to chemotherapy data from the clinical studies (method 5) and the same parametric curves with a population adjustment because the populations in these clinical studies had fewer prior treatments than the EXP‑3B:5 cohort (method 6).The committee noted that methods 3, 4 and 6 had been dismissed at the technical engagement stage. The company preferred method 5, mainly because of concerns about whether the assumption of proportional hazards held for the duration of the model with methods 1 and 2. But the company said that methods 1 and 2 were also plausible approaches. The ERG had concerns about methods 1, 2 and 5, but considered that they were all plausible, and agreed that method 5 was preferred as the least problematic option. The committee agreed with the ERG that all the proposed indirect comparison methods were highly uncertain, but disagreed that methods 1 and 2 were reliable because of how the company had done the MAIC. The committee agreed that the company's approach of weighting patients in cohorts EXP‑2:3A and EXP‑3B:5 to match the patient characteristics of the populations from the ALUR and ASCEND‑5 and PROFILE 1001 and PROFILE 1005 trials was correct. But it was concerned about how the MAIC had been implemented. The committee noted that matching the 2 pooled cohorts (EXP‑2:3A and EXP‑3B:5) to the same chemotherapy arm trial populations should have resulted in very similar hazard ratios being generated. Presenting hazard ratios from the MAIC that were not similar (and which resulted in large ICER differences) for EXP‑2:3A (method 1) compared with EXP‑3B:5 (method 2) showed that the matching adjustments used in the MAIC had failed. This was likely to be because of insufficient covariates being matched. The committee would have preferred a sensitivity analysis around the choice of variables included in the MAIC. The results that used methods 1 and 2 were therefore unreliable and unsuitable for decision making. The committee further discussed the company's rationale for doing the MAIC with both pooled cohorts. In general, the committee felt that using cohort EXP‑2:3A for matching with the chemotherapy arm populations was not appropriate because this pooled cohort had a different treatment history and considerably different baseline characteristics to cohort EXP‑3B:5. The clinical experts confirmed that cohorts EXP‑4 and EXP‑5 had already had 2 or 3 lines of treatment and had considerably more brain metastases than cohort EXP‑2:3A. But the committee acknowledged that, overall, this was much less important than its fundamental concern that the results of the MAIC were unsuitable for decision making, leaving only method 5 for consideration. The committee also agreed that the results of method 5, the indirect treatment comparison from applying independent curves without population adjustment, were highly uncertain.
# Clinical effectiveness evidence in the economic model
## The evidence for the PDC arm of the economic model is uncertain
The clinical effectiveness data for the PDC arm of the economic model were from the ALUR and ASCEND‑5 trials (for progression-free survival) and the PROFILE 1001 and PROFILE 1005 trials (for overall survival). The ERG emphasised its concerns about the quality and suitability of the trial data. This was because most patients in these studies had previously had PDC and crizotinib (closely matching the treatment history of cohort EXP‑2:3A from study 1001). Also, the patients in the chemotherapy arms of these trials had singlet chemotherapy (pemetrexed or docetaxel) rather than PDC. The committee agreed with the ERG and clinical experts that the company's assumption of equivalent clinical efficacy between doublet and singlet chemotherapy was not supported by clinical evidence, and that doublet chemotherapy was expected to be somewhat more effective than singlet chemotherapy. The committee noted that adjusting the hazard ratio by 20% to 0.8 to account for the difference in clinical efficacy between PDC and singlet chemotherapy was agreed to be appropriate at the technical engagement stage. It concluded that the treatment history differences between the trial populations used for PDC efficacy in the model and those of cohort EXP‑3B:5 from study 1001 meant that the clinical effectiveness evidence for the PDC arm of the model was uncertain.
## Population adjustment for ABCP overall survival is appropriate
The IMpower150 trial (comparing ABCP with bevacizumab plus carboplatin plus paclitaxel in people with chemotherapy-naive non-squamous NSCLC) was used to create an unanchored, unadjusted comparison of ABCP with lorlatinib. A mixed subgroup including patients with epidermal growth factor receptor (EGFR)-positive and ALK-positive NSCLC was the only evidence available on using ABCP in ALK-positive NSCLC. The company applied a population adjustment to reflect that most of the relevant subgroup from IMpower150 had EGFR-positive NSCLC (n=30) rather than ALK-positive disease (n=11). The company claimed that the prognosis for ALK-positive NSCLC was poorer than for EGFR-positive disease, so a failure to adjust would bias the results against lorlatinib. The committee heard that there was a lack of robust evidence to support the company's claim. To do the adjustment, the company used data from the IMPRESS study (comparing continued treatment with gefitinib plus chemotherapy with placebo plus chemotherapy after first-line gefitinib in people with EGFR-positive NSCLC). The company compared response to chemotherapy in patients with EGFR-positive disease (using the IMPRESS data) with response to chemotherapy in patients with ALK-positive NSCLC (using data from ALUR and ASCEND-5 for progression-free survival and from PROFILE 1001 and PROFILE 1005 for overall survival). This provided hazard ratios, which were then applied to the fitted log-logistic and exponential curves for the mixed cohort with EGFR-positive and ALK-positive disease to derive curves for a cohort with only ALK-positive disease. The ERG stated that there was not enough evidence to provide validity for the extent of this adjustment, which shifts both the progression-free survival and overall survival in favour of lorlatinib. With the 20% hazard ratio adjustment made to the PDC arm data after the technical engagement stage (see section 3.5), the ERG explained that the overall survival curve for ABCP was now almost identical to the curve for PDC in the model, and this lacked clinical plausibility. The company and experts agreed that ABCP would be expected to be more effective than PDC, especially in patients without brain metastases. To correct this, the ERG suggested reducing the company's log hazard ratio adjustment to the ABCP curve for overall survival by 25% to improve clinical plausibility relative to the overall survival curve for PDC. The exact hazard ratios were considered academic in confidence by the company and cannot be reported here. The committee agreed with the ERG that the company's log hazard ratio adjustment of the ABCP curve was uncertain and that the ERG's 25% reduction to this adjustment seemed more clinically plausible for ABCP overall survival relative to PDC overall survival in the model.
# Overall survival
## -year survival in this population is uncertain
To derive long-term overall survival for lorlatinib, parametric curves were fitted to the lorlatinib overall survival data taken from the EXP‑3B:5 cohort from study 1001. The exponential curve had the best statistical fit, but the generalised gamma curve was selected as a compromise between the exponential curve and the log‑normal curve preferred by the company's clinical experts based on the 10-year survival predictions. The exact overall survival values were considered academic in confidence by the company and cannot be reported here. The clinical expert consulted by the ERG considered that 10% projected survival at 10 years would be too optimistic and 2% would be more plausible. The clinical experts at the meeting confirmed that predicting 10‑year survival in small populations with a very high incidence of brain metastases was highly uncertain because of a lack of reliable evidence. The committee heard that, in the absence of biomarkers for disease progression, brain metastases were the most reliable predictor of survival in patients with advanced ALK-positive NSCLC, and these patients would be expected to survive only for a few months. The committee noted that 66.9% of the pooled cohort EXP‑3B:5 from study 1001 and 80.4% of cohort EXP‑5 (3 or more prior ALK TKI therapies with or without any number of prior chemotherapy regimens) had brain metastases at baseline. The clinical experts at the meeting agreed that 10% projected survival at 10 years for this population was too high, and that lower values would be more plausible. The committee noted that the incremental cost-effectiveness ratio (ICER) was sensitive to the choice of curve and that using the exponential curve substantially increased the base-case ICER for lorlatinib compared with PDC. It concluded that although the generalised gamma curve had been agreed at the technical engagement stage, projecting 10-year survival in this population remained highly uncertain and it would take this uncertainty into account in its decision making.
# Utility values in the economic model
## The committee prefers a utility of 0.65 for progression on treatment and 0.46 for progression off treatment in both arms
The company did a systematic literature review to identify relevant studies with published utility values for ALK‑positive NSCLC. The study by Labbé et al. (2017) was the largest published source of NSCLC ALK-positive EQ-5D questionnaire utility values, and the company selected the value of 0.65 from the study for the progressed disease state in both arms. The ERG was concerned that this value was likely to represent the health state shortly after progression rather than the whole progressed period and was therefore too high. The committee recalled that the ERG preferred the values from Chouaid et al. (2013) for progressed disease after second-line treatment (0.59) and after third or fourth lines of treatment (0.46). The clinical experts said that the best evidence for quality of life in this population was the QUARTZ study (Mulvenna et al. 2016), which looked at the quality of life of patients after treatment for brain metastases that were unsuitable for resection or stereotactic radiotherapy. The average utility for patients ranged from 0.5 to less than 0.4. But the population in QUARTZ was considerably less well than the population in study 1001 and had higher levels of comorbidity. So they felt that the value of 0.46 was too low for progressed disease in this appraisal because some people will continue to have lorlatinib treatment after progression. The committee asked the clinical experts which of the 3 options were most clinically plausible:
a progressed health state utility value of 0.59
a value of 0.65 for lorlatinib patients in progression on treatment and 0.59 for progressed disease and off treatment in both arms
a value of 0.65 for lorlatinib patients in progression on treatment and 0.46 for progressed disease and off treatment in both arms.The committee heard that because the disease and how it affects people varies, both 0.46 and 0.59 were plausible as averages across the progressed disease and off-treatment health state. One clinical expert strongly supported a 2-part utility value for progressed disease, on the basis that disease progression does not immediately correspond to an increase in a patient's symptom burden. But they were uncertain whether the second value should be 0.59 or 0.46. The committee asked the clinical and patient experts how the utility level declines for patients after symptomatic progression to understand which value would better reflect the average utility in progression off treatment with lorlatinib. The clinical experts agreed that some people, particularly with brain metastases, can deteriorate very quickly to a low level of utility with a very high symptom burden. On balance, given that patients had previously had treatment with surgery (56.1%) and radiotherapy (68.3%) and had a very high incidence of brain metastases (66.9%), the committee concluded that the preferred utility values were 0.65 for lorlatinib patients in progression on treatment and 0.46 for patients who had progressed and were off treatment in both arms.
# Results of the cost-effectiveness analysis
## The committee has preferred assumptions for decision making
The committee's preferred assumptions for decision making for PDC were:
lorlatinib treatment for 3.5 months after progression
hazard ratio of 0.8 for the relative efficacy of PDC compared with singlet chemotherapy
MAIC method 5
progressed disease utility of 0.65 for lorlatinib patients on treatment and 0.46 for lorlatinib patients off treatment, in both arms.For ABCP its preferred assumptions were:
company's population adjustment of ABCP overall survival reduced by 25%
lorlatinib treatment for 3.5 months after progression
progressed disease utility of 0.65 for lorlatinib patients on treatment and 0.46 for lorlatinib patients off treatment, in both arms.At consultation, the company submitted analyses that incorporated the committee's preferred assumptions and an updated commercial arrangement.
## The range of most plausible cost-effectiveness estimates for lorlatinib is less than £50,000 per QALY gained
Because lorlatinib and the comparators have commercial arrangements, the exact ICERs are confidential and cannot be reported here. The committee noted that its preferred assumptions produced a range of deterministic ICERs for lorlatinib compared with PDC and ABCP which were less than £50,000 per quality-adjusted life year (QALY) gained.
# End of life
## Lorlatinib meets the criteria to be considered a life-extending, end-of-life treatment compared with PDC and ABCP
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. For PDC, average life expectancy was well below 2 years in the company's base case and remained under 2 years across the scenarios assessed. Despite the limitations in the comparative evidence base, it was plausible that lorlatinib treatment would result in a survival gain of more than 3 months compared with PDC. Although there was some uncertainty around the average life expectancy with ABCP treatment because of the population adjustment applied by the company to the fitted curve, this was also expected to be less than 2 years. Also, life expectancy with ABCP remained under 2 years when the log hazard ratio for the population adjustment of overall survival was reduced by 25%, as agreed by the committee. The survival gains for lorlatinib compared with ABCP were more than 3 months across all scenarios assessed. The committee concluded that lorlatinib met the criteria to be considered a life-extending, end-of-life treatment when compared with both PDC and ABCP.
# Innovation
## The model adequately captures the benefits of lorlatinib
The company considered lorlatinib to be innovative, highlighting that it was a third-generation ALK TKI that penetrates the central nervous system and is retained in the intracranial space. So it potentially addresses the unmet need for additional treatment options for patients who develop brain metastases. It was specifically designed to inhibit resistant ALK mutations, including the ALKG1202R mutation that increases significantly after treatment with second-generation ALK TKIs. The clinical experts agreed that lorlatinib was an effective third-generation ALK TKI with good brain penetration and that people would welcome additional treatment options. The committee concluded that it had not been presented with any additional evidence of benefits that were not captured in the measurement of the QALYs and the resulting cost-effectiveness estimates.
# Other factors
No equality or social value judgements were identified.
# Conclusion
## Lorlatinib is recommended for routine commissioning
The committee acknowledged the need for treatment options for people with previously treated ALK-positive advanced NSCLC. Because the range of plausible ICERs was less than £50,000 per QALY gained, the committee concluded that lorlatinib can be considered cost effective. Therefore, it can be recommended for routine commissioning as an option for previously treated ALK-positive advanced NSCLC.
|
{'Recommendations': "Lorlatinib is recommended, within its marketing authorisation, as an option for treating anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer (NSCLC) in adults whose disease has progressed after:\n\nalectinib or ceritinib as the first ALK tyrosine kinase inhibitor or\n\ncrizotinib and at least 1\xa0other ALK tyrosine kinase inhibitor.It is recommended only if the company provides lorlatinib according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nAdvanced ALK-positive NSCLC is usually first treated with an ALK tyrosine kinase inhibitor (alectinib or ceritinib, or crizotinib followed by either brigatinib or ceritinib). People then have either platinum doublet chemotherapy (PDC) or atezolizumab with bevacizumab, carboplatin and paclitaxel (ABCP).\n\nLorlatinib, another ALK tyrosine kinase inhibitor, has not been compared directly with other drugs. But analyses indirectly comparing lorlatinib with PDC and ABCP suggest that people who take lorlatinib:\n\nhave longer before their disease progresses and may live longer than people who take PDC\n\nhave longer before their disease progresses and may live longer than people who take ABCP.\n\nLorlatinib meets NICE's criteria to be considered a life-extending treatment at the end of life. Although the methods and results of the cost-effectiveness modelling are uncertain, the most likely cost-effectiveness estimates are within what NICE normally considers an acceptable use of NHS resources. Therefore, lorlatinib is recommended.", 'Information about lorlatinib': "# Marketing authorisation indication\n\nLorlatinib (Lorviqua, Pfizer) as monotherapy is indicated for 'the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) whose disease has progressed after:\n\nalectinib or ceritinib as the first ALK tyrosine kinase inhibitor (TKI) therapy; or\n\ncrizotinib and at least one other ALK TKI'.\n\n# Dosage in the marketing authorisation\n\nThe recommended dose is 100\xa0mg lorlatinib taken orally once daily. Treatment with lorlatinib is recommended as long as the patient is benefitting from therapy without unacceptable toxicity.\n\n# Price\n\nThe list price of lorlatinib is £7,044.00 per 120-tablet pack of 25-mg tablets, and £5,283.00 per 30-tablet pack of 100-mg tablets (excluding VAT; BNF online accessed January 2020). The company has a commercial arrangement. This makes lorlatinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Pfizer, a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:\n\nIncluding atezolizumab with bevacizumab, carboplatin and paclitaxel (ABCP) as a comparator in the appraisal was appropriate (issue\xa01, see technical report page\xa016).\n\nA hazard ratio of 0.8 was a reasonable estimate of the comparative efficacy between platinum doublet chemotherapy (PDC) and singlet chemotherapy (issue\xa02, see technical report page\xa018).\n\nOf the 6\xa0proposed methods for indirect comparison with PDC, methods\xa03, 4\xa0and\xa06 were dismissed by the company and ERG, leaving methods\xa01, 2\xa0and\xa05 for committee consideration (issue\xa03, see technical report page 22).\n\nThe generalised gamma curve was the most appropriate for measuring overall survival on lorlatinib (issue\xa04, see technical report page\xa026).\n\nLorlatinib treatment for 3.5\xa0months after progression was appropriate (issue\xa06, see technical report page 33).\n\nThe revised assumptions for subsequent treatment discussed at the technical engagement stage were appropriate:\n\n\n\nAfter lorlatinib: 45% of patients have subsequent treatments and the remaining 55% have best supportive care. Of the 45%, 66% have ABCP and 33% have PDC.\n\nAfter PDC: 45% of patients have subsequent treatments and the remaining 55% have best supportive care. The 45% have immunotherapies in the proportions in the original company submission (69% atezolizumab, 31% bevacizumab based on NICE's technology appraisal guidance on atezolizumab in combination).\n\nAfter ABCP: 75% of patients have docetaxel and 25% have best supportive care (issue\xa07, see technical report page\xa035).\n\n\n\nThe company was not making a case for lorlatinib as a candidate for the Cancer Drugs Fund. This was appropriate because the ongoing lorlatinib clinical trials would not provide the evidence needed to resolve the uncertainties in this appraisal (issue\xa08, see technical report page\xa037).\n\nThe committee recognised that there were remaining areas of uncertainty associated with the analyses presented and took these into account in its decision making. It discussed the following issues (issues\xa03 and\xa05; see technical report, pages\xa019 and\xa027), which were outstanding after the technical engagement stage.\n\n# Clinical need\n\n## A third-generation ALK TKI would offer significant benefit to patients\n\nThe patient expert explained that there was a significant unmet need for patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC), even though 4\xa0ALK tyrosine kinase inhibitor (TKI) treatments are available. The committee noted that neither crizotinib nor ceritinib are preferred for untreated disease since the availability of alectinib. Brigatinib has been approved for previously treated disease only after crizotinib. If alectinib's treatment effect wanes the only current option is chemotherapy. ALK TKI treatments are a significant improvement over chemotherapy. People can live relatively normally and do not need to go to hospital for treatment. They do not have distressing symptoms associated with chemotherapy such as hair loss. The patient expert explained that lorlatinib may be better tolerated than other ALK TKIs, appearing to cause less fatigue and fewer sun sensitivity and gastrointestinal problems. The clinical experts confirmed that there was a high unmet need for patients with ALK-positive NSCLC, because there is no cure for metastatic disease. Also, more than 50% of patients with ALK-positive NSCLC develop brain metastases, associated with high morbidity and mortality. Lorlatinib's ability to reach the brain means that patients whose brain tumours respond to treatment may have improved quality of life, allowing them to return to their usual activities. First and second-generation ALK TKIs (alectinib, ceritinib, crizotinib and brigatinib) are associated with the development of drug resistant mutations, leading to disease progression. Brain metastases and drug resistant mutations limit the duration of disease control and benefit from current ALK TKIs. For patients to survive for longer, and to avoid the devastating consequences of brain metastases, effective treatment that can penetrate the brain and overcome ALK-resistance mutations is needed. The committee noted that lorlatinib would be another line of ALK TKI treatment before a patient has chemotherapy or chemoimmunotherapy. The committee agreed that there was an unmet clinical need in ALK-positive NSCLC and that a third-generation ALK TKI, such as lorlatinib, would significantly benefit patients.\n\n# Clinical management\n\n## Current treatments after ALK TKIs are not effective for brain metastases\n\nCurrent treatment options after ALK TKIs are standard care PDC, ABCP or best supportive care. The clinical experts explained that there was weak evidence for PDC-based regimens for this patient population, with a relative lack of efficacy in patients with brain metastases. The clinical experts explained that ABCP also has poor brain penetration and was not available to patients in the NHS in England with symptomatically active brain or leptomeningeal (central nervous system) metastases, which are common in ALK-positive NSCLC. In the absence of a third-generation ALK TKI such as lorlatinib, ABCP is expected to be used more in people without symptomatically active central nervous system metastases. The committee agreed that the evidence for the efficacy of current treatments after ALK TKIs was weak in ALK-positive NSCLC and it was unclear how much benefit they had in people with brain metastases.\n\n# Clinical evidence\n\n## The main clinical evidence comes from a single-arm study\n\nThe main clinical evidence for lorlatinib came from study\xa01001, a single-arm, open-label, multicentre phase\xa01 to 2 trial, done in 13\xa0countries but not in the UK. This study investigated the effect of lorlatinib in adults with metastatic (stage\xa04) ALK-positive NSCLC. It comprised 7\xa0cohorts with 5\xa0(EXP‑2, EXP‑3A, EXP‑3B, EXP‑4, EXP‑5) representing populations having a mix of ALK TKIs and chemotherapy regimens. The company presented evidence for the combined cohort EXP‑3B:5 of 139\xa0patients. This was the pooled cohort of patients from cohorts\xa0EXP‑3B, EXP‑4\xa0and\xa0EXP‑5 whose treatment history most closely resembled that of the patient population covered by the marketing authorisation. Cohort\xa0EXP‑3B was made up of 28\xa0patients who had had first-line treatment with alectinib or ceritinib, with or without prior chemotherapy. The clinical experts explained that most patients would have alectinib as first-line treatment in the NHS, meaning that this cohort was the closest match to the NHS population. Cohort\xa0EXP‑4 was made up of 65\xa0patients who had previous treatment with 2\xa0ALK TKIs, with or without prior chemotherapy. Cohort\xa0EXP‑5 consisted of 46\xa0patients who had previous treatment with 3\xa0or more ALK TKIs, with or without prior chemotherapy. The primary outcome of study\xa01001 was objective response rate. Secondary outcomes included overall survival and progression‑free survival. The results showed an objective response rate of 40.3% (95% confidence interval [CI] 32.1 to 48.9) with lorlatinib. The results also showed a progression-free survival of 6.9\xa0months (95% CI 5.4 to 8.2) and a median overall survival of 20.4\xa0months (95% CI 16.1 to not reached).\n\n# Indirect treatment comparisons\n\n## The results of the indirect treatment comparisons are uncertain\n\nThe company did an unanchored matching-adjusted indirect comparison (MAIC; as recommended in the NICE Decision Support Unit's technical support document 18), to compare the single-arm trial data for lorlatinib with trial data for PDC. The company chose 4\xa0variables for matching:\n\nEastern Cooperative Oncology Group performance status (0\xa0and\xa01 or more than\xa01)\n\nbrain metastases (yes or no)\n\nfamily origin (Asian or non-Asian)\n\nsex (male or female).The PDC data in the indirect comparisons were from the ALUR and ASCEND-5 trials (for progression-free survival) and the PROFILE\xa01001 and PROFILE\xa01005 trials (for overall survival). In the trials everyone had advanced or metastatic ALK-positive NSCLC:\n\nALUR compared alectinib with chemotherapy after previous treatment with PDC and crizotinib.\n\nASCEND‑5 compared ceritinib with chemotherapy after previous treatment with PDC and crizotinib.\n\nPROFILE\xa01001 was a single-arm phase\xa01 trial of crizotinib.\n\nPROFILE\xa01005 was a single-arm phase\xa02 trial of crizotinib after failure of\xa01 or more lines of systemic treatment for locally advanced or metastatic disease.The company explained that in addition to the MAIC it used 2\xa0further approaches for the indirect treatment comparison, giving 6\xa0methods in total:\n\nhazard ratios estimated using a MAIC with EXP‑2:3A (method\xa01) and EXP‑3B:5 (method\xa02)\n\nhazard ratios estimated using an unadjusted indirect comparison with EXP‑2:3A (method\xa03) and EXP‑3B:5 (method\xa04)\n\ndirect estimation of progression-free and overall survival by fitting parametric curves to chemotherapy data from the clinical studies (method\xa05) and the same parametric curves with a population adjustment because the populations in these clinical studies had fewer prior treatments than the EXP‑3B:5 cohort (method\xa06).The committee noted that methods\xa03, 4 and 6 had been dismissed at the technical engagement stage. The company preferred method\xa05, mainly because of concerns about whether the assumption of proportional hazards held for the duration of the model with methods\xa01 and\xa02. But the company said that methods\xa01 and\xa02 were also plausible approaches. The ERG had concerns about methods\xa01, 2 and 5, but considered that they were all plausible, and agreed that method\xa05 was preferred as the least problematic option. The committee agreed with the ERG that all the proposed indirect comparison methods were highly uncertain, but disagreed that methods\xa01 and\xa02 were reliable because of how the company had done the MAIC. The committee agreed that the company's approach of weighting patients in cohorts EXP‑2:3A and EXP‑3B:5 to match the patient characteristics of the populations from the ALUR and ASCEND‑5 and PROFILE\xa01001 and PROFILE\xa01005 trials was correct. But it was concerned about how the MAIC had been implemented. The committee noted that matching the 2\xa0pooled cohorts (EXP‑2:3A and EXP‑3B:5) to the same chemotherapy arm trial populations should have resulted in very similar hazard ratios being generated. Presenting hazard ratios from the MAIC that were not similar (and which resulted in large ICER differences) for EXP‑2:3A (method\xa01) compared with EXP‑3B:5 (method\xa02) showed that the matching adjustments used in the MAIC had failed. This was likely to be because of insufficient covariates being matched. The committee would have preferred a sensitivity analysis around the choice of variables included in the MAIC. The results that used methods\xa01 and\xa02 were therefore unreliable and unsuitable for decision making. The committee further discussed the company's rationale for doing the MAIC with both pooled cohorts. In general, the committee felt that using cohort EXP‑2:3A for matching with the chemotherapy arm populations was not appropriate because this pooled cohort had a different treatment history and considerably different baseline characteristics to cohort EXP‑3B:5. The clinical experts confirmed that cohorts\xa0EXP‑4 and EXP‑5 had already had 2\xa0or 3\xa0lines of treatment and had considerably more brain metastases than cohort EXP‑2:3A. But the committee acknowledged that, overall, this was much less important than its fundamental concern that the results of the MAIC were unsuitable for decision making, leaving only method\xa05 for consideration. The committee also agreed that the results of method\xa05, the indirect treatment comparison from applying independent curves without population adjustment, were highly uncertain.\n\n# Clinical effectiveness evidence in the economic model\n\n## The evidence for the PDC arm of the economic model is uncertain\n\nThe clinical effectiveness data for the PDC arm of the economic model were from the ALUR and ASCEND‑5 trials (for progression-free survival) and the PROFILE\xa01001 and PROFILE\xa01005 trials (for overall survival). The ERG emphasised its concerns about the quality and suitability of the trial data. This was because most patients in these studies had previously had PDC and crizotinib (closely matching the treatment history of cohort EXP‑2:3A from study\xa01001). Also, the patients in the chemotherapy arms of these trials had singlet chemotherapy (pemetrexed or docetaxel) rather than PDC. The committee agreed with the ERG and clinical experts that the company's assumption of equivalent clinical efficacy between doublet and singlet chemotherapy was not supported by clinical evidence, and that doublet chemotherapy was expected to be somewhat more effective than singlet chemotherapy. The committee noted that adjusting the hazard ratio by 20% to 0.8 to account for the difference in clinical efficacy between PDC and singlet chemotherapy was agreed to be appropriate at the technical engagement stage. It concluded that the treatment history differences between the trial populations used for PDC efficacy in the model and those of cohort EXP‑3B:5 from study\xa01001 meant that the clinical effectiveness evidence for the PDC arm of the model was uncertain.\n\n## Population adjustment for ABCP overall survival is appropriate\n\nThe IMpower150 trial (comparing ABCP with bevacizumab plus carboplatin plus paclitaxel in people with chemotherapy-naive non-squamous NSCLC) was used to create an unanchored, unadjusted comparison of ABCP with lorlatinib. A mixed subgroup including patients with epidermal growth factor receptor (EGFR)-positive and ALK-positive NSCLC was the only evidence available on using ABCP in ALK-positive NSCLC. The company applied a population adjustment to reflect that most of the relevant subgroup from IMpower150 had EGFR-positive NSCLC (n=30) rather than ALK-positive disease (n=11). The company claimed that the prognosis for ALK-positive NSCLC was poorer than for EGFR-positive disease, so a failure to adjust would bias the results against lorlatinib. The committee heard that there was a lack of robust evidence to support the company's claim. To do the adjustment, the company used data from the IMPRESS study (comparing continued treatment with gefitinib plus chemotherapy with placebo plus chemotherapy after first-line gefitinib in people with EGFR-positive NSCLC). The company compared response to chemotherapy in patients with EGFR-positive disease (using the IMPRESS data) with response to chemotherapy in patients with ALK-positive NSCLC (using data from ALUR and ASCEND-5 for progression-free survival and from PROFILE\xa01001 and PROFILE\xa01005 for overall survival). This provided hazard ratios, which were then applied to the fitted log-logistic and exponential curves for the mixed cohort with EGFR-positive and ALK-positive disease to derive curves for a cohort with only ALK-positive disease. The ERG stated that there was not enough evidence to provide validity for the extent of this adjustment, which shifts both the progression-free survival and overall survival in favour of lorlatinib. With the 20% hazard ratio adjustment made to the PDC arm data after the technical engagement stage (see section\xa03.5), the ERG explained that the overall survival curve for ABCP was now almost identical to the curve for PDC in the model, and this lacked clinical plausibility. The company and experts agreed that ABCP would be expected to be more effective than PDC, especially in patients without brain metastases. To correct this, the ERG suggested reducing the company's log hazard ratio adjustment to the ABCP curve for overall survival by 25% to improve clinical plausibility relative to the overall survival curve for PDC. The exact hazard ratios were considered academic in confidence by the company and cannot be reported here. The committee agreed with the ERG that the company's log hazard ratio adjustment of the ABCP curve was uncertain and that the ERG's 25% reduction to this adjustment seemed more clinically plausible for ABCP overall survival relative to PDC overall survival in the model.\n\n# Overall survival\n\n## -year survival in this population is uncertain\n\nTo derive long-term overall survival for lorlatinib, parametric curves were fitted to the lorlatinib overall survival data taken from the EXP‑3B:5 cohort from study\xa01001. The exponential curve had the best statistical fit, but the generalised gamma curve was selected as a compromise between the exponential curve and the log‑normal curve preferred by the company's clinical experts based on the 10-year survival predictions. The exact overall survival values were considered academic in confidence by the company and cannot be reported here. The clinical expert consulted by the ERG considered that 10% projected survival at 10\xa0years would be too optimistic and 2% would be more plausible. The clinical experts at the meeting confirmed that predicting 10‑year survival in small populations with a very high incidence of brain metastases was highly uncertain because of a lack of reliable evidence. The committee heard that, in the absence of biomarkers for disease progression, brain metastases were the most reliable predictor of survival in patients with advanced ALK-positive NSCLC, and these patients would be expected to survive only for a few months. The committee noted that 66.9% of the pooled cohort EXP‑3B:5 from study\xa01001 and 80.4% of cohort\xa0EXP‑5 (3\xa0or more prior ALK TKI therapies with or without any number of prior chemotherapy regimens) had brain metastases at baseline. The clinical experts at the meeting agreed that 10% projected survival at 10\xa0years for this population was too high, and that lower values would be more plausible. The committee noted that the incremental cost-effectiveness ratio (ICER) was sensitive to the choice of curve and that using the exponential curve substantially increased the base-case ICER for lorlatinib compared with PDC. It concluded that although the generalised gamma curve had been agreed at the technical engagement stage, projecting 10-year survival in this population remained highly uncertain and it would take this uncertainty into account in its decision making.\n\n# Utility values in the economic model\n\n## The committee prefers a utility of 0.65 for progression on treatment and 0.46 for progression off treatment in both arms\n\nThe company did a systematic literature review to identify relevant studies with published utility values for ALK‑positive NSCLC. The study by Labbé et al. (2017) was the largest published source of NSCLC ALK-positive EQ-5D questionnaire utility values, and the company selected the value of 0.65 from the study for the progressed disease state in both arms. The ERG was concerned that this value was likely to represent the health state shortly after progression rather than the whole progressed period and was therefore too high. The committee recalled that the ERG preferred the values from Chouaid et al. (2013) for progressed disease after second-line treatment (0.59) and after third or fourth lines of treatment (0.46). The clinical experts said that the best evidence for quality of life in this population was the QUARTZ study (Mulvenna et al. 2016), which looked at the quality of life of patients after treatment for brain metastases that were unsuitable for resection or stereotactic radiotherapy. The average utility for patients ranged from 0.5 to less than 0.4. But the population in QUARTZ was considerably less well than the population in study\xa01001 and had higher levels of comorbidity. So they felt that the value of 0.46 was too low for progressed disease in this appraisal because some people will continue to have lorlatinib treatment after progression. The committee asked the clinical experts which of the 3\xa0options were most clinically plausible:\n\na progressed health state utility value of 0.59\n\na value of 0.65 for lorlatinib patients in progression on treatment and 0.59 for progressed disease and off treatment in both arms\n\na value of 0.65 for lorlatinib patients in progression on treatment and 0.46 for progressed disease and off treatment in both arms.The committee heard that because the disease and how it affects people varies, both 0.46 and 0.59 were plausible as averages across the progressed disease and off-treatment health state. One clinical expert strongly supported a 2-part utility value for progressed disease, on the basis that disease progression does not immediately correspond to an increase in a patient's symptom burden. But they were uncertain whether the second value should be 0.59 or 0.46. The committee asked the clinical and patient experts how the utility level declines for patients after symptomatic progression to understand which value would better reflect the average utility in progression off treatment with lorlatinib. The clinical experts agreed that some people, particularly with brain metastases, can deteriorate very quickly to a low level of utility with a very high symptom burden. On balance, given that patients had previously had treatment with surgery (56.1%) and radiotherapy (68.3%) and had a very high incidence of brain metastases (66.9%), the committee concluded that the preferred utility values were 0.65 for lorlatinib patients in progression on treatment and 0.46 for patients who had progressed and were off treatment in both arms.\n\n# Results of the cost-effectiveness analysis\n\n## The committee has preferred assumptions for decision making\n\nThe committee's preferred assumptions for decision making for PDC were:\n\nlorlatinib treatment for 3.5\xa0months after progression\n\nhazard ratio of 0.8 for the relative efficacy of PDC compared with singlet chemotherapy\n\nMAIC method\xa05\n\nprogressed disease utility of 0.65 for lorlatinib patients on treatment and 0.46 for lorlatinib patients off treatment, in both arms.For ABCP its preferred assumptions were:\n\ncompany's population adjustment of ABCP overall survival reduced by 25%\n\nlorlatinib treatment for 3.5\xa0months after progression\n\nprogressed disease utility of 0.65 for lorlatinib patients on treatment and 0.46 for lorlatinib patients off treatment, in both arms.At consultation, the company submitted analyses that incorporated the committee's preferred assumptions and an updated commercial arrangement.\n\n## The range of most plausible cost-effectiveness estimates for lorlatinib is less than £50,000 per QALY gained\n\nBecause lorlatinib and the comparators have commercial arrangements, the exact ICERs are confidential and cannot be reported here. The committee noted that its preferred assumptions produced a range of deterministic ICERs for lorlatinib compared with PDC and ABCP which were less than £50,000 per quality-adjusted life year (QALY) gained.\n\n# End of life\n\n## Lorlatinib meets the criteria to be considered a life-extending, end-of-life treatment compared with PDC and ABCP\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. For PDC, average life expectancy was well below 2\xa0years in the company's base case and remained under 2\xa0years across the scenarios assessed. Despite the limitations in the comparative evidence base, it was plausible that lorlatinib treatment would result in a survival gain of more than 3\xa0months compared with PDC. Although there was some uncertainty around the average life expectancy with ABCP treatment because of the population adjustment applied by the company to the fitted curve, this was also expected to be less than 2\xa0years. Also, life expectancy with ABCP remained under 2\xa0years when the log hazard ratio for the population adjustment of overall survival was reduced by 25%, as agreed by the committee. The survival gains for lorlatinib compared with ABCP were more than 3\xa0months across all scenarios assessed. The committee concluded that lorlatinib met the criteria to be considered a life-extending, end-of-life treatment when compared with both PDC and ABCP.\n\n# Innovation\n\n## The model adequately captures the benefits of lorlatinib\n\nThe company considered lorlatinib to be innovative, highlighting that it was a third-generation ALK TKI that penetrates the central nervous system and is retained in the intracranial space. So it potentially addresses the unmet need for additional treatment options for patients who develop brain metastases. It was specifically designed to inhibit resistant ALK mutations, including the ALKG1202R mutation that increases significantly after treatment with second-generation ALK TKIs. The clinical experts agreed that lorlatinib was an effective third-generation ALK TKI with good brain penetration and that people would welcome additional treatment options. The committee concluded that it had not been presented with any additional evidence of benefits that were not captured in the measurement of the QALYs and the resulting cost-effectiveness estimates.\n\n# Other factors\n\nNo equality or social value judgements were identified.\n\n# Conclusion\n\n## Lorlatinib is recommended for routine commissioning\n\nThe committee acknowledged the need for treatment options for people with previously treated ALK-positive advanced NSCLC. Because the range of plausible ICERs was less than £50,000 per QALY gained, the committee concluded that lorlatinib can be considered cost effective. Therefore, it can be recommended for routine commissioning as an option for previously treated ALK-positive advanced NSCLC."}
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https://www.nice.org.uk/guidance/ta628
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Evidence-based recommendations on lorlatinib (Lorviqua) for previously treated ALK-positive advanced non-small-cell lung cancer in adults.
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ab515d779ce9338033e97217108815208d4fc545
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nice
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Obinutuzumab with bendamustine for treating follicular lymphoma after rituximab
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Obinutuzumab with bendamustine for treating follicular lymphoma after rituximab
Evidence-based recommendations on obinutuzumab (Gazyvaro) with bendamustine for follicular lymphoma that has not responded or has progressed up to 6 months after treatment with rituximab or a rituximab-containing regimen in adults.
# Recommendations
Obinutuzumab with bendamustine followed by obinutuzumab maintenance is recommended, within its marketing authorisation, as an option for treating follicular lymphoma that did not respond or progressed up to 6 months after treatment with rituximab or a rituximab-containing regimen. It is recommended only if the company provides it according to the commercial arrangement.
Why the committee made these recommendations
Evidence from the Cancer Drugs Fund is limited but appears to support the clinical trial evidence. This evidence is in people who had rituximab as first-line treatment. It shows that when follicular lymphoma has not responded well enough (refractory) to rituximab, obinutuzumab with bendamustine improves how long people have before their disease progresses and how long they live compared with bendamustine alone.
Cost-effectiveness estimates for obinutuzumab with bendamustine are in the range usually considered a cost-effective use of NHS resources. Therefore, it is recommended.# Information about obinutuzumab
# Marketing authorisation indication
Obinutuzumab (Gazyvaro, Roche) with bendamustine followed by obinutuzumab maintenance has a marketing authorisation for 'the treatment of patients with follicular lymphoma who did not respond or who progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
Obinutuzumab costs £3,312 per 1,000 mg/40 ml concentrate for solution for infusion vial (excluding VAT; BNF online, accessed May 2020).
The company has a commercial arrangement. This makes obinutuzumab with bendamustine available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Roche, a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that it had not been possible to fully resolve some key issues during the technical engagement stage.
It recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, table 3, page 31), and took these into account in its decision making. It discussed the following issues (issues 1 and 2), which were outstanding after the technical engagement stage.
# Treatment pathway and clinical need
## There is an unmet clinical need for people with rituximab-refractory disease
Follicular lymphoma is the most common type of indolent non-Hodgkin lymphoma and is not considered curable. The aim of treatment is to induce response and control disease progression for as long as possible. The clinical expert explained that treatment is characterised by multiple lines of treatment as the disease responds and relapses. For treatment of advanced (stage 3 or stage 4) disease that is asymptomatic, NICE's guideline on non-Hodgkin lymphoma recommends rituximab monotherapy as a first-line treatment option. For symptomatic advanced follicular lymphoma, NICE's technology appraisal guidance recommends first-line treatment with rituximab and chemotherapy (rituximab–chemotherapy) followed by rituximab maintenance therapy. The committee noted that since the original appraisal of obinutuzumab with bendamustine, NICE has published technology appraisal guidance recommending obinutuzumab with chemotherapy followed by obinutuzumab maintenance as a first-line treatment option for advanced follicular lymphoma in adults with a Follicular Lymphoma International Prognostic Index (FLIPI) score of 2 or more. The clinical expert explained that in clinical practice about half of patients now have obinutuzumab with chemotherapy as first-line treatment, and that second-line treatment depends on the timing of relapse and the chemotherapy agents that were used first line. Disease that relapses after obinutuzumab with chemotherapy may be treated with rituximab–chemotherapy, or with rituximab alone if there is resistance or intolerance to chemotherapy. The clinical expert also explained that when the disease becomes refractory to rituximab the treatment options are limited, and patients have a poor prognosis. Treatment options include chemotherapy (such as cyclophosphamide, fludarabine, bendamustine or chlorambucil) and best supportive care. The committee concluded that there is a high unmet clinical need in patients whose disease is refractory to rituximab.
## People with rituximab-refractory follicular lymphoma would welcome another treatment option
The patient expert explained in their written submission that follicular lymphoma can have a significant effect on the quality of life of patients and their carers. The concern about relapse and the need for repeated courses of treatment is physically and psychologically challenging. People know that they will develop rituximab-refractory disease at some stage, after which the treatment options are limited. It is important for the mental wellbeing of patients to know that new and effective treatment options are available should their disease relapse. New treatments that allow people to live for longer without their disease progressing and with fewer side effects are highly valued by patients. The committee concluded that new treatments for follicular lymphoma that is refractory to rituximab would be welcomed by patients.
# Clinical evidence
## Obinutuzumab with bendamustine improves progression-free survival and overall survival compared with bendamustine alone
The clinical effectiveness evidence came from GADOLIN, an open-label randomised controlled trial. It compared obinutuzumab with bendamustine induction treatment followed by obinutuzumab maintenance, against bendamustine induction therapy alone. The intention-to-treat population in GADOLIN was people with indolent non-Hodgkin lymphoma, of whom about 81% had follicular lymphoma. Patients were included in the trial if their disease was refractory to induction treatment with rituximab monotherapy, refractory to induction treatment with rituximab–chemotherapy, or relapsed during or within 6 months of completing 2‑year maintenance treatment with rituximab monotherapy. The main clinical uncertainty identified by the committee in the original appraisal of obinutuzumab with bendamustine was the amount of survival benefit for obinutuzumab with bendamustine. It had concluded that more mature overall-survival data from GADOLIN would be likely to resolve uncertainty around the treatment effect of obinutuzumab with bendamustine, and allow more reliable cost-effectiveness estimates. The current appraisal reviewed the most recent data from GADLOLIN. This showed statistically significant improvements in progression-free survival and overall survival, which is consistent with the primary analysis. Median overall survival was not reached in the obinutuzumab with bendamustine group and was 60.3 months in the bendamustine group (hazard ratio 0.71, 95% confidence interval 0.51 to 0.98, p=0.0343). This suggests a 29% reduction in the risk of death with obinutuzumab with bendamustine. The committee concluded that mature data from GADOLIN show that obinutuzumab with bendamustine improves progression-free survival and overall survival compared with bendamustine induction treatment alone.
## The systemic anticancer therapy (SACT) data are not robust enough to use in the economic model
Observational data for patients in the Cancer Drugs Fund obtained from the SACT dataset were presented by the company, but were not included in its economic analysis. The length of follow up for overall survival in SACT ranged from 4 months to 23 months, and the median follow up was 12.4 months. This limited length of follow up was the result of the company providing further GADOLIN data earlier than intended. It means that an estimate of median survival cannot be provided by the SACT data because they are too immature. The committee acknowledged that the Kaplan–Meier estimates of overall survival at 12 months were similar from the SACT data and GADOLIN, and had overlapping confidence intervals. However it noted the ERG's comment that any comparison between single groups from separate studies is subject to bias and should be interpreted with caution. The ERG also highlighted that time on treatment appears to be lower in SACT than in GADOLIN. The committee accepted the comments from the Cancer Drugs Fund clinical lead that SACT included a higher proportion of people with multiple-relapsed disease, who therefore had a poorer prognosis compared with the trial population. It also accepted that the immaturity of the SACT data made it difficult to make meaningful comparisons. The committee concluded that the SACT data provide a useful insight into the use of obinutuzumab with bendamustine in clinical practice and early real-world evidence, but are not robust enough to be used in economic modelling.
# Generalisability of GADOLIN results to NHS clinical practice
## GADOLIN data are generalisable to people whose disease responded satisfactorily to first-line treatment with obinutuzumab, bendamustine or both
The clinical expert explained that the survival benefit for obinutuzumab with bendamustine has only been demonstrated for people who had rituximab–chemotherapy as first-line treatment. People who had bendamustine or obinutuzumab with chemotherapy first line were not included in GADOLIN, and the effect of further obinutuzumab with bendamustine is not known in this population. The committee recalled that about half of the clinical population eligible for obinutuzumab with bendamustine will have had obinutuzumab with chemotherapy first line, following publication of NICE's technology appraisal guidance for untreated advanced follicular lymphoma (see section 3.1). It therefore considered whether the results from GADOLIN were generalisable to these patients. The clinical expert explained that there is no reason to expect that retreatment with obinutuzumab and bendamustine would not benefit people with disease that had responded to these treatments earlier in the treatment pathway, and that had not relapsed early after stopping treatment. He noted that some people have a very good response to first-line treatment with bendamustine or obinutuzumab with chemotherapy and remain disease free for a long period. It would be reasonable to assume that retreatment with obinutuzumab with bendamustine could offer further benefit when disease relapses after rituximab–chemotherapy. However, retreatment would not be expected to be beneficial if there had not been a good response, or early relapse, with first-line treatment with obinutuzumab and chemotherapy. The committee concluded that the results from GADOLIN are generalisable to people with rituximab-refractory disease that responded to treatment with obinutuzumab with chemotherapy earlier in the treatment pathway.
## Obinutuzumab with bendamustine is suitable for patients for whom a stem cell transplant is intended
The clinical expert highlighted that second-line chemotherapy may be used as a bridge to a stem cell transplant in younger and fitter patients in clinical practice in the NHS. The committee noted that 11 patients in SACT had an autologous stem cell transplant instead of maintenance therapy with obinutuzumab. In GADOLIN 10% of people went on to have an autologous or allogenic stem cell transplant, and this was reflected in the economic model. The clinical expert explained that obinutuzumab with bendamustine would be a suitable option in people for whom a stem cell transplant is an option because it is associated with better minimal residual rates, which improve the outcome of a stem cell transplant. The committee concluded that obinutuzumab with bendamustine is suitable for patients for whom a stem cell transplant is intended.
# Cost effectiveness
## The company's updated model uses the committee's preferred assumptions
The committee considered the preferred committee assumptions from the original appraisal of obinutuzumab with bendamustine. It recalled that variation in the cost-effectiveness estimates was largely dependent on the extrapolation of overall survival, which was uncertain because the trial data were immature. The committee had concluded that there was a plausible potential for obinutuzumab with bendamustine to be cost effective, and that updated survival data could reduce the uncertainty and produce more reliable cost-effectiveness estimates using the original economic model. The ERG explained that the company had largely adhered to the preferred committee assumptions, with some exceptions (see section 3.8 and section 3.9). The committee concluded that the company had satisfactorily acknowledged the preferred assumptions from the original appraisal of obinutuzumab with bendamustine.
## A random change-point model is appropriate for estimating overall survival
The company presented its original model with updated survival data. The updated base case used dependent Weibull functions assuming proportional hazards, fitted to overall-survival data from the most recent data cut of GADOLIN throughout the time horizon of the model. The committee noted that this approach differed from that used in the original appraisal, in which overall survival was modelled using Kaplan–Meier data up to the time of the last observed event in the trial followed by parametric extrapolation. The new approach no longer applied a cap on the maximum duration of treatment effect for obinutuzumab with bendamustine because the company considered that the updated GADOLIN data did not support a declining treatment effect over time. The ERG explained that the company had acknowledged that the Kaplan–Meier survival data from GADOLIN shows 'a clear separation of curves in favour of the obinutuzumab with bendamustine arm from 6 months and beyond', corresponding to the time of switching from induction to maintenance treatment. Therefore, the company's approach of using a single hazard function over the lifetime of patients in the model is not appropriate. This is also supported by log cumulative hazard plots against time showing that the proportional hazards assumption does not hold and that a change in the relative hazards occurs after about 6 months. The ERG considered that using a random change-point model, which allows the hazard function to change during the observed period in GADOLIN, provides a better visual representation of the observed overall-survival data over the early and late phase of GADOLIN and it used this in its preferred base-case analysis. The company also provided a fixed change-point model with a fixed change-point at exactly 6 months, corresponding to the time of the first obinutuzumab maintenance dose. The ERG preferred the random change-point model because there is uncertainty about the precise timing of a change in the hazard function. The company accepted the ERG's approach after technical engagement. The committee also agreed with the ERG's comments about the modelling approach. It concluded that a random change-point model was appropriate for estimating overall survival.
## A single Weibull function over the horizon of the model may underestimate the progression-free survival benefit of obinutuzumab with bendamustine
The company fitted independent parametric models to the updated progression-free survival data from GADOLIN because the proportional hazards' assumption did not hold and it was the preferred approach in the original appraisal. The ERG considered that the models used by the company in its base case did not provide a realistic model for the GADOLIN data. Log cumulative hazard functions against time showed that a single Weibull function to predict progression-free survival over a patient's lifetime may underestimate the benefit of obinutuzumab with bendamustine on progression-free survival, and that an analysis which incorporates a change-point in the hazard function may be more appropriate. The company accepted the ERG's approach after technical engagement. The committee agreed with the ERG's comments, and it concluded that a random change-point model was appropriate for estimating progression-free survival.
# Cost-effectiveness results
## The estimates are within the range considered a cost-effective use of NHS resources
The company's incremental cost-effectiveness ratios (ICERs) estimated using the Weibull survival functions with fixed or random change-points preferred by the committee (see section 3.8 and section 3.9) ranged from £15,587 per quality-adjusted life year (QALY) gained to £17,322 per QALY gained. Using the ERG's preferred random change-point models for both progression-free survival and overall survival, with an updated price for bendamustine, the ICER was £15,045 per QALY gained. These ICERs are within the range normally considered to be a cost-effective use of NHS resources (£20,000 to £30,000 per QALY gained). The committee concluded that obinutuzumab with bendamustine could be recommended for routine commissioning for treating follicular lymphoma that is refractory to rituximab or a rituximab-containing regimen.
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{'Recommendations': 'Obinutuzumab with bendamustine followed by obinutuzumab maintenance is recommended, within its marketing authorisation, as an option for treating follicular lymphoma that did not respond or progressed up to 6\xa0months after treatment with rituximab or a rituximab-containing regimen. It is recommended only if the company provides it according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nEvidence from the Cancer Drugs Fund is limited but appears to support the clinical trial evidence. This evidence is in people who had rituximab as first-line treatment. It shows that when follicular lymphoma has not responded well enough (refractory) to rituximab, obinutuzumab with bendamustine improves how long people have before their disease progresses and how long they live compared with bendamustine alone.\n\nCost-effectiveness estimates for obinutuzumab with bendamustine are in the range usually considered a cost-effective use of NHS resources. Therefore, it is recommended.', 'Information about obinutuzumab': "# Marketing authorisation indication\n\nObinutuzumab (Gazyvaro, Roche) with bendamustine followed by obinutuzumab maintenance has a marketing authorisation for 'the treatment of patients with follicular lymphoma who did not respond or who progressed during or up to 6\xa0months after treatment with rituximab or a rituximab-containing regimen'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nObinutuzumab costs £3,312 per 1,000\xa0mg/40\xa0ml concentrate for solution for infusion vial (excluding VAT; BNF online, accessed May\xa02020).\n\nThe company has a commercial arrangement. This makes obinutuzumab with bendamustine available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Roche, a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that it had not been possible to fully resolve some key issues during the technical engagement stage.\n\nIt recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, table\xa03, page\xa031), and took these into account in its decision making. It discussed the following issues (issues\xa01\xa0and\xa02), which were outstanding after the technical engagement stage.\n\n# Treatment pathway and clinical need\n\n## There is an unmet clinical need for people with rituximab-refractory disease\n\nFollicular lymphoma is the most common type of indolent non-Hodgkin lymphoma and is not considered curable. The aim of treatment is to induce response and control disease progression for as long as possible. The clinical expert explained that treatment is characterised by multiple lines of treatment as the disease responds and relapses. For treatment of advanced (stage\xa03 or stage\xa04) disease that is asymptomatic, NICE's guideline on non-Hodgkin lymphoma recommends rituximab monotherapy as a first-line treatment option. For symptomatic advanced follicular lymphoma, NICE's technology appraisal guidance recommends first-line treatment with rituximab and chemotherapy (rituximab–chemotherapy) followed by rituximab maintenance therapy. The committee noted that since the original appraisal of obinutuzumab with bendamustine, NICE has published technology appraisal guidance recommending obinutuzumab with chemotherapy followed by obinutuzumab maintenance as a first-line treatment option for advanced follicular lymphoma in adults with a Follicular Lymphoma International Prognostic Index (FLIPI) score of 2\xa0or more. The clinical expert explained that in clinical practice about half of patients now have obinutuzumab with chemotherapy as first-line treatment, and that second-line treatment depends on the timing of relapse and the chemotherapy agents that were used first line. Disease that relapses after obinutuzumab with chemotherapy may be treated with rituximab–chemotherapy, or with rituximab alone if there is resistance or intolerance to chemotherapy. The clinical expert also explained that when the disease becomes refractory to rituximab the treatment options are limited, and patients have a poor prognosis. Treatment options include chemotherapy (such as cyclophosphamide, fludarabine, bendamustine or chlorambucil) and best supportive care. The committee concluded that there is a high unmet clinical need in patients whose disease is refractory to rituximab.\n\n## People with rituximab-refractory follicular lymphoma would welcome another treatment option\n\nThe patient expert explained in their written submission that follicular lymphoma can have a significant effect on the quality of life of patients and their carers. The concern about relapse and the need for repeated courses of treatment is physically and psychologically challenging. People know that they will develop rituximab-refractory disease at some stage, after which the treatment options are limited. It is important for the mental wellbeing of patients to know that new and effective treatment options are available should their disease relapse. New treatments that allow people to live for longer without their disease progressing and with fewer side effects are highly valued by patients. The committee concluded that new treatments for follicular lymphoma that is refractory to rituximab would be welcomed by patients.\n\n# Clinical evidence\n\n## Obinutuzumab with bendamustine improves progression-free survival and overall survival compared with bendamustine alone\n\nThe clinical effectiveness evidence came from GADOLIN, an open-label randomised controlled trial. It compared obinutuzumab with bendamustine induction treatment followed by obinutuzumab maintenance, against bendamustine induction therapy alone. The intention-to-treat population in GADOLIN was people with indolent non-Hodgkin lymphoma, of whom about 81% had follicular lymphoma. Patients were included in the trial if their disease was refractory to induction treatment with rituximab monotherapy, refractory to induction treatment with rituximab–chemotherapy, or relapsed during or within 6\xa0months of completing 2‑year maintenance treatment with rituximab monotherapy. The main clinical uncertainty identified by the committee in the original appraisal of obinutuzumab with bendamustine was the amount of survival benefit for obinutuzumab with bendamustine. It had concluded that more mature overall-survival data from GADOLIN would be likely to resolve uncertainty around the treatment effect of obinutuzumab with bendamustine, and allow more reliable cost-effectiveness estimates. The current appraisal reviewed the most recent data from GADLOLIN. This showed statistically significant improvements in progression-free survival and overall survival, which is consistent with the primary analysis. Median overall survival was not reached in the obinutuzumab with bendamustine group and was 60.3\xa0months in the bendamustine group (hazard ratio\xa00.71, 95%\xa0confidence interval 0.51\xa0to\xa00.98, p=0.0343). This suggests a 29%\xa0reduction in the risk of death with obinutuzumab with bendamustine. The committee concluded that mature data from GADOLIN show that obinutuzumab with bendamustine improves progression-free survival and overall survival compared with bendamustine induction treatment alone.\n\n## The systemic anticancer therapy (SACT) data are not robust enough to use in the economic model\n\nObservational data for patients in the Cancer Drugs Fund obtained from the SACT dataset were presented by the company, but were not included in its economic analysis. The length of follow up for overall survival in SACT ranged from 4\xa0months to 23\xa0months, and the median follow up was 12.4\xa0months. This limited length of follow up was the result of the company providing further GADOLIN data earlier than intended. It means that an estimate of median survival cannot be provided by the SACT data because they are too immature. The committee acknowledged that the Kaplan–Meier estimates of overall survival at 12\xa0months were similar from the SACT data and GADOLIN, and had overlapping confidence intervals. However it noted the ERG's comment that any comparison between single groups from separate studies is subject to bias and should be interpreted with caution. The ERG also highlighted that time on treatment appears to be lower in SACT than in GADOLIN. The committee accepted the comments from the Cancer Drugs Fund clinical lead that SACT included a higher proportion of people with multiple-relapsed disease, who therefore had a poorer prognosis compared with the trial population. It also accepted that the immaturity of the SACT data made it difficult to make meaningful comparisons. The committee concluded that the SACT data provide a useful insight into the use of obinutuzumab with bendamustine in clinical practice and early real-world evidence, but are not robust enough to be used in economic modelling.\n\n# Generalisability of GADOLIN results to NHS clinical practice\n\n## GADOLIN data are generalisable to people whose disease responded satisfactorily to first-line treatment with obinutuzumab, bendamustine or both\n\nThe clinical expert explained that the survival benefit for obinutuzumab with bendamustine has only been demonstrated for people who had rituximab–chemotherapy as first-line treatment. People who had bendamustine or obinutuzumab with chemotherapy first line were not included in GADOLIN, and the effect of further obinutuzumab with bendamustine is not known in this population. The committee recalled that about half of the clinical population eligible for obinutuzumab with bendamustine will have had obinutuzumab with chemotherapy first line, following publication of NICE's technology appraisal guidance for untreated advanced follicular lymphoma (see section 3.1). It therefore considered whether the results from GADOLIN were generalisable to these patients. The clinical expert explained that there is no reason to expect that retreatment with obinutuzumab and bendamustine would not benefit people with disease that had responded to these treatments earlier in the treatment pathway, and that had not relapsed early after stopping treatment. He noted that some people have a very good response to first-line treatment with bendamustine or obinutuzumab with chemotherapy and remain disease free for a long period. It would be reasonable to assume that retreatment with obinutuzumab with bendamustine could offer further benefit when disease relapses after rituximab–chemotherapy. However, retreatment would not be expected to be beneficial if there had not been a good response, or early relapse, with first-line treatment with obinutuzumab and chemotherapy. The committee concluded that the results from GADOLIN are generalisable to people with rituximab-refractory disease that responded to treatment with obinutuzumab with chemotherapy earlier in the treatment pathway.\n\n## Obinutuzumab with bendamustine is suitable for patients for whom a stem cell transplant is intended\n\nThe clinical expert highlighted that second-line chemotherapy may be used as a bridge to a stem cell transplant in younger and fitter patients in clinical practice in the NHS. The committee noted that 11\xa0patients in SACT had an autologous stem cell transplant instead of maintenance therapy with obinutuzumab. In GADOLIN 10%\xa0of people went on to have an autologous or allogenic stem cell transplant, and this was reflected in the economic model. The clinical expert explained that obinutuzumab with bendamustine would be a suitable option in people for whom a stem cell transplant is an option because it is associated with better minimal residual rates, which improve the outcome of a stem cell transplant. The committee concluded that obinutuzumab with bendamustine is suitable for patients for whom a stem cell transplant is intended.\n\n# Cost effectiveness\n\n## The company's updated model uses the committee's preferred assumptions\n\nThe committee considered the preferred committee assumptions from the original appraisal of obinutuzumab with bendamustine. It recalled that variation in the cost-effectiveness estimates was largely dependent on the extrapolation of overall survival, which was uncertain because the trial data were immature. The committee had concluded that there was a plausible potential for obinutuzumab with bendamustine to be cost effective, and that updated survival data could reduce the uncertainty and produce more reliable cost-effectiveness estimates using the original economic model. The ERG explained that the company had largely adhered to the preferred committee assumptions, with some exceptions (see section 3.8 and section 3.9). The committee concluded that the company had satisfactorily acknowledged the preferred assumptions from the original appraisal of obinutuzumab with bendamustine.\n\n## A random change-point model is appropriate for estimating overall survival\n\nThe company presented its original model with updated survival data. The updated base case used dependent Weibull functions assuming proportional hazards, fitted to overall-survival data from the most recent data cut of GADOLIN throughout the time horizon of the model. The committee noted that this approach differed from that used in the original appraisal, in which overall survival was modelled using Kaplan–Meier data up to the time of the last observed event in the trial followed by parametric extrapolation. The new approach no longer applied a cap on the maximum duration of treatment effect for obinutuzumab with bendamustine because the company considered that the updated GADOLIN data did not support a declining treatment effect over time. The ERG explained that the company had acknowledged that the Kaplan–Meier survival data from GADOLIN shows 'a clear separation of curves in favour of the obinutuzumab with bendamustine arm from 6\xa0months and beyond', corresponding to the time of switching from induction to maintenance treatment. Therefore, the company's approach of using a single hazard function over the lifetime of patients in the model is not appropriate. This is also supported by log cumulative hazard plots against time showing that the proportional hazards assumption does not hold and that a change in the relative hazards occurs after about 6\xa0months. The ERG considered that using a random change-point model, which allows the hazard function to change during the observed period in GADOLIN, provides a better visual representation of the observed overall-survival data over the early and late phase of GADOLIN and it used this in its preferred base-case analysis. The company also provided a fixed change-point model with a fixed change-point at exactly 6\xa0months, corresponding to the time of the first obinutuzumab maintenance dose. The ERG preferred the random change-point model because there is uncertainty about the precise timing of a change in the hazard function. The company accepted the ERG's approach after technical engagement. The committee also agreed with the ERG's comments about the modelling approach. It concluded that a random change-point model was appropriate for estimating overall survival.\n\n## A single Weibull function over the horizon of the model may underestimate the progression-free survival benefit of obinutuzumab with bendamustine\n\nThe company fitted independent parametric models to the updated progression-free survival data from GADOLIN because the proportional hazards' assumption did not hold and it was the preferred approach in the original appraisal. The ERG considered that the models used by the company in its base case did not provide a realistic model for the GADOLIN data. Log cumulative hazard functions against time showed that a single Weibull function to predict progression-free survival over a patient's lifetime may underestimate the benefit of obinutuzumab with bendamustine on progression-free survival, and that an analysis which incorporates a change-point in the hazard function may be more appropriate. The company accepted the ERG's approach after technical engagement. The committee agreed with the ERG's comments, and it concluded that a random change-point model was appropriate for estimating progression-free survival.\n\n# Cost-effectiveness results\n\n## The estimates are within the range considered a cost-effective use of NHS resources\n\nThe company's incremental cost-effectiveness ratios (ICERs) estimated using the Weibull survival functions with fixed or random change-points preferred by the committee (see section 3.8 and section 3.9) ranged from £15,587\xa0per quality-adjusted life year (QALY) gained to £17,322\xa0per QALY gained. Using the ERG's preferred random change-point models for both progression-free survival and overall survival, with an updated price for bendamustine, the ICER was £15,045\xa0per QALY gained. These ICERs are within the range normally considered to be a cost-effective use of NHS resources (£20,000 to £30,000 per QALY gained). The committee concluded that obinutuzumab with bendamustine could be recommended for routine commissioning for treating follicular lymphoma that is refractory to rituximab or a rituximab-containing regimen."}
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https://www.nice.org.uk/guidance/ta629
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Evidence-based recommendations on obinutuzumab (Gazyvaro) with bendamustine for follicular lymphoma that has not responded or has progressed up to 6 months after treatment with rituximab or a rituximab-containing regimen in adults.
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6a7c666417106fb94861bd224c057874472d23b1
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nice
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PneuX to prevent ventilator-associated pneumonia
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PneuX to prevent ventilator-associated pneumonia
Evidence-based recommendations on PneuX to prevent ventilator-associated pneumonia.
# Recommendations
PneuX shows promise for preventing ventilator-associated pneumonia in adults. However, there is currently not enough good-quality evidence to support the case for routine adoption in the NHS.
Research is recommended to address uncertainties about the clinical benefits of using PneuX. This research should:
assess whether PneuX reduces the incidence of ventilator-associated pneumonia in all people needing ventilation
compare PneuX with current NHS clinical practice, that is, the use of endotracheal tubes with subglottic drainage
evaluate PneuX within the care bundle for ventilator-associated pneumonia prevention
be clear about the criteria used to diagnose ventilator-associated pneumonia in the study.
Why the committee made these recommendations
PneuX is a tube placed through the mouth or through a small cut in the throat (tracheostomy) when someone needs a ventilator to help them breathe. It's designed to prevent ventilator-associated pneumonia (VAP) which can happen when secretions from the mouth leak past the tube into the lungs. PneuX has a tight seal to prevent leaks, and ports that a nurse can use to drain the secretions away from above the seal.
The evidence for the clinical effectiveness of PneuX is mainly from a trial that was done in people who were ventilated for a relatively short period of time after cardiac surgery. People in this trial were classed as high risk because of their age, or heart disease, or both. While they did have less VAP compared with people who were on a ventilator tube without drainage, it's not clear if the same benefits would be seen in people who are ventilated for other reasons and for longer periods of time. The use of a ventilator tube that allows secretions to be drained is regarded as best practice for VAP prevention. However, it's not clear from the current evidence if PneuX is better than other ventilator tubes with drainage.
PneuX shows promise for preventing VAP but further research is recommended.# The technology
Technology
The PneuX system is a single-use endotracheal or tracheostomy tube (ETT) designed to prevent ventilator-associated pneumonia (VAP) by minimising the risk of pulmonary aspiration and micro‑aspiration during mechanical ventilation. Aspiration occurs when secretions from the mouth leak past the cuff into the lungs. The system has 3 components: a tube, a tracheal seal monitor, and a 2 m extension tube.
It has a low-volume, low‑pressure cuff made from a soft silicone material. The tracheal seal monitor is an electronic automated pressure controller which controls and maintains safe intracuff/tracheal wall seal pressure. It has 3 subglottic secretion drainage and irrigation ports above the proximal end of the cuff so that subglottic drainage and irrigation can be done even if one of the ports is blocked. The subglottic ports are small to prevent damage to the tracheal mucosa. Subglottic drainage can also be done with PneuX. This involves using a cleaning fluid (usually saline) to wash out the space above the cuff and oro-pharyngeal space.
PneuX was formerly known as the 'Venner PneuX PY VAP Prevention System and the Lo-Trach system'. There are no functional differences between the 2 versions.
The PneuX system is not compatible with other ETTs.
Innovative aspects
An automated tracheal seal monitor/cuff pressure controller and 3 subglottic ports.
Intended use
PneuX is intended for use in people who are expected to be intubated for 24 hours or longer. There is no evidence for the use of PneuX in children.
Clinical staff will need to be trained in subglottic secretion drainage using the PneuX ports. They will need to do this at regular intervals.
The company provides training and support.
Costs
The PneuX system costs £150, based on the NHS Innovation and Technology Tariff (ITT-03 2017-19).
For more details, see the website for PneuX.# Evidence
# Clinical evidence
## The main clinical evidence comprises 3 studies reported in 4 publications
The clinical evidence comprises 3 studies reported in 4 publications including a total of 341 adults in cardiac or general intensive care. One of these studies was a randomised controlled trial comparing PneuX with a standard endotracheal tube (ETT) without drainage (Gopal et al. 2014). The other studies were non-comparative (Smith et al. 2014, Doyle et al. 2011 and Hodd et al. 2009). For full details of the clinical evidence, see section 3 of the assessment report, which is in the supporting documents for this guidance.
## The randomised controlled trial is only in people needing ventilation after cardiac surgery
The Gopal et al. (2014) study recruited patients who needed ventilation during and after cardiac surgery. Patients were randomly selected to be ventilated using PneuX or a standard ETT without subglottic drainage. All patients in the study were classified as high risk (over 70 or with a left ventricular ejection fraction of under 50%, or both) and were therefore considered more likely to contract ventilator-associated pneumonia (VAP). People in this study were ventilated for a relatively short period of time, 15 hours and 13 hours (median) in the treatment and control groups respectively.
## The other 2 studies include people needing ventilation with a wider range of health conditions but do not compare PneuX to any other ETT
The evidence from the non-comparative studies is more generalisable to people needing ventilation with a wider range of health conditions. Nonetheless, the lack of a control group makes it difficult to draw any conclusions about the efficacy of PneuX. There was also wide variation in the outcomes measured in these studies (for example, mortality was 1.6% to 35.8% and unplanned tube removal 0.1% to 17%). However, the rates of VAP and unplanned tube removal are very low in these studies. All 3 studies used different definitions for diagnosing VAP.
# Cost evidence
## Two UK studies are included in the economic modelling
The company identified 2 relevant studies, Andronis et al. (2018) and NHS Innovation Accelerator (2017). No additional economic analyses were identified by the external assessment centre (EAC). Both the studies compared PneuX with standard ETTs and were carried out in the UK.
## The company's economic model compares PneuX to ETT without subglottic drainage in a cardiac surgery population
The company model uses a simple decision tree structure based on the model published in Andronis et al. (2018; see figure 2 of the assessment report in the supporting documents for this guidance). The population modelled is adult patients requiring mechanical ventilation following major heart surgery. The model compares PneuX with conventional ETT without subglottic secretion drainage. The key clinical parameter used in the model is the risk of VAP as reported in the comparative study Gopal et al. (2014), which was 10.8% for PneuX and 20.8% for ETT without subglottic drainage. For full details of the cost evidence, see section 4 of the assessment report.
## The model is appropriate for people who have had cardiac surgery but may not be generalisable to all people
The EAC considered the simple model structure to be adequate to capture the costs and consequences of the technology and did not make any changes. It said that all assumptions were acceptable except for the generalisability of the results from people who had cardiac surgery to a broader population of patients for whom PneuX is intended. The EAC also said the costs of treating VAP may not be generalisable to a wider population given the shorter stay in intensive care in the cardiac surgical studies (Gopal et al. 2014 and Luckraz et al. 2018) compared with all people who might need ventilation.
## The company model results in cost savings of £738 per person because of a reduced risk of VAP
The results of the company model indicate a cost saving of £738 per patient after cardiac surgery when PneuX is used instead of an ETT without subglottic drainage. This saving is from an absolute reduction in the risk of VAP of around 10% for PneuX and the associated reduction in resource consumption based on avoided costs of around £9,000 per VAP prevented. In the model, the expected cost of needing to treat VAP is around £900 less for patients given PneuX than for those having ETTs without subglottic drainage. This cost saving is substantially greater than the additional cost of using PneuX instead of ETT without subglottic drainage (PneuX costs £150 and ETT without drainage £5).
## PneuX remains cost saving in the company's sensitivity analyses
The company did scenario analyses by varying 3 parameters:
reduction in baseline risk of VAP from 20.8% to 10%
reduction in cost of standard ETT from £5 to £1.12
inclusion of a training cost to use PneuX of £10 per patient. PneuX remained cost saving for all 3 scenarios. The company also reported:
a one-way sensitivity analysis of the cost of treating VAP
a two-way sensitivity analysis of the baseline risk of VAP (0% to 50%)
the relative risk of VAP with PneuX (0 to 1)
a probabilistic sensitivity analysis to characterise the impact of uncertainty in the model parameters. The one-way sensitivity analysis indicated that PneuX is cost saving even if the cost of treating VAP is as low as £4,000. In the two-way analysis, PneuX remained cost saving for most combinations of the 2 parameters. The probabilistic sensitivity analysis indicated that there is a 96% likelihood that PneuX is cost saving compared with ETT without subglottic drainage.
## Additional analysis by the EAC shows PneuX may be slightly cost saving compared with an ETT with subglottic drainage
There are other ETTs with subglottic drainage but there are no trials available that directly compare these with PneuX. There was only 1 other study that compared an ETT with subglottic drainage (Portex Blue Line, Smiths Medical) with an ETT with no drainage (Jena et al. 2016). The EAC did an additional cost analysis using results from the Gopal and Jena studies to indirectly compare PneuX and Portex ETTs. Portex Blue Line costs less than PneuX (£20, compared with £150 for PneuX), and the relative risk reduction of VAP in the 2 studies in question was 0.52 for PneuX and 0.60 for Portex Blue Line. This led to a slight cost saving for PneuX of £18. The EAC cautioned that the relative risk of VAP for Portex Blue Line came from a very small trial, the results of which were not statistically significant, although they were consistent with data from a large meta-analysis (Mao et al. 2016).# Committee discussion
# Clinical-effectiveness overview
## PneuX is an innovative technology which shows promise for preventing ventilator-associated pneumonia (VAP)
The clinical experts who had experience of using PneuX explained that it differed from other endotracheal tubes (ETTs) with subglottic drainage because of several design features such as the automated pressure cuff and fold-free, soft, flexible material. The clinical experts noted that the automated pressure cuff is good at preventing micro-aspirations because it maintains a tight seal, even when the patient is moving, and subglottic drainage and irrigation can be done. The committee agreed that PneuX has an innovative design and there is a plausible clinical benefit. But it concluded that there is currently no evidence to show that its additional features, particularly the ability to perform subglottic irrigation, convey any benefits to patients over other ETTs with subglottic drainage.
## The main study of PneuX may not be generalisable to all people needing ventilation
The only comparative study for PneuX was in people who had cardiac surgery and who were classified by the investigators as at higher risk of complications (including VAP) because they were over 70 or had impaired left ventricular function (or both). The committee noted that people in the Gopal et al. (2014) study were ventilated for a relatively short period of time (less than 24 hours). The expert advisers explained that people who are ventilated in general intensive care have a much broader range of underlying conditions and complications. The committee concluded that, although there was evidence that PneuX reduces VAP compared with ETT without subglottic drainage in the high-risk cardiac surgical population, this evidence could not be generalised to all people needing ventilation.
## The main study compares PneuX with a non-drainage tube, which is not standard practice in the NHS
The use of an ETT with subglottic drainage is a recommended part of care bundles for preventing VAP (for example, The Faculty of Intensive Care Medicine's guidelines for the provision of intensive care services). The clinical experts stated that introducing subglottic drainage ETTs has reduced VAP by up to 50%, and that they are now standard care in the NHS. The committee noted there are no studies that directly compare the incidence of VAP with PneuX and other ETTs with subglottic drainage. Therefore, the committee concluded that there was no evidence for additional clinical benefits of using PneuX compared with other ETTs with subglottic drainage.
## In the main evidence for PneuX people were ventilated for less time than usually needed to develop VAP
In the Gopal et al. (2014) study, patients were ventilated for a median time of 15 hours with PneuX and 13 hours with ETT without subglottic drainage. The definitions for VAP state that patients will have been ventilated for a minimum of 24 or 48 hours. The clinical experts explained that it was possible to develop VAP in less than 24 hours and that this was more likely in a high-risk cardiac surgery population. The clinical experts estimated that patients in a wider intensive care population are likely to be ventilated for a median of 2 to 3 days but advised that this may be much longer in some patients. One clinical expert stated that they would use PneuX in people who are expected to be ventilated for longer than 12 hours. But all experts agreed that it is difficult to predict how long ventilation will be needed for. The committee concluded that the evidence collected from people having cardiac surgery in the Gopal study may not accurately represent all people having ventilation in hospital.
## Definition and diagnosis of VAP is subjective and poorly recorded across the NHS
The clinical experts explained that there are several definitions for VAP that incorporate clinical, radiological and microbiological testing. These definitions are used variably both in clinical practice and in the published studies. The clinical experts also explained that VAP incidence may not be recorded accurately in many centres. The committee recognised that all of these factors make research into VAP prevention particularly challenging and limit the legitimacy of between-study comparisons in this area.
## VAP is likely to increase mortality but the PneuX studies are underpowered for this outcome
NHS England reports that between 3,000 and 6,000 people die from VAP each year. The clinical experts noted that VAP is also likely to lead to an increase in the length of time ventilation is needed, length of critical care and hospital stay, risk of recurrent pneumonia, prolonged illness and spread of infection to other organs. The committee noted that the studies for PneuX were underpowered to measure any difference in mortality and length of stay, and so concluded that it is uncertain whether PneuX has any impact on these outcomes.
# NHS considerations overview
## Training and support are provided by the company free of charge
The company described to the committee how it provides training and support for all staff and centres using PneuX. The company offers a range of training sessions to all staff, lasting between 1 and 4 hours, which can be delivered in a classroom, or by the bedside, as needed. The clinical experts confirmed that the support from the company was adequate to train staff how to use PneuX correctly.
## A higher volume of secretions drained and irrigation may slightly increase nurse time for subglottic drainage
The clinical experts with experience of using PneuX noted that a higher volume of secretions can be drained with PneuX than with other ETTs with subglottic drainage, and that subglottic irrigation, when undertaken, takes an additional 2 to 3 minutes. The committee concluded that using PneuX may lead to a slight increase in nurse time spent on subglottic drainage and irrigation.
# Cost modelling overview
## The company model is robust but it is not certain that the cost savings will apply to all people needing ventilation
The committee noted that the company's model was well constructed and robust to uncertainty. It showed that PneuX is cost saving compared with ETTs without subglottic drainage in a high-risk cardiac surgery population. However, the main cost driver in the model was the absolute reduction in the risk of VAP between the PneuX and ETT without drainage arms. As these values were sourced from the Gopal et al. (2014) study, the committee concluded that there was substantial uncertainty that the cost savings would be realised for all people needing ventilation.
## Comparisons between PneuX and other ETTs with subglottic drainage may be more appropriate for the NHS
The committee heard from the clinical experts that subglottic drainage is becoming standard practice in the NHS. The external assessment centre (EAC) modelled an indirect cost comparison of PneuX with Portex Blue Line. However, the committee felt there was considerable uncertainty in this because of the lack of comparative evidence. The committee concluded that the uncertainties associated with this analysis, as well as the small cost difference in results, meant that this was not enough evidence on which to base a positive recommendation. Overall, the committee considered that the current economic evidence does not support the routine adoption of PneuX in the NHS.
# Further research
## Further research would help address the uncertainty in the evidence
The committee concluded that further research would help resolve the uncertainties about the potential benefits of using PneuX. The research should determine if using PneuX reduces:
VAP incidence in all people needing ventilation
VAP incidence compared with other ETTs with subglottic drainage (including the effect of subglottic irrigation)
time on a ventilator, and critical care and length of stay in hospital mortality. In this research, the committee recommended that the:
criteria used for defining VAP should be carefully considered and recorded
use of PneuX should be considered within the context of the wider care bundle for VAP prevention
population recruited should be large enough and follow up long enough to capture the important clinical endpoints.
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{'Recommendations': "PneuX shows promise for preventing ventilator-associated pneumonia in adults. However, there is currently not enough good-quality evidence to support the case for routine adoption in the NHS.\n\nResearch is recommended to address uncertainties about the clinical benefits of using PneuX. This research should:\n\nassess whether PneuX reduces the incidence of ventilator-associated pneumonia in all people needing ventilation\n\ncompare PneuX with current NHS clinical practice, that is, the use of endotracheal tubes with subglottic drainage\n\nevaluate PneuX within the care bundle for ventilator-associated pneumonia prevention\n\nbe clear about the criteria used to diagnose ventilator-associated pneumonia in the study.\n\nWhy the committee made these recommendations\n\nPneuX is a tube placed through the mouth or through a small cut in the throat (tracheostomy) when someone needs a ventilator to help them breathe. It's designed to prevent ventilator-associated pneumonia (VAP) which can happen when secretions from the mouth leak past the tube into the lungs. PneuX has a tight seal to prevent leaks, and ports that a nurse can use to drain the secretions away from above the seal.\n\nThe evidence for the clinical effectiveness of PneuX is mainly from a trial that was done in people who were ventilated for a relatively short period of time after cardiac surgery. People in this trial were classed as high risk because of their age, or heart disease, or both. While they did have less VAP compared with people who were on a ventilator tube without drainage, it's not clear if the same benefits would be seen in people who are ventilated for other reasons and for longer periods of time. The use of a ventilator tube that allows secretions to be drained is regarded as best practice for VAP prevention. However, it's not clear from the current evidence if PneuX is better than other ventilator tubes with drainage.\n\nPneuX shows promise for preventing VAP but further research is recommended.", 'The technology': "Technology\n\nThe PneuX system is a single-use endotracheal or tracheostomy tube (ETT) designed to prevent ventilator-associated pneumonia (VAP) by minimising the risk of pulmonary aspiration and micro‑aspiration during mechanical ventilation. Aspiration occurs when secretions from the mouth leak past the cuff into the lungs. The system has 3 components: a tube, a tracheal seal monitor, and a 2\xa0m extension tube.\n\nIt has a low-volume, low‑pressure cuff made from a soft silicone material. The tracheal seal monitor is an electronic automated pressure controller which controls and maintains safe intracuff/tracheal wall seal pressure. It has 3 subglottic secretion drainage and irrigation ports above the proximal end of the cuff so that subglottic drainage and irrigation can be done even if one of the ports is blocked. The subglottic ports are small to prevent damage to the tracheal mucosa. Subglottic drainage can also be done with PneuX. This involves using a cleaning fluid (usually saline) to wash out the space above the cuff and oro-pharyngeal space.\n\nPneuX was formerly known as the 'Venner PneuX PY VAP Prevention System and the Lo-Trach system'. There are no functional differences between the 2 versions.\n\nThe PneuX system is not compatible with other ETTs.\n\nInnovative aspects\n\nAn automated tracheal seal monitor/cuff pressure controller and 3 subglottic ports.\n\nIntended use\n\nPneuX is intended for use in people who are expected to be intubated for 24\xa0hours or longer. There is no evidence for the use of PneuX in children.\n\nClinical staff will need to be trained in subglottic secretion drainage using the PneuX ports. They will need to do this at regular intervals.\n\nThe company provides training and support.\n\nCosts\n\nThe PneuX system costs £150, based on the NHS Innovation and Technology Tariff (ITT-03 2017-19).\n\nFor more details, see the website for PneuX.", 'Evidence': "# Clinical evidence\n\n## The main clinical evidence comprises 3\xa0studies reported in 4 publications\n\nThe clinical evidence comprises 3\xa0studies reported in 4 publications including a total of 341\xa0adults in cardiac or general intensive care. One of these studies was a randomised controlled trial comparing PneuX with a standard endotracheal tube (ETT) without drainage (Gopal et al. 2014). The other studies were non-comparative (Smith et al. 2014, Doyle et al. 2011 and Hodd et al. 2009). For full details of the clinical evidence, see section\xa03 of the assessment report, which is in the supporting documents for this guidance.\n\n## The randomised controlled trial is only in people needing ventilation after cardiac surgery\n\nThe Gopal et al. (2014) study recruited patients who needed ventilation during and after cardiac surgery. Patients were randomly selected to be ventilated using PneuX or a standard ETT without subglottic drainage. All patients in the study were classified as high risk (over 70 or with a left ventricular ejection fraction of under 50%, or both) and were therefore considered more likely to contract ventilator-associated pneumonia (VAP). People in this study were ventilated for a relatively short period of time, 15\xa0hours and 13\xa0hours (median) in the treatment and control groups respectively.\n\n## The other 2\xa0studies include people needing ventilation with a wider range of health conditions but do not compare PneuX to any other ETT\n\nThe evidence from the non-comparative studies is more generalisable to people needing ventilation with a wider range of health conditions. Nonetheless, the lack of a control group makes it difficult to draw any conclusions about the efficacy of PneuX. There was also wide variation in the outcomes measured in these studies (for example, mortality was 1.6% to 35.8% and unplanned tube removal 0.1% to 17%). However, the rates of VAP and unplanned tube removal are very low in these studies. All 3\xa0studies used different definitions for diagnosing VAP.\n\n# Cost evidence\n\n## Two UK studies are included in the economic modelling\n\nThe company identified 2 relevant studies, Andronis et al. (2018) and NHS Innovation Accelerator (2017). No additional economic analyses were identified by the external assessment centre (EAC). Both the studies compared PneuX with standard ETTs and were carried out in the UK.\n\n## The company's economic model compares PneuX to ETT without subglottic drainage in a cardiac surgery population\n\nThe company model uses a simple decision tree structure based on the model published in Andronis et al. (2018; see figure\xa02 of the assessment report in the supporting documents for this guidance). The population modelled is adult patients requiring mechanical ventilation following major heart surgery. The model compares PneuX with conventional ETT without subglottic secretion drainage. The key clinical parameter used in the model is the risk of VAP as reported in the comparative study Gopal et al. (2014), which was 10.8% for PneuX and 20.8% for ETT without subglottic drainage. For full details of the cost evidence, see section\xa04 of the assessment report.\n\n## The model is appropriate for people who have had cardiac surgery but may not be generalisable to all people\n\nThe EAC considered the simple model structure to be adequate to capture the costs and consequences of the technology and did not make any changes. It said that all assumptions were acceptable except for the generalisability of the results from people who had cardiac surgery to a broader population of patients for whom PneuX is intended. The EAC also said the costs of treating VAP may not be generalisable to a wider population given the shorter stay in intensive care in the cardiac surgical studies (Gopal et al. 2014 and Luckraz et al. 2018) compared with all people who might need ventilation.\n\n## The company model results in cost savings of £738 per person because of a reduced risk of VAP\n\nThe results of the company model indicate a cost saving of £738 per patient after cardiac surgery when PneuX is used instead of an ETT without subglottic drainage. This saving is from an absolute reduction in the risk of VAP of around 10% for PneuX and the associated reduction in resource consumption based on avoided costs of around £9,000 per VAP prevented. In the model, the expected cost of needing to treat VAP is around £900 less for patients given PneuX than for those having ETTs without subglottic drainage. This cost saving is substantially greater than the additional cost of using PneuX instead of ETT without subglottic drainage (PneuX costs £150 and ETT without drainage £5).\n\n## PneuX remains cost saving in the company's sensitivity analyses\n\nThe company did scenario analyses by varying 3 parameters:\n\nreduction in baseline risk of VAP from 20.8% to 10%\n\nreduction in cost of standard ETT from £5 to £1.12\n\ninclusion of a training cost to use PneuX of £10 per patient. PneuX remained cost saving for all 3 scenarios. The company also reported:\n\na one-way sensitivity analysis of the cost of treating VAP\n\na two-way sensitivity analysis of the baseline risk of VAP (0% to 50%)\n\nthe relative risk of VAP with PneuX (0\xa0to\xa01)\n\na probabilistic sensitivity analysis to characterise the impact of uncertainty in the model parameters. The one-way sensitivity analysis indicated that PneuX is cost saving even if the cost of treating VAP is as low as £4,000. In the two-way analysis, PneuX remained cost saving for most combinations of the 2\xa0parameters. The probabilistic sensitivity analysis indicated that there is a 96% likelihood that PneuX is cost saving compared with ETT without subglottic drainage.\n\n## Additional analysis by the EAC shows PneuX may be slightly cost saving compared with an ETT with subglottic drainage\n\nThere are other ETTs with subglottic drainage but there are no trials available that directly compare these with PneuX. There was only 1 other study that compared an ETT with subglottic drainage (Portex Blue Line, Smiths Medical) with an ETT with no drainage (Jena et al. 2016). The EAC did an additional cost analysis using results from the Gopal and Jena studies to indirectly compare PneuX and Portex ETTs. Portex Blue Line costs less than PneuX (£20, compared with £150 for PneuX), and the relative risk reduction of VAP in the 2\xa0studies in question was 0.52 for PneuX and 0.60 for Portex Blue Line. This led to a slight cost saving for PneuX of £18. The EAC cautioned that the relative risk of VAP for Portex Blue Line came from a very small trial, the results of which were not statistically significant, although they were consistent with data from a large meta-analysis (Mao et al. 2016).", 'Committee discussion': "# Clinical-effectiveness overview\n\n## PneuX is an innovative technology which shows promise for preventing ventilator-associated pneumonia (VAP)\n\nThe clinical experts who had experience of using PneuX explained that it differed from other endotracheal tubes (ETTs) with subglottic drainage because of several design features such as the automated pressure cuff and fold-free, soft, flexible material. The clinical experts noted that the automated pressure cuff is good at preventing micro-aspirations because it maintains a tight seal, even when the patient is moving, and subglottic drainage and irrigation can be done. The committee agreed that PneuX has an innovative design and there is a plausible clinical benefit. But it concluded that there is currently no evidence to show that its additional features, particularly the ability to perform subglottic irrigation, convey any benefits to patients over other ETTs with subglottic drainage.\n\n## The main study of PneuX may not be generalisable to all people needing ventilation\n\nThe only comparative study for PneuX was in people who had cardiac surgery and who were classified by the investigators as at higher risk of complications (including VAP) because they were over 70 or had impaired left ventricular function (or both). The committee noted that people in the Gopal et al. (2014) study were ventilated for a relatively short period of time (less than 24\xa0hours). The expert advisers explained that people who are ventilated in general intensive care have a much broader range of underlying conditions and complications. The committee concluded that, although there was evidence that PneuX reduces VAP compared with ETT without subglottic drainage in the high-risk cardiac surgical population, this evidence could not be generalised to all people needing ventilation.\n\n## The main study compares PneuX with a non-drainage tube, which is not standard practice in the NHS\n\nThe use of an ETT with subglottic drainage is a recommended part of care bundles for preventing VAP (for example, The Faculty of Intensive Care Medicine's guidelines for the provision of intensive care services). The clinical experts stated that introducing subglottic drainage ETTs has reduced VAP by up to 50%, and that they are now standard care in the NHS. The committee noted there are no studies that directly compare the incidence of VAP with PneuX and other ETTs with subglottic drainage. Therefore, the committee concluded that there was no evidence for additional clinical benefits of using PneuX compared with other ETTs with subglottic drainage.\n\n## In the main evidence for PneuX people were ventilated for less time than usually needed to develop VAP\n\nIn the Gopal et al. (2014) study, patients were ventilated for a median time of 15\xa0hours with PneuX and 13\xa0hours with ETT without subglottic drainage. The definitions for VAP state that patients will have been ventilated for a minimum of 24 or 48\xa0hours. The clinical experts explained that it was possible to develop VAP in less than 24\xa0hours and that this was more likely in a high-risk cardiac surgery population. The clinical experts estimated that patients in a wider intensive care population are likely to be ventilated for a median of 2 to 3\xa0days but advised that this may be much longer in some patients. One clinical expert stated that they would use PneuX in people who are expected to be ventilated for longer than 12\xa0hours. But all experts agreed that it is difficult to predict how long ventilation will be needed for. The committee concluded that the evidence collected from people having cardiac surgery in the Gopal study may not accurately represent all people having ventilation in hospital.\n\n## Definition and diagnosis of VAP is subjective and poorly recorded across the NHS\n\nThe clinical experts explained that there are several definitions for VAP that incorporate clinical, radiological and microbiological testing. These definitions are used variably both in clinical practice and in the published studies. The clinical experts also explained that VAP incidence may not be recorded accurately in many centres. The committee recognised that all of these factors make research into VAP prevention particularly challenging and limit the legitimacy of between-study comparisons in this area.\n\n## VAP is likely to increase mortality but the PneuX studies are underpowered for this outcome\n\nNHS England reports that between 3,000 and 6,000 people die from VAP each year. The clinical experts noted that VAP is also likely to lead to an increase in the length of time ventilation is needed, length of critical care and hospital stay, risk of recurrent pneumonia, prolonged illness and spread of infection to other organs. The committee noted that the studies for PneuX were underpowered to measure any difference in mortality and length of stay, and so concluded that it is uncertain whether PneuX has any impact on these outcomes.\n\n# NHS considerations overview\n\n## Training and support are provided by the company free of charge\n\nThe company described to the committee how it provides training and support for all staff and centres using PneuX. The company offers a range of training sessions to all staff, lasting between 1 and 4\xa0hours, which can be delivered in a classroom, or by the bedside, as needed. The clinical experts confirmed that the support from the company was adequate to train staff how to use PneuX correctly.\n\n## A higher volume of secretions drained and irrigation may slightly increase nurse time for subglottic drainage\n\nThe clinical experts with experience of using PneuX noted that a higher volume of secretions can be drained with PneuX than with other ETTs with subglottic drainage, and that subglottic irrigation, when undertaken, takes an additional 2 to 3\xa0minutes. The committee concluded that using PneuX may lead to a slight increase in nurse time spent on subglottic drainage and irrigation.\n\n# Cost modelling overview\n\n## The company model is robust but it is not certain that the cost savings will apply to all people needing ventilation\n\nThe committee noted that the company's model was well constructed and robust to uncertainty. It showed that PneuX is cost saving compared with ETTs without subglottic drainage in a high-risk cardiac surgery population. However, the main cost driver in the model was the absolute reduction in the risk of VAP between the PneuX and ETT without drainage arms. As these values were sourced from the Gopal et al. (2014) study, the committee concluded that there was substantial uncertainty that the cost savings would be realised for all people needing ventilation.\n\n## Comparisons between PneuX and other ETTs with subglottic drainage may be more appropriate for the NHS\n\nThe committee heard from the clinical experts that subglottic drainage is becoming standard practice in the NHS. The external assessment centre (EAC) modelled an indirect cost comparison of PneuX with Portex Blue Line. However, the committee felt there was considerable uncertainty in this because of the lack of comparative evidence. The committee concluded that the uncertainties associated with this analysis, as well as the small cost difference in results, meant that this was not enough evidence on which to base a positive recommendation. Overall, the committee considered that the current economic evidence does not support the routine adoption of PneuX in the NHS.\n\n# Further research\n\n## Further research would help address the uncertainty in the evidence\n\nThe committee concluded that further research would help resolve the uncertainties about the potential benefits of using PneuX. The research should determine if using PneuX reduces:\n\nVAP incidence in all people needing ventilation\n\nVAP incidence compared with other ETTs with subglottic drainage (including the effect of subglottic irrigation)\n\ntime on a ventilator, and critical care and length of stay in hospital mortality. In this research, the committee recommended that the:\n\ncriteria used for defining VAP should be carefully considered and recorded\n\nuse of PneuX should be considered within the context of the wider care bundle for VAP prevention\n\npopulation recruited should be large enough and follow up long enough to capture the important clinical endpoints."}
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https://www.nice.org.uk/guidance/mtg48
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Evidence-based recommendations on PneuX to prevent ventilator-associated pneumonia.
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519dd5293123fbf025169f1eea64ec945fcac764
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nice
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Lenalidomide with rituximab for previously treated follicular lymphoma
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Lenalidomide with rituximab for previously treated follicular lymphoma
Evidence-based recommendations on lenalidomide (Revlimid) with rituximab for previously treated follicular lymphoma (grade 1 to 3A) in adults.
# Recommendations
Lenalidomide with rituximab is recommended, within its marketing authorisation, as an option for previously treated follicular lymphoma (grade 1 to 3A) in adults. It is only recommended if the company provides lenalidomide according to the commercial arrangement.
Why the committee made these recommendations
Follicular lymphoma is usually treated with an anti‑CD20 antibody (such as rituximab) with chemotherapy. Treatment options are limited, especially if the disease relapses early after a rituximab-based treatment. Lenalidomide is the first approved targeted treatment for follicular lymphoma that is not an anti‑CD20 antibody. Lenalidomide is taken orally, and when used with rituximab is a chemotherapy-free combination.
Clinical-effectiveness evidence shows that, when people take lenalidomide with rituximab, their follicular lymphoma does not progress as quickly as when they take rituximab with chemotherapy. There is also evidence that lenalidomide with rituximab helps people live longer than rituximab with chemotherapy, although it is too early to tell for how much longer.
Lenalidomide with rituximab costs more than rituximab with chemotherapy. However, its cost-effectiveness estimate is within the range that NICE normally considers an acceptable use of NHS resources. Therefore, lenalidomide with rituximab is recommended.# Information about lenalidomide with rituximab
# Marketing authorisation indication
Lenalidomide (Revlimid, Celgene) with rituximab is indicated 'for the treatment of adult patients with previously treated follicular lymphoma (Grade 1 – 3A)'.
# Dosage in the marketing authorisation
The recommended starting dosage of lenalidomide is 20 mg, orally once daily on days 1 to 21 of repeated 28‑day cycles for up to 12 cycles of treatment. The recommended starting dosage of rituximab is 375 mg/m2 intravenously every week in cycle 1 (days 1, 8, 15, and 22) and day 1 of every 28‑day cycle for cycles 2 to 5.
# Price
Lenalidomide is available as a 21‑capsule pack. The cost per pack is £4,168.50 (20 mg; excluding VAT; BNF online, accessed January 2020). The company has a commercial arrangement. This makes lenalidomide available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount. The list price of rituximab (MabThera) is £349.25 per two 100‑mg vials and £873.15 per one 500‑mg vial (excluding VAT; BNF online, accessed January 2020). Napp and Sandoz have agreed a nationally available price reduction for biosimilar rituximab with the Commercial Medicines Unit. The prices agreed through the framework are commercial in confidence.# Committee discussion
The appraisal committee considered evidence submitted by Celgene, a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.
After technical engagement, there were remaining areas of uncertainty associated with the analyses presented. The committee took these into account in its decision making. It discussed the following issues (issues 1 to 6), which were outstanding after the technical engagement stage.
# The condition and current treatment
## There is an unmet need for new treatment options for this disease
The clinical and patient experts noted that people with previously treated follicular lymphoma have limited treatment options. The choice of treatment for previously treated follicular lymphoma depends on individual circumstances and takes into account previous chemotherapy, the age and fitness of the patient, plus clinician and patient preferences. The patient experts explained that chemotherapy has unpleasant side effects and any treatment that avoided chemotherapy would be welcomed. The committee concluded that lenalidomide with rituximab would be welcomed as a new treatment option for people with previously treated follicular lymphoma.
## Current treatment for follicular lymphoma is rituximab with chemotherapy (CHOP or CVP)
The clinical experts noted that rituximab monotherapy, which is the comparator used in the AUGMENT trial used in this appraisal (see section 3.3), would rarely be given to people whose disease had relapsed. The company included obinutuzumab with bendamustine as a comparator, but this combination is only recommended for use in the Cancer Drugs Fund. The committee did not consider obinutuzumab with bendamustine to be used in routine commissioning and did not consider it a relevant comparator. The committee understood that rituximab with either CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) or CVP (cyclophosphamide, vincristine and prednisolone) is used to treat follicular lymphoma in people who have had at least 1 previous treatment. The clinical experts noted that the company's proposed treatment pathway originally separated treatments for previously treated follicular lymphoma depending on whether the disease was refractory to rituximab or not. The clinical experts considered that being refractory to rituximab or not was not a clinically appropriate way to separate treatment choices, and that time until relapse after initial chemo-immunotherapy may be more relevant for determining treatment choices in clinical practice. The committee agreed that the most appropriate comparators for this appraisal were rituximab with chemotherapy (CHOP or CVP).
# Clinical effectiveness
## Clinical evidence for lenalidomide with rituximab and rituximab with chemotherapy is compared using a matching-adjusted indirect comparison
The evidence for lenalidomide with rituximab came from AUGMENT, a phase 3 multicentre randomised controlled trial that used rituximab monotherapy as the comparator. In the absence of direct comparative evidence of lenalidomide plus rituximab compared with rituximab plus CHOP (R‑CHOP) or rituximab plus CVP (R‑CVP), the company provided a matching-adjusted indirect comparison to compare both treatments. Data for R‑CHOP and R‑CVP are from either Van Oers et al. (2006) or the Haematological Malignancy Research Network (HMRN) registry. The committee agreed that using the Van Oers data was not appropriate, because patients were not from the UK and had not had previous treatment with rituximab. The committee concluded that the HMRN registry data were most suitable for R‑CHOP and R‑CVP because the data were from the UK and include people who had had previous treatment with rituximab.
## R-CHOP and R-CVP are assumed to be clinically equivalent
The company combined the R‑CHOP and R‑CVP populations for the matching-adjusted indirect comparison to increase the sample size of the comparator. The matching-adjusted indirect comparison showed an improvement in progression-free survival for lenalidomide with rituximab compared with R‑CHOP and R‑CVP (exact data are confidential and cannot be reported here). It also showed an improvement in overall survival for lenalidomide with rituximab compared with R‑CHOP and R‑CVP (exact data are confidential and cannot be reported here). Median progression-free survival and overall survival could not be estimated because the follow-up data were immature (not yet complete). When assessing the validity of combining R‑CHOP and R‑CVP, the committee understood that observed data for R‑CHOP in the HMRN registry for overall survival, progression-free survival and time to next anti-lymphoma treatment appeared similar to R‑CVP. The committee also understood that Cox proportional hazards model analyses of overall survival, progression-free survival and time to next anti-lymphoma treatment showed no statistically significant difference in outcomes between R‑CHOP and R‑CVP. The clinical experts noted that, in untreated follicular lymphoma, R‑CHOP and R‑CVP are not clinically equivalent. They considered that R‑CHOP has a longer time to treatment failure than R‑CVP (despite similar response rates) and progression-free survival is longer with R‑CHOP. They also noted that R‑CHOP is given to younger, fitter patients who can tolerate the additional chemotherapy component (doxorubicin) in CHOP, while R‑CVP is given to older, less fit patients. The clinical experts acknowledged that there was no evidence for R‑CHOP and R‑CVP in previously treated follicular lymphoma. They accepted that, without any other data sources, it may be appropriate to assume R‑CHOP is clinically equivalent to R‑CVP. The committee concluded that it was appropriate to assume R‑CHOP is clinically equivalent to R‑CVP in the economic model.
## The matching-adjusted indirect comparison is as closely matched as possible
The ERG noted that the matching-adjusted indirect comparison did not account for all potentially relevant matching criteria. Potentially relevant matching criteria included the diameter of the largest node, haemoglobin levels, duration since last treatment, high lactate dehydrogenase levels, and Follicular Lymphoma International Prognostic Index (FLIPI) risk group status. The committee understood that the most important criteria identified by clinical experts were included in the matching-adjusted indirect comparison, and that other potentially relevant matching criteria were not collected by HMRN. The committee agreed that, given the data limitations, the matching-adjusted indirect comparison could not be improved further.
# Economic model
## The partitioned survival model structure is appropriate
The company used a partitioned survival model to determine the difference in overall survival and progression-free survival for lenalidomide with rituximab and R‑CHOP and R‑CVP. The ERG said that a state transition model would have helped to assess the validity of the extrapolations in overall survival and progression-free survival in the partitioned survival model. Following technical engagement, the company provided a state transition model for lenalidomide with rituximab compared with rituximab monotherapy (not R‑CHOP and R‑CVP). The committee did not consider this appropriate because rituximab monotherapy is not a relevant treatment for patients in the NHS. The committee also noted that a state transition model for lenalidomide with rituximab compared with R‑CHOP and R‑CVP would have its own uncertainty because of the limitations in the data. The AUGMENT data were immature, with a maximum follow up of 3.9 years, and the R‑CHOP and R‑CVP data were from a small effective sample. The committee agreed that accurately modelling transitions between intermediate health states would be difficult, and providing a state transition model would not help validate the partitioned survival model. The committee concluded that a partitioned survival model was appropriate, and that a state transition model was not needed on this occasion.
## Health-related quality-of-life values for lenalidomide with rituximab should be capped in the economic model
Patients in AUGMENT had health-related quality-of-life values that were higher than the general population for the same age group, in all health states. The clinical experts said that someone with follicular lymphoma would not have higher quality of life than a member of the general population in any health state. At best, their quality of life would be equal to a member of the general population at the same age. The company proposed capping the least severe health-related quality-of-life values (values for progression-free survival) in the economic model to published age-matched UK general population values. The company calculated the quality of life for the post-progression (on or off treatment) health states by adding relative decrements in quality of life observed in AUGMENT to the progression-free survival value. The committee agreed that capping the progression-free survival health state in the economic model to general population values, and using relative decrements from AUGMENT for other health states, was appropriate.
## A 5-year treatment effect duration for lenalidomide with rituximab is appropriate
The clinical experts said that overall-survival estimates for lenalidomide with rituximab will be better than overall-survival estimates for R‑CHOP and R‑CVP for several years once treatment begins. However, these estimates will gradually decline over time and eventually become the same as overall-survival estimates for R‑CHOP and R‑CVP. The clinical experts noted that it is uncertain how long the overall-survival benefit for lenalidomide with rituximab will last, but said that it will likely start to reduce 5 to 10 years after treatment starts. The company and the ERG's estimates of treatment effect duration was 5 years in its base cases. The committee noted that this was the most conservative estimate, given the clinical expert opinion of 5 to 10 years. The committee concluded that a treatment effect duration of 5 years was appropriate, with no evidence to the contrary.
## The exponential distribution is appropriate for extrapolating overall survival
NICE's Decision Support Unit technical support document 14 states that, if parametric models are fitted separately to individual treatment arms, it is advisable to use the same type of distribution for extrapolating both arms. For overall survival, the company selected the exponential distribution for both arms to best reflect the average 20‑year prognosis for follicular lymphoma when treated with R‑CHOP and R‑CVP. The clinical experts noted that the Weibull distribution may have also been appropriate for both arms, and the committee noted that it was a slightly better statistical fit than the exponential distribution. The committee also noted that the Weibull distribution produced a higher cost-effectiveness estimate in the probabilistic sensitivity analysis results than it did in the deterministic sensitivity analysis results. The committee was aware that this was caused by lenalidomide with rituximab having lower quality-adjusted life years (QALYs) than R‑CHOP and R‑CVP in the probabilistic sensitivity analysis results compared with the deterministic sensitivity analysis results. More specifically, lenalidomide with rituximab had lower quality of life or extension of life than R‑CHOP and R‑CVP in 267 of the 1,000 iterations in the probabilistic sensitivity analysis. The clinical experts said that this was not clinically plausible. The committee agreed that the reduction in QALYs for lenalidomide with rituximab in the probabilistic sensitivity analysis results (when using a Weibull distribution for overall survival) was unusual. The committee noted that this might have been due to an error in the model or an unstable covariance matrix. Because of this, the committee did not consider the output of the probabilistic sensitivity analysis to be robust, and did not think it appropriate to use the Weibull distribution. The committee considered that the exponential distribution had good statistical fit for the observed Kaplan–Meier data and concluded that the exponential distribution was appropriate for extrapolating overall survival.
## Different methods are needed to extrapolate progression-free survival for lenalidomide with rituximab and R-CHOP and R-CVP
The standard approach for extrapolating survival curves is to fit a parametric distribution to the available data, which is then used to estimate survival at any point in time. This method was used to fit the Weibull function for R‑CHOP and R‑CVP. However, the committee noted that all the standard parametric extrapolations for lenalidomide with rituximab estimated worse progression-free survival outcomes compared with R‑CHOP and R‑CVP. The clinical experts said that it was clinically implausible for the average progression-free survival of lenalidomide with rituximab to be worse than the average progression-free survival of R‑CHOP and R‑CVP. The committee understood that the relatively worse progression-free survival estimates for lenalidomide with rituximab may have been a result of the immature follow-up data from the AUGMENT trial (3.9‑year follow up), compared with the longer follow up for R‑CHOP and R‑CVP (11.6 years). To avoid the implausible crossing of progression-free survival curves, the company used the observed AUGMENT data, and then, in the absence of further trial data, the company fitted a Weibull distribution to the end of these data. The ERG noted that this approach generated a larger progression-free survival benefit for lenalidomide with rituximab than applying the standard parametric distributions. Additionally, the ERG was concerned that, by extrapolating from the end of the observed AUGMENT data when there were fewer patients to inform the extrapolation, the mean progression-free survival benefit for lenalidomide with rituximab may have been further overestimated. The committee agreed that using the observed AUGMENT data with a Weibull distribution extrapolation was the most appropriate method for estimating progression-free survival for lenalidomide with rituximab. This was because this method takes account of the clinical plausibility of a progression-free survival benefit for lenalidomide with rituximab. The committee concluded that the AUGMENT data should have been extrapolated from the midpoint, rather than from the end, because this would have reduced the uncertainty in the extrapolation by using a relatively larger sample size.
# Cost-effectiveness estimate
## Lenalidomide with rituximab is a cost-effective use of NHS resources
NICE's guide to the methods of technology appraisal says that, above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per QALY gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. Therefore, because of the uncertainty in the equivalence of R‑CHOP and R‑CVP (see section 3.4), matching-adjusted indirect comparison (see section 3.5) and treatment effect duration (see section 3.8), the committee agreed that an acceptable ICER would be around the lower end of the £20,000 to £30,000 per QALY gained range. The company's deterministic base case showed that the ICER for lenalidomide with rituximab compared with R‑CVP was £20,156 per QALY gained (including the patient access scheme for lenalidomide). The ERG presented 6 analyses, each using a different parametric distribution to extrapolate overall survival. The ERG's analyses also included the confidential commercial arrangement for obinutuzumab and biosimilar rituximab. The ICERs were within or below the range that NICE usually considers an acceptable use of NHS resources (the exact ICERs are confidential and cannot be reported here). The committee agreed that an extrapolation with an exponential distribution was appropriate for overall survival in both lenalidomide with rituximab and R‑CHOP and R‑CVP. The committee also agreed that AUGMENT data with a Weibull distribution (extrapolated from AUGMENT data midpoint) was the most appropriate for estimating progression-free survival for lenalidomide with rituximab, and that a standard parametric Weibull distribution should have been used to extrapolate R‑CHOP and R‑CVP (see sections 3.9 and 3.10). These assumptions generated a most plausible ICER that was below the range that NICE usually considers an acceptable use of NHS resources (the exact ICER is confidential and cannot be reported here). The committee therefore recommended lenalidomide with rituximab as an option for previously treated follicular lymphoma (grades 1 to 3A).
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{'Recommendations': 'Lenalidomide with rituximab is recommended, within its marketing authorisation, as an option for previously treated follicular lymphoma (grade\xa01\xa0to\xa03A) in adults. It is only recommended if the company provides lenalidomide according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nFollicular lymphoma is usually treated with an anti‑CD20 antibody (such as rituximab) with chemotherapy. Treatment options are limited, especially if the disease relapses early after a rituximab-based treatment. Lenalidomide is the first approved targeted treatment for follicular lymphoma that is not an anti‑CD20 antibody. Lenalidomide is taken orally, and when used with rituximab is a chemotherapy-free combination.\n\nClinical-effectiveness evidence shows that, when people take lenalidomide with rituximab, their follicular lymphoma does not progress as quickly as when they take rituximab with chemotherapy. There is also evidence that lenalidomide with rituximab helps people live longer than rituximab with chemotherapy, although it is too early to tell for how much longer.\n\nLenalidomide with rituximab costs more than rituximab with chemotherapy. However, its cost-effectiveness estimate is within the range that NICE normally considers an acceptable use of NHS resources. Therefore, lenalidomide with rituximab is recommended.', 'Information about lenalidomide with rituximab': "# Marketing authorisation indication\n\nLenalidomide (Revlimid, Celgene) with rituximab is indicated 'for the treatment of adult patients with previously treated follicular lymphoma (Grade\xa01\xa0–\xa03A)'.\n\n# Dosage in the marketing authorisation\n\nThe recommended starting dosage of lenalidomide is 20\xa0mg, orally once daily on days\xa01 to\xa021 of repeated 28‑day cycles for up to 12\xa0cycles of treatment. The recommended starting dosage of rituximab is 375\xa0mg/m2 intravenously every week in cycle\xa01 (days\xa01, 8,\xa015, and\xa022) and day\xa01 of every 28‑day cycle for cycles\xa02\xa0to\xa05.\n\n# Price\n\nLenalidomide is available as a 21‑capsule pack. The cost per pack is £4,168.50 (20\xa0mg; excluding VAT; BNF online, accessed January 2020). The company has a commercial arrangement. This makes lenalidomide available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount. The list price of rituximab (MabThera) is £349.25 per two 100‑mg vials and £873.15 per one 500‑mg vial (excluding VAT; BNF online, accessed January 2020). Napp and Sandoz have agreed a nationally available price reduction for biosimilar rituximab with the Commercial Medicines Unit. The prices agreed through the framework are commercial in confidence.", 'Committee discussion': "The appraisal committee considered evidence submitted by Celgene, a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.\n\nAfter technical engagement, there were remaining areas of uncertainty associated with the analyses presented. The committee took these into account in its decision making. It discussed the following issues (issues\xa01\xa0to\xa06), which were outstanding after the technical engagement stage.\n\n# The condition and current treatment\n\n## There is an unmet need for new treatment options for this disease\n\nThe clinical and patient experts noted that people with previously treated follicular lymphoma have limited treatment options. The choice of treatment for previously treated follicular lymphoma depends on individual circumstances and takes into account previous chemotherapy, the age and fitness of the patient, plus clinician and patient preferences. The patient experts explained that chemotherapy has unpleasant side effects and any treatment that avoided chemotherapy would be welcomed. The committee concluded that lenalidomide with rituximab would be welcomed as a new treatment option for people with previously treated follicular lymphoma.\n\n## Current treatment for follicular lymphoma is rituximab with chemotherapy (CHOP or CVP)\n\nThe clinical experts noted that rituximab monotherapy, which is the comparator used in the AUGMENT trial used in this appraisal (see section\xa03.3), would rarely be given to people whose disease had relapsed. The company included obinutuzumab with bendamustine as a comparator, but this combination is only recommended for use in the Cancer Drugs Fund. The committee did not consider obinutuzumab with bendamustine to be used in routine commissioning and did not consider it a relevant comparator. The committee understood that rituximab with either CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) or CVP (cyclophosphamide, vincristine and prednisolone) is used to treat follicular lymphoma in people who have had at least 1\xa0previous treatment. The clinical experts noted that the company's proposed treatment pathway originally separated treatments for previously treated follicular lymphoma depending on whether the disease was refractory to rituximab or not. The clinical experts considered that being refractory to rituximab or not was not a clinically appropriate way to separate treatment choices, and that time until relapse after initial chemo-immunotherapy may be more relevant for determining treatment choices in clinical practice. The committee agreed that the most appropriate comparators for this appraisal were rituximab with chemotherapy (CHOP or CVP).\n\n# Clinical effectiveness\n\n## Clinical evidence for lenalidomide with rituximab and rituximab with chemotherapy is compared using a matching-adjusted indirect comparison\n\nThe evidence for lenalidomide with rituximab came from AUGMENT, a phase\xa03 multicentre randomised controlled trial that used rituximab monotherapy as the comparator. In the absence of direct comparative evidence of lenalidomide plus rituximab compared with rituximab plus CHOP (R‑CHOP) or rituximab plus CVP (R‑CVP), the company provided a matching-adjusted indirect comparison to compare both treatments. Data for R‑CHOP and R‑CVP are from either Van Oers et al. (2006) or the Haematological Malignancy Research Network (HMRN) registry. The committee agreed that using the Van Oers data was not appropriate, because patients were not from the UK and had not had previous treatment with rituximab. The committee concluded that the HMRN registry data were most suitable for R‑CHOP and R‑CVP because the data were from the UK and include people who had had previous treatment with rituximab.\n\n## R-CHOP and R-CVP are assumed to be clinically equivalent\n\nThe company combined the R‑CHOP and R‑CVP populations for the matching-adjusted indirect comparison to increase the sample size of the comparator. The matching-adjusted indirect comparison showed an improvement in progression-free survival for lenalidomide with rituximab compared with R‑CHOP and R‑CVP (exact data are confidential and cannot be reported here). It also showed an improvement in overall survival for lenalidomide with rituximab compared with R‑CHOP and R‑CVP (exact data are confidential and cannot be reported here). Median progression-free survival and overall survival could not be estimated because the follow-up data were immature (not yet complete). When assessing the validity of combining R‑CHOP and R‑CVP, the committee understood that observed data for R‑CHOP in the HMRN registry for overall survival, progression-free survival and time to next anti-lymphoma treatment appeared similar to R‑CVP. The committee also understood that Cox proportional hazards model analyses of overall survival, progression-free survival and time to next anti-lymphoma treatment showed no statistically significant difference in outcomes between R‑CHOP and R‑CVP. The clinical experts noted that, in untreated follicular lymphoma, R‑CHOP and R‑CVP are not clinically equivalent. They considered that R‑CHOP has a longer time to treatment failure than R‑CVP (despite similar response rates) and progression-free survival is longer with R‑CHOP. They also noted that R‑CHOP is given to younger, fitter patients who can tolerate the additional chemotherapy component (doxorubicin) in CHOP, while R‑CVP is given to older, less fit patients. The clinical experts acknowledged that there was no evidence for R‑CHOP and R‑CVP in previously treated follicular lymphoma. They accepted that, without any other data sources, it may be appropriate to assume R‑CHOP is clinically equivalent to R‑CVP. The committee concluded that it was appropriate to assume R‑CHOP is clinically equivalent to R‑CVP in the economic model.\n\n## The matching-adjusted indirect comparison is as closely matched as possible\n\nThe ERG noted that the matching-adjusted indirect comparison did not account for all potentially relevant matching criteria. Potentially relevant matching criteria included the diameter of the largest node, haemoglobin levels, duration since last treatment, high lactate dehydrogenase levels, and Follicular Lymphoma International Prognostic Index (FLIPI) risk group status. The committee understood that the most important criteria identified by clinical experts were included in the matching-adjusted indirect comparison, and that other potentially relevant matching criteria were not collected by HMRN. The committee agreed that, given the data limitations, the matching-adjusted indirect comparison could not be improved further.\n\n# Economic model\n\n## The partitioned survival model structure is appropriate\n\nThe company used a partitioned survival model to determine the difference in overall survival and progression-free survival for lenalidomide with rituximab and R‑CHOP and R‑CVP. The ERG said that a state transition model would have helped to assess the validity of the extrapolations in overall survival and progression-free survival in the partitioned survival model. Following technical engagement, the company provided a state transition model for lenalidomide with rituximab compared with rituximab monotherapy (not R‑CHOP and R‑CVP). The committee did not consider this appropriate because rituximab monotherapy is not a relevant treatment for patients in the NHS. The committee also noted that a state transition model for lenalidomide with rituximab compared with R‑CHOP and R‑CVP would have its own uncertainty because of the limitations in the data. The AUGMENT data were immature, with a maximum follow up of 3.9\xa0years, and the R‑CHOP and R‑CVP data were from a small effective sample. The committee agreed that accurately modelling transitions between intermediate health states would be difficult, and providing a state transition model would not help validate the partitioned survival model. The committee concluded that a partitioned survival model was appropriate, and that a state transition model was not needed on this occasion.\n\n## Health-related quality-of-life values for lenalidomide with rituximab should be capped in the economic model\n\nPatients in AUGMENT had health-related quality-of-life values that were higher than the general population for the same age group, in all health states. The clinical experts said that someone with follicular lymphoma would not have higher quality of life than a member of the general population in any health state. At best, their quality of life would be equal to a member of the general population at the same age. The company proposed capping the least severe health-related quality-of-life values (values for progression-free survival) in the economic model to published age-matched UK general population values. The company calculated the quality of life for the post-progression (on or off treatment) health states by adding relative decrements in quality of life observed in AUGMENT to the progression-free survival value. The committee agreed that capping the progression-free survival health state in the economic model to general population values, and using relative decrements from AUGMENT for other health states, was appropriate.\n\n## A 5-year treatment effect duration for lenalidomide with rituximab is appropriate\n\nThe clinical experts said that overall-survival estimates for lenalidomide with rituximab will be better than overall-survival estimates for R‑CHOP and R‑CVP for several years once treatment begins. However, these estimates will gradually decline over time and eventually become the same as overall-survival estimates for R‑CHOP and R‑CVP. The clinical experts noted that it is uncertain how long the overall-survival benefit for lenalidomide with rituximab will last, but said that it will likely start to reduce 5\xa0to 10\xa0years after treatment starts. The company and the ERG's estimates of treatment effect duration was 5\xa0years in its base cases. The committee noted that this was the most conservative estimate, given the clinical expert opinion of 5\xa0to 10\xa0years. The committee concluded that a treatment effect duration of 5\xa0years was appropriate, with no evidence to the contrary.\n\n## The exponential distribution is appropriate for extrapolating overall survival\n\nNICE's Decision Support Unit technical support document\xa014 states that, if parametric models are fitted separately to individual treatment arms, it is advisable to use the same type of distribution for extrapolating both arms. For overall survival, the company selected the exponential distribution for both arms to best reflect the average 20‑year prognosis for follicular lymphoma when treated with R‑CHOP and R‑CVP. The clinical experts noted that the Weibull distribution may have also been appropriate for both arms, and the committee noted that it was a slightly better statistical fit than the exponential distribution. The committee also noted that the Weibull distribution produced a higher cost-effectiveness estimate in the probabilistic sensitivity analysis results than it did in the deterministic sensitivity analysis results. The committee was aware that this was caused by lenalidomide with rituximab having lower quality-adjusted life years (QALYs) than R‑CHOP and R‑CVP in the probabilistic sensitivity analysis results compared with the deterministic sensitivity analysis results. More specifically, lenalidomide with rituximab had lower quality of life or extension of life than R‑CHOP and R‑CVP in 267 of the 1,000\xa0iterations in the probabilistic sensitivity analysis. The clinical experts said that this was not clinically plausible. The committee agreed that the reduction in QALYs for lenalidomide with rituximab in the probabilistic sensitivity analysis results (when using a Weibull distribution for overall survival) was unusual. The committee noted that this might have been due to an error in the model or an unstable covariance matrix. Because of this, the committee did not consider the output of the probabilistic sensitivity analysis to be robust, and did not think it appropriate to use the Weibull distribution. The committee considered that the exponential distribution had good statistical fit for the observed Kaplan–Meier data and concluded that the exponential distribution was appropriate for extrapolating overall survival.\n\n## Different methods are needed to extrapolate progression-free survival for lenalidomide with rituximab and R-CHOP and R-CVP\n\nThe standard approach for extrapolating survival curves is to fit a parametric distribution to the available data, which is then used to estimate survival at any point in time. This method was used to fit the Weibull function for R‑CHOP and R‑CVP. However, the committee noted that all the standard parametric extrapolations for lenalidomide with rituximab estimated worse progression-free survival outcomes compared with R‑CHOP and R‑CVP. The clinical experts said that it was clinically implausible for the average progression-free survival of lenalidomide with rituximab to be worse than the average progression-free survival of R‑CHOP and R‑CVP. The committee understood that the relatively worse progression-free survival estimates for lenalidomide with rituximab may have been a result of the immature follow-up data from the AUGMENT trial (3.9‑year follow up), compared with the longer follow up for R‑CHOP and R‑CVP (11.6\xa0years). To avoid the implausible crossing of progression-free survival curves, the company used the observed AUGMENT data, and then, in the absence of further trial data, the company fitted a Weibull distribution to the end of these data. The ERG noted that this approach generated a larger progression-free survival benefit for lenalidomide with rituximab than applying the standard parametric distributions. Additionally, the ERG was concerned that, by extrapolating from the end of the observed AUGMENT data when there were fewer patients to inform the extrapolation, the mean progression-free survival benefit for lenalidomide with rituximab may have been further overestimated. The committee agreed that using the observed AUGMENT data with a Weibull distribution extrapolation was the most appropriate method for estimating progression-free survival for lenalidomide with rituximab. This was because this method takes account of the clinical plausibility of a progression-free survival benefit for lenalidomide with rituximab. The committee concluded that the AUGMENT data should have been extrapolated from the midpoint, rather than from the end, because this would have reduced the uncertainty in the extrapolation by using a relatively larger sample size.\n\n# Cost-effectiveness estimate\n\n## Lenalidomide with rituximab is a cost-effective use of NHS resources\n\nNICE's guide to the methods of technology appraisal says that, above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per QALY gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. Therefore, because of the uncertainty in the equivalence of R‑CHOP and R‑CVP (see section\xa03.4), matching-adjusted indirect comparison (see section\xa03.5) and treatment effect duration (see section\xa03.8), the committee agreed that an acceptable ICER would be around the lower end of the £20,000 to £30,000 per QALY gained range. The company's deterministic base case showed that the ICER for lenalidomide with rituximab compared with R‑CVP was £20,156 per QALY gained (including the patient access scheme for lenalidomide). The ERG presented 6\xa0analyses, each using a different parametric distribution to extrapolate overall survival. The ERG's analyses also included the confidential commercial arrangement for obinutuzumab and biosimilar rituximab. The ICERs were within or below the range that NICE usually considers an acceptable use of NHS resources (the exact ICERs are confidential and cannot be reported here). The committee agreed that an extrapolation with an exponential distribution was appropriate for overall survival in both lenalidomide with rituximab and R‑CHOP and R‑CVP. The committee also agreed that AUGMENT data with a Weibull distribution (extrapolated from AUGMENT data midpoint) was the most appropriate for estimating progression-free survival for lenalidomide with rituximab, and that a standard parametric Weibull distribution should have been used to extrapolate R‑CHOP and R‑CVP (see sections\xa03.9 and\xa03.10). These assumptions generated a most plausible ICER that was below the range that NICE usually considers an acceptable use of NHS resources (the exact ICER is confidential and cannot be reported here). The committee therefore recommended lenalidomide with rituximab as an option for previously treated follicular lymphoma (grades\xa01\xa0to\xa03A)."}
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https://www.nice.org.uk/guidance/ta627
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Evidence-based recommendations on lenalidomide (Revlimid) with rituximab for previously treated follicular lymphoma (grade 1 to 3A) in adults.
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91e42c63b2f96b568437a300d825b69698e1654e
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nice
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Venous thromboembolic diseases: diagnosis, management and thrombophilia testing
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Venous thromboembolic diseases: diagnosis, management and thrombophilia testing
This guideline covers diagnosing and managing venous thromboembolic diseases in adults. It aims to support rapid diagnosis and effective treatment for people who develop deep vein thrombosis (DVT) or pulmonary embolism (PE). It also covers testing for conditions that can make a DVT or PE more likely, such as thrombophilia (a blood clotting disorder) and cancer.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Diagnosis and initial management
NICE has produced a visual summary of the recommendations on diagnosis and initial management of suspected deep vein thrombosis (DVT) and pulmonary embolism (PE).
## Signs or symptoms of DVT
For people who present with signs or symptoms of DVT, such as a swollen or painful leg, assess their general medical history and do a physical examination to exclude other causes.
If DVT is suspected, use the 2‑level DVT Wells score (table 1) to estimate the clinical probability of DVT.
Clinical feature
Points
Active cancer (treatment ongoing, within 6 months, or palliative)
Paralysis, paresis or recent plaster immobilisation of the lower extremities
Recently bedridden for 3 days or more, or major surgery within 12 weeks requiring general or regional anaesthesia
Localised tenderness along the distribution of the deep venous system
Entire leg swollen
Calf swelling at least 3 cm larger than asymptomatic side
Pitting oedema confined to the symptomatic leg
Collateral superficial veins (non-varicose)
Previously documented DVT
An alternative diagnosis is at least as likely as DVT
Clinical probability simplified score
Points
DVT likely
points or more
DVT unlikely
point or less
Adapted with permission from Wells et al. (2003) Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis.
Offer people with a likely DVT Wells score (2 points or more):
a proximal leg vein ultrasound scan, with the result available within 4 hours if possible (if the scan result cannot be obtained within 4 hours follow recommendation 1.1.4)
a D-dimer test if the scan result is negative.
If a proximal leg vein ultrasound scan result cannot be obtained within 4 hours, offer people with a DVT Wells score of 2 points or more:
a D-dimer test, then
interim therapeutic anticoagulation (see the section on interim therapeutic anticoagulation for suspected DVT or PE) and
a proximal leg vein ultrasound scan with the result available within 24 hours.
For people with a positive proximal leg vein ultrasound scan:
-ffer or continue anticoagulation treatment (see the section on anticoagulation treatment for confirmed DVT or PE) or
if anticoagulation treatment is contraindicated, offer a mechanical intervention (see the section on mechanical interventions). For people with symptomatic iliofemoral DVT see the section on thrombolytic therapy.
For people with a negative proximal leg vein ultrasound scan and a positive D-dimer test result:
stop interim therapeutic anticoagulation (but do not stop long-term anticoagulation if being used for secondary prevention)
-ffer a repeat proximal leg vein ultrasound scan 6 to 8 days later and
if the repeat scan result is positive, follow the actions in recommendation 1.1.5
if the repeat scan result is negative, follow the actions in recommendation 1.1.7.
For people with a negative proximal leg vein ultrasound scan and a negative D-dimer test result:
stop interim therapeutic anticoagulation (but do not stop long-term anticoagulation if being used for secondary prevention)
think about alternative diagnoses
tell the person that it is not likely they have DVT. Discuss with them the signs and symptoms of DVT and when and where to seek further medical help.
Offer people with an unlikely DVT Wells score (1 point or less):
a D‑dimer test with the result available within 4 hours (see the section on D-dimer testing) or
if the D-dimer test result cannot be obtained within 4 hours, offer interim therapeutic anticoagulation while awaiting the result (see the section on interim therapeutic anticoagulation for suspected DVT or PE).
If the D-dimer test result is negative, follow the actions in recommendation 1.1.7.
If the D-dimer test result is positive, offer:
a proximal leg vein ultrasound scan, with the result available within 4 hours if possible or
interim therapeutic anticoagulation (see the section on interim therapeutic anticoagulation for suspected DVT or PE) and a proximal leg vein ultrasound scan with the result available within 24 hours.
If the proximal leg vein ultrasound scan is:
positive, follow the actions in recommendation 1.1.5
negative, follow the actions in recommendation 1.1.7, that is:
stop interim therapeutic anticoagulation (but do not stop long-term anticoagulation if being used for secondary prevention)
think about alternative diagnoses
tell the person that it is not likely they have DVT. Discuss with them the signs and symptoms of DVT and when and where to seek further medical help.
When offering D-dimer testing for suspected DVT or PE, consider a point‑of‑care test if laboratory facilities are not immediately available.
If using a point-of-care D-dimer test, choose a fully quantitative test.
When using a point-of-care or laboratory D-dimer test, consider an age‑adjusted D-dimer test threshold for people aged over 50.
For a short explanation of why the committee made these 2020 recommendations and how they might affect practice, see the rationale and impact section on D-dimer testing .
Full details of the evidence and the committee's discussion are in evidence review A: D-dimer testing in the diagnosis of deep vein thrombosis and pulmonary embolism.
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## Signs or symptoms of PE
For people who present with signs or symptoms of PE, such as chest pain, shortness of breath or coughing up blood, assess their general medical history, do a physical examination and offer a chest X‑ray to exclude other causes.
If clinical suspicion of PE is low (the clinician estimates the likelihood of PE to be less than 15% based on the overall clinical impression, and other diagnoses are feasible), consider using the pulmonary embolism rule-out criteria (PERC) to help determine whether any further investigations for PE are needed.
For a short explanation of why the committee made the 2020 recommendation and how it might affect practice, see the rationale and impact section on the PERC rule .
Full details of the evidence and the committee's discussion are in evidence review B: the use of the pulmonary embolism rule-out criteria for diagnosis of pulmonary embolism
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If PE is suspected, use the 2‑level PE Wells score (table 2) to estimate the clinical probability of PE.
Clinical feature
Points
Clinical signs and symptoms of DVT (minimum of leg swelling and pain with palpation of the deep veins)
An alternative diagnosis is less likely than PE
Heart rate more than 100 beats per minute
Immobilisation for more than 3 days or surgery in the previous 4 weeks
Previous DVT/PE
Haemoptysis
Malignancy (on treatment, treated in the last 6 months, or palliative)
Clinical probability simplified score
Points
PE likely
More than 4 points
PE unlikely
points or less
Adapted with permission from Wells et al. (2000) Derivation of a simple clinical model to categorize patients' probability of pulmonary embolism: increasing the model's utility with the SimpliRED D-dimer.
For people with a likely PE Wells score (more than 4 points):
-ffer a computed tomography pulmonary angiogram (CTPA) immediately if possible or
for people with an allergy to contrast media, severe renal impairment (estimated creatinine clearance less than 30 ml/min) or a high risk from irradiation, assess the suitability of a ventilation/perfusion single photon emission computed tomography (V/Q SPECT) scan or, if a V/Q SPECT scan is not available, a V/Q planar scan, as an alternative to CTPA.If a CTPA, V/Q SPECT or V/Q planar scan cannot be done immediately, offer interim therapeutic anticoagulation (see the section on interim therapeutic anticoagulation for suspected DVT or PE).
If PE is identified by CTPA, V/Q SPECT or V/Q planar scan:
-ffer or continue anticoagulation treatment (see the section on anticoagulation treatment for confirmed DVT or PE) or
if anticoagulation treatment is contraindicated, consider a mechanical intervention (see the section on mechanical interventions).For people with PE and haemodynamic instability see the section on thrombolytic therapy.
If PE is not identified by CTPA, V/Q SPECT or V/Q planar scan:
consider a proximal leg vein ultrasound scan if DVT is suspected
if DVT is not suspected:
stop interim therapeutic anticoagulation (but do not stop long-term anticoagulation if being used for secondary prevention)
think about alternative diagnoses
tell the person that it is not likely they have PE. Discuss with them the signs and symptoms of PE and when and where to seek further medical help.
Offer people with an unlikely PE Wells score (4 points or less):
a D-dimer test with the result available within 4 hours if possible (see the section on D-dimer testing) or
if the D-dimer test result cannot be obtained within 4 hours (in any setting), offer interim therapeutic anticoagulation while awaiting the result (see the section on interim therapeutic anticoagulation for suspected DVT or PE).If the D-dimer test result is:
positive, follow the actions in recommendations 1.1.18 and 1.1.19
negative:
stop interim therapeutic anticoagulation (but do not stop long-term anticoagulation if being used for secondary prevention)
think about alternative diagnoses
tell the person that it is not likely they have PE. Discuss with them the signs and symptoms of PE and when and where to seek further medical help.
## Signs or symptoms of both DVT and PE
For people who present with signs or symptoms of both DVT and PE, carry out initial diagnostic investigations for either DVT or PE, basing the choice of diagnostic investigations on clinical judgement.
# Outpatient treatment for low-risk PE
Consider outpatient treatment for suspected or confirmed low-risk PE, using a validated risk stratification tool to determine the suitability of outpatient treatment.
When offering outpatient treatment to people with suspected PE, follow recommendations 1.1.15 to 1.1.21 on diagnosis and initial management.
When offering outpatient treatment to people with confirmed PE, follow the recommendations in the section on anticoagulation treatment for confirmed DVT or PE.
Agree a plan for monitoring and follow-up with people having outpatient treatment for suspected or confirmed low-risk PE. Give them:
written information on symptoms and signs to look out for, including the potential complications of thrombosis and of treatment
direct contact details of a healthcare professional or team with expertise in thrombosis who can discuss any new symptoms or signs, or other concerns
information about out-of-hours services they can contact when their healthcare team is not available.
For a short explanation of why the committee made the 2020 recommendations and how they might affect practice, see the rationale and impact section on outpatient treatment for low-risk PE .
Full details of the evidence and the committee's discussion are in evidence review E: outpatient treatment of low-risk pulmonary embolism
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# Anticoagulation treatment for suspected or confirmed DVT or PE
NICE has produced a visual summary of the recommendations on anticoagulation treatment for DVT or PE.
When offering anticoagulation treatment, follow the recommendations on shared decision making and supporting adherence in the NICE guidelines on medicines optimisation, medicines adherence, patient experience in adult NHS services and shared decision making.
## Interim therapeutic anticoagulation for suspected DVT or PE
Follow the recommendations on when to offer interim therapeutic anticoagulation for suspected proximal DVT or PE in the section on diagnosis and initial management.
If possible, choose an interim anticoagulant that can be continued if DVT or PE is confirmed (see the section on anticoagulation treatment for confirmed DVT or PE). In March 2020, direct-acting anticoagulants and some low molecular weight heparins (LMWHs) were off label for the treatment of suspected DVT or PE. See NICE's information on prescribing medicines.
When using interim therapeutic anticoagulation for suspected proximal DVT or PE:
carry out baseline blood tests including full blood count, renal and hepatic function, prothrombin time (PT) and activated partial thromboplastin time (APTT)
do not wait for the results of baseline blood tests before starting anticoagulation treatment
review, and if necessary act on, the results of baseline blood tests within 24 hours of starting interim therapeutic anticoagulation.
## Anticoagulation treatment for confirmed DVT or PE
Offer anticoagulation treatment for at least 3 months to people with confirmed proximal DVT or PE. For recommendations on treatment after 3 months see the section on long-term anticoagulation for secondary prevention.
If not already done, carry out baseline blood tests, as outlined in recommendation 1.3.4, when starting anticoagulation treatment.
When offering anticoagulation treatment, take into account comorbidities, contraindications and the person's preferences.Follow the recommendations on anticoagulation treatment in the sections on:
DVT or PE in people at extremes of body weight
PE with haemodynamic instability
DVT or PE with renal impairment or established renal failure
DVT or PE with active cancer
DVT or PE with triple positive antiphospholipid syndrome.
Offer either apixaban or rivaroxaban to people with confirmed proximal DVT or PE (but see recommendations 1.3.11 to 1.3.20 for people with any of the clinical features listed in recommendation 1.3.7). If neither apixaban nor rivaroxaban is suitable offer:
LMWH for at least 5 days followed by dabigatran or edoxaban or
LMWH concurrently with a vitamin K antagonist (VKA) for at least 5 days, or until the INR is at least 2.0 in 2 consecutive readings, followed by a VKA on its own.
Do not routinely offer unfractionated heparin (UFH) with a VKA to treat confirmed proximal DVT or PE unless the person has renal impairment or established renal failure (see recommendations 1.3.13 and 1.3.14) or an increased risk of bleeding.
Do not routinely offer self‑management or self‑monitoring of INR to people who have had DVT or PE and are having treatment with a VKA.
Consider anticoagulation treatment with regular monitoring of therapeutic levels for people with confirmed proximal DVT or PE who weigh less than 50 kg or more than 120 kg, to ensure effective anticoagulation. Note the cautions and requirements for dose adjustment and monitoring in the medicine's summary of product characteristics (SPC), and follow locally agreed protocols or advice from a specialist or multidisciplinary team.
For people with confirmed PE and haemodynamic instability, offer continuous UFH infusion and consider thrombolytic therapy (see the section on thrombolytic therapy).
In March 2020, some LMWHs were off label for the treatment of DVT or PE in people with severe renal impairment (estimated creatinine clearance 15 ml/min to 30 ml/min) or established renal failure (estimated creatinine clearance less than 15 ml/min). See NICE's information on prescribing medicines.
Offer people with confirmed proximal DVT or PE and renal impairment (estimated creatinine clearance between 15 ml/min and 50 ml/min) one of:
apixaban
rivaroxaban
LMWH for at least 5 days followed by:
edoxaban or
dabigatran if estimated creatinine clearance is 30 ml/min or above
LMWH or UFH, given concurrently with a VKA for at least 5 days or until the INR is at least 2.0 in 2 consecutive readings, followed by a VKA on its own.Note the cautions and requirements for dose adjustment and monitoring in the medicine's SPC, and follow locally agreed protocols or advice from a specialist or multidisciplinary team.
Offer people with confirmed proximal DVT or PE and established renal failure (estimated creatinine clearance less than 15 ml/min) one of:
LMWH
UFH
LMWH or UFH concurrently with a VKA for at least 5 days or until the INR is at least 2.0 in 2 consecutive readings, followed by a VKA on its own.Note the cautions and requirements for dose adjustment and monitoring in the medicine's SPC, and follow locally agreed protocols or advice from a specialist or multidisciplinary team.
In March 2020, most anticoagulants were off label for the treatment of DVT or PE in people with active cancer. See NICE's information on prescribing medicines.
Offer people with active cancer and confirmed proximal DVT or PE anticoagulation treatment for 3 to 6 months. Review at 3 to 6 months according to clinical need. For recommendations on treatment after 3 to 6 months see the section on long-term anticoagulation for secondary prevention.
When choosing anticoagulation treatment for people with active cancer and confirmed proximal DVT or PE, take into account the tumour site, interactions with other drugs including those used to treat cancer, and the person's bleeding risk.
Consider a direct-acting oral anticoagulant (DOAC) for people with active cancer and confirmed proximal DVT or PE.
If a DOAC is unsuitable consider LMWH alone or LMWH concurrently with a VKA for at least 5 days, or until the INR is at least 2.0 in 2 consecutive readings, followed by a VKA on its own.
For people with confirmed DVT or PE and cancer that is in remission, follow the recommendations in the section on anticoagulation treatment for confirmed DVT or PE.
Offer people with confirmed proximal DVT or PE and an established diagnosis of triple positive antiphospholipid syndrome LMWH concurrently with a VKA for at least 5 days, or until the INR is at least 2.0 in 2 consecutive readings, followed by a VKA on its own.
## Treatment failure
If anticoagulation treatment fails:
check adherence to anticoagulation treatment
address other sources of hypercoagulability
increase the dose of anticoagulant or change to an anticoagulant with a different mode of action.
## NICE technology appraisal guidance on anticoagulation treatment for confirmed DVT or PE
For NICE technology appraisal guidance see:
apixaban for the treatment and secondary prevention of deep vein thrombosis and/or pulmonary embolism
dabigatran etexilate for the treatment and secondary prevention of deep vein thrombosis and/or pulmonary embolism
edoxaban for treating and for preventing deep vein thrombosis and pulmonary embolism
rivaroxaban for treating pulmonary embolism and preventing recurrent venous thromboembolism
rivaroxaban for the treatment of deep vein thrombosis and prevention of recurrent deep vein thrombosis and pulmonary embolism.
For a short explanation of why the committee made the 2020 recommendations and how they might affect practice, see the rationale and impact section on anticoagulation treatment for confirmed DVT or PE .
Full details of the evidence and the committee's discussion are in evidence review D: pharmacological treatment in people with suspected or confirmed deep vein thrombosis and/or pulmonary embolism.
Evidence review G: economic modelling report for pharmacological treatment also underpins recommendations 1.3.8, 1.3.9, 1.3.17 and 1.3.18.
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# Long-term anticoagulation for secondary prevention
Assess and discuss the benefits and risks of continuing, stopping or changing the anticoagulant with people who have had anticoagulation treatment for 3 months (3 to 6 months for people with active cancer) after a proximal DVT or PE. Follow the recommendations on shared decision making and supporting adherence in the NICE guidelines on medicines optimisation, medicines adherence and patient experience in adult NHS services.
Consider stopping anticoagulation treatment 3 months (3 to 6 months for people with active cancer) after a provoked DVT or PE if the provoking factor is no longer present and the clinical course has been uncomplicated. If anticoagulation treatment is stopped, give advice about the risk of recurrence and provide:
written information on symptoms and signs to look out for
direct contact details of a healthcare professional or team with expertise in thrombosis who can discuss any new symptoms or signs, or other concerns
information about out-of-hours services they can contact when their healthcare team is not available.
Consider continuing anticoagulation beyond 3 months (6 months for people with active cancer) after an unprovoked DVT or PE. Base the decision on the balance between the person's risk of venous thromboembolism (VTE) recurrence and their risk of bleeding. Discuss the risks and benefits of long-term anticoagulation with the person, and take their preferences into account.
Explain to people with unprovoked DVT or PE and a low bleeding risk that the benefits of continuing anticoagulation treatment are likely to outweigh the risks.
Do not rely solely on predictive risk tools to assess the need for long-term anticoagulation treatment.
Consider using the HAS-BLED score for major bleeding risk to assess the risk of major bleeding in people having anticoagulation treatment for unprovoked proximal DVT or PE. Discuss stopping anticoagulation if the HAS-BLED score is 4 or more and cannot be modified.
Take into account the person's preferences and their clinical situation when selecting an anticoagulant for long-term treatment.
For people who do not have renal impairment, active cancer, established triple positive antiphospholipid syndrome or extreme body weight (less than 50 kg or more than 120 kg):
-ffer continued treatment with the current anticoagulant if it is well tolerated or
if the current treatment is not well tolerated, or the clinical situation or person's preferences have changed, consider switching to apixaban if the current treatment is a direct-acting anticoagulant other than apixaban.
For people with renal impairment, active cancer, established triple positive antiphospholipid syndrome or extreme body weight (less than 50 kg or more than 120 kg), consider carrying on with the current treatment if it is well tolerated.
If anticoagulation treatment fails follow the recommendation on treatment failure.
For people who decline continued anticoagulation treatment, consider aspirin 75 mg or 150 mg daily. In March 2020, the use of aspirin for secondary prevention of DVT or PE was off label. See NICE's information on prescribing medicines.
Review general health, risk of VTE recurrence, bleeding risk and treatment preferences at least once a year for people taking long-term anticoagulation treatment or aspirin.
For a short explanation of why the committee made the 2020 recommendations on reviewing anticoagulation treatment and how they might affect practice, see the rationale and impact section on long-term anticoagulation for secondary prevention .
Full details of the evidence and the committee's discussion are in:
evidence review F: what factors determine the optimum duration of pharmacological treatment for DVT or PE in people with a VTE?
evidence review D: pharmacological treatment in people with suspected or confirmed deep vein thrombosis and/or pulmonary embolism (for recommendations 1.4.1 and 1.4.7 to 1.4.11).
Evidence review G: economic modelling report for pharmacological treatment also underpins recommendation 1.4.8.
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# Information and support for people having anticoagulation treatment
Give people having anticoagulation treatment verbal and written information about:
how to use anticoagulants
how long to take anticoagulants
possible side effects of anticoagulants and what to do if these occur
how other medications, foods and alcohol can affect oral anticoagulation treatment
any monitoring needed for their anticoagulant treatment
how anticoagulants may affect their dental treatment
taking anticoagulants if they are planning pregnancy or become pregnant
how anticoagulants may affect activities such as sports and travel
when and how to seek medical help.
Give people who are having anticoagulation treatment information and an 'anticoagulant alert card' that is specific to their treatment. Advise them to carry the 'anticoagulant alert card' at all times.
Be aware that heparins are of animal origin and that apixaban and rivaroxaban contain lactose from cow's milk. For people who have concerns about using animal products because of a religious or ethical belief, or a food intolerance, see the section on giving information and planning for discharge in the NICE guideline on venous thromboembolism in over 16s.
# Thrombolytic therapy
## DVT
Consider catheter-directed thrombolytic therapy for people with symptomatic iliofemoral DVT who have:
symptoms lasting less than 14 days and
good functional status and
a life expectancy of 1 year or more and
a low risk of bleeding.
See NICE interventional procedures guidance on ultrasound-enhanced, catheter-directed thrombolysis for deep vein thrombosis.
## PE
Consider pharmacological systemic thrombolytic therapy for people with PE and haemodynamic instability(see also the section on anticoagulation treatment for PE with haemodynamic instability).
Do not offer pharmacological systemic thrombolytic therapy to people with PE and haemodynamic stability with or without right ventricular dysfunction (see also the section on anticoagulation treatment for DVT or PE). If the person develops haemodynamic instability, refer to recommendation 1.6.2.
See NICE interventional procedures guidance on ultrasound-enhanced, catheter-directed thrombolysis for pulmonary embolism.
# Mechanical interventions
## Inferior vena caval filters
Do not offer an inferior vena caval (IVC) filter to people with proximal DVT or PE unless:
it is part of a prospective clinical study or
anticoagulation is contraindicated or a PE has occurred during anticoagulation treatment (see recommendations 1.7.2 and 1.7.3).
Consider an IVC filter for people with proximal DVT or PE when anticoagulation treatment is contraindicated. Remove the IVC filter when anticoagulation treatment is no longer contraindicated and has been established.
Consider an IVC filter for people with proximal DVT or PE who have a PE while taking anticoagulation treatment only after taking the steps outlined in the recommendation on treatment failure.
Before fitting an IVC filter, ensure that there is a strategy in place for it to be removed at the earliest possible opportunity. Document the strategy and review it if the clinical situation changes.
For a short explanation of why the committee made the 2020 recommendations and how they might affect practice, see the rationale and impact section on IVC filters .
Full details of the evidence and the committee's discussion are in evidence review H: inferior vena caval filters for people with venous thromboembolism.
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## Elastic graduated compression stockings
Do not offer elastic graduated compression stockings to prevent post-thrombotic syndrome or VTE recurrence after a DVT. This recommendation does not cover the use of elastic stockings for the management of leg symptoms after DVT.
If offering elastic graduated compression stockings to manage leg symptoms after DVT, explain how to apply and use them, how long they should be worn and when they should be replaced.
## Percutaneous mechanical thrombectomy
See NICE interventional procedures guidance on percutaneous mechanical thrombectomy for acute deep vein thrombosis of the leg.
# Investigations for cancer
For people with unprovoked DVT or PE who are not known to have cancer, review the medical history and baseline blood test results including full blood count, renal and hepatic function, PT and APTT, and offer a physical examination.
Do not offer further investigations for cancer to people with unprovoked DVT or PE unless they have relevant clinical symptoms or signs (for further information see the NICE guideline on suspected cancer).
For a short explanation of why the committee made the 2020 recommendations and how they might affect practice, see the rationale and impact section on investigations for cancer .
Full details of the evidence and the committee's discussion are in evidence review C: investigations for cancer in people with unprovoked venous thromboembolism
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# Thrombophilia testing
Do not offer testing for hereditary thrombophilia to people who are continuing anticoagulation treatment.
Do not offer thrombophilia testing to people who have had provoked DVT or PE.
Consider testing for antiphospholipid antibodies in people who have had unprovoked DVT or PE if it is planned to stop anticoagulation treatment, but be aware that these tests can be affected by anticoagulants and specialist advice may be needed.
Consider testing for hereditary thrombophilia in people who have had unprovoked DVT or PE and who have a first‑degree relative who has had DVT or PE if it is planned to stop anticoagulation treatment, but be aware that these tests can be affected by anticoagulants and specialist advice may be needed.
Do not routinely offer thrombophilia testing to first‑degree relatives of people with a history of DVT or PE and thrombophilia.
# Terms used in this guideline
## Active cancer
Receiving active antimitotic treatment; or diagnosed within the past 6 months; or recurrent or metastatic; or inoperable. Excludes squamous skin cancer and basal cell carcinoma.
## Estimated creatinine clearance
Creatinine clearance estimated using the Cockcroft and Gault formula; see the BNF's information on prescribing in renal impairment.
## Provoked DVT or PE
DVT or PE in a person with a recent (within 3 months) and transient major clinical risk factor for VTE, such as surgery, trauma, significant immobility (bedbound, unable to walk unaided or likely to spend a substantial proportion of the day in bed or in a chair), pregnancy or puerperium – or in a person who is having hormonal therapy (combined oral contraceptive pill or hormone replacement therapy).
## Proximal DVT
DVT at or above the level of the popliteal trifurcation area.
## Unprovoked DVT or PE
DVT or PE in a person with no recent major clinical risk factor for VTE (see provoked DVT or PE) who is not having hormonal therapy (combined oral contraceptive pill or hormone replacement therapy).
## Wells score
Clinical prediction rule for estimating the probability of DVT or PE. There are a number of versions of Wells scores available. This guideline recommends the 2‑level DVT Wells score and the 2-level PE Wells score.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Key recommendations for research
## Clinical and cost effectiveness of inferior vena caval filters in people with venous thromboembolism
What is the short- and long-term clinical and cost effectiveness of inferior vena caval filters in people with venous thromboembolism (VTE)?
For a short explanation of why the committee made the recommendation for research, see the rationale on inferior vena caval filters .
Full details of the evidence and the committee's discussion are in evidence review H: inferior vena caval filters for people with VTE.
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## Clinical and cost effectiveness of direct-acting oral anticoagulants based on individual patient data
What is the clinical and cost effectiveness of direct-acting oral anticoagulants (DOACs) compared with each other, with low molecular weight heparin (LMWH) plus a vitamin K antagonist (VKA), with LMWH alone, with placebo and with aspirin for the initial and long‑term treatment of deep vein thrombosis (DVT) or pulmonary embolism (PE) based on individual patient data from existing trials?
For a short explanation of why the committee made the recommendation for research, see the rationale on anticoagulation treatment for confirmed DVT or PE .
Full details of the evidence and the committee's discussion are in evidence review D: pharmacological treatment in people with suspected or confirmed DVT and/or PE.
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## Prediction tools compared with clinical judgement
What is the prognostic accuracy of a tool to predict both VTE recurrence and major bleeding compared with clinical judgement in people with unprovoked proximal DVT or PE?
For a short explanation of why the committee made the recommendation for research, see the rationale on long-term anticoagulation for secondary prevention .
Full details of the evidence and the committee's discussion are in evidence review F: what factors determine the optimum duration of pharmacological treatment for DVT or PE in people with a VTE?
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## Lower-dose thrombolysis for people with acute PE and right ventricular dysfunction
Does lower-dose thrombolysis reduce the risk of major bleeding and improve outcomes for people with acute PE and right ventricular dysfunction?
## Diagnosis of DVT
What is the clinical and cost effectiveness of a whole‑leg ultrasound scan compared with a proximal leg vein ultrasound scan in the diagnosis of acute DVT?
# Other recommendations for research
## Treatment strategy for people who use intravenous drugs
What is the optimal pharmacological treatment strategy for DVT or PE in people who use intravenous drugs?
For a short explanation of why the committee made the recommendation for research, see the rationale on anticoagulation treatment for DVT or PE in people who use intravenous drugs .
Full details of the evidence and the committee's discussion are in evidence review D: pharmacological treatment in people with suspected or confirmed DVT and/or PE.
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## Predicting VTE recurrence and major bleeding
What is the prognostic accuracy of a tool to predict both VTE recurrence and major bleeding after 3 months of initial anticoagulation treatment and in the long term?
For a short explanation of why the committee made the recommendation for research, see the rationale on long-term anticoagulation for secondary prevention .
Full details of the evidence and the committee's discussion are in evidence review F: what factors determine the optimum duration of pharmacological treatment for DVT or PE in people with a VTE?
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## Thrombolytic therapy for DVT
What is the clinical and cost effectiveness of clot removal using catheter‑directed thrombolytic therapy or pharmacomechanical thrombolysis compared with standard anticoagulation therapy for the treatment of acute proximal DVT? # Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.
# D-dimer testing
Recommendations 1.1.12 to 1.1.14
## Why the committee made the recommendations
The committee agreed that, if both laboratory-based and point-of-care D-dimer testing are immediately available, laboratory testing is preferable because it provides more rigorous quality assurance and greater certainty of diagnostic accuracy. However, if laboratory-based testing is not immediately available, the committee were in agreement that offering immediate point-of-care testing is more beneficial for patients than delaying diagnosis by waiting for laboratory testing. Although point-of-care tests are more expensive than laboratory tests, a cost-effectiveness analysis showed that the additional cost may be offset by faster results that reduce the need for additional GP time and unnecessary interim anticoagulation.
Evidence on fully quantitative point-of-care D-dimer tests for deep vein thrombosis (DVT) suggested that they are as accurate as laboratory tests and more accurate than qualitative or semi‑quantitative tests. There is little evidence on these tests for pulmonary embolism (PE) but the committee agreed that the evidence on DVT is applicable to PE because it is very unlikely that there is a biological reason that the accuracy of the tests would differ between these groups. The committee were aware that quantitative tests are more commonly used than qualitative or semi-quantitative tests. However, because the latter types of tests are still used in some services, they specified that point-of-care tests should be fully quantitative.
In people aged over 50, there was limited prospective evidence available for DVT and only retrospective evidence available for PE. This evidence suggested that adjusting D-dimer test thresholds for age improves the usefulness of these tests for ruling out venous thromboembolism (VTE) in this age group. The evidence also suggested that age adjustment does not reduce the accuracy of the tests in identifying VTE. The committee noted that adjusting test thresholds for age could be beneficial in reducing anxiety and unnecessary imaging for people with suspected DVT or PE. Although the evidence was not plentiful, the committee agreed that, taken together with the potential benefits, it was sufficient to support a recommendation suggesting age adjustment in D-dimer test thresholds for people aged over 50.
## How the recommendations might affect practice
Services that do not currently provide quantitative point-of-care D-dimer tests may need to acquire new equipment and provide training on how to conduct and interpret the tests. It is uncertain what impact this would have on practice, because it is unclear what proportion of primary care centres already use point-of-care testing. Facilities for point-of-care testing are only needed if rapid laboratory testing is not available.
The number of D-dimer tests that are adjusted for age is likely to increase, leading to a reduction in the number of additional investigations for VTE.
Return to recommendations
# Pulmonary embolism rule-out criteria (the PERC rule)
Recommendation 1.1.16
## Why the committee made the recommendation
In people with signs or symptoms of PE, but in whom clinical suspicion of PE is low (the clinician estimates the likelihood of PE to be less than 15% based on the overall clinical impression and other diagnoses are feasible), there was some evidence showing that the PERC rule can accurately eliminate PE as a possible diagnosis. The committee agreed that using the PERC rule can reduce anxiety and avoid unnecessary D-dimer testing, imaging and interim anticoagulation treatment for people with a low probability of PE and none of the PERC criteria for PE. However, the evidence was limited so the committee agreed to recommend that the PERC rule be considered as part of initial assessment. The committee noted that the studies evaluating PERC all took place in emergency departments but they could see no reason why its use should be limited to this setting or why the diagnostic accuracy of PERC would differ in other settings.
## How the recommendation might affect practice
The PERC rule is not widely used in current practice. This recommendation is expected to increase its use within a subgroup of people in whom clinical suspicion of PE is low and for whom discharge is being considered. Increased use of PERC can be expected to reduce the need for D-dimer testing and imaging for people with none of the PERC criteria for PE, leading to some reductions in waiting times in primary care and emergency departments. It will also help to avoid unnecessary anticoagulation treatment. However, the overall impact of this recommendation is not expected to be substantial because of the limited population it affects.
Return to recommendation
# Outpatient treatment for low-risk pulmonary embolism
Recommendations 1.2.1 to 1.2.4
## Why the committee made the recommendations
The committee noted that outpatient treatment for people with PE who have a low risk of poor outcomes is increasingly being used in settings such as ambulatory care units. There was limited evidence comparing outpatient with inpatient treatment for PE so the committee were unable to reach firm conclusions about the overall benefits and risks of outpatient treatment. However, no evidence showed that outpatient treatment is less effective or less safe than inpatient treatment for people with low-risk PE. The committee agreed that outpatient care offers substantial benefits for people with PE and for hospital services and should be considered for those with suspected or confirmed low-risk PE.
The committee emphasised the importance of clear arrangements for monitoring and follow-up to ensure that outpatients receive the same quality of care as inpatients. They noted that specialist services with expertise in thrombosis are not available at all times and agreed that it is important for people with VTE to know who they can contact if they need advice outside normal service hours.
## How the recommendations might affect practice
Outpatient treatment for PE is common practice in many services with ambulatory care units. These recommendations might lead to the establishment of ambulatory care units in services that do not currently have them, and this will reduce hospital stays in those services.
Return to recommendations
# Anticoagulation treatment for suspected or confirmed deep vein thrombosis or pulmonary embolism
Recommendations 1.3.1 to 1.3.21
## Why the committee made the recommendations
There was no evidence specifically on interim anticoagulation treatment for suspected DVT or PE. However, the committee agreed that it is vital to start treatment if DVT or PE is suspected and diagnostic test results are delayed by more than 4 hours. They reasoned that anticoagulation treatments that are effective for confirmed DVT or PE are likely to be equally effective when used as interim treatment while awaiting a confirmed diagnosis. They also noted that continuing the same anticoagulant treatment after diagnosis offers benefits in terms of safety and convenience. However, they acknowledged that local protocols or availability of anticoagulants for suspected VTE may necessitate the use of different anticoagulants before and after diagnosis.
The committee agreed that when choosing an interim anticoagulant, clinicians should always take individual clinical circumstances into account, including whether the person is at an extreme of body weight, has PE with haemodynamic instability, renal impairment, active cancer or established triple positive antiphospholipid syndrome.
Evidence suggested that treatment with a direct-acting oral anticoagulant (DOAC) is less likely to result in bleeding complications than treatment with low molecular weight heparin (LMWH) and a vitamin K antagonist (VKA). Additionally, people taking a DOAC benefit by being able to have an oral treatment and avoid the frequent monitoring that is necessary with other types of anticoagulation treatment.
Within the DOACs, there was evidence showing that apixaban is the most cost‑effective option. because it results in the fewest bleeds. Rivaroxaban is the second most cost-effective option and only slightly less cost effective than apixaban. However, the committee had reservations about this evidence because the inclusion criteria setting out which patients took part in the studies were not the same in each study. In particular, the apixaban study did not include patients with provoked VTE unless it was caused by a persistent risk factor, so a larger proportion of patients in the apixaban study had unprovoked VTE compared with the rivaroxaban studies. This made it difficult to compare the results of the studies. Because of this, the committee were not confident that apixaban should be the only option for a DOAC and recommended a choice of apixaban or rivaroxaban. Sensitivity analyses were carried out varying the drug prices but these analyses did not change any of the conclusions from the economic model.
The committee recognised that apixaban or rivaroxaban might not be suitable for everyone, so they included options for treatment with LMWH followed by dabigatran or edoxaban, or LMWH with a VKA. The committee also made a recommendation for research on DOACs compared with each other and with other anticoagulants.
The evidence did not support a recommendation for fondaparinux. It showed that fondaparinux is more likely to result in bleeding and is less cost effective than other treatments. However, the committee decided not to make a recommendation precluding its use because they were aware that it may be needed in rare circumstances.
Unfractionated heparin (UFH) was associated with increased bleeding complications, greater recurrence rates of VTE and higher mortality rates than other treatments so the committee did not think it should be offered routinely. They recognised that it may be a suitable option for some people with VTE.
Body weight can influence the absorption, distribution and elimination of anticoagulants, and their therapeutic effect can be altered at extremes of body weight. Because of this, and based on their knowledge and experience, the committee agreed that body weight should be taken into account and therapeutic monitoring considered when choosing anticoagulation for people whose weight is outside the range of 50 kg to 120 kg.
There was little evidence on the comparative effectiveness of different anticoagulants for people at extremes of body weight, and the evidence was limited to obesity defined as a body mass index of 30 kg/m2 and above rather than body weight. However, the committee noted that the summaries of product characteristics (SPCs) for several anticoagulants specify body weight rather than obesity and agreed that using the same criterion as the SPCs would make the recommendations clearer and easier to implement.
Because of the uncertainty about the most effective anticoagulant treatment for this group, the committee included a subgroup based on body weight in their recommendation for research on DOACs compared with each other and with other anticoagulants.
The committee agreed that intravenous UFH should be offered to people with PE and haemodynamic instability because the anticoagulant effect needs to be carefully controlled for these people. People with haemodynamic instability have poor peripheral circulation and because UFH is administered intravenously it allows for a more certain therapeutic effect. Additionally, the anticoagulant effect of UFH wears off relatively quickly if treatment needs to be stopped.
The committee did not review the evidence on thrombolytic therapy and the 2012 recommendation that it be considered for this population is unchanged.
Renal impairment increases the risk of anticoagulants accumulating in the body, which can increase bleeding risk. There was very limited evidence on anticoagulant treatment for VTE in people with renal impairment.
Based on their expertise and the SPC for each treatment, the committee agreed that LMWH, UFH or DOACs are suitable options to treat VTE in people with renal impairment. However, dabigatran is not an option for people with more severe renal impairment (estimated creatinine clearance 15 ml/min to 29 ml/min) based on its SPC. For people with estimated creatinine clearance less than 15 ml/min the main options are UFH or LMWH given either on their own or with a VKA until oral anticoagulation is established and in the therapeutic range. The committee emphasised the importance of following the SPCs and locally agreed protocols, and seeking advice from specialist colleagues or a multidisciplinary team to ensure correct dosing and monitoring.
There was very little evidence available on the duration of anticoagulation treatment for people with DVT or PE and active cancer. The committee agreed, based on the evidence and their experience, that anticoagulation treatment should continue for 3 to 6 months and then be reviewed. They noted that most of the evidence on VTE in people with active cancer looked at treatment over a period of 6 months, but agreed that some people need shorter treatment durations and it is good practice to determine the length of treatment on a case-by-case basis.
The effectiveness of DOACs compared with other anticoagulation treatments in people with active cancer has not been studied sufficiently to enable firm conclusions to be made. Evidence from studies in people without cancer may not be applicable because cancer could affect the action of these drugs. In studies that recruited only people with active cancer and VTE, rivaroxaban, edoxaban and LMWH were found to be similarly effective, although bleeding complications were more frequent with DOACs. These studies did not look at apixaban or dabigatran. In studies that looked at apixaban and dabigatran and in which a small number of people within the study population had active cancer, the effects of apixaban and dabigatran were similar in people with and without cancer. Economic evidence based on these studies showed apixaban to be the most cost-effective option, although the evidence for apixaban was based on a relatively small number of people.
The committee agreed that, if suitable, a DOAC should be considered to treat VTE in people with active cancer but, because of the limitations of the evidence, they could not be more specific about the choice of DOAC.
The committee noted the potential for interactions between anticoagulants and other drugs people with active cancer may be taking, such as chemotherapy drugs, and the possibility of an increased risk of bleeding with some types of tumours. The evidence suggested a higher rate of gastrointestinal and genitourinary bleeds in people with active cancer having treatment with a DOAC compared with those having LMWH. The committee agreed that DOACs may be unsuitable for people with tumours that are associated with an increased risk of these types of bleeds (such as people with gastrointestinal malignancies). However, they agreed that treatment decisions for people with active cancer need to be made on a case-by-case basis.
The committee made provision for people with active cancer if a DOAC is not suitable by including LMWH alone and LMWH with a VKA as alternatives. Although LMWH alone is commonly used in practice and is the only licensed option to treat VTE in active cancer, it is not cost effective compared with DOACs and reducing its use would be beneficial in conserving NHS resources. Sensitivity analyses were carried out varying the drug prices but these analyses did not change any of the conclusions from the economic model.
The committee recognised that there are circumstances in which LMWH is the most suitable treatment option and agreed that it could be considered when this is the case. They were aware that LMWH with a VKA is often impractical for people with active cancer because of difficulties with INR monitoring and maintaining INR within the therapeutic range. They agreed that it is less clinically effective than LMWH alone but is less costly and remains a suitable option in some circumstances.
The committee were aware of an MHRA safety alert warning of an increase in VTE recurrence in people with diagnosed triple positive antiphospholipid syndrome taking a DOAC compared with those taking LMWH and a VKA. Although people with antiphospholipid syndrome were not included in the evidence review, the committee agreed that it is important to include a recommendation highlighting the need to offer LMWH with a VKA to this group.
VTE can be difficult to treat in people who use intravenous drugs. They often have problems with access to medical care and adherence to prescribed treatments. There is a lack of good evidence on the comparative clinical and cost effectiveness of treatments and doses for VTE in this population. The committee made a recommendation for research with the aim of improving VTE treatment in people who use intravenous drugs.
The committee acknowledged that VTE can recur despite anticoagulant treatment and used their knowledge and experience to outline steps that can be taken if treatment fails.
## How the recommendations might affect practice
The recommendations are expected to lead to increased use of DOACs, particularly apixaban and rivaroxaban, to treat suspected and confirmed VTE. This should reduce the need for resources to monitor INR, manage bleeding complications and administer parenteral anticoagulation. The recommendation to start anticoagulation treatment before blood test results are available may increase community prescribing of anticoagulation treatment. However, more use of DOACs may also increase the need for expensive reversal agents.
Current VTE management for people at extremes of body weight is not expected to change substantially.
For people with haemodynamically unstable PE, UFH is currently used in clinical practice and the recommendation is not expected to affect the frequency of its use in this group.
More people with renal impairment are likely to be offered a DOAC or LMWH, reducing the use of UFH. This can be expected to produce cost savings by increasing the number of people with renal impairment who can have outpatient care for VTE.
For people with active cancer, it is expected that there will be an increase in the use of DOACs and a concomitant decrease in the use of more expensive treatments such as LMWH alone. This will also reduce the amount of district nursing support needed to provide assistance with parenteral therapies.
For people with VTE and antiphospholipid syndrome, the use of DOACs is expected to decrease.
Return to recommendations
# Long-term anticoagulation for secondary prevention
Recommendations 1.4.1 to 1.4.12
## Why the committee made the recommendations
The committee agreed that the benefits of anticoagulation treatment become less certain over time, and that after 3 months (or 3 to 6 months in people with active cancer) treatment needs to be reviewed and a decision made about whether to continue or stop treatment. They agreed that, at this point, the aim of anticoagulation changes from treatment to reducing the risk of recurrence.
The committee noted that continuing anticoagulation treatment after 3 months is less beneficial for people who have had a provoked DVT or PE if the provoking factor is no longer present, because of the lower rate of recurrence compared with unprovoked DVT or PE.
For people with unprovoked DVT or PE, the benefits and risks of continuing anticoagulation treatment are less certain and the committee agreed that they need to be carefully balanced. However, for most people with a low bleeding risk, the committee agreed that the benefits of continuing anticoagulation treatment outweigh the risks.
The committee agreed that the tools currently available to predict the risk of recurrence of VTE or the risk of bleeding are not sufficiently accurate or validated to be used as the sole basis for a decision, and that using them in such a manner might result in incorrect predictions and subsequent harm to the person. However, they also agreed that, in certain circumstances, a clinical prediction tool can be a useful adjunct to discussion with people offered long-term anticoagulation treatment. For bleeding risk, evidence on the HAS-BLED score showed that it can identify people with unprovoked proximal DVT or PE who are at particularly high risk of major bleeding and might benefit from stopping anticoagulation. For VTE recurrence, there was very limited evidence, and that evidence suggested that these tools are not sufficiently accurate to be used in practice.
Because of the uncertainty in predicting VTE recurrence and the risk of major bleeding, the committee made recommendations for research to develop a new prediction tool for VTE recurrence and major bleeding combined and research to compare this tool with clinical judgement.
The committee agreed that there are risks involved in switching anticoagulant treatment, particularly if there have been no adverse events with the current treatment. They also expressed concerns about convenience for people who are asked to switch from a DOAC with no monitoring to a VKA regimen with frequent monitoring, or problems with adherence if switching from a VKA to a DOAC. Based on these concerns and their clinical experience, the committee agreed that if treatment is continued beyond 3 months, the first option for most people should be to continue the current treatment if it is well tolerated.
Some evidence indicated that there are fewer major bleeds with apixaban than with rivaroxaban, dabigatran or a VKA. However, the committee were not entirely convinced by this evidence because the study of apixaban had stricter inclusion criteria, setting out which patients took part, than the other studies. Additionally, the studies recorded a very low number of major bleeds, leading to uncertainty about the effects of the different anticoagulation treatments on the likelihood of major bleeding. Apixaban was shown by the economic evidence to be the most cost-effective long-term treatment so the committee agreed that switching to apixaban should be considered as an option for people currently taking a DOAC other than apixaban. Sensitivity analyses were carried out varying the drug prices but these analyses did not change any of the conclusions from the economic model.
There was a lack of evidence on longer-term treatment for people with renal impairment, active cancer, antiphospholipid syndrome or extremes of body weight. Based on their clinical experience, the committee agreed that continuing the current treatment, if it is well tolerated, should be considered for people in these groups, taking into account their preferences and clinical situation.
For people who do not continue anticoagulation treatment, evidence showed that aspirin is better than no treatment at reducing DVT or PE recurrence for up to 2 years, although there was no difference in DVT or PE recurrence between aspirin and no treatment at 4 years. On balance, the committee agreed that aspirin can be considered as an option for people who wish to stop anticoagulation treatment, using a prophylactic dose based on current UK practice (75 mg daily or 150 mg daily).
To ensure that treatment is guided by the person's changing balance of benefits and risks, and changes in their preferences over time, the committee agreed that people taking long-term anticoagulation treatment or aspirin should have their risk of VTE recurrence, bleeding risk and general health reviewed at least once a year.
## How the recommendations might affect practice
The recommendations to review anticoagulation treatment at 3 months (3 to 6 months for people with active cancer), and annually thereafter, reflect most current practice but may increase the number of appointments and clinician time needed in services that do not currently provide these reviews. Giving patients who stop anticoagulation treatment information on signs and symptoms and a point of contact should ensure that a comprehensive safety net is in place.
Discussions about the benefits and risks of stopping or continuing anticoagulation treatment may increase the time needed for consultations, particularly if a prediction tool is used as part of the decision-making process. Using HAS-BLED can be expected to reduce long-term anticoagulation treatment in people with a high risk of major bleeding.
The recommendations are not expected to change practice for people with renal impairment or extremes of body weight. For people with antiphospholipid syndrome, it is expected that DOAC use will decrease, with a concomitant increase in the use of LMWH with a VKA. For people with active cancer, DOAC use can be expected to increase, with LMWH on its own becoming a less common treatment. For people with none of these clinical features, greater use of DOACs, particularly apixaban, for long-term treatment can be expected to lower costs by reducing the need for clinical visits, INR monitoring and managing bleeding events. The use of aspirin may increase for people who decline long-term anticoagulation. This may reduce VTE recurrence in people who would otherwise not receive treatment.
Return to recommendations
# Inferior vena caval filters
Recommendations 1.7.1 to 1.7.4
## Why the committee made the recommendations
There was little good evidence on inferior vena caval (IVC) filters. The evidence in a number of populations, including people about to have surgery, people with cancer, people with a high risk of having a subsequent PE and people with a high risk of a poor outcome from a subsequent PE, did not show a benefit from IVC filters. The committee therefore agreed that the use of IVC filters should be restricted to prospective clinical studies (including but not limited to prospective cohort studies and randomised controlled trials) unless anticoagulation is contraindicated or a PE has occurred during anticoagulation treatment. They made a recommendation for research to further investigate the effectiveness of IVC filters.
For people with proximal DVT or PE and a contraindication to anticoagulation treatment, a small amount of new evidence has become available since the 2012 guideline was published. This evidence did not show a clear difference in outcomes such as mortality and VTE recurrence between people who were given IVC filters and those who were not. One study found evidence of an increase in DVT occurrence (in people with an undefined initial VTE event) at 1 year in the group given IVC filters. However, based on their experience and knowledge of IVC filters, the committee agreed that they can help to reduce the risk of PE when therapeutic anticoagulation cannot be given. The committee also had concerns about the inherent risks involved in using IVC filters, including the invasive nature of the procedure for placing them and the potential for complications such as migration or fracture of the filter. In light of this, the committee agreed that the evidence was not sufficient to retain the 2012 recommendation to offer temporary IVC filters to people who cannot have anticoagulation treatment. However, they recognised that these people have a high risk of recurrent VTE and a limited number of alternative treatments, so agreed that a recommendation to consider an IVC filter for them is justified. They also agreed to retain the 2012 advice to remove the IVC filter when anticoagulation is no longer contraindicated, adding that anticoagulation treatment should be established before the IVC filter is removed.
There was very limited evidence on the use of IVC filters for people who have a PE while taking anticoagulation treatment for an initial proximal DVT or PE. The evidence suggested a reduction in short-term mortality from all causes in people in this group who had an IVC filter fitted. Because of the limited amount of evidence, the committee agreed that IVC filters could be considered for people in this group only after problems with adherence or other causes of hypercoagulability have been excluded, and different anticoagulation treatments or treatment regimens have been explored. The committee reasoned that, in many cases, optimising anticoagulation treatment will obviate the need for an IVC filter.
The committee noted that the type of IVC filter used is the same whether it is intended to be temporary or permanent. They agreed that, although the decision between a temporary and permanent IVC filter would be made on a case-by-case basis, most IVC filters are likely to be temporary. It is therefore prudent to have a plan in place for removal of the IVC filter at the time of fitting it, to ensure it is removed promptly when no longer needed.
## How the recommendations might affect practice
It is expected that the overall impact of the recommendations will be to reduce the use of IVC filters. For people with VTE at acute risk of thrombosis, clinicians may fit an IVC filter as part of a clinical trial.
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# Investigations for cancer
Recommendations 1.8.1 and 1.8.2
## Why the committee made the recommendations
Unprovoked VTE is associated with an increased risk of cancer, which may be undiagnosed when the VTE occurs. The committee agreed that a physical examination and review of medical history (including previous investigations such as imaging) are worthwhile precautions for people who have had an apparently unprovoked DVT or PE. However, the evidence did not show any benefit from further investigations for cancer for people who have no signs or symptoms. Moreover, these investigations can be costly, time consuming, potentially invasive or pose a radiation risk, and cause anxiety. The committee therefore agreed that further investigations for cancer should not be offered to people without relevant signs or symptoms.
## How the recommendations might affect practice
A physical examination and a review of medical history is current practice for people with unprovoked DVT or PE. The recommendations can be expected to reduce costs by reducing further investigations for cancer in people without symptoms or signs.
Return to recommendations# Context
In venous thromboembolism (VTE), a blood clot forms in a vein, usually in the deep veins of the legs or pelvis. This is known as deep vein thrombosis, or deep vein thrombosis (DVT). The blood clot can dislodge and travel in the blood, particularly to the pulmonary arteries. This is known as pulmonary embolism (PE). The term 'VTE' includes both DVT and PE.
Failure to diagnose and treat VTE correctly can result in fatal PE, in which the blood clot blocks the blood supply to the lungs. However, diagnosis of VTE is not always straightforward. This guideline includes advice on the Wells score, D-dimer measurement, ultrasound and radiological imaging. It also offers guidance on treating VTE, investigations for cancer in people with VTE and thrombophilia testing. The guideline covers adults with suspected or confirmed DVT or PE. It does not cover children or young people aged under 18, or women who are pregnant.
Since publication of the original guideline in 2012, new evidence has emerged and practice has changed in relation to the use of direct oral anticoagulants, prognostic tools, diagnosis of VTE using age-adjusted and point-of-care D-dimer testing, pulmonary embolism rule-out criteria, outpatient treatment for PE, inferior vena caval filters and investigations for cancer in people with unprovoked VTE. This 2020 update includes new and updated recommendations in these areas.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Diagnosis and initial management\n\nNICE has produced a visual summary of the recommendations on diagnosis and initial management of suspected deep vein thrombosis (DVT) and pulmonary embolism (PE).\n\n## Signs or symptoms of DVT\n\nFor people who present with signs or symptoms of DVT, such as a swollen or painful leg, assess their general medical history and do a physical examination to exclude other causes. \n\nIf DVT is suspected, use the 2‑level DVT Wells score (table\xa01) to estimate the clinical probability of DVT. \n\nClinical feature\n\nPoints\n\nActive cancer (treatment ongoing, within 6\xa0months, or palliative)\n\n\n\nParalysis, paresis or recent plaster immobilisation of the lower extremities\n\n\n\nRecently bedridden for 3\xa0days or more, or major surgery within 12\xa0weeks requiring general or regional anaesthesia\n\n\n\nLocalised tenderness along the distribution of the deep venous system\n\n\n\nEntire leg swollen\n\n\n\nCalf swelling at least 3\xa0cm larger than asymptomatic side\n\n\n\nPitting oedema confined to the symptomatic leg\n\n\n\nCollateral superficial veins (non-varicose)\n\n\n\nPreviously documented DVT\n\n\n\nAn alternative diagnosis is at least as likely as DVT\n\n-2\n\nClinical probability simplified score\n\nPoints\n\nDVT likely\n\npoints or more\n\nDVT unlikely\n\npoint or less\n\nAdapted with permission from Wells et al. (2003) Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis.\n\nOffer people with a likely DVT Wells score (2\xa0points or more):\n\na proximal leg vein ultrasound scan, with the result available within 4\xa0hours if possible (if the scan result cannot be obtained within 4\xa0hours follow recommendation\xa01.1.4)\n\na D-dimer test if the scan result is negative. \n\nIf a proximal leg vein ultrasound scan result cannot be obtained within 4\xa0hours, offer people with a DVT Wells score of 2\xa0points or more:\n\na D-dimer test, then\n\ninterim therapeutic anticoagulation (see the section on interim therapeutic anticoagulation for suspected DVT or PE) and\n\na proximal leg vein ultrasound scan with the result available within 24\xa0hours. [2012, amended 2020]\n\nFor people with a positive proximal leg vein ultrasound scan:\n\noffer or continue anticoagulation treatment (see the section on anticoagulation treatment for confirmed DVT or PE) or\n\nif anticoagulation treatment is contraindicated, offer a mechanical intervention (see the section on mechanical interventions). For people with symptomatic iliofemoral DVT see the section on thrombolytic therapy. \n\nFor people with a negative proximal leg vein ultrasound scan and a positive D-dimer test result:\n\nstop interim therapeutic anticoagulation (but do not stop long-term anticoagulation if being used for secondary prevention)\n\noffer a repeat proximal leg vein ultrasound scan 6 to 8\xa0days later and\n\n\n\nif the repeat scan result is positive, follow the actions in recommendation\xa01.1.5\n\nif the repeat scan result is negative, follow the actions in recommendation\xa01.1.7. [2012, amended 2020]\n\n\n\nFor people with a negative proximal leg vein ultrasound scan and a negative D-dimer test result:\n\nstop interim therapeutic anticoagulation (but do not stop long-term anticoagulation if being used for secondary prevention)\n\nthink about alternative diagnoses\n\ntell the person that it is not likely they have DVT. Discuss with them the signs and symptoms of DVT and when and where to seek further medical help. [2012, amended 2020]\n\nOffer people with an unlikely DVT Wells score (1\xa0point or less):\n\na D‑dimer test with the result available within 4\xa0hours (see the section on D-dimer testing) or\n\nif the D-dimer test result cannot be obtained within 4\xa0hours, offer interim therapeutic anticoagulation while awaiting the result (see the section on interim therapeutic anticoagulation for suspected DVT or PE). [2012, amended 2020]\n\nIf the D-dimer test result is negative, follow the actions in recommendation\xa01.1.7. \n\nIf the D-dimer test result is positive, offer:\n\na proximal leg vein ultrasound scan, with the result available within 4\xa0hours if possible or\n\ninterim therapeutic anticoagulation (see the section on interim therapeutic anticoagulation for suspected DVT or PE) and a proximal leg vein ultrasound scan with the result available within 24\xa0hours. [2012, amended 2020]\n\nIf the proximal leg vein ultrasound scan is:\n\npositive, follow the actions in recommendation 1.1.5\n\nnegative, follow the actions in recommendation 1.1.7, that is:\n\n\n\nstop interim therapeutic anticoagulation (but do not stop long-term anticoagulation if being used for secondary prevention)\n\nthink about alternative diagnoses\n\ntell the person that it is not likely they have DVT. Discuss with them the signs and symptoms of DVT and when and where to seek further medical help. \n\n\n\nWhen offering D-dimer testing for suspected DVT or PE, consider a point‑of‑care test if laboratory facilities are not immediately available. \n\nIf using a point-of-care D-dimer test, choose a fully quantitative test. \n\nWhen using a point-of-care or laboratory D-dimer test, consider an age‑adjusted D-dimer test threshold for people aged over 50. \n\nFor a short explanation of why the committee made these 2020 recommendations and how they might affect practice, see the rationale and impact section on D-dimer testing\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: D-dimer testing in the diagnosis of deep vein thrombosis and pulmonary embolism.\n\nLoading. Please wait.\n\n## Signs or symptoms of PE\n\nFor people who present with signs or symptoms of PE, such as chest pain, shortness of breath or coughing up blood, assess their general medical history, do a physical examination and offer a chest X‑ray to exclude other causes. \n\nIf clinical suspicion of PE is low (the clinician estimates the likelihood of PE to be less than 15% based on the overall clinical impression, and other diagnoses are feasible), consider using the pulmonary embolism rule-out criteria (PERC) to help determine whether any further investigations for PE are needed. \n\nFor a short explanation of why the committee made the 2020 recommendation and how it might affect practice, see the rationale and impact section on the PERC rule\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: the use of the pulmonary embolism rule-out criteria for diagnosis of pulmonary embolism\n\nLoading. Please wait.\n\nIf PE is suspected, use the 2‑level PE Wells score (table\xa02) to estimate the clinical probability of PE. \n\nClinical feature\n\nPoints\n\nClinical signs and symptoms of DVT (minimum of leg swelling and pain with palpation of the deep veins)\n\n\n\nAn alternative diagnosis is less likely than PE\n\n\n\nHeart rate more than 100\xa0beats per minute\n\n\n\nImmobilisation for more than 3\xa0days or surgery in the previous 4\xa0weeks\n\n\n\nPrevious DVT/PE\n\n\n\nHaemoptysis\n\n\n\nMalignancy (on treatment, treated in the last 6\xa0months, or palliative)\n\n\n\nClinical probability simplified score\n\nPoints\n\nPE likely\n\nMore than 4\xa0points\n\nPE unlikely\n\npoints or less\n\nAdapted with permission from Wells et al. (2000) Derivation of a simple clinical model to categorize patients' probability of pulmonary embolism: increasing the model's utility with the SimpliRED D-dimer.\n\nFor people with a likely PE Wells score (more than 4\xa0points):\n\noffer a computed tomography pulmonary angiogram (CTPA) immediately if possible or\n\nfor people with an allergy to contrast media, severe renal impairment (estimated creatinine clearance less than 30\xa0ml/min) or a high risk from irradiation, assess the suitability of a ventilation/perfusion single photon emission computed tomography (V/Q\xa0SPECT) scan or, if a V/Q\xa0SPECT scan is not available, a V/Q\xa0planar scan, as an alternative to CTPA.If a CTPA, V/Q\xa0SPECT or V/Q\xa0planar scan cannot be done immediately, offer interim therapeutic anticoagulation (see the section on interim therapeutic anticoagulation for suspected DVT or PE). [2012, amended 2020]\n\nIf PE is identified by CTPA, V/Q\xa0SPECT or V/Q\xa0planar scan:\n\noffer or continue anticoagulation treatment (see the section on anticoagulation treatment for confirmed DVT or PE) or\n\nif anticoagulation treatment is contraindicated, consider a mechanical intervention (see the section on mechanical interventions).For people with PE and haemodynamic instability see the section on thrombolytic therapy. [2012, amended 2020]\n\nIf PE is not identified by CTPA, V/Q SPECT or V/Q planar scan:\n\nconsider a proximal leg vein ultrasound scan if DVT is suspected\n\nif DVT is not suspected:\n\n\n\nstop interim therapeutic anticoagulation (but do not stop long-term anticoagulation if being used for secondary prevention)\n\nthink about alternative diagnoses\n\ntell the person that it is not likely they have PE. Discuss with them the signs and symptoms of PE and when and where to seek further medical help. [2012, amended 2020]\n\n\n\nOffer people with an unlikely PE Wells score (4\xa0points or less):\n\na D-dimer test with the result available within 4\xa0hours if possible (see the section on D-dimer testing) or\n\nif the D-dimer test result cannot be obtained within 4\xa0hours (in any setting), offer interim therapeutic anticoagulation while awaiting the result (see the section on interim therapeutic anticoagulation for suspected DVT or PE).If the D-dimer test result is:\n\npositive, follow the actions in recommendations 1.1.18 and 1.1.19\n\nnegative:\n\n\n\nstop interim therapeutic anticoagulation (but do not stop long-term anticoagulation if being used for secondary prevention)\n\nthink about alternative diagnoses\n\n\n\ntell the person that it is not likely they have PE. Discuss with them the signs and symptoms of PE and when and where to seek further medical help. [2012, amended 2020]\n\n## Signs or symptoms of both DVT and PE\n\nFor people who present with signs or symptoms of both DVT and PE, carry out initial diagnostic investigations for either DVT or PE, basing the choice of diagnostic investigations on clinical judgement. \n\n# Outpatient treatment for low-risk PE\n\nConsider outpatient treatment for suspected or confirmed low-risk PE, using a validated risk stratification tool to determine the suitability of outpatient treatment. \n\nWhen offering outpatient treatment to people with suspected PE, follow recommendations 1.1.15 to 1.1.21 on diagnosis and initial management. \n\nWhen offering outpatient treatment to people with confirmed PE, follow the recommendations in the section on anticoagulation treatment for confirmed DVT or PE. \n\nAgree a plan for monitoring and follow-up with people having outpatient treatment for suspected or confirmed low-risk PE. Give them:\n\nwritten information on symptoms and signs to look out for, including the potential complications of thrombosis and of treatment\n\ndirect contact details of a healthcare professional or team with expertise in thrombosis who can discuss any new symptoms or signs, or other concerns\n\ninformation about out-of-hours services they can contact when their healthcare team is not available. \n\nFor a short explanation of why the committee made the 2020 recommendations and how they might affect practice, see the rationale and impact section on outpatient treatment for low-risk PE\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: outpatient treatment of low-risk pulmonary embolism\n\nLoading. Please wait.\n\n# Anticoagulation treatment for suspected or confirmed DVT or PE\n\nNICE has produced a visual summary of the recommendations on anticoagulation treatment for DVT or PE.\n\nWhen offering anticoagulation treatment, follow the recommendations on shared decision making and supporting adherence in the NICE guidelines on medicines optimisation, medicines adherence, patient experience in adult NHS services and shared decision making. \n\n## Interim therapeutic anticoagulation for suspected DVT or PE\n\nFollow the recommendations on when to offer interim therapeutic anticoagulation for suspected proximal DVT or PE in the section on diagnosis and initial management. \n\nIf possible, choose an interim anticoagulant that can be continued if DVT or PE is confirmed (see the section on anticoagulation treatment for confirmed DVT or PE). In March 2020, direct-acting anticoagulants and some low molecular weight heparins (LMWHs) were off label for the treatment of suspected DVT or PE. See NICE's information on prescribing medicines.\n\nWhen using interim therapeutic anticoagulation for suspected proximal DVT or PE:\n\ncarry out baseline blood tests including full blood count, renal and hepatic function, prothrombin time (PT) and activated partial thromboplastin time (APTT)\n\ndo not wait for the results of baseline blood tests before starting anticoagulation treatment\n\nreview, and if necessary act on, the results of baseline blood tests within 24\xa0hours of starting interim therapeutic anticoagulation. \n\n## Anticoagulation treatment for confirmed DVT or PE\n\nOffer anticoagulation treatment for at least 3\xa0months to people with confirmed proximal DVT or PE. For recommendations on treatment after 3\xa0months see the section on long-term anticoagulation for secondary prevention. \n\nIf not already done, carry out baseline blood tests, as outlined in recommendation\xa01.3.4, when starting anticoagulation treatment. \n\nWhen offering anticoagulation treatment, take into account comorbidities, contraindications and the person's preferences.Follow the recommendations on anticoagulation treatment in the sections on:\n\nDVT or PE in people at extremes of body weight\n\nPE with haemodynamic instability\n\nDVT or PE with renal impairment or established renal failure\n\nDVT or PE with active cancer\n\nDVT or PE with triple positive antiphospholipid syndrome. \n\nOffer either apixaban or rivaroxaban to people with confirmed proximal DVT or PE (but see recommendations\xa01.3.11 to 1.3.20 for people with any of the clinical features listed in recommendation\xa01.3.7). If neither apixaban nor rivaroxaban is suitable offer:\n\nLMWH for at least 5\xa0days followed by dabigatran or edoxaban or\n\nLMWH concurrently with a vitamin\xa0K antagonist (VKA) for at least 5\xa0days, or until the INR is at least 2.0 in 2 consecutive readings, followed by a VKA on its own. \n\nDo not routinely offer unfractionated heparin (UFH) with a VKA to treat confirmed proximal DVT or PE unless the person has renal impairment or established renal failure (see recommendations\xa01.3.13 and 1.3.14) or an increased risk of bleeding. \n\nDo not routinely offer self‑management or self‑monitoring of INR to people who have had DVT or PE and are having treatment with a VKA. \n\nConsider anticoagulation treatment with regular monitoring of therapeutic levels for people with confirmed proximal DVT or PE who weigh less than 50\xa0kg or more than 120\xa0kg, to ensure effective anticoagulation. Note the cautions and requirements for dose adjustment and monitoring in the medicine's summary of product characteristics (SPC), and follow locally agreed protocols or advice from a specialist or multidisciplinary team. \n\nFor people with confirmed PE and haemodynamic instability, offer continuous UFH infusion and consider thrombolytic therapy (see the section on thrombolytic therapy). \n\nIn March 2020, some LMWHs were off label for the treatment of DVT or PE in people with severe renal impairment (estimated creatinine clearance 15\xa0ml/min to 30\xa0ml/min) or established renal failure (estimated creatinine clearance less than 15\xa0ml/min). See NICE's information on prescribing medicines.\n\nOffer people with confirmed proximal DVT or PE and renal impairment (estimated creatinine clearance between 15\xa0ml/min and 50\xa0ml/min) one of:\n\napixaban\n\nrivaroxaban\n\nLMWH for at least 5\xa0days followed by:\n\n\n\nedoxaban or\n\ndabigatran if estimated creatinine clearance is 30\xa0ml/min or above\n\n\n\nLMWH or UFH, given concurrently with a VKA for at least 5\xa0days or until the INR is at least 2.0 in 2 consecutive readings, followed by a VKA on its own.Note the cautions and requirements for dose adjustment and monitoring in the medicine's SPC, and follow locally agreed protocols or advice from a specialist or multidisciplinary team. \n\nOffer people with confirmed proximal DVT or PE and established renal failure (estimated creatinine clearance less than 15\xa0ml/min) one of:\n\nLMWH\n\nUFH\n\nLMWH or UFH concurrently with a VKA for at least 5\xa0days or until the INR is at least 2.0 in 2 consecutive readings, followed by a VKA on its own.Note the cautions and requirements for dose adjustment and monitoring in the medicine's SPC, and follow locally agreed protocols or advice from a specialist or multidisciplinary team. \n\nIn March 2020, most anticoagulants were off label for the treatment of DVT or PE in people with active cancer. See NICE's information on prescribing medicines.\n\nOffer people with active cancer and confirmed proximal DVT or PE anticoagulation treatment for 3 to 6\xa0months. Review at 3 to 6\xa0months according to clinical need. For recommendations on treatment after 3 to 6\xa0months see the section on long-term anticoagulation for secondary prevention. \n\nWhen choosing anticoagulation treatment for people with active cancer and confirmed proximal DVT or PE, take into account the tumour site, interactions with other drugs including those used to treat cancer, and the person's bleeding risk. \n\nConsider a direct-acting oral anticoagulant (DOAC) for people with active cancer and confirmed proximal DVT or PE. \n\nIf a DOAC is unsuitable consider LMWH alone or LMWH concurrently with a VKA for at least 5\xa0days, or until the INR is at least 2.0 in 2 consecutive readings, followed by a VKA on its own. \n\nFor people with confirmed DVT or PE and cancer that is in remission, follow the recommendations in the section on anticoagulation treatment for confirmed DVT or PE. \n\nOffer people with confirmed proximal DVT or PE and an established diagnosis of triple positive antiphospholipid syndrome LMWH concurrently with a VKA for at least 5\xa0days, or until the INR is at least 2.0 in 2 consecutive readings, followed by a VKA on its own. \n\n## Treatment failure\n\nIf anticoagulation treatment fails:\n\ncheck adherence to anticoagulation treatment\n\naddress other sources of hypercoagulability\n\nincrease the dose of anticoagulant or change to an anticoagulant with a different mode of action. \n\n## NICE technology appraisal guidance on anticoagulation treatment for confirmed DVT or PE\n\nFor NICE technology appraisal guidance see:\n\napixaban for the treatment and secondary prevention of deep vein thrombosis and/or pulmonary embolism\n\ndabigatran etexilate for the treatment and secondary prevention of deep vein thrombosis and/or pulmonary embolism\n\nedoxaban for treating and for preventing deep vein thrombosis and pulmonary embolism\n\nrivaroxaban for treating pulmonary embolism and preventing recurrent venous thromboembolism\n\nrivaroxaban for the treatment of deep vein thrombosis and prevention of recurrent deep vein thrombosis and pulmonary embolism.\n\nFor a short explanation of why the committee made the 2020 recommendations and how they might affect practice, see the rationale and impact section on anticoagulation treatment for confirmed DVT or PE\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: pharmacological treatment in people with suspected or confirmed deep vein thrombosis and/or pulmonary embolism.\n\nEvidence review G: economic modelling report for pharmacological treatment also underpins recommendations 1.3.8, 1.3.9, 1.3.17 and 1.3.18.\n\nLoading. Please wait.\n\n# Long-term anticoagulation for secondary prevention\n\nAssess and discuss the benefits and risks of continuing, stopping or changing the anticoagulant with people who have had anticoagulation treatment for 3\xa0months (3 to 6\xa0months for people with active cancer) after a proximal DVT or PE. Follow the recommendations on shared decision making and supporting adherence in the NICE guidelines on medicines optimisation, medicines adherence and patient experience in adult NHS services. \n\nConsider stopping anticoagulation treatment 3\xa0months (3 to 6\xa0months for people with active cancer) after a provoked DVT or PE if the provoking factor is no longer present and the clinical course has been uncomplicated. If anticoagulation treatment is stopped, give advice about the risk of recurrence and provide:\n\nwritten information on symptoms and signs to look out for\n\ndirect contact details of a healthcare professional or team with expertise in thrombosis who can discuss any new symptoms or signs, or other concerns\n\ninformation about out-of-hours services they can contact when their healthcare team is not available. \n\nConsider continuing anticoagulation beyond 3\xa0months (6\xa0months for people with active cancer) after an unprovoked DVT or PE. Base the decision on the balance between the person's risk of venous thromboembolism (VTE) recurrence and their risk of bleeding. Discuss the risks and benefits of long-term anticoagulation with the person, and take their preferences into account. \n\nExplain to people with unprovoked DVT or PE and a low bleeding risk that the benefits of continuing anticoagulation treatment are likely to outweigh the risks. \n\nDo not rely solely on predictive risk tools to assess the need for long-term anticoagulation treatment. \n\nConsider using the HAS-BLED score for major bleeding risk to assess the risk of major bleeding in people having anticoagulation treatment for unprovoked proximal DVT or PE. Discuss stopping anticoagulation if the HAS-BLED score is 4 or more and cannot be modified. \n\nTake into account the person's preferences and their clinical situation when selecting an anticoagulant for long-term treatment. \n\nFor people who do not have renal impairment, active cancer, established triple positive antiphospholipid syndrome or extreme body weight (less than 50\xa0kg or more than 120\xa0kg):\n\noffer continued treatment with the current anticoagulant if it is well tolerated or\n\nif the current treatment is not well tolerated, or the clinical situation or person's preferences have changed, consider switching to apixaban if the current treatment is a direct-acting anticoagulant other than apixaban. \n\nFor people with renal impairment, active cancer, established triple positive antiphospholipid syndrome or extreme body weight (less than 50\xa0kg or more than 120\xa0kg), consider carrying on with the current treatment if it is well tolerated. \n\nIf anticoagulation treatment fails follow the recommendation on treatment failure. \n\nFor people who decline continued anticoagulation treatment, consider aspirin 75\xa0mg or 150\xa0mg daily. In March 2020, the use of aspirin for secondary prevention of DVT or PE was off label. See NICE's information on prescribing medicines. \n\nReview general health, risk of VTE recurrence, bleeding risk and treatment preferences at least once a year for people taking long-term anticoagulation treatment or aspirin. \n\nFor a short explanation of why the committee made the 2020 recommendations on reviewing anticoagulation treatment and how they might affect practice, see the rationale and impact section on long-term anticoagulation for secondary prevention\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0F: what factors determine the optimum duration of pharmacological treatment for DVT or PE in people with a VTE?\n\nevidence review\xa0D: pharmacological treatment in people with suspected or confirmed deep vein thrombosis and/or pulmonary embolism (for recommendations 1.4.1 and 1.4.7 to 1.4.11).\n\nEvidence review G: economic modelling report for pharmacological treatment also underpins recommendation 1.4.8.\n\nLoading. Please wait.\n\n# Information and support for people having anticoagulation treatment\n\nGive people having anticoagulation treatment verbal and written information about:\n\nhow to use anticoagulants\n\nhow long to take anticoagulants\n\npossible side effects of anticoagulants and what to do if these occur\n\nhow other medications, foods and alcohol can affect oral anticoagulation treatment\n\nany monitoring needed for their anticoagulant treatment\n\nhow anticoagulants may affect their dental treatment\n\ntaking anticoagulants if they are planning pregnancy or become pregnant\n\nhow anticoagulants may affect activities such as sports and travel\n\nwhen and how to seek medical help. \n\nGive people who are having anticoagulation treatment information and an 'anticoagulant alert card' that is specific to their treatment. Advise them to carry the 'anticoagulant alert card' at all times. \n\nBe aware that heparins are of animal origin and that apixaban and rivaroxaban contain lactose from cow's milk. For people who have concerns about using animal products because of a religious or ethical belief, or a food intolerance, see the section on giving information and planning for discharge in the NICE guideline on venous thromboembolism in over\xa016s. [2012, amended 2020]\n\n# Thrombolytic therapy\n\n## DVT\n\nConsider catheter-directed thrombolytic therapy for people with symptomatic iliofemoral DVT who have:\n\nsymptoms lasting less than 14\xa0days and\n\ngood functional status and\n\na life expectancy of 1\xa0year or more and\n\na low risk of bleeding. \n\nSee NICE interventional procedures guidance on ultrasound-enhanced, catheter-directed thrombolysis for deep vein thrombosis.\n\n## PE\n\nConsider pharmacological systemic thrombolytic therapy for people with PE and haemodynamic instability(see also the section on anticoagulation treatment for PE with haemodynamic instability). \n\nDo not offer pharmacological systemic thrombolytic therapy to people with PE and haemodynamic stability with or without right ventricular dysfunction (see also the section on anticoagulation treatment for DVT or PE). If the person develops haemodynamic instability, refer to recommendation\xa01.6.2. \n\nSee NICE interventional procedures guidance on ultrasound-enhanced, catheter-directed thrombolysis for pulmonary embolism.\n\n# Mechanical interventions\n\n## Inferior vena caval filters\n\nDo not offer an inferior vena caval (IVC) filter to people with proximal DVT or PE unless:\n\nit is part of a prospective clinical study or\n\nanticoagulation is contraindicated or a PE has occurred during anticoagulation treatment (see recommendations\xa01.7.2 and 1.7.3). \n\nConsider an IVC filter for people with proximal DVT or PE when anticoagulation treatment is contraindicated. Remove the IVC filter when anticoagulation treatment is no longer contraindicated and has been established. \n\nConsider an IVC filter for people with proximal DVT or PE who have a PE while taking anticoagulation treatment only after taking the steps outlined in the recommendation on treatment failure. \n\nBefore fitting an IVC filter, ensure that there is a strategy in place for it to be removed at the earliest possible opportunity. Document the strategy and review it if the clinical situation changes. \n\nFor a short explanation of why the committee made the 2020 recommendations and how they might affect practice, see the rationale and impact section on IVC filters\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: inferior vena caval filters for people with venous thromboembolism.\n\nLoading. Please wait.\n\n## Elastic graduated compression stockings\n\nDo not offer elastic graduated compression stockings to prevent post-thrombotic syndrome or VTE recurrence after a DVT. This recommendation does not cover the use of elastic stockings for the management of leg symptoms after DVT. \n\nIf offering elastic graduated compression stockings to manage leg symptoms after DVT, explain how to apply and use them, how long they should be worn and when they should be replaced. \n\n## Percutaneous mechanical thrombectomy\n\nSee NICE interventional procedures guidance on percutaneous mechanical thrombectomy for acute deep vein thrombosis of the leg.\n\n# Investigations for cancer\n\nFor people with unprovoked DVT or PE who are not known to have cancer, review the medical history and baseline blood test results including full blood count, renal and hepatic function, PT and APTT, and offer a physical examination. \n\nDo not offer further investigations for cancer to people with unprovoked DVT or PE unless they have relevant clinical symptoms or signs (for further information see the NICE guideline on suspected cancer). \n\nFor a short explanation of why the committee made the 2020 recommendations and how they might affect practice, see the rationale and impact section on investigations for cancer\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: investigations for cancer in people with unprovoked venous thromboembolism\n\nLoading. Please wait.\n\n# Thrombophilia testing\n\nDo not offer testing for hereditary thrombophilia to people who are continuing anticoagulation treatment. [2012, amended 2020]\n\nDo not offer thrombophilia testing to people who have had provoked DVT or PE. \n\nConsider testing for antiphospholipid antibodies in people who have had unprovoked DVT or PE if it is planned to stop anticoagulation treatment, but be aware that these tests can be affected by anticoagulants and specialist advice may be needed. [2012, amended 2020]\n\nConsider testing for hereditary thrombophilia in people who have had unprovoked DVT or PE and who have a first‑degree relative who has had DVT or PE if it is planned to stop anticoagulation treatment, but be aware that these tests can be affected by anticoagulants and specialist advice may be needed. [2012, amended 2020]\n\nDo not routinely offer thrombophilia testing to first‑degree relatives of people with a history of DVT or PE and thrombophilia. \n\n# Terms used in this guideline\n\n## Active cancer\n\nReceiving active antimitotic treatment; or diagnosed within the past 6\xa0months; or recurrent or metastatic; or inoperable. Excludes squamous skin cancer and basal cell carcinoma.\n\n## Estimated creatinine clearance\n\nCreatinine clearance estimated using the Cockcroft and Gault formula; see the BNF's information on prescribing in renal impairment.\n\n## Provoked DVT or PE\n\nDVT or PE in a person with a recent (within 3\xa0months) and transient major clinical risk factor for VTE, such as surgery, trauma, significant immobility (bedbound, unable to walk unaided or likely to spend a substantial proportion of the day in bed or in a chair), pregnancy or puerperium – or in a person who is having hormonal therapy (combined oral contraceptive pill or hormone replacement therapy).\n\n## Proximal DVT\n\nDVT at or above the level of the popliteal trifurcation area.\n\n## Unprovoked DVT or PE\n\nDVT or PE in a person with no recent major clinical risk factor for VTE (see provoked DVT or PE) who is not having hormonal therapy (combined oral contraceptive pill or hormone replacement therapy).\n\n## Wells score\n\nClinical prediction rule for estimating the probability of DVT or PE. There are a number of versions of Wells scores available. This guideline recommends the 2‑level DVT Wells score and the 2-level PE Wells score.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Clinical and cost effectiveness of inferior vena caval filters in people with venous thromboembolism\n\nWhat is the short- and long-term clinical and cost effectiveness of inferior vena caval filters in people with venous thromboembolism (VTE)? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on inferior vena caval filters\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: inferior vena caval filters for people with VTE.\n\nLoading. Please wait.\n\n## Clinical and cost effectiveness of direct-acting oral anticoagulants based on individual patient data\n\nWhat is the clinical and cost effectiveness of direct-acting oral anticoagulants (DOACs) compared with each other, with low molecular weight heparin (LMWH) plus a vitamin K antagonist (VKA), with LMWH alone, with placebo and with aspirin for the initial and long‑term treatment of deep vein thrombosis (DVT) or pulmonary embolism (PE) based on individual patient data from existing trials? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on anticoagulation treatment for confirmed DVT or PE\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: pharmacological treatment in people with suspected or confirmed DVT and/or PE.\n\nLoading. Please wait.\n\n## Prediction tools compared with clinical judgement\n\nWhat is the prognostic accuracy of a tool to predict both VTE recurrence and major bleeding compared with clinical judgement in people with unprovoked proximal DVT or PE? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on long-term anticoagulation for secondary prevention\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: what factors determine the optimum duration of pharmacological treatment for DVT or PE in people with a VTE?\n\nLoading. Please wait.\n\n## Lower-dose thrombolysis for people with acute PE and right ventricular dysfunction\n\nDoes lower-dose thrombolysis reduce the risk of major bleeding and improve outcomes for people with acute PE and right ventricular dysfunction? \n\n## Diagnosis of DVT\n\nWhat is the clinical and cost effectiveness of a whole‑leg ultrasound scan compared with a proximal leg vein ultrasound scan in the diagnosis of acute DVT? \n\n# Other recommendations for research\n\n## Treatment strategy for people who use intravenous drugs\n\nWhat is the optimal pharmacological treatment strategy for DVT or PE in people who use intravenous drugs? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on anticoagulation treatment for DVT or PE in people who use intravenous drugs\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: pharmacological treatment in people with suspected or confirmed DVT and/or PE.\n\nLoading. Please wait.\n\n## Predicting VTE recurrence and major bleeding\n\nWhat is the prognostic accuracy of a tool to predict both VTE recurrence and major bleeding after 3\xa0months of initial anticoagulation treatment and in the long term? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on long-term anticoagulation for secondary prevention\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: what factors determine the optimum duration of pharmacological treatment for DVT or PE in people with a VTE?\n\nLoading. Please wait.\n\n## Thrombolytic therapy for DVT\n\nWhat is the clinical and cost effectiveness of clot removal using catheter‑directed thrombolytic therapy or pharmacomechanical thrombolysis compared with standard anticoagulation therapy for the treatment of acute proximal DVT? ", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.\n\n# D-dimer testing\n\nRecommendations 1.1.12 to 1.1.14\n\n## Why the committee made the recommendations\n\nThe committee agreed that, if both laboratory-based and point-of-care D-dimer testing are immediately available, laboratory testing is preferable because it provides more rigorous quality assurance and greater certainty of diagnostic accuracy. However, if laboratory-based testing is not immediately available, the committee were in agreement that offering immediate point-of-care testing is more beneficial for patients than delaying diagnosis by waiting for laboratory testing. Although point-of-care tests are more expensive than laboratory tests, a cost-effectiveness analysis showed that the additional cost may be offset by faster results that reduce the need for additional GP time and unnecessary interim anticoagulation.\n\nEvidence on fully quantitative point-of-care D-dimer tests for deep vein thrombosis (DVT) suggested that they are as accurate as laboratory tests and more accurate than qualitative or semi‑quantitative tests. There is little evidence on these tests for pulmonary embolism (PE) but the committee agreed that the evidence on DVT is applicable to PE because it is very unlikely that there is a biological reason that the accuracy of the tests would differ between these groups. The committee were aware that quantitative tests are more commonly used than qualitative or semi-quantitative tests. However, because the latter types of tests are still used in some services, they specified that point-of-care tests should be fully quantitative.\n\nIn people aged over 50, there was limited prospective evidence available for DVT and only retrospective evidence available for PE. This evidence suggested that adjusting D-dimer test thresholds for age improves the usefulness of these tests for ruling out venous thromboembolism (VTE) in this age group. The evidence also suggested that age adjustment does not reduce the accuracy of the tests in identifying VTE. The committee noted that adjusting test thresholds for age could be beneficial in reducing anxiety and unnecessary imaging for people with suspected DVT or PE. Although the evidence was not plentiful, the committee agreed that, taken together with the potential benefits, it was sufficient to support a recommendation suggesting age adjustment in D-dimer test thresholds for people aged over 50.\n\n## How the recommendations might affect practice\n\nServices that do not currently provide quantitative point-of-care D-dimer tests may need to acquire new equipment and provide training on how to conduct and interpret the tests. It is uncertain what impact this would have on practice, because it is unclear what proportion of primary care centres already use point-of-care testing. Facilities for point-of-care testing are only needed if rapid laboratory testing is not available.\n\nThe number of D-dimer tests that are adjusted for age is likely to increase, leading to a reduction in the number of additional investigations for VTE.\n\nReturn to recommendations\n\n# Pulmonary embolism rule-out criteria (the PERC rule)\n\nRecommendation 1.1.16\n\n## Why the committee made the recommendation\n\nIn people with signs or symptoms of PE, but in whom clinical suspicion of PE is low (the clinician estimates the likelihood of PE to be less than 15% based on the overall clinical impression and other diagnoses are feasible), there was some evidence showing that the PERC rule can accurately eliminate PE as a possible diagnosis. The committee agreed that using the PERC rule can reduce anxiety and avoid unnecessary D-dimer testing, imaging and interim anticoagulation treatment for people with a low probability of PE and none of the PERC criteria for PE. However, the evidence was limited so the committee agreed to recommend that the PERC rule be considered as part of initial assessment. The committee noted that the studies evaluating PERC all took place in emergency departments but they could see no reason why its use should be limited to this setting or why the diagnostic accuracy of PERC would differ in other settings.\n\n## How the recommendation might affect practice\n\nThe PERC rule is not widely used in current practice. This recommendation is expected to increase its use within a subgroup of people in whom clinical suspicion of PE is low and for whom discharge is being considered. Increased use of PERC can be expected to reduce the need for D-dimer testing and imaging for people with none of the PERC criteria for PE, leading to some reductions in waiting times in primary care and emergency departments. It will also help to avoid unnecessary anticoagulation treatment. However, the overall impact of this recommendation is not expected to be substantial because of the limited population it affects.\n\nReturn to recommendation\n\n# Outpatient treatment for low-risk pulmonary embolism\n\nRecommendations 1.2.1 to 1.2.4\n\n## Why the committee made the recommendations\n\nThe committee noted that outpatient treatment for people with PE who have a low risk of poor outcomes is increasingly being used in settings such as ambulatory care units. There was limited evidence comparing outpatient with inpatient treatment for PE so the committee were unable to reach firm conclusions about the overall benefits and risks of outpatient treatment. However, no evidence showed that outpatient treatment is less effective or less safe than inpatient treatment for people with low-risk PE. The committee agreed that outpatient care offers substantial benefits for people with PE and for hospital services and should be considered for those with suspected or confirmed low-risk PE.\n\nThe committee emphasised the importance of clear arrangements for monitoring and follow-up to ensure that outpatients receive the same quality of care as inpatients. They noted that specialist services with expertise in thrombosis are not available at all times and agreed that it is important for people with VTE to know who they can contact if they need advice outside normal service hours.\n\n## How the recommendations might affect practice\n\nOutpatient treatment for PE is common practice in many services with ambulatory care units. These recommendations might lead to the establishment of ambulatory care units in services that do not currently have them, and this will reduce hospital stays in those services.\n\nReturn to recommendations\n\n# Anticoagulation treatment for suspected or confirmed deep vein thrombosis or pulmonary embolism\n\nRecommendations 1.3.1 to 1.3.21\n\n## Why the committee made the recommendations\n\nThere was no evidence specifically on interim anticoagulation treatment for suspected DVT or PE. However, the committee agreed that it is vital to start treatment if DVT or PE is suspected and diagnostic test results are delayed by more than 4\xa0hours. They reasoned that anticoagulation treatments that are effective for confirmed DVT or PE are likely to be equally effective when used as interim treatment while awaiting a confirmed diagnosis. They also noted that continuing the same anticoagulant treatment after diagnosis offers benefits in terms of safety and convenience. However, they acknowledged that local protocols or availability of anticoagulants for suspected VTE may necessitate the use of different anticoagulants before and after diagnosis.\n\nThe committee agreed that when choosing an interim anticoagulant, clinicians should always take individual clinical circumstances into account, including whether the person is at an extreme of body weight, has PE with haemodynamic instability, renal impairment, active cancer or established triple positive antiphospholipid syndrome.\n\nEvidence suggested that treatment with a direct-acting oral anticoagulant (DOAC) is less likely to result in bleeding complications than treatment with low molecular weight heparin (LMWH) and a vitamin K antagonist (VKA). Additionally, people taking a DOAC benefit by being able to have an oral treatment and avoid the frequent monitoring that is necessary with other types of anticoagulation treatment.\n\nWithin the DOACs, there was evidence showing that apixaban is the most cost‑effective option. because it results in the fewest bleeds. Rivaroxaban is the second most cost-effective option and only slightly less cost effective than apixaban. However, the committee had reservations about this evidence because the inclusion criteria setting out which patients took part in the studies were not the same in each study. In particular, the apixaban study did not include patients with provoked VTE unless it was caused by a persistent risk factor, so a larger proportion of patients in the apixaban study had unprovoked VTE compared with the rivaroxaban studies. This made it difficult to compare the results of the studies. Because of this, the committee were not confident that apixaban should be the only option for a DOAC and recommended a choice of apixaban or rivaroxaban. Sensitivity analyses were carried out varying the drug prices but these analyses did not change any of the conclusions from the economic model.\n\nThe committee recognised that apixaban or rivaroxaban might not be suitable for everyone, so they included options for treatment with LMWH followed by dabigatran or edoxaban, or LMWH with a VKA. The committee also made a recommendation for research on DOACs compared with each other and with other anticoagulants.\n\nThe evidence did not support a recommendation for fondaparinux. It showed that fondaparinux is more likely to result in bleeding and is less cost effective than other treatments. However, the committee decided not to make a recommendation precluding its use because they were aware that it may be needed in rare circumstances.\n\nUnfractionated heparin (UFH) was associated with increased bleeding complications, greater recurrence rates of VTE and higher mortality rates than other treatments so the committee did not think it should be offered routinely. They recognised that it may be a suitable option for some people with VTE.\n\nBody weight can influence the absorption, distribution and elimination of anticoagulants, and their therapeutic effect can be altered at extremes of body weight. Because of this, and based on their knowledge and experience, the committee agreed that body weight should be taken into account and therapeutic monitoring considered when choosing anticoagulation for people whose weight is outside the range of 50\xa0kg to 120\xa0kg.\n\nThere was little evidence on the comparative effectiveness of different anticoagulants for people at extremes of body weight, and the evidence was limited to obesity defined as a body mass index of\xa030\xa0kg/m2 and above rather than body weight. However, the committee noted that the summaries of product characteristics (SPCs) for several anticoagulants specify body weight rather than obesity and agreed that using the same criterion as the SPCs would make the recommendations clearer and easier to implement.\n\nBecause of the uncertainty about the most effective anticoagulant treatment for this group, the committee included a subgroup based on body weight in their recommendation for research on DOACs compared with each other and with other anticoagulants.\n\nThe committee agreed that intravenous UFH should be offered to people with PE and haemodynamic instability because the anticoagulant effect needs to be carefully controlled for these people. People with haemodynamic instability have poor peripheral circulation and because UFH is administered intravenously it allows for a more certain therapeutic effect. Additionally, the anticoagulant effect of UFH wears off relatively quickly if treatment needs to be stopped.\n\nThe committee did not review the evidence on thrombolytic therapy and the 2012 recommendation that it be considered for this population is unchanged.\n\nRenal impairment increases the risk of anticoagulants accumulating in the body, which can increase bleeding risk. There was very limited evidence on anticoagulant treatment for VTE in people with renal impairment.\n\nBased on their expertise and the SPC for each treatment, the committee agreed that LMWH, UFH or DOACs are suitable options to treat VTE in people with renal impairment. However, dabigatran is not an option for people with more severe renal impairment (estimated creatinine clearance 15\xa0ml/min\xa0to\xa029\xa0ml/min) based on its SPC. For people with estimated creatinine clearance less than 15\xa0ml/min the main options are UFH or LMWH given either on their own or with a VKA until oral anticoagulation is established and in the therapeutic range. The committee emphasised the importance of following the SPCs and locally agreed protocols, and seeking advice from specialist colleagues or a multidisciplinary team to ensure correct dosing and monitoring.\n\nThere was very little evidence available on the duration of anticoagulation treatment for people with DVT or PE and active cancer. The committee agreed, based on the evidence and their experience, that anticoagulation treatment should continue for 3\xa0to\xa06\xa0months and then be reviewed. They noted that most of the evidence on VTE in people with active cancer looked at treatment over a period of 6\xa0months, but agreed that some people need shorter treatment durations and it is good practice to determine the length of treatment on a case-by-case basis.\n\nThe effectiveness of DOACs compared with other anticoagulation treatments in people with active cancer has not been studied sufficiently to enable firm conclusions to be made. Evidence from studies in people without cancer may not be applicable because cancer could affect the action of these drugs. In studies that recruited only people with active cancer and VTE, rivaroxaban, edoxaban and LMWH were found to be similarly effective, although bleeding complications were more frequent with DOACs. These studies did not look at apixaban or dabigatran. In studies that looked at apixaban and dabigatran and in which a small number of people within the study population had active cancer, the effects of apixaban and dabigatran were similar in people with and without cancer. Economic evidence based on these studies showed apixaban to be the most cost-effective option, although the evidence for apixaban was based on a relatively small number of people.\n\nThe committee agreed that, if suitable, a DOAC should be considered to treat VTE in people with active cancer but, because of the limitations of the evidence, they could not be more specific about the choice of DOAC.\n\nThe committee noted the potential for interactions between anticoagulants and other drugs people with active cancer may be taking, such as chemotherapy drugs, and the possibility of an increased risk of bleeding with some types of tumours. The evidence suggested a higher rate of gastrointestinal and genitourinary bleeds in people with active cancer having treatment with a DOAC compared with those having LMWH. The committee agreed that DOACs may be unsuitable for people with tumours that are associated with an increased risk of these types of bleeds (such as people with gastrointestinal malignancies). However, they agreed that treatment decisions for people with active cancer need to be made on a case-by-case basis.\n\nThe committee made provision for people with active cancer if a DOAC is not suitable by including LMWH alone and LMWH with a VKA as alternatives. Although LMWH alone is commonly used in practice and is the only licensed option to treat VTE in active cancer, it is not cost effective compared with DOACs and reducing its use would be beneficial in conserving NHS resources. Sensitivity analyses were carried out varying the drug prices but these analyses did not change any of the conclusions from the economic model.\n\nThe committee recognised that there are circumstances in which LMWH is the most suitable treatment option and agreed that it could be considered when this is the case. They were aware that LMWH with a VKA is often impractical for people with active cancer because of difficulties with INR monitoring and maintaining INR within the therapeutic range. They agreed that it is less clinically effective than LMWH alone but is less costly and remains a suitable option in some circumstances.\n\nThe committee were aware of an MHRA safety alert warning of an increase in VTE recurrence in people with diagnosed triple positive antiphospholipid syndrome taking a DOAC compared with those taking LMWH and a VKA. Although people with antiphospholipid syndrome were not included in the evidence review, the committee agreed that it is important to include a recommendation highlighting the need to offer LMWH with a VKA to this group.\n\nVTE can be difficult to treat in people who use intravenous drugs. They often have problems with access to medical care and adherence to prescribed treatments. There is a lack of good evidence on the comparative clinical and cost effectiveness of treatments and doses for VTE in this population. The committee made a recommendation for research with the aim of improving VTE treatment in people who use intravenous drugs.\n\nThe committee acknowledged that VTE can recur despite anticoagulant treatment and used their knowledge and experience to outline steps that can be taken if treatment fails.\n\n## How the recommendations might affect practice\n\nThe recommendations are expected to lead to increased use of DOACs, particularly apixaban and rivaroxaban, to treat suspected and confirmed VTE. This should reduce the need for resources to monitor INR, manage bleeding complications and administer parenteral anticoagulation. The recommendation to start anticoagulation treatment before blood test results are available may increase community prescribing of anticoagulation treatment. However, more use of DOACs may also increase the need for expensive reversal agents.\n\nCurrent VTE management for people at extremes of body weight is not expected to change substantially.\n\nFor people with haemodynamically unstable PE, UFH is currently used in clinical practice and the recommendation is not expected to affect the frequency of its use in this group.\n\nMore people with renal impairment are likely to be offered a DOAC or LMWH, reducing the use of UFH. This can be expected to produce cost savings by increasing the number of people with renal impairment who can have outpatient care for VTE.\n\nFor people with active cancer, it is expected that there will be an increase in the use of DOACs and a concomitant decrease in the use of more expensive treatments such as LMWH alone. This will also reduce the amount of district nursing support needed to provide assistance with parenteral therapies.\n\nFor people with VTE and antiphospholipid syndrome, the use of DOACs is expected to decrease.\n\nReturn to recommendations\n\n# Long-term anticoagulation for secondary prevention\n\nRecommendations 1.4.1 to 1.4.12\n\n## Why the committee made the recommendations\n\nThe committee agreed that the benefits of anticoagulation treatment become less certain over time, and that after 3\xa0months (or 3 to 6\xa0months in people with active cancer) treatment needs to be reviewed and a decision made about whether to continue or stop treatment. They agreed that, at this point, the aim of anticoagulation changes from treatment to reducing the risk of recurrence.\n\nThe committee noted that continuing anticoagulation treatment after 3\xa0months is less beneficial for people who have had a provoked DVT or PE if the provoking factor is no longer present, because of the lower rate of recurrence compared with unprovoked DVT or PE.\n\nFor people with unprovoked DVT or PE, the benefits and risks of continuing anticoagulation treatment are less certain and the committee agreed that they need to be carefully balanced. However, for most people with a low bleeding risk, the committee agreed that the benefits of continuing anticoagulation treatment outweigh the risks.\n\nThe committee agreed that the tools currently available to predict the risk of recurrence of VTE or the risk of bleeding are not sufficiently accurate or validated to be used as the sole basis for a decision, and that using them in such a manner might result in incorrect predictions and subsequent harm to the person. However, they also agreed that, in certain circumstances, a clinical prediction tool can be a useful adjunct to discussion with people offered long-term anticoagulation treatment. For bleeding risk, evidence on the HAS-BLED score showed that it can identify people with unprovoked proximal DVT or PE who are at particularly high risk of major bleeding and might benefit from stopping anticoagulation. For VTE recurrence, there was very limited evidence, and that evidence suggested that these tools are not sufficiently accurate to be used in practice.\n\nBecause of the uncertainty in predicting VTE recurrence and the risk of major bleeding, the committee made recommendations for research to develop a new prediction tool for VTE recurrence and major bleeding combined and research to compare this tool with clinical judgement.\n\nThe committee agreed that there are risks involved in switching anticoagulant treatment, particularly if there have been no adverse events with the current treatment. They also expressed concerns about convenience for people who are asked to switch from a DOAC with no monitoring to a VKA regimen with frequent monitoring, or problems with adherence if switching from a VKA to a DOAC. Based on these concerns and their clinical experience, the committee agreed that if treatment is continued beyond 3\xa0months, the first option for most people should be to continue the current treatment if it is well tolerated.\n\nSome evidence indicated that there are fewer major bleeds with apixaban than with rivaroxaban, dabigatran or a VKA. However, the committee were not entirely convinced by this evidence because the study of apixaban had stricter inclusion criteria, setting out which patients took part, than the other studies. Additionally, the studies recorded a very low number of major bleeds, leading to uncertainty about the effects of the different anticoagulation treatments on the likelihood of major bleeding. Apixaban was shown by the economic evidence to be the most cost-effective long-term treatment so the committee agreed that switching to apixaban should be considered as an option for people currently taking a DOAC other than apixaban. Sensitivity analyses were carried out varying the drug prices but these analyses did not change any of the conclusions from the economic model.\n\nThere was a lack of evidence on longer-term treatment for people with renal impairment, active cancer, antiphospholipid syndrome or extremes of body weight. Based on their clinical experience, the committee agreed that continuing the current treatment, if it is well tolerated, should be considered for people in these groups, taking into account their preferences and clinical situation.\n\nFor people who do not continue anticoagulation treatment, evidence showed that aspirin is better than no treatment at reducing DVT or PE recurrence for up to 2\xa0years, although there was no difference in DVT or PE recurrence between aspirin and no treatment at 4\xa0years. On balance, the committee agreed that aspirin can be considered as an option for people who wish to stop anticoagulation treatment, using a prophylactic dose based on current UK practice (75\xa0mg daily or 150\xa0mg daily).\n\nTo ensure that treatment is guided by the person's changing balance of benefits and risks, and changes in their preferences over time, the committee agreed that people taking long-term anticoagulation treatment or aspirin should have their risk of VTE recurrence, bleeding risk and general health reviewed at least once a year.\n\n## How the recommendations might affect practice\n\nThe recommendations to review anticoagulation treatment at 3\xa0months (3 to 6\xa0months for people with active cancer), and annually thereafter, reflect most current practice but may increase the number of appointments and clinician time needed in services that do not currently provide these reviews. Giving patients who stop anticoagulation treatment information on signs and symptoms and a point of contact should ensure that a comprehensive safety net is in place.\n\nDiscussions about the benefits and risks of stopping or continuing anticoagulation treatment may increase the time needed for consultations, particularly if a prediction tool is used as part of the decision-making process. Using HAS-BLED can be expected to reduce long-term anticoagulation treatment in people with a high risk of major bleeding.\n\nThe recommendations are not expected to change practice for people with renal impairment or extremes of body weight. For people with antiphospholipid syndrome, it is expected that DOAC use will decrease, with a concomitant increase in the use of LMWH with a VKA. For people with active cancer, DOAC use can be expected to increase, with LMWH on its own becoming a less common treatment. For people with none of these clinical features, greater use of DOACs, particularly apixaban, for long-term treatment can be expected to lower costs by reducing the need for clinical visits, INR monitoring and managing bleeding events. The use of aspirin may increase for people who decline long-term anticoagulation. This may reduce VTE recurrence in people who would otherwise not receive treatment.\n\nReturn to recommendations\n\n# Inferior vena caval filters\n\nRecommendations 1.7.1 to 1.7.4\n\n## Why the committee made the recommendations\n\nThere was little good evidence on inferior vena caval (IVC) filters. The evidence in a number of populations, including people about to have surgery, people with cancer, people with a high risk of having a subsequent PE and people with a high risk of a poor outcome from a subsequent PE, did not show a benefit from IVC filters. The committee therefore agreed that the use of IVC filters should be restricted to prospective clinical studies (including but not limited to prospective cohort studies and randomised controlled trials) unless anticoagulation is contraindicated or a PE has occurred during anticoagulation treatment. They made a recommendation for research to further investigate the effectiveness of IVC filters.\n\nFor people with proximal DVT or PE and a contraindication to anticoagulation treatment, a small amount of new evidence has become available since the 2012 guideline was published. This evidence did not show a clear difference in outcomes such as mortality and VTE recurrence between people who were given IVC filters and those who were not. One study found evidence of an increase in DVT occurrence (in people with an undefined initial VTE event) at 1\xa0year in the group given IVC filters. However, based on their experience and knowledge of IVC filters, the committee agreed that they can help to reduce the risk of PE when therapeutic anticoagulation cannot be given. The committee also had concerns about the inherent risks involved in using IVC filters, including the invasive nature of the procedure for placing them and the potential for complications such as migration or fracture of the filter. In light of this, the committee agreed that the evidence was not sufficient to retain the 2012 recommendation to offer temporary IVC filters to people who cannot have anticoagulation treatment. However, they recognised that these people have a high risk of recurrent VTE and a limited number of alternative treatments, so agreed that a recommendation to consider an IVC filter for them is justified. They also agreed to retain the 2012 advice to remove the IVC filter when anticoagulation is no longer contraindicated, adding that anticoagulation treatment should be established before the IVC filter is removed.\n\nThere was very limited evidence on the use of IVC filters for people who have a PE while taking anticoagulation treatment for an initial proximal DVT or PE. The evidence suggested a reduction in short-term mortality from all causes in people in this group who had an IVC filter fitted. Because of the limited amount of evidence, the committee agreed that IVC filters could be considered for people in this group only after problems with adherence or other causes of hypercoagulability have been excluded, and different anticoagulation treatments or treatment regimens have been explored. The committee reasoned that, in many cases, optimising anticoagulation treatment will obviate the need for an IVC filter.\n\nThe committee noted that the type of IVC filter used is the same whether it is intended to be temporary or permanent. They agreed that, although the decision between a temporary and permanent IVC filter would be made on a case-by-case basis, most IVC filters are likely to be temporary. It is therefore prudent to have a plan in place for removal of the IVC filter at the time of fitting it, to ensure it is removed promptly when no longer needed.\n\n## How the recommendations might affect practice\n\nIt is expected that the overall impact of the recommendations will be to reduce the use of IVC filters. For people with VTE at acute risk of thrombosis, clinicians may fit an IVC filter as part of a clinical trial.\n\nReturn to recommendations\n\n# Investigations for cancer\n\nRecommendations 1.8.1 and 1.8.2\n\n## Why the committee made the recommendations\n\nUnprovoked VTE is associated with an increased risk of cancer, which may be undiagnosed when the VTE occurs. The committee agreed that a physical examination and review of medical history (including previous investigations such as imaging) are worthwhile precautions for people who have had an apparently unprovoked DVT or PE. However, the evidence did not show any benefit from further investigations for cancer for people who have no signs or symptoms. Moreover, these investigations can be costly, time consuming, potentially invasive or pose a radiation risk, and cause anxiety. The committee therefore agreed that further investigations for cancer should not be offered to people without relevant signs or symptoms.\n\n## How the recommendations might affect practice\n\nA physical examination and a review of medical history is current practice for people with unprovoked DVT or PE. The recommendations can be expected to reduce costs by reducing further investigations for cancer in people without symptoms or signs.\n\nReturn to recommendations", 'Context': "In venous thromboembolism (VTE), a blood clot forms in a vein, usually in the deep veins of the legs or pelvis. This is known as deep vein thrombosis, or deep vein thrombosis (DVT). The blood clot can dislodge and travel in the blood, particularly to the pulmonary arteries. This is known as pulmonary embolism (PE). The term 'VTE' includes both DVT and PE.\n\nFailure to diagnose and treat VTE correctly can result in fatal PE, in which the blood clot blocks the blood supply to the lungs. However, diagnosis of VTE is not always straightforward. This guideline includes advice on the Wells score, D-dimer measurement, ultrasound and radiological imaging. It also offers guidance on treating VTE, investigations for cancer in people with VTE and thrombophilia testing. The guideline covers adults with suspected or confirmed DVT or PE. It does not cover children or young people aged under\xa018, or women who are pregnant.\n\nSince publication of the original guideline in 2012, new evidence has emerged and practice has changed in relation to the use of direct oral anticoagulants, prognostic tools, diagnosis of VTE using age-adjusted and point-of-care D-dimer testing, pulmonary embolism rule-out criteria, outpatient treatment for PE, inferior vena caval filters and investigations for cancer in people with unprovoked VTE. This 2020 update includes new and updated recommendations in these areas."}
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https://www.nice.org.uk/guidance/ng158
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This guideline covers diagnosing and managing venous thromboembolic diseases in adults. It aims to support rapid diagnosis and effective treatment for people who develop deep vein thrombosis (DVT) or pulmonary embolism (PE). It also covers testing for conditions that can make a DVT or PE more likely, such as thrombophilia (a blood clotting disorder) and cancer.
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5c0adef6ae632391a108c7b88ed836cce1c1c538
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nice
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Abdominal aortic aneurysm: diagnosis and management
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Abdominal aortic aneurysm: diagnosis and management
This guideline covers diagnosing and managing abdominal aortic aneurysms. It aims to improve care by helping people who are at risk to get tested, specifying how often to monitor asymptomatic aneurysms, and identifying when aneurysm repair is needed and which procedure will work best.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Diagnosis
## Identifying people at risk of abdominal aortic aneurysms
Inform all men aged 66 or over who have not already been screened about the NHS abdominal aortic aneurysm (AAA) screening programme, and advise them that they can self-refer.
Encourage men aged 66 or over to self-refer to the NHS AAA screening programme if they have not already been screened and they have any of the following risk factors:
chronic obstructive pulmonary disease (COPD)
coronary, cerebrovascular or peripheral arterial disease
family history of AAA
hyperlipidaemia
hypertension
they smoke or used to smoke.
Consider an aortic ultrasound for women aged 70 and over if AAA has not already been excluded on abdominal imaging and they have any of the following risk factors:
COPD
coronary, cerebrovascular or peripheral arterial disease
family history of AAA
hyperlipidaemia
hypertension
they smoke or used to smoke.
Be aware that people of European family origin are at a higher risk of an AAA.
## Identifying asymptomatic abdominal aortic aneurysms
Offer an aortic ultrasound to people in whom a diagnosis of asymptomatic AAA is being considered if they are not already in the NHS screening programme.
Refer people with an AAA that is 5.5 cm or larger to a regional vascular service, to be seen within 2 weeks of diagnosis.
Refer people with an AAA that is 3.0 cm to 5.4 cm to a regional vascular service, to be seen within 12 weeks of diagnosis.
Offer an aortic ultrasound to people with a suspected AAA on abdominal palpation.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on identifying asymptomatic abdominal aortic aneurysms .
Full details of the evidence and the committee's discussion are in evidence review A: risk factors for predicting presence of an abdominal aortic aneurysm and evidence review B: imaging techniques to diagnose abdominal aortic aneurysms.
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## Identifying symptomatic or ruptured abdominal aortic aneurysms
Think about the possibility of ruptured AAA in people with new abdominal and/or back pain, cardiovascular collapse, or loss of consciousness. Be aware that ruptured AAA is more likely if they also have any of the following risk factors:
an existing diagnosis of AAA
age over 60
they smoke or used to smoke
history of hypertension.
Be aware that AAAs are more likely to rupture in women than men.
Offer an immediate bedside aortic ultrasound to people in whom a diagnosis of symptomatic and/or ruptured AAA is being considered. Discuss immediately with a regional vascular service if:
the ultrasound shows an AAA or
the ultrasound is not immediately available or it is non-diagnostic, and an AAA is still suspected.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on identifying symptomatic or ruptured abdominal aortic aneurysms .
Full details of the evidence and the committee's discussion are in evidence review B: imaging techniques to diagnose abdominal aortic aneurysms and evidence review N: signs, symptoms and risk factors predicting ruptured or symptomatic unruptured aneurysms before arrival at the hospital, and in non-specialist hospital settings.
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## Imaging technique
When measuring aortic size with ultrasound, report the inner-to-inner maximum anterior-posterior aortic diameter, in accordance with the NHS AAA screening programme. Clearly document any additional measurements taken.
Offer thin-slice contrast-enhanced arterial-phase CT angiography to people who are being evaluated for elective AAA repair.
Consider thin-slice contrast-enhanced arterial-phase CT angiography for people with a suspected ruptured AAA who are being evaluated for AAA repair.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on imaging technique .
Full details of the evidence and the committee's discussion are in evidence review B: imaging techniques to diagnose abdominal aortic aneurysms.
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## Providing information to people with a diagnosed AAA
Give people with AAA of any size information explaining:
what an AAA is
that most AAAs do not cause any problems
that AAAs can rupture, and what this means
that AAAs are likely to get larger over time, and that larger AAAs are more likely to rupture
that AAA may run in families, so they should tell close relatives that they may have an increased risk of AAA and may need assessment (see recommendations 1.1.2 and 1.1.3)
what options for aneurysm repair are available, when repair should be considered and the potential benefits and risks (see recommendations 1.5.1 and 1.5.2), and when it might be better to not have repair (see recommendation 1.1.14)
their risk of cardiovascular disease and how this risk can be reduced (see recommendation 1.4.6, and see the section on identifying and assessing cardiovascular disease risk in the NICE guideline on cardiovascular disease).
If AAA repair is not currently suitable for a person, explain why, based on their individual circumstances. For example:
Small AAAs only have a very low chance of rupture and there are risks to aneurysm repair, so in this case people do not benefit from repair.
AAA growth is unpredictable, so until their AAA meets the criteria in recommendation 1.5.1 it is not possible to know whether repair will be suitable for a particular person.
On average, people with poor overall health do not benefit from AAA repair. There is no reliable way to assess whether a particular person will benefit or be harmed, so repair for people with poor overall health is an unnecessary risk even if their AAA meets the criteria in recommendation 1.5.1.
Check that people understand their options, and give them time for reflection and discussion. Encourage them to discuss the options with their family and friends.
For more guidance on providing information, see the section on enabling patients to actively participate in their care in the NICE guideline on patient experience in adult NHS services.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on providing information to people with a diagnosed AAA .
Full details of the evidence and the committee's discussion are in evidence review K: effectiveness of endovascular aneurysm repair, open surgical repair and non-surgical management of unruptured abdominal aortic aneurysms.
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# Monitoring and reducing the risk of rupture
## Reducing the risk of rupture
Offer a referral to a stop smoking service to people with an abdominal aortic aneurysm (AAA) who smoke. For more guidance, see the NICE guideline on tobacco: preventing uptake, promoting quitting and treating dependence.
Ensure that people with an AAA who have hypertension receive care in line with the NICE guideline on hypertension in adults.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on reducing the risk of rupture .
Full details of the evidence and the committee's discussion are in evidence review C: risk factors associated with abdominal aortic aneurysm growth or rupture.
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## Monitoring the risk of rupture
Offer surveillance with aortic ultrasound to people with an asymptomatic AAA. Use the same surveillance frequency as the NHS AAA screening programme.
See recommendation 1.1.5 on when to refer people to a regional vascular unit.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on monitoring the risk of rupture .
Full details of the evidence and the committee's discussion are in evidence review D: monitoring for abdominal aortic aneurysm expansion and risk of rupture.
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# Emergency transfer to regional vascular services
Be aware that there is no evidence that any single symptom, sign or prognostic risk assessment tool can be used to determine whether people with a suspected or confirmed ruptured abdominal aortic aneurysm (AAA) should be transferred to a regional vascular service.
When making transfer decisions, be aware that people with a confirmed ruptured AAA who have a cardiac arrest and/or have a persistent loss of consciousness have a negligible chance of surviving AAA repair.
For guidance on care of people with a ruptured AAA for whom repair is considered inappropriate, see the NICE guideline on care of dying adults in the last days of life.
When people with a suspected ruptured or symptomatic unruptured AAA have been accepted by a regional vascular service for emergency assessment, ensure that they leave the referring unit within 30 minutes of the decision to transfer.
Emergency departments, ambulance services and regional vascular services should collaborate to:
provide a protocol for the safe and rapid transfer of people with a suspected ruptured or symptomatic unruptured AAA who need emergency assessment at a regional vascular service
train clinical staff involved in the care of people with a suspected ruptured or symptomatic unruptured AAA in the transfer protocol
review the transfer protocol at least every 3 years.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on emergency transfer to regional vascular services .
Full details of the evidence and the committee's discussion are in evidence review O: signs, symptoms and risk factors indicating suitability for transfer to a regional vascular service and evidence review P: time period for transfer to regional vascular services.
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## Supporting people during transfer
Consider a restrictive approach to volume resuscitation (permissive hypotension) for people with a suspected ruptured or symptomatic AAA during emergency transfer to a regional vascular service.
For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on supporting people during transfer .
Full details of the evidence and the committee's discussion are in evidence review Q: permissive hypotension during transfer of people with ruptured abdominal aortic aneurysm to regional vascular services.
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# Predicting and improving surgical outcomes
## Predicting surgical outcomes for unruptured aneurysms
Consider cardiopulmonary exercise testing when assessing people for elective repair of an asymptomatic abdominal aortic aneurysm (AAA), if it will assist in shared decision making.
For guidance on other preoperative tests, see the NICE guideline on routine preoperative tests for elective surgery.
Do not use the following risk assessment tools to determine whether or not repair is suitable for a person with an asymptomatic unruptured AAA:
British Aneurysm Repair score
Carlisle Calculator
Comorbidity Severity Score
Glasgow Aneurysm Scale
Medicare risk prediction tool
Modified Leiden score
Physiological and Operative Severity Score for enUmeration of Mortality (POSSUM)
Vascular-POSSUM
Vascular Biochemical and Haematological Outcome Model (VBHOM)
Vascular Governance North West (VGNW) risk model.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on predicting surgical outcomes in unruptured aneurysms .
Full details of the evidence and the committee's discussion are in evidence review G: tests for predicting outcomes after repair of unruptured abdominal aortic aneurysms and evidence review H: risk assessment tools for predicting surgical outcomes of patients who undergo elective abdominal aortic aneurysm repair.
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## Predicting surgical outcomes for ruptured aneurysms
Do not use any single symptom, sign or patient-related risk factor to determine whether aneurysm repair is suitable for a person with a ruptured AAA.
Do not use patient risk assessment tools (scoring systems) to determine whether aneurysm repair is suitable for a person with a ruptured AAA.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on predicting surgical outcomes for ruptured aneurysms .
Full details of the evidence and the committee's discussion are in evidence review S: risk factors for predicting survival after abdominal aortic aneurysm rupture.
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## Improving surgical outcomes
Offer people with an AAA information, support and interventions for secondary prevention of cardiovascular disease. For more information refer to the NICE guidance on:
tobacco: preventing uptake, promoting quitting and treating dependence
diet, nutrition and obesity and exercise
medicines optimisation
lipid modification and statin therapy
diabetes management
hypertension diagnosis and management.
Do not routinely offer preoperative beta blockers to people having AAA repair.
Do not offer remote ischaemic preconditioning to people having AAA repair.
For guidance on preventing and treating surgical site infections and on preventing venous thromboembolism, see the NICE guidelines on surgical site infections and reducing the risk of venous thromboembolism.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on improving surgical outcomes .
Full details of the evidence and the committee's discussion are in evidence review J: pre- and postoperative interventions to optimise outcomes after abdominal aortic aneurysm repair.
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# Repairing unruptured aneurysms
## When to consider repair
Consider aneurysm repair for people with an unruptured abdominal aortic aneurysm (AAA), if it is:
symptomatic
asymptomatic, larger than 4.0 cm and has grown by more than 1 cm in 1 year (measured inner-to-inner maximum anterior-posterior aortic diameter on ultrasound)
asymptomatic and 5.5 cm or larger (measured inner-to-inner maximum anterior-posterior aortic diameter on ultrasound).
## Discussing the benefits and risks of repair or conservative management
When discussing aneurysm repair with people who have an unruptured AAA, explain the overall balance of benefits and risks with repair and with conservative management, based on their current health and their expected future health. The decision on whether repair is preferred over conservative management should be made jointly by the person and their clinician after assessment of a number of factors, including:
aneurysm size and morphology
the person's age, life expectancy, fitness for surgery, and any other conditions they have
the risk of AAA rupture if they do not have repair
the short- and long-term benefits and risks, and the other disadvantages of repair such as having to stay in hospital, the risks of the operation, the recovery period, the potential need for further procedures and the need for surveillance imaging appointments
the uncertainties around estimates of risk for AAAs larger than 5.5 cm (measured inner-to-inner maximum anterior-posterior aortic diameter on ultrasound).
## Open surgical repair, standard endovascular aneurysm repair or conservative management
Offer open surgical repair for people with unruptured AAAs meeting the criteria in recommendation 1.5.1, unless it is contraindicated because of their abdominal copathology, anaesthetic risks, and/or medical comorbidities.
Consider endovascular aneurysm repair (EVAR) for people with unruptured AAAs who meet the criteria in recommendation 1.5.1 and who have abdominal copathology, such as a hostile abdomen, horseshoe kidney or a stoma, or other considerations, specific to and discussed with the person, that may make EVAR the preferred option.
Consider EVAR or conservative management for people with unruptured AAAs meeting the criteria in recommendation 1.5.1 who have anaesthetic risks and/or medical comorbidities that would contraindicate open surgical repair.
## Complex endovascular aneurysm repair
If open surgical repair and complex EVAR are both suitable options, only consider complex EVAR if:
the following has been discussed with the person:
the risks of complex EVAR compared with the risks of open surgical repair
the uncertainties around whether complex EVAR improves perioperative survival or long-term outcomes, when compared with open surgical repair
it will be performed with special arrangements for consent and for audit and research that will determine the clinical and cost effectiveness of complex EVAR when compared with open surgical repair, and all patients are entered onto the National Vascular Registry.
For people who have anaesthetic risks and/or medical comorbidities that would contraindicate open surgical repair, only consider complex EVAR if:
the following has been discussed with the person:
the risks of complex EVAR compared with the risks of conservative management
the uncertainties around whether complex EVAR improves perioperative survival or long-term outcomes
it will be performed with special arrangements for consent and for audit and research that will determine the clinical and cost effectiveness of complex EVAR when compared with conservative management, and all patients are entered onto the National Vascular Registry.
NICE amended recommendations 1.5.1 to 1.5.7, after the committee's proposed recommendations were reviewed by NICE's Board.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on repairing unruptured aneurysms .
Full details of the evidence and the committee's discussion are in:
evidence review F: thresholds for abdominal aortic aneurysm repair
evidence review K: effectiveness of endovascular aneurysm repair, open surgical repair and non-surgical management of unruptured abdominal aortic aneurysms
evidence review K2: observational evidence on the effectiveness of endovascular aneurysm repair compared with open surgical repair of unruptured abdominal aortic aneurysms.
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## Anaesthesia and analgesia
Consider epidural analgesia in addition to general anaesthesia for people having open surgical repair of an unruptured AAA.
For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on anaesthesia and analgesia during unruptured aneurysm repair .
Full details of the evidence and the committee's discussion are in evidence review L: anaesthesia and analgesia for people having surgical repair of an abdominal aortic aneurysm.
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# Repairing ruptured aneurysms
Consider endovascular aneurysm repair (EVAR) or open surgical repair for people with a ruptured infrarenal abdominal aortic aneurysm (AAA). Be aware that:
EVAR provides more benefit than open surgical repair for most people, especially men over 70 and women of any age
-pen surgical repair is likely to provide a better balance of benefits and harms in men under 70.
Consider open surgical repair for people with a ruptured AAA if standard EVAR is unsuitable.
Do not offer complex EVAR to people with a ruptured AAA if open surgical repair is suitable, except as part of a randomised controlled trial comparing complex EVAR with open surgical repair.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on repairing ruptured aneurysms .
Full details of the evidence and the committee's discussion are in evidence review T: effectiveness of endovascular aneurysm repair compared with open surgical repair of ruptured abdominal aortic aneurysms.
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## Anaesthesia and analgesia
Consider using local infiltrative anaesthesia alone for people having EVAR of a ruptured AAA.
For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on anaesthesia and analgesia during ruptured aneurysm repair .
Full details of the evidence and the committee's discussion are in evidence review L: anaesthesia and analgesia for people having surgical repair of an abdominal aortic aneurysm.
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## Abdominal compartment syndrome
Be aware that people can develop abdominal compartment syndrome after EVAR or open surgical repair of a ruptured AAA.
Assess people for abdominal compartment syndrome if their condition does not improve after EVAR or open surgical repair of a ruptured AAA.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on abdominal compartment syndrome .
Full details of the evidence and the committee's discussion are in evidence review U: preventing abdominal compartment syndrome following repair of ruptured abdominal aortic aneurysm.
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# Monitoring for complications after endovascular aneurysm repair
Enrol people who have had endovascular aneurysm repair (EVAR) into a surveillance imaging programme.
Base the frequency of surveillance imaging on the person's risk of EVAR-related complications.
Consider contrast-enhanced CT angiography or colour duplex ultrasound for assessing abdominal aortic aneurysm (AAA) diameter and EVAR device limb kinking.
Use contrast-enhanced CT angiography if an endoleak is suspected. If contrast-enhanced CT angiography is contraindicated, use contrast-enhanced ultrasound.
Do not exclude endoleaks based on a negative colour duplex ultrasound alone in people who have had EVAR.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on monitoring for complications after endovascular aneurysm repair .
Full details of the evidence and the committee's discussion are in evidence review V: postoperative surveillance after surgical repair of abdominal aortic aneurysms and evidence review W: accuracy of imaging techniques in identifying complications after surgery.
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# Managing endoleaks after endovascular aneurysm repair
Consider open, endovascular or percutaneous intervention for type 1 and type 3 endoleaks following endovascular aneurysm repair (EVAR).
Consider intervention for type 2 endoleaks in people who have abdominal aortic aneurysm (AAA) expansion following EVAR.
Consider further investigation of type 5 endoleaks following EVAR.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on managing endoleaks after endovascular aneurysm repair .
Full details of the evidence and the committee's discussion are in evidence review X: managing complications after abdominal aortic aneurysm repair.
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# Terms used in this guideline
This section defines terms that have been used in a specific way for this guideline. For general definitions, please see the NICE glossary.
## Standard and complex EVAR
Standard EVAR is defined as any EVAR procedure:
using a standard infrarenal device (an unmodified off-the-shelf stent graft) and
following the manufacturer's 'instructions for use' for the device used and
without any adjunctive procedures (planned use of endo-anchors and planned permanent instrumentation of aortic branch vessels, such as 'chimney' or 'snorkel' procedures).
Any EVAR procedure that does not fit into the definition above is classed as 'complex EVAR'. Complex EVAR also covers fenestrated, branched, customised or internal iliac branch devices, and physician-modified stent grafts.
## Endoleak
The persistence of blood flow outside an endovascular stent–graft but within the aneurysm sac in which the graft is placed. There are 5 types of endoleak:
Type 1 – blood flowing into the aneurysm because of an incomplete or ineffective seal at either end of a stent–graft
Type 2 – blood flowing into an AAA from side branches of the aorta
Type 3 – blood flowing into an AAA through defects in the endograft
Type 4 – blood flowing through the stent–graft fabric into an AAA
Type 5 – continued AAA expansion without radiographic evidence of a leak site.
## Hostile abdomen
An abdomen that is difficult to perform open surgery within, because of adverse anatomical features. For AAA repair, these features can include large abdominal wall defects or intra-abdominal adhesions. A hostile abdomen is most common in people who have had multiple previous episodes of intra-abdominal open surgery.
## Infrarenal abdominal aortic aneurysm
An abdominal aortic aneurysm arising below the arteries that supply the kidneys.
## Permissive hypotension
A method of fluid administration that aims to reduce bleeding by keeping a person's blood pressure within a lower-than-normal range.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Key recommendations for research
## Monitoring frequencies and repair thresholds
What are the most effective and cost-effective frequencies for monitoring people with unruptured abdominal aortic aneurysms (AAA) of different diameters, and what is the optimal AAA threshold size (inner-to-inner maximum anterior-posterior diameter on ultrasound) for repair?
More frequent monitoring increases the chances of identifying aneurysms that have grown large enough to be considered for repair. However, monitoring requires resources and the absolute risk of AAA rupture is relatively low, so there are opportunity costs to consider. It is important to establish how often aneurysms should be monitored to keep the risk of rupture as low as possible while making the best use of NHS resources.
The optimal threshold for repair of an AAA is not clear. There is good evidence that in most cases people do not need repair for aneurysms measuring smaller than 5.5 cm (inner-to-inner maximum anterior-posterior aortic diameter) on ultrasound. However, for some people a threshold above 5.5 cm may be more appropriate.
## Effectiveness of endovascular aneurysm repair and open surgical repair of complex unruptured and ruptured abdominal aortic aneurysms
What is the effectiveness and cost effectiveness of complex endovascular aneurysm repair (EVAR) versus open surgical repair in people for whom open surgical repair is suitable for:
elective repair of an unruptured AAA or
emergency repair of a ruptured AAA?
EVAR is a widely performed non-invasive alternative to open surgical repair. However, it is more expensive. Although standard EVAR has been shown to produce no long-term benefit over open surgical repair in people with an unruptured infrarenal abdominal aortic aneurysm, it is less clear whether this is the same in people with who would need complex EVAR to repair their AAA. The committee's view was that, because current practice is subject to strong prior beliefs about the relative benefits and harms of EVAR and open surgical repair for complex AAA, randomisation is critical to provide an unbiased estimate of comparative effectiveness.
## Macrolides for slowing aneurysm growth and reducing the risk of rupture
What are the benefits and harms of macrolides (such as azithromycin) for reducing AAA growth rates and the risk of rupture?
Small AAAs are currently managed by monitoring, until the aneurysm reaches a diameter at which surgical repair is considered. There are currently no non-surgical interventions available to prevent AAAs from growing, and subsequently rupturing. A randomised controlled trial would be useful to determine whether macrolides reduce the rate of AAA growth and the risk of rupture.
## Metformin for slowing aneurysm growth and reducing the risk of rupture
What are the benefits and harms of metformin for reducing AAA growth rates and the risk of rupture?
Observational study data suggest an association between diabetes and slower AAA growth, and it has been proposed that this may be due to the use of metformin. A randomised controlled trial is needed to determine whether metformin reduces the rate of AAA growth and the risk of rupture.
## Tranexamic acid for preventing and treating excessive blood loss during EVAR or open surgical repair
Does tranexamic acid reduce blood loss and so improve survival in people who are having repair (EVAR or open surgical repair) of a ruptured AAA?
Tranexamic acid is used to reduce blood loss in major trauma, postpartum bleeding and surgery. By slowing down blood loss from a ruptured AAA, the use of tranexamic acid may improve survival from ruptured AAA. A randomised controlled trial is needed to determine whether tranexamic acid improves survival in people having EVAR or open surgical repair of a ruptured AAA.
## Prehabilitation (including preoperative exercise programmes) for improving the outcome of aneurysm repair
What is the clinical effectiveness and cost effectiveness of prehabilitation, including preoperative exercise programmes, for improving outcomes of people who are having repair of an AAA?
NHS providers have started devoting resources to prehabilitation programmes, based on a relatively small body of evidence. Research is needed to determine if prehabilitation is effective and the optimal form it should take.
# Other recommendations for research
## Direct oral anticoagulants after abdominal aortic aneurysm repair
What are the benefits of postoperative use of direct oral anticoagulants (DOACs) for improving outcomes after repair of AAA?
## Permissive hypotension
Does permissive hypotension improve survival of patients undergoing repair of ruptured AAA?
## Surveillance after endovascular aneurysm repair
What are the risks, benefits and cost implications of different surveillance protocols in people who have undergone EVAR?# Rationale and impact
# Identifying asymptomatic abdominal aortic aneurysms
## Why the committee made the recommendations
Recommendations 1.1.1 to 1.1.6
The committee were mindful that the NHS abdominal aortic aneurysm (AAA) screening programme does not cover men under 65 or women of any age. This means some men and all women who are at risk of AAA are not currently screened. The recommendations highlight these groups and specify risk factors significantly associated with AAA that could be used to help with opportunistic screening.
There are also men who have no risk factors for AAA and were not seen by the screening programme when they turned 65. As their risk of AAA is low, the committee only recommended informing them about the NHS AAA screening programme and how it works. Men can then self-refer if they feel screening is right for them. Evidence from cross-sectional studies also found that people of Hispanic, African-American and Asian family origin were individually less likely than people of European family origin to have an AAA, so the committee wished to raise awareness of this.
Aortic ultrasound is recommended because it is the standard technique used in clinical practice and in the screening programme. It has high diagnostic accuracy, and is associated with lower costs and fewer side effects than CT. People with an AAA diameter of 5.5 cm or larger (inner-to-inner maximum anterior-posterior aortic diameter on ultrasound) need to be seen by a regional vascular service within 2 weeks because their aneurysm is at higher risk of rupture. The committee recommended that people with aneurysms less than 5.5 cm in diameter are seen within 12 weeks of diagnosis because this is the timeframe set by the NHS AAA screening programme.
## How the recommendations might affect practice
The recommendations outlining key risk factors will increase the number of people being screened and improve AAA diagnosis. The recommendations should also promote equal access to healthcare, because they provide guidance on when a potential AAA should be investigated in women, who are currently not covered by the NHS AAA screening programme.
Using aortic ultrasound to detect AAAs is good practice. The recommendations ensure that the time within which people with newly-identified aneurysms are seen by regional vascular services is proportional to the risk of rupture. These timings match the timeframe the NHS AAA screening programme uses for people they assess.
Return to recommendations
# Identifying symptomatic or ruptured abdominal aortic aneurysms
## Why the committee made the recommendations
Recommendations 1.1.7 to 1.1.9
Based on their own experience, the committee highlighted the most important signs and symptoms of ruptured AAAs, because:
non-specialists commonly fail to diagnose them
improved diagnosis should increase the chance of survival
urgent discussion of a suspected ruptured AAA with a regional vascular service will improve the chances of appropriate treatment and survival.
Aortic ultrasound is the standard technique for detecting the presence of AAA in a person with a suspected ruptured aneurysm. A ruptured AAA is a surgical emergency, and bedside ultrasound is the quickest reliable method to confirm the presence of an AAA. An immediate discussion with the regional vascular unit ensures appropriate management is started as soon as possible. The committee recognised that the sensitivity of aortic ultrasound is not 100% and several factors can make it difficult to visualise the aorta. Since AAA rupture is a life-threatening surgical emergency, they agreed that it would be safest to discuss any non-diagnostic ultrasound findings with the regional vascular unit.
## How the recommendations might affect practice
There is variation in awareness of AAA among non-specialists. Implementing the recommendations should reduce this variation and increase the chance of ruptured AAA being diagnosed earlier.
Using bedside aortic ultrasound to detect AAAs is common practice. Preventing delays to repair through immediate discussions with a regional vascular unit should improve outcomes for people with ruptured AAAs.
Return to recommendations
# Imaging technique
## Why the committee made the recommendations
Recommendations 1.1.10 to 1.1.12
The committee agreed that it was important to take consistent measurements of aneurysm size throughout the NHS, so that results are comparable. The NHS AAA screening programme specifies inner-to-inner maximum anterior-posterior aortic diameter on ultrasound, and the committee agreed this would be the most appropriate measurement on which to base practice across the whole NHS.
The committee recommended thin-slice contrast-enhanced arterial-phase CT angiography for imaging in people being evaluated for elective repair, because it is widely recognised as the gold standard technique for assessing aneurysm anatomy before repair. For suspected ruptured AAAs, CT angiography should also be considered. However, the committee recognised that some people will need immediate transfer for repair without waiting for a CT scan.
No evidence was found demonstrating whether or not post-processing techniques affected postoperative outcomes for people having elective or emergency AAA repair. As post-processing techniques are an established part of clinical practice, the committee agreed not to make recommendations in this area.
## How the recommendations might affect practice
Implementing a consistent measurement method to be used across the NHS (and that matches the method used in the NHS AAA screening programme) will improve the reproducibility of results, improving surveillance for individuals with AAA and the ability to analyse data at the population level.
Thin-slice contrast-enhanced arterial-phase CT angiography is widely used for imaging in people being evaluated for AAA repair, so this recommendation is unlikely to make a major difference to current practice. The recommended timings reflect current standards within the NHS AAA screening programme.
As post-processing techniques are established in practice, a lack of recommendations on these will not have an impact.
Return to recommendations
# Providing information to people with a diagnosed AAA
## Why the committee made the recommendations
Recommendations 1.1.13 to 1.1.15
The committee agreed some consensus recommendations on what information should be provided to people who have been diagnosed with an AAA. In particular, the recommendations cover information for people who are not being considered for repair, either because their AAA is too small (data from the NHS screening programme show that the risk of rupture for an AAA below 5.5 cm is only 0.4% per year) or because their medical comorbidities mean the risks of repair outweigh the benefits. It is important to avoid making people anxious about not being offered repair, but also to avoid giving the impression that AAA repair is always beneficial if the aneurysm meets the criteria for treatment (see recommendation 1.5.1). Explaining how the decision to repair is made (based on the person's health at that particular time) and the uncertainties around this will help people to better understand the options available.
The committee emphasised that clinicians should ensure that people understand their options and the balance of risks they face. They noted that several clinic visits, including opinions from specialists such as anaesthetists, geriatricians, and cardiologists, are likely to be needed.
Return to recommendations
# Reducing the risk of rupture
## Why the committee made the recommendations
Recommendations 1.2.1 and 1.2.2
The committee focused on modifiable risk factors that could influence the management of people with known AAAs. There was some evidence that high blood pressure increases the chance of AAA growth and rupture, and the committee knew from their own experience that people with an AAA do not always receive appropriate management for high blood pressure. There is also evidence that smoking increases the risk of AAA rupture. As a result, the committee referred to the NICE guidelines on these topics.
The committee agreed that there was not enough high-quality evidence to make clinical recommendations on non-surgical interventions for slowing aneurysm growth and reducing the risk of rupture. In light of this, they made research recommendations on 2 drug interventions that might reduce aneurysm growth and rupture risk.
## How the recommendations might affect practice
The NICE guidelines on hypertension and stop smoking services cover current practice, so organisations are unlikely to need to change practice.
Non-surgical interventions for small AAAs are not usually used outside of clinical trials, so a lack of recommendations will have little impact on practice.
Return to recommendations
# Monitoring the risk of rupture
## Why the committee made the recommendations
Recommendations 1.2.3 and 1.2.4
The committee recommended ultrasound surveillance because ultrasound is current practice and no evidence was found for other imaging techniques. They recommended that monitoring frequency should be in line with the NHS AAA screening programme to ensure consistency across the whole NHS. The screening programme surveillance intervals are based on evidence on risk of rupture, depending on the size of the AAA. This means that people with larger aneurysms are monitored more frequently, offering the best balance between benefits and costs.
The committee are aware that the NHS AAA screening programme may change the surveillance intervals it uses in the future. If this happens, the committee agreed that regional vascular services should change to match the new intervals, to ensure that they continue to provide care based on best practice.
## How the recommendations might affect practice
Changing monitoring intervals to reflect those used in the NHS AAA screening programme will maintain a consistent standard across the NHS, and ensure that the most effective imaging intervals are used.
Return to recommendations
# Emergency transfer to regional vascular services
## Why the committee made the recommendations
Recommendations 1.3.1 to 1.3.5
There was no evidence on symptoms, signs or risk assessment tools for deciding whether people with ruptured aneurysms are likely to survive transfer to a regional vascular service. Based on their own experience, the committee highlighted specific circumstances (cardiac arrest and persistent loss of consciousness) in which people are unlikely to survive transfer and subsequent aortic repair. This will help reduce the number of people being given ineffective and invasive treatment at the end of life.
The committee referred to the NICE guideline on care of dying adults in the last days of life to ensure that appropriate and compassionate care is given to people with a ruptured AAA when the decision has been made not to operate.
There was also no evidence on how quickly people with ruptured AAA should be transferred to regional vascular units. In the absence of evidence, the committee adapted recommendations from the NICE guideline on service delivery for major trauma. They agreed, based on their experience of emergency transfer, that the timing specified for people with major trauma was appropriate for people with ruptured AAA and manageable for referring units.
## How the recommendations might affect practice
The recommendations on assessing people for transfer will raise awareness among emergency staff, but will have little resource impact on clinical practice. The recommendations on transfer speed will improve practice by minimising variation in transfer times across the NHS. The timeframe recommended is the same as for major trauma, and the committee agreed that this is a reasonably similar situation.
The NICE guideline on care of dying adults cover current practice, so organisations are unlikely to need to change practice.
Return to recommendations
# Supporting people during transfer
## Why the committee made the recommendation
Recommendation 1.3.6
As there was no evidence specific to the use of permissive hypotension during transfer of people with ruptured or symptomatic AAA, the committee agreed that a consensus recommendation was needed in this important clinical area. As a result the committee adapted recommendations from the NICE guideline on assessment and initial management for major trauma.
## How the recommendation might affect practice
The recommendation will reduce the likelihood of inappropriate fluid administration during transfer of people with ruptured AAA. This, in turn, will improve the outcomes of endovascular aneurysm repair and open surgical repair procedures. The recommendation is in line with NICE recommendations on fluid administration for other major trauma, and the committee agreed that this was appropriate for ruptured AAA.
Return to recommendation
# Predicting surgical outcomes in unruptured aneurysms
## Why the committee made the recommendations
Recommendations 1.4.1 and 1.4.3
There was limited evidence that cardiopulmonary exercise testing can help predict outcomes following endovascular aneurysm repair (EVAR) and open surgical repair. While the evidence was limited, the committee agreed that cardiopulmonary exercise testing could have a useful role in shared decision-making between healthcare professionals and patients when the benefits and harms of surgery are uncertain.
There are other tests for assessing people before surgery, but there was no evidence available for them. One study found that higher estimated glomerular filtration rate (eGFR) was associated with improved outcomes after elective EVAR, but it did not give clear eGFR thresholds that could be used in decision-making. In the absence of evidence, the committee referred to the NICE guideline on routine preoperative tests for elective surgery. Some of the studies reviewed for that guideline focused on people having elective AAA repair.
The evidence highlighted that none of the risk assessment tools had a high enough predictive accuracy at predicting postoperative outcomes. The specific tools listed are the ones for which evidence was available. This evidence led the committee to conclude that these tools would not improve decision-making and could potentially lead to inappropriate decisions about patient management. They agreed that this could lead to harm, and therefore advised that risk assessment tools should not be used.
## How the recommendations might affect practice
The use of cardiopulmonary exercise testing will have limited impact on practice as it is only recommended in situations where it will help in shared decision-making.
Risk assessment tools are not widely used outside the context of research on AAA. Therefore, the recommendations will have little impact on practice.
Return to recommendations
# Predicting surgical outcomes for ruptured aneurysms
## Why the committee made the recommendations
Recommendations 1.4.4 and 1.4.5
There is evidence that some risk factors and risk assessment tools are associated with poor postoperative outcomes. However, it is not clear how any particular factor or combination of factors could be used to decide if aneurysm repair is suitable for a person with a ruptured AAA. The committee emphasised that there is a potential for harm if clinicians base their decision to repair solely on risk assessment tools and scores, because some people would be inappropriately offered or denied repair.
## How the recommendations might affect practice
The recommendations will have a beneficial impact, by ensuring decisions about care are not made based on inappropriate factors or tools. This, in turn, should prevent inappropriate decisions being made about whether or not to offer repair.
Return to recommendations
# Improving surgical outcomes
## Why the committee made the recommendations
Recommendations 1.4.6 to 1.4.9
The committee made a recommendation on cardiovascular disease because it is common in people with AAA and it is best practice to reduce the risk of problems in people who have it. The other NICE guidelines that are referenced include recommendations to help reduce this risk.
The evidence showed that giving beta blockers just before surgery is not beneficial, and may be harmful by lowering low blood pressure and heart rate. The committee noted that some people with AAA may need to take beta blockers for other conditions (such as atrial fibrillation). As a result, they recommended against routine use before AAA repair, rather than recommending against beta blockers altogether.
Remote ischaemic preconditioning was not recommended because there was evidence that it does not improve outcomes and that it can cause problems such as an irregular heartbeat.
The committee recommended further research because there was not enough evidence to make recommendations on prehabilitation (including exercise programmes before surgery), or on any interventions after AAA repair.
## How the recommendations might affect practice
Providing support to reduce the risk of problems from cardiovascular disease is already current practice. In addition, beta blockers and routine ischaemic preconditioning are not currently in routine use before AAA repair, so these recommendations should have a minimal impact on practice.
Return to recommendations
# Repairing unruptured aneurysms
## Why NICE made the recommendations
Recommendations 1.5.1 to 1.5.7
A number of factors should be considered before treating asymptomatic aneurysms, one of which is size.
It is standard practice to repair large aneurysms (over 5.5 cm in diameter on ultrasound, measured using an anterior-posterior diameter inner-to-inner), and to monitor smaller aneurysms (less than 4 cm in diameter) until they become larger. Repair is sometimes offered for aneurysms below 5.5 cm if they are growing rapidly, or if they are symptomatic. However, data from the NHS screening programme show that, for aneurysms below 5.5 cm, the risk of rupture remains very low (0.4% per year). It is clear from the evidence that there is no benefit to repairing aneurysms that are below 5.5 cm, asymptomatic and not growing rapidly. Based on this evidence, we highlighted factors that would help healthcare professionals decide when to repair aneurysms.
Given the risks and other disadvantages of AAA repair, conservative management is sometimes a better option. Because of this, healthcare professionals need to explain the balance of benefits and risks to people with AAAs, so they can make an informed decision.
The evidence showed that, compared with open surgical repair for people with an unruptured infrarenal abdominal aortic aneurysm, elective EVAR has medium- and long-term harms that outweigh its short-term benefits. EVAR is associated with fewer perioperative deaths, and less time in hospital in general (and critical care in particular). But it also has worse long-term survival than open surgical repair, and more long-term complications, leading to further procedures.
Even when taking the short-term benefits of EVAR into account, all plausible cost-effectiveness estimates show that EVAR either:
has higher net costs and lower net benefits than open surgical repair or
is substantially above the range NICE normally considers to be a cost-effective use of NHS resources.
There is a small group of people who have abdominal copathology or other considerations that mean open surgical repair is unsuitable. Examples of copathologies include people who have internal scar-tissue from previous abdominal surgery (a so-called hostile abdomen), people who have a single, fused kidney that is wrapped around the aorta ('horseshoe kidney'), and people who have a stoma. Although there was no evidence on this population, EVAR is a potential option for these people, as the risks of open surgical repair may be much higher for them. This recommendation should not be used to extend EVAR to people who could reasonably have open surgical repair.
Open surgical repair is contraindicated for some people with an unruptured AAA because of anaesthetic risks and/or medical comorbidities. For these people, the risk of their AAA rupturing if no repair is attempted has to be balanced against:
the perioperative risks and long-term complications of EVAR
the uncertainty around whether they will benefit from EVAR
the large costs of EVAR.
With all this in mind, it is clear that practice needs to be rebalanced. Conservative management is a better option than EVAR for many people. However, NICE also acknowledged stakeholder comments highlighting the importance of individualised care. For some people, EVAR may be appropriate. Clinicians should discuss the risks of EVAR and conservative management with people with AAAs, taking into account the uncertainty that EVAR will provide a benefit.
People who are not offered repair may be anxious about having an AAA but not receiving treatment for it. However, a better explanation of the risks they face, in the context of their other life-limiting comorbidities, can help with anxiety. To help with this, the committee made consensus recommendations (see recommendations 1.1.13 to 1.1.14) on the information to cover when discussing repair with people who have an AAA.
The evidence for complex EVAR was limited in quantity and quality. However, complex EVAR grafts and procedures are much more expensive than standard EVAR, so the difference in cost between EVAR and open surgical repair is likely to be even greater than for infrarenal AAAs. In addition, using standard EVAR stent grafts for complex AAA usually violates the manufacturer's 'instructions for use'.
Although there is currently no evidence that complex EVAR has better outcomes than open surgical repair, people with complex AAAs have higher perioperative mortality rates than people with infrarenal AAAs. Because of this, an increased perioperative survival benefit may be more important for them, and may justify the use of complex EVAR. This would differentiate complex EVAR from standard EVAR, which clearly does not provide enough short-term benefits to outweigh the worse long-term outcomes or the increased cost (when compared with open surgical repair).
Open surgical repair is contraindicated for some people with an unruptured AAA because of anaesthetic risks and/or medical comorbidities. For these people, the risk of their AAA rupturing if no repair is attempted has to be balanced against:
the perioperative risks and long-term complications of complex EVAR
the uncertainty around whether they will benefit from complex EVAR
the large costs of complex EVAR.
With all this in mind, it is clear that conservative management is a better option than complex EVAR for many people. However, NICE also acknowledged stakeholder comments highlighting the importance of individualised care. For some people, complex EVAR may be appropriate. Clinicians should discuss the risks of complex EVAR and conservative management with people with AAAs, taking into account the uncertainty that complex EVAR will provide a benefit.
As with standard EVAR, NICE acknowledged that in the face of the evidence reviewed, practice needs to be rebalanced towards open surgical repair in this scenario as well. But, because of the limited evidence for complex EVAR and the importance of individualised care, NICE concluded that it is important for clinicians and people with AAA to discuss the uncertainties and weigh up the risks and benefits of repair, in order to make an informed decision.
More evidence on this procedure would be helpful, and NICE has made a recommendation for research comparing complex EVAR with open surgical repair.
For each of the recommendations, NICE considered whether there were any specific groups that would benefit from standard or complex EVAR for unruptured AAAs. We explored groups defined by age, sex, AAA diameter and life expectancy, but it was not possible with the current evidence to identify any specific groups in which the benefits would outweigh the harm and costs.
The key randomised controlled trials (RCTs) in this area are relatively old. NICE looked at more recent observational evidence, to see if changes in surgical and endovascular techniques and technology have led to different outcomes. The observational studies are at high risk of bias, but their findings are broadly in line with the RCTs. They show that, while outcomes from EVAR have improved over the last 15 years, outcomes from open surgical repair have also improved by roughly the same amount. This means the difference in outcomes between the two has remained fairly constant.
Registries like the National Vascular Registry can provide a useful snapshot of current practice, and the analyses that informed NICE's decision-making made use of data from them. However, they are not designed to evaluate the comparative benefits and harms of different surgical approaches, such as EVAR and open surgical repair. Therefore, they cannot be considered a reasonable alternative to RCT data. In addition, an analysis using the registry data showed that EVAR still did not provide greater long-term benefits than open surgical repair, and that it still has higher net costs.
NICE acknowledged the need to rebalance practice towards open repair and identified the possible implementation challenges.
Possible increased perioperative mortality with open surgical repair: Improvements in practice since the RCTs were published have led to better standards for open surgical repair and EVAR alike. In addition, the NHS AAA screening programme means that AAAs are more likely to be diagnosed earlier than in the past, so people can have repair when they are younger and healthier. For these reasons, open surgical repair of unruptured AAAs can be provided with a low incidence of morbidity and mortality.
The risk that vascular units will have trouble meeting an increased demand for open surgical repair: All vascular surgeons should be competent to perform open surgical repair of AAAs, and the Intercollegiate Surgical Curriculum Programme's Vascular surgery curriculum puts more emphasis on open surgical repair than on EVAR. This means that future surgeons should be well prepared to provide open surgical repair with a low incidence of morbidity and mortality.
Potential shortage of beds in the NHS: As people who have open surgical repair spend more time in hospital immediately after the procedure, there may be a small, short-term increase in waiting times for AAA repair. However, an analysis comparing waiting times showed that open surgical repair would still provide greater benefit than EVAR for a lower cost even with a substantial increase in waiting times for open surgical repair.
The possibility that reducing the number of EVAR procedures performed for unruptured aneurysms will make it difficult to provide EVAR for ruptured aneurysms: There are a number of ways this implementation issue might be addressed:
vascular services could be centralised further (for example by establishing aortic units)
in line with the recommendations, EVAR can be offered in certain situations.
The evidence did not show any benefit from goal-directed therapy for people having repair of an unruptured AAA. Goal-directed therapy covers a broad range of different haemodynamic monitoring and management practices, some of which are routinely performed during major surgery. The committee recognised that it was not possible to specify which practices should or should not be performed and agreed that drafting recommendations would be too prescriptive.
## How the recommendations might affect practice
The recommendation on when to repair unruptured aneurysms is unlikely to impact on current clinical practice because it reflects what is already being done within the NHS. Data from the NHS AAA screening programme indicate that the risk of rupture for AAAs that are smaller than 5.5 cm is very low.
The recommendations on EVAR could have a large impact on practice and will also affect the timing and type of information about treatment options given to patients. In light of the evidence reviewed, practice needs to be rebalanced towards open surgical repair for infrarenal aneurysms. The recommendations will minimise harm by reducing long-term mortality and the need for re-intervention as a result of the problems with EVAR. The reduction in EVAR, and so EVAR-related re-interventions, will result in significant cost savings for the NHS.
A lack of recommendations on goal-directed therapy will not impact on practice. Basic haemodynamic management is routinely performed during most surgical procedures, but goal-directed therapy is not widely adopted during AAA surgery.
Return to recommendations
# Anaesthesia and analgesia during unruptured aneurysm repair
## Why the committee made the recommendation
Recommendation 1.5.8
The committee noted that there was some evidence that adding an epidural to general anaesthesia reduced the need for further analgesia for people having open surgical repair of an unruptured AAA. This was consistent with their own clinical experience of better pain control and reduced postoperative respiratory complications with an epidural. Adding an epidural is fairly widespread in current practice, and the committee agreed that it should be recommended as an option.
No evidence was found on anaesthesia and analgesia for people undergoing EVAR for unruptured AAA. The committee agreed that no recommendations were needed in this area because they had recommended that EVAR should not be used to treat unruptured infrarenal abdominal aortic aneurysm, except in clinical trials or for people for whom open surgical repair is unsuitable because of abdominal copathology.
## How the recommendations might affect practice
The use of an epidural in addition to general anaesthesia for people having open surgical repair of an unruptured AAA is already fairly widespread in current practice. Therefore the overall impact of the recommendation is likely to be small, although it may reduce existing variation.
Return to recommendation
# Repairing ruptured aneurysms
## Why the committee made the recommendations
Recommendations 1.6.1 to 1.6.3
The evidence showed that, compared with open surgical repair, a strategy that uses EVAR (where anatomically possible) to repair ruptured infrarenal abdominal aortic aneurysm provides a reasonable balance of benefits and costs.
As the average cost-effectiveness results for EVAR were favourable, the committee discussed whether they should recommend EVAR whenever it is possible. They decided not to, for 2 reasons.
Firstly, there is uncertainty in the evidence for EVAR from the IMPROVE trial. People who had EVAR for a ruptured AAA in this trial were followed up for at most 7 years. People who had EVAR for an unruptured AAA in the EVAR-1 trial were followed up for 15 years, and the committee noted that these data indicate that EVAR leads to increasingly worse survival when compared with open surgical repair, because follow-up duration increases (see why NICE made the recommendations on repairing unruptured aneurysms). The medium-term survival data from the IMPROVE trial give some indication that a similar long-term pattern may develop in trials of ruptured AAA, with the survival curves converging as follow-up gets longer. Therefore, it is possible that longer-term data would show EVAR to be worse than open surgical repair for people with ruptured AAA as well.
Secondly, there was evidence that the balance of benefits and costs for EVAR varies between different groups of people with ruptured AAAs. In particular, most women have better short-term survival after EVAR, whereas the evidence favours open surgical repair for younger men. Therefore, the committee recommended that either EVAR or open surgical repair can be considered, and provided detail on the groups for which each approach is likely to be best.
Complex EVAR is only recommended within the context of an RCT because there is currently no evidence to support it as an option for people with ruptured complex AAA. Open surgical repair of these aneurysms is recommended as the only approach that should be used in people for whom emergency repair is suitable until the safety and effectiveness of complex EVAR has been established in this setting.
No evidence on the use of tranexamic acid in people with a ruptured AAA was identified. The committee was aware that tranexamic acid is included in some major haemorrhage protocols and some patients, without major trauma, may receive it before undergoing surgery. In the committee's experience, tranexamic acid is not routinely used in people with a ruptured AAA, so it agreed to recommend research in this area.
There was no evidence on goal-directed therapy for people having repair of a ruptured aneurysm. Goal-directed therapy covers a broad range of different haemodynamic monitoring and management practices; some of which are routinely performed during major surgery. The committee recognised that it was not possible to specify which practices should or should not be performed and agreed that drafting recommendations would be too prescriptive.
## How the recommendations might affect practice
The recommendations will have little impact on current practice, as both standard EVAR and open surgical repair are currently offered to people with ruptured infrarenal AAAs. In relation to complex EVAR, the recommendation not to use it outside of RCTs will limit the use of a technically complex and expensive procedure in people for whom open surgery is a safe and suitable option.
Because the guideline recommends that fewer EVAR procedures should be performed for unruptured aneurysms (see the section on repairing unruptured aneurysms), surgical teams may have less opportunity to develop the skills they need to provide EVAR in emergency cases. The committee were mindful of this issue, but were convinced by the evidence showing that, overall, people with AAAs would be worse off if EVAR procedures were performed for unruptured aneurysms just to maintain EVAR expertise. Elective EVAR will still be available in certain circumstances and centralisation of aortic services may maintain expertise. However, neither training nor service models were in the scope of this guideline, so the committee did not review any evidence and were unable to make any specific recommendations in these areas.
A lack of recommendations on goal-directed therapy will not impact on practice. Basic haemodynamic management is routinely performed during most surgical procedures, but goal-directed therapy is not widely adopted during AAA surgery.
A lack of recommendations on tranexamic acid will have little impact on practice. Tranexamic acid is used in varying degrees across the NHS, but it is not standard practice for people with ruptured or symptomatic AAAs who are being transferred before surgery.
Return to recommendations
# Anaesthesia and analgesia during ruptured aneurysm repair
## Why the committee made the recommendation
Recommendation 1.6.4
No evidence was identified on the optimal use of anaesthesia and analgesia in people having open surgical repair or EVAR of a ruptured AAA. The committee agreed, based on their knowledge and experience, that general anaesthesia alone is widely accepted as best practice for open surgical repair, so did not make a recommendation on this. The committee made a recommendation on the use of local infiltrative anaesthesia alone in people having EVAR for ruptured AAA because it was considered that increased awareness of this option was needed.
## How the recommendation might affect practice
The committee agreed that the potential impact of this recommendation on practice is unclear, because it is difficult to predict the proportion of people for whom EVAR under local infiltrative anaesthesia might be an option. The main aim of this recommendation is to raise awareness of this option.
Return to recommendation
# Abdominal compartment syndrome
## Why the committee made the recommendations
Recommendations 1.6.5 and 1.6.6
There was no evidence relating to preventing or managing abdominal compartment syndrome in people who are having AAA repair. The committee agreed it was important to raise awareness of this potentially life-threatening condition, and made recommendations to highlight that it can occur after both endovascular aneurysm repair and open surgical repair.
## How the recommendations might affect practice
The recommendations will ensure that clinicians are aware of abdominal compartment syndrome in people who have undergone repair of ruptured AAA. This may result in better postoperative assessment and management.
Return to recommendations
# Monitoring for complications after endovascular aneurysm repair
## Why the committee made the recommendations
Recommendations 1.7.1 to 1.7.5
Imaging surveillance is needed after EVAR, because there is a risk that people will develop complications from the procedure or need another operation. These risks are lower after open surgical repair, so surveillance is not standard practice and in this case the committee did not recommend it.
The committee noted that the frequency of EVAR surveillance is highly variable in practice. In the absence of evidence on how often imaging should be done, the committee agreed a recommendation to tailor surveillance to the perceived risk of complications. This should focus attention and resources on the people at greatest risk, and help to identify complications earlier.
In practice, identifying complications after EVAR usually involves sequential imaging, with ultrasound frequently used as the first-line test and other imaging modalities used to detect specific complications. Imaging modalities may be complimentary, and the clinical significance of some imaging findings remains unclear, which makes identifying a true reference standard difficult.
Contrast-enhanced CT angiography was widely used as a gold standard in the evidence that was reviewed. However, this has led to some abnormalities that are detected on other imaging modalities, but not on CT, being defined as false positives (for that modality, rather than as false negatives for CT). This may have introduced bias, and makes it difficult to rely on CT as a reference standard.
The evidence showed that colour duplex ultrasound was highly accurate at identifying changes in sac size when compared with contrast-enhanced CT angiography. Increases in sac size are often believed to indicate an endoleak even if no leak can be seen on the ultrasound. There was little evidence on graft kinking, but the committee agreed based on their experience that colour duplex ultrasound and CT angiography were equally as effective at detecting this type of complication.
In the evidence reviewed, contrast-enhanced ultrasound was the only imaging technique that had acceptable accuracy for directly identifying endoleaks when compared with contrast-enhanced CT angiography. Importantly, other imaging techniques had unacceptably high rates of false-negative results. For this reason, the committee agreed that in situations where the definitive exclusion (or identification) of endoleak is important (for example where endoleak is suspected) either contrast-enhanced CT angiography or contrast-enhanced ultrasound should be used. Contrast-enhanced ultrasound was not recommended for assessing other complications because the evidence for its use only covered endoleaks.
The committee agreed that it is particularly important not to falsely exclude an endoleak, so the sensitivity of a diagnostic test is more important than its specificity. While colour duplex ultrasound is highly accurate at identifying changes in sac size (which may indicate an endoleak), the available evidence shows that it has suboptimal sensitivity for directly detecting type I and III endoleaks. In addition, the accuracy of ultrasound was shown to be dependent on the operator, so its accuracy may be variable in practice. This variability in diagnostic accuracy, and resultant potential for harm if an endoleak is missed, led the committee to recommend that colour duplex ultrasound alone should not be used to confirm or exclude the presence of endoleaks.
## How the recommendations might affect practice
There is variation in which imaging techniques are used for surveillance. Some centres use ultrasound only, and some use contrast-enhanced CT angiography and ultrasound. Colour duplex ultrasound is widely used, but contrast-enhanced ultrasound is not. These recommendations are not likely to alter surveillance regimens substantially because many centres use imaging tests in a complementary fashion, often relying on sac size as a trigger for further investigation if necessary. Sonographers will need training in administering contrast agents if contrast-enhanced ultrasound is to be more widely adopted.
Return to recommendations
# Managing endoleaks after endovascular aneurysm repair
## Why the committee made the recommendations
Recommendations 1.8.1 to 1.8.3
Endoleaks following EVAR are common. They can have a negative impact on patient prognosis and long-term quality of life, and further interventions are frequently needed to repair them. In the absence of evidence, the committee made recommendations based on their experience because:
it is good practice to repair type I and III endoleaks and some type II endoleaks
healthcare professionals are not all aware that type II endoleaks without sac expansion can be managed conservatively
there are circumstances when sac expansion occurs without imaging evidence of a leak site (called type V endoleak), and these situations need further investigation.
## How the recommendations might affect practice
The recommendations will have minimal impact on current practice because it is common practice to intervene for type I and type III endoleaks, and type II endoleaks if there is evidence of aneurysm sac expansion.
Return to recommendations# Context
Abdominal aortic aneurysms develop when the wall of the aorta in the abdomen weakens, causing it to bulge and form a balloon-like expansion. When the abdominal aorta reaches a diameter at least 1.5 times the normal size, or greater than 3 cm in total, it is called an abdominal aortic aneurysm (AAA).
The increased stress on the aortic wall may eventually cause the AAA to rupture (burst). The subsequent internal bleeding is frequently fatal before emergency repair can be attempted. When people have emergency repair for rupture, up to half will not survive to leave hospital.
There is a long period of growth before an AAA ruptures. The rate of growth may depend on a number of factors, including increasing age, smoking, blood pressure and a family history of aneurysm.
Most AAAs are asymptomatic, and they are often diagnosed opportunistically during clinical examination or investigation for another condition. Because of this it is difficult to establish their prevalence. There is a national screening programme which enrols men at age 65 and suggests a prevalence of about 1.3% in this population. The prevalence is falling.
The prevalence of AAAs is approximately 6 times lower in women, but the rate of aneurysm rupture is significantly higher. The guideline committee carefully considered the impact of their recommendations on women during guideline development.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Diagnosis\n\n## Identifying people at risk of abdominal aortic aneurysms\n\nInform all men aged 66 or over who have not already been screened about the NHS abdominal aortic aneurysm (AAA) screening programme, and advise them that they can self-refer.\n\nEncourage men aged 66 or over to self-refer to the NHS AAA screening programme if they have not already been screened and they have any of the following risk factors:\n\nchronic obstructive pulmonary disease (COPD)\n\ncoronary, cerebrovascular or peripheral arterial disease\n\nfamily history of AAA\n\nhyperlipidaemia\n\nhypertension\n\nthey smoke or used to smoke.\n\nConsider an aortic ultrasound for women aged 70 and over if AAA has not already been excluded on abdominal imaging and they have any of the following risk factors:\n\nCOPD\n\ncoronary, cerebrovascular or peripheral arterial disease\n\nfamily history of AAA\n\nhyperlipidaemia\n\nhypertension\n\nthey smoke or used to smoke.\n\nBe aware that people of European family origin are at a higher risk of an AAA.\n\n## Identifying asymptomatic abdominal aortic aneurysms\n\nOffer an aortic ultrasound to people in whom a diagnosis of asymptomatic AAA is being considered if they are not already in the NHS screening programme.\n\nRefer people with an AAA that is 5.5\xa0cm or larger to a regional vascular service, to be seen within 2\xa0weeks of diagnosis.\n\nRefer people with an AAA that is 3.0 cm\xa0to 5.4\xa0cm to a regional vascular service, to be seen within 12\xa0weeks of diagnosis.\n\nOffer an aortic ultrasound to people with a suspected AAA on abdominal palpation.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on identifying asymptomatic abdominal aortic aneurysms\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: risk factors for predicting presence of an abdominal aortic aneurysm and evidence review B: imaging techniques to diagnose abdominal aortic aneurysms.\n\nLoading. Please wait.\n\n## Identifying symptomatic or ruptured abdominal aortic aneurysms\n\nThink about the possibility of ruptured AAA in people with new abdominal and/or back pain, cardiovascular collapse, or loss of consciousness. Be aware that ruptured AAA is more likely if they also have any of the following risk factors:\n\nan existing diagnosis of AAA\n\nage over 60\n\nthey smoke or used to smoke\n\nhistory of hypertension.\n\nBe aware that AAAs are more likely to rupture in women than men.\n\nOffer an immediate bedside aortic ultrasound to people in whom a diagnosis of symptomatic and/or ruptured AAA is being considered. Discuss immediately with a regional vascular service if:\n\nthe ultrasound shows an AAA or\n\nthe ultrasound is not immediately available or it is non-diagnostic, and an AAA is still suspected.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on identifying symptomatic or ruptured abdominal aortic aneurysms\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B: imaging techniques to diagnose abdominal aortic aneurysms and evidence review N: signs, symptoms and risk factors predicting ruptured or symptomatic unruptured aneurysms before arrival at the hospital, and in non-specialist hospital settings.\n\nLoading. Please wait.\n\n## Imaging technique\n\nWhen measuring aortic size with ultrasound, report the inner-to-inner maximum anterior-posterior aortic diameter, in accordance with the NHS AAA screening programme. Clearly document any additional measurements taken.\n\nOffer thin-slice contrast-enhanced arterial-phase CT angiography to people who are being evaluated for elective AAA repair.\n\nConsider thin-slice contrast-enhanced arterial-phase CT angiography for people with a suspected ruptured AAA who are being evaluated for AAA repair.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on imaging technique\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B: imaging techniques to diagnose abdominal aortic aneurysms.\n\nLoading. Please wait.\n\n## Providing information to people with a diagnosed AAA\n\nGive people with AAA of any size information explaining:\n\nwhat an AAA is\n\nthat most AAAs do not cause any problems\n\nthat AAAs can rupture, and what this means\n\nthat AAAs are likely to get larger over time, and that larger AAAs are more likely to rupture\n\nthat AAA may run in families, so they should tell close relatives that they may have an increased risk of AAA and may need assessment (see recommendations 1.1.2 and 1.1.3)\n\nwhat options for aneurysm repair are available, when repair should be considered and the potential benefits and risks (see recommendations 1.5.1 and 1.5.2), and when it might be better to not have repair (see recommendation 1.1.14)\n\ntheir risk of cardiovascular disease and how this risk can be reduced (see recommendation 1.4.6, and see the section on identifying and assessing cardiovascular disease risk in the NICE guideline on cardiovascular disease).\n\nIf AAA repair is not currently suitable for a person, explain why, based on their individual circumstances. For example:\n\nSmall AAAs only have a very low chance of rupture and there are risks to aneurysm repair, so in this case people do not benefit from repair.\n\nAAA growth is unpredictable, so until their AAA meets the criteria in recommendation 1.5.1 it is not possible to know whether repair will be suitable for a particular person.\n\nOn average, people with poor overall health do not benefit from AAA repair. There is no reliable way to assess whether a particular person will benefit or be harmed, so repair for people with poor overall health is an unnecessary risk even if their AAA meets the criteria in recommendation 1.5.1.\n\nCheck that people understand their options, and give them time for reflection and discussion. Encourage them to discuss the options with their family and friends.\n\nFor more guidance on providing information, see the section on enabling patients to actively participate in their care in the NICE guideline on patient experience in adult NHS services.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on providing information to people with a diagnosed AAA\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review K: effectiveness of endovascular aneurysm repair, open surgical repair and non-surgical management of unruptured abdominal aortic aneurysms.\n\nLoading. Please wait.\n\n# Monitoring and reducing the risk of rupture\n\n## Reducing the risk of rupture\n\nOffer a referral to a stop smoking service to people with an abdominal aortic aneurysm (AAA) who smoke. For more guidance, see the NICE guideline on tobacco: preventing uptake, promoting quitting and treating dependence.\n\nEnsure that people with an AAA who have hypertension receive care in line with the NICE guideline on hypertension in adults.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on reducing the risk of rupture\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: risk factors associated with abdominal aortic aneurysm growth or rupture.\n\nLoading. Please wait.\n\n## Monitoring the risk of rupture\n\nOffer surveillance with aortic ultrasound to people with an asymptomatic AAA. Use the same surveillance frequency as the NHS AAA screening programme.\n\nSee recommendation 1.1.5 on when to refer people to a regional vascular unit.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on monitoring the risk of rupture\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: monitoring for abdominal aortic aneurysm expansion and risk of rupture.\n\nLoading. Please wait.\n\n# Emergency transfer to regional vascular services\n\nBe aware that there is no evidence that any single symptom, sign or prognostic risk assessment tool can be used to determine whether people with a suspected or confirmed ruptured abdominal aortic aneurysm (AAA) should be transferred to a regional vascular service.\n\nWhen making transfer decisions, be aware that people with a confirmed ruptured AAA who have a cardiac arrest and/or have a persistent loss of consciousness have a negligible chance of surviving AAA repair.\n\nFor guidance on care of people with a ruptured AAA for whom repair is considered inappropriate, see the NICE guideline on care of dying adults in the last days of life.\n\nWhen people with a suspected ruptured or symptomatic unruptured AAA have been accepted by a regional vascular service for emergency assessment, ensure that they leave the referring unit within 30\xa0minutes of the decision to transfer.\n\nEmergency departments, ambulance services and regional vascular services should collaborate to:\n\nprovide a protocol for the safe and rapid transfer of people with a suspected ruptured or symptomatic unruptured AAA who need emergency assessment at a regional vascular service\n\ntrain clinical staff involved in the care of people with a suspected ruptured or symptomatic unruptured AAA in the transfer protocol\n\nreview the transfer protocol at least every 3\xa0years.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on emergency transfer to regional vascular services\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review O: signs, symptoms and risk factors indicating suitability for transfer to a regional vascular service and evidence review P: time period for transfer to regional vascular services.\n\nLoading. Please wait.\n\n## Supporting people during transfer\n\nConsider a restrictive approach to volume resuscitation (permissive hypotension) for people with a suspected ruptured or symptomatic AAA during emergency transfer to a regional vascular service.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on supporting people during transfer\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review Q: permissive hypotension during transfer of people with ruptured abdominal aortic aneurysm to regional vascular services.\n\nLoading. Please wait.\n\n# Predicting and improving surgical outcomes\n\n## Predicting surgical outcomes for unruptured aneurysms\n\nConsider cardiopulmonary exercise testing when assessing people for elective repair of an asymptomatic abdominal aortic aneurysm (AAA), if it will assist in shared decision making.\n\nFor guidance on other preoperative tests, see the NICE guideline on routine preoperative tests for elective surgery.\n\nDo not use the following risk assessment tools to determine whether or not repair is suitable for a person with an asymptomatic unruptured AAA:\n\nBritish Aneurysm Repair score\n\nCarlisle Calculator\n\nComorbidity Severity Score\n\nGlasgow Aneurysm Scale\n\nMedicare risk prediction tool\n\nModified Leiden score\n\nPhysiological and Operative Severity Score for enUmeration of Mortality (POSSUM)\n\nVascular-POSSUM\n\nVascular Biochemical and Haematological Outcome Model (VBHOM)\n\nVascular Governance North West (VGNW) risk model.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on predicting surgical outcomes in unruptured aneurysms\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review G: tests for predicting outcomes after repair of unruptured abdominal aortic aneurysms and evidence review H: risk assessment tools for predicting surgical outcomes of patients who undergo elective abdominal aortic aneurysm repair.\n\nLoading. Please wait.\n\n## Predicting surgical outcomes for ruptured aneurysms\n\nDo not use any single symptom, sign or patient-related risk factor to determine whether aneurysm repair is suitable for a person with a ruptured AAA.\n\nDo not use patient risk assessment tools (scoring systems) to determine whether aneurysm repair is suitable for a person with a ruptured AAA.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on predicting surgical outcomes for ruptured aneurysms\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review S: risk factors for predicting survival after abdominal aortic aneurysm rupture.\n\nLoading. Please wait.\n\n## Improving surgical outcomes\n\nOffer people with an AAA information, support and interventions for secondary prevention of cardiovascular disease. For more information refer to the NICE guidance on:\n\ntobacco: preventing uptake, promoting quitting and treating dependence\n\ndiet, nutrition and obesity and exercise\n\nmedicines optimisation\n\nlipid modification and statin therapy\n\ndiabetes management\n\nhypertension diagnosis and management.\n\nDo not routinely offer preoperative beta blockers to people having AAA repair.\n\nDo not offer remote ischaemic preconditioning to people having AAA repair.\n\nFor guidance on preventing and treating surgical site infections and on preventing venous thromboembolism, see the NICE guidelines on surgical site infections and reducing the risk of venous thromboembolism.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on improving surgical outcomes\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review J: pre- and postoperative interventions to optimise outcomes after abdominal aortic aneurysm repair.\n\nLoading. Please wait.\n\n# Repairing unruptured aneurysms\n\n## When to consider repair\n\nConsider aneurysm repair for people with an unruptured abdominal aortic aneurysm (AAA), if it is:\n\nsymptomatic\n\nasymptomatic, larger than 4.0 cm and has grown by more than 1 cm in 1 year (measured inner-to-inner maximum anterior-posterior aortic diameter on ultrasound)\n\nasymptomatic and 5.5 cm or larger (measured inner-to-inner maximum anterior-posterior aortic diameter on ultrasound).\n\n## Discussing the benefits and risks of repair or conservative management\n\nWhen discussing aneurysm repair with people who have an unruptured AAA, explain the overall balance of benefits and risks with repair and with conservative management, based on their current health and their expected future health. The decision on whether repair is preferred over conservative management should be made jointly by the person and their clinician after assessment of a number of factors, including:\n\naneurysm size and morphology\n\nthe person's age, life expectancy, fitness for surgery, and any other conditions they have\n\nthe risk of AAA rupture if they do not have repair\n\nthe short- and long-term benefits and risks, and the other disadvantages of repair such as having to stay in hospital, the risks of the operation, the recovery period, the potential need for further procedures and the need for surveillance imaging appointments\n\nthe uncertainties around estimates of risk for AAAs larger than 5.5 cm (measured inner-to-inner maximum anterior-posterior aortic diameter on ultrasound).\n\n## Open surgical repair, standard endovascular aneurysm repair or conservative management\n\nOffer open surgical repair for people with unruptured AAAs meeting the criteria in recommendation 1.5.1, unless it is contraindicated because of their abdominal copathology, anaesthetic risks, and/or medical comorbidities.\n\nConsider endovascular aneurysm repair (EVAR) for people with unruptured AAAs who meet the criteria in recommendation 1.5.1 and who have abdominal copathology, such as a hostile abdomen, horseshoe kidney or a stoma, or other considerations, specific to and discussed with the person, that may make EVAR the preferred option.\n\nConsider EVAR or conservative management for people with unruptured AAAs meeting the criteria in recommendation 1.5.1 who have anaesthetic risks and/or medical comorbidities that would contraindicate open surgical repair.\n\n## Complex endovascular aneurysm repair\n\nIf open surgical repair and complex EVAR are both suitable options, only consider complex EVAR if:\n\nthe following has been discussed with the person:\n\n\n\nthe risks of complex EVAR compared with the risks of open surgical repair\n\nthe uncertainties around whether complex EVAR improves perioperative survival or long-term outcomes, when compared with open surgical repair\n\n\n\nit will be performed with special arrangements for consent and for audit and research that will determine the clinical and cost effectiveness of complex EVAR when compared with open surgical repair, and all patients are entered onto the National Vascular Registry.\n\nFor people who have anaesthetic risks and/or medical comorbidities that would contraindicate open surgical repair, only consider complex EVAR if:\n\nthe following has been discussed with the person:\n\n\n\nthe risks of complex EVAR compared with the risks of conservative management\n\nthe uncertainties around whether complex EVAR improves perioperative survival or long-term outcomes\n\n\n\nit will be performed with special arrangements for consent and for audit and research that will determine the clinical and cost effectiveness of complex EVAR when compared with conservative management, and all patients are entered onto the National Vascular Registry.\n\nNICE amended recommendations 1.5.1 to 1.5.7, after the committee's proposed recommendations were reviewed by NICE's Board.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on repairing unruptured aneurysms\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review F: thresholds for abdominal aortic aneurysm repair\n\nevidence review K: effectiveness of endovascular aneurysm repair, open surgical repair and non-surgical management of unruptured abdominal aortic aneurysms\n\nevidence review K2: observational evidence on the effectiveness of endovascular aneurysm repair compared with open surgical repair of unruptured abdominal aortic aneurysms.\n\nLoading. Please wait.\n\n## Anaesthesia and analgesia\n\nConsider epidural analgesia in addition to general anaesthesia for people having open surgical repair of an unruptured AAA.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on anaesthesia and analgesia during unruptured aneurysm repair\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review L: anaesthesia and analgesia for people having surgical repair of an abdominal aortic aneurysm.\n\nLoading. Please wait.\n\n# Repairing ruptured aneurysms\n\nConsider endovascular aneurysm repair (EVAR) or open surgical repair for people with a ruptured infrarenal abdominal aortic aneurysm (AAA). Be aware that:\n\nEVAR provides more benefit than open surgical repair for most people, especially men over 70 and women of any age\n\nopen surgical repair is likely to provide a better balance of benefits and harms in men under 70.\n\nConsider open surgical repair for people with a ruptured AAA if standard EVAR is unsuitable.\n\nDo not offer complex EVAR to people with a ruptured AAA if open surgical repair is suitable, except as part of a randomised controlled trial comparing complex EVAR with open surgical repair.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on repairing ruptured aneurysms\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review T: effectiveness of endovascular aneurysm repair compared with open surgical repair of ruptured abdominal aortic aneurysms.\n\nLoading. Please wait.\n\n## Anaesthesia and analgesia\n\nConsider using local infiltrative anaesthesia alone for people having EVAR of a ruptured AAA.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on anaesthesia and analgesia during ruptured aneurysm repair\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review L: anaesthesia and analgesia for people having surgical repair of an abdominal aortic aneurysm.\n\nLoading. Please wait.\n\n## Abdominal compartment syndrome\n\nBe aware that people can develop abdominal compartment syndrome after EVAR or open surgical repair of a ruptured AAA.\n\nAssess people for abdominal compartment syndrome if their condition does not improve after EVAR or open surgical repair of a ruptured AAA.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on abdominal compartment syndrome\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review U: preventing abdominal compartment syndrome following repair of ruptured abdominal aortic aneurysm.\n\nLoading. Please wait.\n\n# Monitoring for complications after endovascular aneurysm repair\n\nEnrol people who have had endovascular aneurysm repair (EVAR) into a surveillance imaging programme.\n\nBase the frequency of surveillance imaging on the person's risk of EVAR-related complications.\n\nConsider contrast-enhanced CT angiography or colour duplex ultrasound for assessing abdominal aortic aneurysm (AAA) diameter and EVAR device limb kinking.\n\nUse contrast-enhanced CT angiography if an endoleak is suspected. If contrast-enhanced CT angiography is contraindicated, use contrast-enhanced ultrasound.\n\nDo not exclude endoleaks based on a negative colour duplex ultrasound alone in people who have had EVAR.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on monitoring for complications after endovascular aneurysm repair\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review V: postoperative surveillance after surgical repair of abdominal aortic aneurysms and evidence review W: accuracy of imaging techniques in identifying complications after surgery.\n\nLoading. Please wait.\n\n# Managing endoleaks after endovascular aneurysm repair\n\nConsider open, endovascular or percutaneous intervention for type 1 and type 3 endoleaks following endovascular aneurysm repair (EVAR).\n\nConsider intervention for type 2 endoleaks in people who have abdominal aortic aneurysm (AAA) expansion following EVAR.\n\nConsider further investigation of type 5 endoleaks following EVAR.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on managing endoleaks after endovascular aneurysm repair\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review X: managing complications after abdominal aortic aneurysm repair.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a specific way for this guideline. For general definitions, please see the NICE glossary.\n\n## Standard and complex EVAR\n\nStandard EVAR is defined as any EVAR procedure:\n\nusing a standard infrarenal device (an unmodified off-the-shelf stent graft) and\n\nfollowing the manufacturer's 'instructions for use' for the device used and\n\nwithout any adjunctive procedures (planned use of endo-anchors and planned permanent instrumentation of aortic branch vessels, such as 'chimney' or 'snorkel' procedures).\n\nAny EVAR procedure that does not fit into the definition above is classed as 'complex EVAR'. Complex EVAR also covers fenestrated, branched, customised or internal iliac branch devices, and physician-modified stent grafts.\n\n## Endoleak\n\nThe persistence of blood flow outside an endovascular stent–graft but within the aneurysm sac in which the graft is placed. There are 5 types of endoleak:\n\nType 1 – blood flowing into the aneurysm because of an incomplete or ineffective seal at either end of a stent–graft\n\nType 2 – blood flowing into an AAA from side branches of the aorta\n\nType 3 – blood flowing into an AAA through defects in the endograft\n\nType 4 – blood flowing through the stent–graft fabric into an AAA\n\nType 5 – continued AAA expansion without radiographic evidence of a leak site.\n\n## Hostile abdomen\n\nAn abdomen that is difficult to perform open surgery within, because of adverse anatomical features. For AAA repair, these features can include large abdominal wall defects or intra-abdominal adhesions. A hostile abdomen is most common in people who have had multiple previous episodes of intra-abdominal open surgery.\n\n## Infrarenal abdominal aortic aneurysm\n\nAn abdominal aortic aneurysm arising below the arteries that supply the kidneys.\n\n## Permissive hypotension\n\nA method of fluid administration that aims to reduce bleeding by keeping a person's blood pressure within a lower-than-normal range.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Monitoring frequencies and repair thresholds\n\nWhat are the most effective and cost-effective frequencies for monitoring people with unruptured abdominal aortic aneurysms (AAA) of different diameters, and what is the optimal AAA threshold size (inner-to-inner maximum anterior-posterior diameter on ultrasound) for repair?\n\nMore frequent monitoring increases the chances of identifying aneurysms that have grown large enough to be considered for repair. However, monitoring requires resources and the absolute risk of AAA rupture is relatively low, so there are opportunity costs to consider. It is important to establish how often aneurysms should be monitored to keep the risk of rupture as low as possible while making the best use of NHS resources.\n\nThe optimal threshold for repair of an AAA is not clear. There is good evidence that in most cases people do not need repair for aneurysms measuring smaller than 5.5\xa0cm (inner-to-inner maximum anterior-posterior aortic diameter) on ultrasound. However, for some people a threshold above 5.5\xa0cm may be more appropriate.\n\n## Effectiveness of endovascular aneurysm repair and open surgical repair of complex unruptured and ruptured abdominal aortic aneurysms\n\nWhat is the effectiveness and cost effectiveness of complex endovascular aneurysm repair (EVAR) versus open surgical repair in people for whom open surgical repair is suitable for:\n\nelective repair of an unruptured AAA or\n\nemergency repair of a ruptured AAA?\n\nEVAR is a widely performed non-invasive alternative to open surgical repair. However, it is more expensive. Although standard EVAR has been shown to produce no long-term benefit over open surgical repair in people with an unruptured infrarenal abdominal aortic aneurysm, it is less clear whether this is the same in people with who would need complex EVAR to repair their AAA. The committee's view was that, because current practice is subject to strong prior beliefs about the relative benefits and harms of EVAR and open surgical repair for complex AAA, randomisation is critical to provide an unbiased estimate of comparative effectiveness.\n\n## Macrolides for slowing aneurysm growth and reducing the risk of rupture\n\nWhat are the benefits and harms of macrolides (such as azithromycin) for reducing AAA growth rates and the risk of rupture?\n\nSmall AAAs are currently managed by monitoring, until the aneurysm reaches a diameter at which surgical repair is considered. There are currently no non-surgical interventions available to prevent AAAs from growing, and subsequently rupturing. A randomised controlled trial would be useful to determine whether macrolides reduce the rate of AAA growth and the risk of rupture.\n\n## Metformin for slowing aneurysm growth and reducing the risk of rupture\n\nWhat are the benefits and harms of metformin for reducing AAA growth rates and the risk of rupture?\n\nObservational study data suggest an association between diabetes and slower AAA growth, and it has been proposed that this may be due to the use of metformin. A randomised controlled trial is needed to determine whether metformin reduces the rate of AAA growth and the risk of rupture.\n\n## Tranexamic acid for preventing and treating excessive blood loss during EVAR or open surgical repair\n\nDoes tranexamic acid reduce blood loss and so improve survival in people who are having repair (EVAR or open surgical repair) of a ruptured AAA?\n\nTranexamic acid is used to reduce blood loss in major trauma, postpartum bleeding and surgery. By slowing down blood loss from a ruptured AAA, the use of tranexamic acid may improve survival from ruptured AAA. A randomised controlled trial is needed to determine whether tranexamic acid improves survival in people having EVAR or open surgical repair of a ruptured AAA.\n\n## Prehabilitation (including preoperative exercise programmes) for improving the outcome of aneurysm repair\n\nWhat is the clinical effectiveness and cost effectiveness of prehabilitation, including preoperative exercise programmes, for improving outcomes of people who are having repair of an AAA?\n\nNHS providers have started devoting resources to prehabilitation programmes, based on a relatively small body of evidence. Research is needed to determine if prehabilitation is effective and the optimal form it should take.\n\n# Other recommendations for research\n\n## Direct oral anticoagulants after abdominal aortic aneurysm repair\n\nWhat are the benefits of postoperative use of direct oral anticoagulants (DOACs) for improving outcomes after repair of AAA?\n\n## Permissive hypotension\n\nDoes permissive hypotension improve survival of patients undergoing repair of ruptured AAA?\n\n## Surveillance after endovascular aneurysm repair\n\nWhat are the risks, benefits and cost implications of different surveillance protocols in people who have undergone EVAR?", 'Rationale and impact': "# Identifying asymptomatic abdominal aortic aneurysms\n\n## Why the committee made the recommendations\n\nRecommendations 1.1.1 to 1.1.6\n\nThe committee were mindful that the NHS abdominal aortic aneurysm (AAA) screening programme does not cover men under 65 or women of any age. This means some men and all women who are at risk of AAA are not currently screened. The recommendations highlight these groups and specify risk factors significantly associated with AAA that could be used to help with opportunistic screening.\n\nThere are also men who have no risk factors for AAA and were not seen by the screening programme when they turned 65. As their risk of AAA is low, the committee only recommended informing them about the NHS AAA screening programme and how it works. Men can then self-refer if they feel screening is right for them. Evidence from cross-sectional studies also found that people of Hispanic, African-American and Asian family origin were individually less likely than people of European family origin to have an AAA, so the committee wished to raise awareness of this.\n\nAortic ultrasound is recommended because it is the standard technique used in clinical practice and in the screening programme. It has high diagnostic accuracy, and is associated with lower costs and fewer side effects than CT. People with an AAA diameter of 5.5\xa0cm or larger (inner-to-inner maximum anterior-posterior aortic diameter on ultrasound) need to be seen by a regional vascular service within 2\xa0weeks because their aneurysm is at higher risk of rupture. The committee recommended that people with aneurysms less than 5.5\xa0cm in diameter are seen within 12\xa0weeks of diagnosis because this is the timeframe set by the NHS AAA screening programme.\n\n## How the recommendations might affect practice\n\nThe recommendations outlining key risk factors will increase the number of people being screened and improve AAA diagnosis. The recommendations should also promote equal access to healthcare, because they provide guidance on when a potential AAA should be investigated in women, who are currently not covered by the NHS AAA screening programme.\n\nUsing aortic ultrasound to detect AAAs is good practice. The recommendations ensure that the time within which people with newly-identified aneurysms are seen by regional vascular services is proportional to the risk of rupture. These timings match the timeframe the NHS AAA screening programme uses for people they assess.\n\nReturn to recommendations\n\n# Identifying symptomatic or ruptured abdominal aortic aneurysms\n\n## Why the committee made the recommendations\n\nRecommendations 1.1.7 to 1.1.9\n\nBased on their own experience, the committee highlighted the most important signs and symptoms of ruptured AAAs, because:\n\nnon-specialists commonly fail to diagnose them\n\nimproved diagnosis should increase the chance of survival\n\nurgent discussion of a suspected ruptured AAA with a regional vascular service will improve the chances of appropriate treatment and survival.\n\nAortic ultrasound is the standard technique for detecting the presence of AAA in a person with a suspected ruptured aneurysm. A ruptured AAA is a surgical emergency, and bedside ultrasound is the quickest reliable method to confirm the presence of an AAA. An immediate discussion with the regional vascular unit ensures appropriate management is started as soon as possible. The committee recognised that the sensitivity of aortic ultrasound is not 100% and several factors can make it difficult to visualise the aorta. Since AAA rupture is a life-threatening surgical emergency, they agreed that it would be safest to discuss any non-diagnostic ultrasound findings with the regional vascular unit.\n\n## How the recommendations might affect practice\n\nThere is variation in awareness of AAA among non-specialists. Implementing the recommendations should reduce this variation and increase the chance of ruptured AAA being diagnosed earlier.\n\nUsing bedside aortic ultrasound to detect AAAs is common practice. Preventing delays to repair through immediate discussions with a regional vascular unit should improve outcomes for people with ruptured AAAs.\n\nReturn to recommendations\n\n# Imaging technique\n\n## Why the committee made the recommendations\n\nRecommendations 1.1.10 to 1.1.12\n\nThe committee agreed that it was important to take consistent measurements of aneurysm size throughout the NHS, so that results are comparable. The NHS AAA screening programme specifies inner-to-inner maximum anterior-posterior aortic diameter on ultrasound, and the committee agreed this would be the most appropriate measurement on which to base practice across the whole NHS.\n\nThe committee recommended thin-slice contrast-enhanced arterial-phase CT angiography for imaging in people being evaluated for elective repair, because it is widely recognised as the gold standard technique for assessing aneurysm anatomy before repair. For suspected ruptured AAAs, CT angiography should also be considered. However, the committee recognised that some people will need immediate transfer for repair without waiting for a CT scan.\n\nNo evidence was found demonstrating whether or not post-processing techniques affected postoperative outcomes for people having elective or emergency AAA repair. As post-processing techniques are an established part of clinical practice, the committee agreed not to make recommendations in this area.\n\n## How the recommendations might affect practice\n\nImplementing a consistent measurement method to be used across the NHS (and that matches the method used in the NHS AAA screening programme) will improve the reproducibility of results, improving surveillance for individuals with AAA and the ability to analyse data at the population level.\n\nThin-slice contrast-enhanced arterial-phase CT angiography is widely used for imaging in people being evaluated for AAA repair, so this recommendation is unlikely to make a major difference to current practice. The recommended timings reflect current standards within the NHS AAA screening programme.\n\nAs post-processing techniques are established in practice, a lack of recommendations on these will not have an impact.\n\nReturn to recommendations\n\n# Providing information to people with a diagnosed AAA\n\n## Why the committee made the recommendations\n\nRecommendations 1.1.13 to 1.1.15\n\nThe committee agreed some consensus recommendations on what information should be provided to people who have been diagnosed with an AAA. In particular, the recommendations cover information for people who are not being considered for repair, either because their AAA is too small (data from the NHS screening programme show that the risk of rupture for an AAA below 5.5\xa0cm is only 0.4% per year) or because their medical comorbidities mean the risks of repair outweigh the benefits. It is important to avoid making people anxious about not being offered repair, but also to avoid giving the impression that AAA repair is always beneficial if the aneurysm meets the criteria for treatment (see recommendation 1.5.1). Explaining how the decision to repair is made (based on the person's health at that particular time) and the uncertainties around this will help people to better understand the options available.\n\nThe committee emphasised that clinicians should ensure that people understand their options and the balance of risks they face. They noted that several clinic visits, including opinions from specialists such as anaesthetists, geriatricians, and cardiologists, are likely to be needed.\n\nReturn to recommendations\n\n# Reducing the risk of rupture\n\n## Why the committee made the recommendations\n\nRecommendations 1.2.1 and 1.2.2\n\nThe committee focused on modifiable risk factors that could influence the management of people with known AAAs. There was some evidence that high blood pressure increases the chance of AAA growth and rupture, and the committee knew from their own experience that people with an AAA do not always receive appropriate management for high blood pressure. There is also evidence that smoking increases the risk of AAA rupture. As a result, the committee referred to the NICE guidelines on these topics.\n\nThe committee agreed that there was not enough high-quality evidence to make clinical recommendations on non-surgical interventions for slowing aneurysm growth and reducing the risk of rupture. In light of this, they made research recommendations on 2 drug interventions that might reduce aneurysm growth and rupture risk.\n\n## How the recommendations might affect practice\n\nThe NICE guidelines on hypertension and stop smoking services cover current practice, so organisations are unlikely to need to change practice.\n\nNon-surgical interventions for small AAAs are not usually used outside of clinical trials, so a lack of recommendations will have little impact on practice.\n\nReturn to recommendations\n\n# Monitoring the risk of rupture\n\n## Why the committee made the recommendations\n\nRecommendations 1.2.3 and 1.2.4\n\nThe committee recommended ultrasound surveillance because ultrasound is current practice and no evidence was found for other imaging techniques. They recommended that monitoring frequency should be in line with the NHS AAA screening programme to ensure consistency across the whole NHS. The screening programme surveillance intervals are based on evidence on risk of rupture, depending on the size of the AAA. This means that people with larger aneurysms are monitored more frequently, offering the best balance between benefits and costs.\n\nThe committee are aware that the NHS AAA screening programme may change the surveillance intervals it uses in the future. If this happens, the committee agreed that regional vascular services should change to match the new intervals, to ensure that they continue to provide care based on best practice.\n\n## How the recommendations might affect practice\n\nChanging monitoring intervals to reflect those used in the NHS AAA screening programme will maintain a consistent standard across the NHS, and ensure that the most effective imaging intervals are used.\n\nReturn to recommendations\n\n# Emergency transfer to regional vascular services\n\n## Why the committee made the recommendations\n\nRecommendations 1.3.1 to 1.3.5\n\nThere was no evidence on symptoms, signs or risk assessment tools for deciding whether people with ruptured aneurysms are likely to survive transfer to a regional vascular service. Based on their own experience, the committee highlighted specific circumstances (cardiac arrest and persistent loss of consciousness) in which people are unlikely to survive transfer and subsequent aortic repair. This will help reduce the number of people being given ineffective and invasive treatment at the end of life.\n\nThe committee referred to the NICE guideline on care of dying adults in the last days of life to ensure that appropriate and compassionate care is given to people with a ruptured AAA when the decision has been made not to operate.\n\nThere was also no evidence on how quickly people with ruptured AAA should be transferred to regional vascular units. In the absence of evidence, the committee adapted recommendations from the NICE guideline on service delivery for major trauma. They agreed, based on their experience of emergency transfer, that the timing specified for people with major trauma was appropriate for people with ruptured AAA and manageable for referring units.\n\n## How the recommendations might affect practice\n\nThe recommendations on assessing people for transfer will raise awareness among emergency staff, but will have little resource impact on clinical practice. The recommendations on transfer speed will improve practice by minimising variation in transfer times across the NHS. The timeframe recommended is the same as for major trauma, and the committee agreed that this is a reasonably similar situation.\n\nThe NICE guideline on care of dying adults cover current practice, so organisations are unlikely to need to change practice.\n\nReturn to recommendations\n\n# Supporting people during transfer\n\n## Why the committee made the recommendation\n\nRecommendation 1.3.6\n\nAs there was no evidence specific to the use of permissive hypotension during transfer of people with ruptured or symptomatic AAA, the committee agreed that a consensus recommendation was needed in this important clinical area. As a result the committee adapted recommendations from the NICE guideline on assessment and initial management for major trauma.\n\n## How the recommendation might affect practice\n\nThe recommendation will reduce the likelihood of inappropriate fluid administration during transfer of people with ruptured AAA. This, in turn, will improve the outcomes of endovascular aneurysm repair and open surgical repair procedures. The recommendation is in line with NICE recommendations on fluid administration for other major trauma, and the committee agreed that this was appropriate for ruptured AAA.\n\nReturn to recommendation\n\n# Predicting surgical outcomes in unruptured aneurysms\n\n## Why the committee made the recommendations\n\nRecommendations 1.4.1 and 1.4.3\n\nThere was limited evidence that cardiopulmonary exercise testing can help predict outcomes following endovascular aneurysm repair (EVAR) and open surgical repair. While the evidence was limited, the committee agreed that cardiopulmonary exercise testing could have a useful role in shared decision-making between healthcare professionals and patients when the benefits and harms of surgery are uncertain.\n\nThere are other tests for assessing people before surgery, but there was no evidence available for them. One study found that higher estimated glomerular filtration rate (eGFR) was associated with improved outcomes after elective EVAR, but it did not give clear eGFR thresholds that could be used in decision-making. In the absence of evidence, the committee referred to the NICE guideline on routine preoperative tests for elective surgery. Some of the studies reviewed for that guideline focused on people having elective AAA repair.\n\nThe evidence highlighted that none of the risk assessment tools had a high enough predictive accuracy at predicting postoperative outcomes. The specific tools listed are the ones for which evidence was available. This evidence led the committee to conclude that these tools would not improve decision-making and could potentially lead to inappropriate decisions about patient management. They agreed that this could lead to harm, and therefore advised that risk assessment tools should not be used.\n\n## How the recommendations might affect practice\n\nThe use of cardiopulmonary exercise testing will have limited impact on practice as it is only recommended in situations where it will help in shared decision-making.\n\nRisk assessment tools are not widely used outside the context of research on AAA. Therefore, the recommendations will have little impact on practice.\n\nReturn to recommendations\n\n# Predicting surgical outcomes for ruptured aneurysms\n\n## Why the committee made the recommendations\n\nRecommendations 1.4.4 and 1.4.5\n\nThere is evidence that some risk factors and risk assessment tools are associated with poor postoperative outcomes. However, it is not clear how any particular factor or combination of factors could be used to decide if aneurysm repair is suitable for a person with a ruptured AAA. The committee emphasised that there is a potential for harm if clinicians base their decision to repair solely on risk assessment tools and scores, because some people would be inappropriately offered or denied repair.\n\n## How the recommendations might affect practice\n\nThe recommendations will have a beneficial impact, by ensuring decisions about care are not made based on inappropriate factors or tools. This, in turn, should prevent inappropriate decisions being made about whether or not to offer repair.\n\nReturn to recommendations\n\n# Improving surgical outcomes\n\n## Why the committee made the recommendations\n\nRecommendations 1.4.6 to 1.4.9\n\nThe committee made a recommendation on cardiovascular disease because it is common in people with AAA and it is best practice to reduce the risk of problems in people who have it. The other NICE guidelines that are referenced include recommendations to help reduce this risk.\n\nThe evidence showed that giving beta blockers just before surgery is not beneficial, and may be harmful by lowering low blood pressure and heart rate. The committee noted that some people with AAA may need to take beta blockers for other conditions (such as atrial fibrillation). As a result, they recommended against routine use before AAA repair, rather than recommending against beta blockers altogether.\n\nRemote ischaemic preconditioning was not recommended because there was evidence that it does not improve outcomes and that it can cause problems such as an irregular heartbeat.\n\nThe committee recommended further research because there was not enough evidence to make recommendations on prehabilitation (including exercise programmes before surgery), or on any interventions after AAA repair.\n\n## How the recommendations might affect practice\n\nProviding support to reduce the risk of problems from cardiovascular disease is already current practice. In addition, beta blockers and routine ischaemic preconditioning are not currently in routine use before AAA repair, so these recommendations should have a minimal impact on practice.\n\nReturn to recommendations\n\n# Repairing unruptured aneurysms\n\n## Why NICE made the recommendations\n\nRecommendations 1.5.1 to 1.5.7\n\nA number of factors should be considered before treating asymptomatic aneurysms, one of which is size.\n\nIt is standard practice to repair large aneurysms (over 5.5\xa0cm in diameter on ultrasound, measured using an anterior-posterior diameter inner-to-inner), and to monitor smaller aneurysms (less than 4\xa0cm in diameter) until they become larger. Repair is sometimes offered for aneurysms below 5.5\xa0cm if they are growing rapidly, or if they are symptomatic. However, data from the NHS screening programme show that, for aneurysms below 5.5\xa0cm, the risk of rupture remains very low (0.4% per year). It is clear from the evidence that there is no benefit to repairing aneurysms that are below 5.5\xa0cm, asymptomatic and not growing rapidly. Based on this evidence, we highlighted factors that would help healthcare professionals decide when to repair aneurysms.\n\nGiven the risks and other disadvantages of AAA repair, conservative management is sometimes a better option. Because of this, healthcare professionals need to explain the balance of benefits and risks to people with AAAs, so they can make an informed decision.\n\nThe evidence showed that, compared with open surgical repair for people with an unruptured infrarenal abdominal aortic aneurysm, elective EVAR has medium- and long-term harms that outweigh its short-term benefits. EVAR is associated with fewer perioperative deaths, and less time in hospital in general (and critical care in particular). But it also has worse long-term survival than open surgical repair, and more long-term complications, leading to further procedures.\n\nEven when taking the short-term benefits of EVAR into account, all plausible cost-effectiveness estimates show that EVAR either:\n\nhas higher net costs and lower net benefits than open surgical repair or\n\nis substantially above the range NICE normally considers to be a cost-effective use of NHS resources.\n\nThere is a small group of people who have abdominal copathology or other considerations that mean open surgical repair is unsuitable. Examples of copathologies include people who have internal scar-tissue from previous abdominal surgery (a so-called hostile abdomen), people who have a single, fused kidney that is wrapped around the aorta ('horseshoe kidney'), and people who have a stoma. Although there was no evidence on this population, EVAR is a potential option for these people, as the risks of open surgical repair may be much higher for them. This recommendation should not be used to extend EVAR to people who could reasonably have open surgical repair.\n\nOpen surgical repair is contraindicated for some people with an unruptured AAA because of anaesthetic risks and/or medical comorbidities. For these people, the risk of their AAA rupturing if no repair is attempted has to be balanced against:\n\nthe perioperative risks and long-term complications of EVAR\n\nthe uncertainty around whether they will benefit from EVAR\n\nthe large costs of EVAR.\n\nWith all this in mind, it is clear that practice needs to be rebalanced. Conservative management is a better option than EVAR for many people. However, NICE also acknowledged stakeholder comments highlighting the importance of individualised care. For some people, EVAR may be appropriate. Clinicians should discuss the risks of EVAR and conservative management with people with AAAs, taking into account the uncertainty that EVAR will provide a benefit.\n\nPeople who are not offered repair may be anxious about having an AAA but not receiving treatment for it. However, a better explanation of the risks they face, in the context of their other life-limiting comorbidities, can help with anxiety. To help with this, the committee made consensus recommendations (see recommendations 1.1.13 to 1.1.14) on the information to cover when discussing repair with people who have an AAA.\n\nThe evidence for complex EVAR was limited in quantity and quality. However, complex EVAR grafts and procedures are much more expensive than standard EVAR, so the difference in cost between EVAR and open surgical repair is likely to be even greater than for infrarenal AAAs. In addition, using standard EVAR stent grafts for complex AAA usually violates the manufacturer's 'instructions for use'.\n\nAlthough there is currently no evidence that complex EVAR has better outcomes than open surgical repair, people with complex AAAs have higher perioperative mortality rates than people with infrarenal AAAs. Because of this, an increased perioperative survival benefit may be more important for them, and may justify the use of complex EVAR. This would differentiate complex EVAR from standard EVAR, which clearly does not provide enough short-term benefits to outweigh the worse long-term outcomes or the increased cost (when compared with open surgical repair).\n\nOpen surgical repair is contraindicated for some people with an unruptured AAA because of anaesthetic risks and/or medical comorbidities. For these people, the risk of their AAA rupturing if no repair is attempted has to be balanced against:\n\nthe perioperative risks and long-term complications of complex EVAR\n\nthe uncertainty around whether they will benefit from complex EVAR\n\nthe large costs of complex EVAR.\n\nWith all this in mind, it is clear that conservative management is a better option than complex EVAR for many people. However, NICE also acknowledged stakeholder comments highlighting the importance of individualised care. For some people, complex EVAR may be appropriate. Clinicians should discuss the risks of complex EVAR and conservative management with people with AAAs, taking into account the uncertainty that complex EVAR will provide a benefit.\n\nAs with standard EVAR, NICE acknowledged that in the face of the evidence reviewed, practice needs to be rebalanced towards open surgical repair in this scenario as well. But, because of the limited evidence for complex EVAR and the importance of individualised care, NICE concluded that it is important for clinicians and people with AAA to discuss the uncertainties and weigh up the risks and benefits of repair, in order to make an informed decision.\n\nMore evidence on this procedure would be helpful, and NICE has made a recommendation for research comparing complex EVAR with open surgical repair.\n\nFor each of the recommendations, NICE considered whether there were any specific groups that would benefit from standard or complex EVAR for unruptured AAAs. We explored groups defined by age, sex, AAA diameter and life expectancy, but it was not possible with the current evidence to identify any specific groups in which the benefits would outweigh the harm and costs.\n\nThe key randomised controlled trials (RCTs) in this area are relatively old. NICE looked at more recent observational evidence, to see if changes in surgical and endovascular techniques and technology have led to different outcomes. The observational studies are at high risk of bias, but their findings are broadly in line with the RCTs. They show that, while outcomes from EVAR have improved over the last 15\xa0years, outcomes from open surgical repair have also improved by roughly the same amount. This means the difference in outcomes between the two has remained fairly constant.\n\nRegistries like the National Vascular Registry can provide a useful snapshot of current practice, and the analyses that informed NICE's decision-making made use of data from them. However, they are not designed to evaluate the comparative benefits and harms of different surgical approaches, such as EVAR and open surgical repair. Therefore, they cannot be considered a reasonable alternative to RCT data. In addition, an analysis using the registry data showed that EVAR still did not provide greater long-term benefits than open surgical repair, and that it still has higher net costs.\n\nNICE acknowledged the need to rebalance practice towards open repair and identified the possible implementation challenges.\n\nPossible increased perioperative mortality with open surgical repair: Improvements in practice since the RCTs were published have led to better standards for open surgical repair and EVAR alike. In addition, the NHS AAA screening programme means that AAAs are more likely to be diagnosed earlier than in the past, so people can have repair when they are younger and healthier. For these reasons, open surgical repair of unruptured AAAs can be provided with a low incidence of morbidity and mortality.\n\nThe risk that vascular units will have trouble meeting an increased demand for open surgical repair: All vascular surgeons should be competent to perform open surgical repair of AAAs, and the Intercollegiate Surgical Curriculum Programme's Vascular surgery curriculum puts more emphasis on open surgical repair than on EVAR. This means that future surgeons should be well prepared to provide open surgical repair with a low incidence of morbidity and mortality.\n\nPotential shortage of beds in the NHS: As people who have open surgical repair spend more time in hospital immediately after the procedure, there may be a small, short-term increase in waiting times for AAA repair. However, an analysis comparing waiting times showed that open surgical repair would still provide greater benefit than EVAR for a lower cost even with a substantial increase in waiting times for open surgical repair.\n\nThe possibility that reducing the number of EVAR procedures performed for unruptured aneurysms will make it difficult to provide EVAR for ruptured aneurysms: There are a number of ways this implementation issue might be addressed:\n\n\n\nvascular services could be centralised further (for example by establishing aortic units)\n\nin line with the recommendations, EVAR can be offered in certain situations.\n\n\n\nThe evidence did not show any benefit from goal-directed therapy for people having repair of an unruptured AAA. Goal-directed therapy covers a broad range of different haemodynamic monitoring and management practices, some of which are routinely performed during major surgery. The committee recognised that it was not possible to specify which practices should or should not be performed and agreed that drafting recommendations would be too prescriptive.\n\n## How the recommendations might affect practice\n\nThe recommendation on when to repair unruptured aneurysms is unlikely to impact on current clinical practice because it reflects what is already being done within the NHS. Data from the NHS AAA screening programme indicate that the risk of rupture for AAAs that are smaller than 5.5\xa0cm is very low.\n\nThe recommendations on EVAR could have a large impact on practice and will also affect the timing and type of information about treatment options given to patients. In light of the evidence reviewed, practice needs to be rebalanced towards open surgical repair for infrarenal aneurysms. The recommendations will minimise harm by reducing long-term mortality and the need for re-intervention as a result of the problems with EVAR. The reduction in EVAR, and so EVAR-related re-interventions, will result in significant cost savings for the NHS.\n\nA lack of recommendations on goal-directed therapy will not impact on practice. Basic haemodynamic management is routinely performed during most surgical procedures, but goal-directed therapy is not widely adopted during AAA surgery.\n\nReturn to recommendations\n\n# Anaesthesia and analgesia during unruptured aneurysm repair\n\n## Why the committee made the recommendation\n\nRecommendation 1.5.8\n\nThe committee noted that there was some evidence that adding an epidural to general anaesthesia reduced the need for further analgesia for people having open surgical repair of an unruptured AAA. This was consistent with their own clinical experience of better pain control and reduced postoperative respiratory complications with an epidural. Adding an epidural is fairly widespread in current practice, and the committee agreed that it should be recommended as an option.\n\nNo evidence was found on anaesthesia and analgesia for people undergoing EVAR for unruptured AAA. The committee agreed that no recommendations were needed in this area because they had recommended that EVAR should not be used to treat unruptured infrarenal abdominal aortic aneurysm, except in clinical trials or for people for whom open surgical repair is unsuitable because of abdominal copathology.\n\n## How the recommendations might affect practice\n\nThe use of an epidural in addition to general anaesthesia for people having open surgical repair of an unruptured AAA is already fairly widespread in current practice. Therefore the overall impact of the recommendation is likely to be small, although it may reduce existing variation.\n\nReturn to recommendation\n\n# Repairing ruptured aneurysms\n\n## Why the committee made the recommendations\n\nRecommendations 1.6.1 to 1.6.3\n\nThe evidence showed that, compared with open surgical repair, a strategy that uses EVAR (where anatomically possible) to repair ruptured infrarenal abdominal aortic aneurysm provides a reasonable balance of benefits and costs.\n\nAs the average cost-effectiveness results for EVAR were favourable, the committee discussed whether they should recommend EVAR whenever it is possible. They decided not to, for 2 reasons.\n\nFirstly, there is uncertainty in the evidence for EVAR from the IMPROVE trial. People who had EVAR for a ruptured AAA in this trial were followed up for at most 7\xa0years. People who had EVAR for an unruptured AAA in the EVAR-1 trial were followed up for 15\xa0years, and the committee noted that these data indicate that EVAR leads to increasingly worse survival when compared with open surgical repair, because follow-up duration increases (see why NICE made the recommendations on repairing unruptured aneurysms). The medium-term survival data from the IMPROVE trial give some indication that a similar long-term pattern may develop in trials of ruptured AAA, with the survival curves converging as follow-up gets longer. Therefore, it is possible that longer-term data would show EVAR to be worse than open surgical repair for people with ruptured AAA as well.\n\nSecondly, there was evidence that the balance of benefits and costs for EVAR varies between different groups of people with ruptured AAAs. In particular, most women have better short-term survival after EVAR, whereas the evidence favours open surgical repair for younger men. Therefore, the committee recommended that either EVAR or open surgical repair can be considered, and provided detail on the groups for which each approach is likely to be best.\n\nComplex EVAR is only recommended within the context of an RCT because there is currently no evidence to support it as an option for people with ruptured complex AAA. Open surgical repair of these aneurysms is recommended as the only approach that should be used in people for whom emergency repair is suitable until the safety and effectiveness of complex EVAR has been established in this setting.\n\nNo evidence on the use of tranexamic acid in people with a ruptured AAA was identified. The committee was aware that tranexamic acid is included in some major haemorrhage protocols and some patients, without major trauma, may receive it before undergoing surgery. In the committee's experience, tranexamic acid is not routinely used in people with a ruptured AAA, so it agreed to recommend research in this area.\n\nThere was no evidence on goal-directed therapy for people having repair of a ruptured aneurysm. Goal-directed therapy covers a broad range of different haemodynamic monitoring and management practices; some of which are routinely performed during major surgery. The committee recognised that it was not possible to specify which practices should or should not be performed and agreed that drafting recommendations would be too prescriptive.\n\n## How the recommendations might affect practice\n\nThe recommendations will have little impact on current practice, as both standard EVAR and open surgical repair are currently offered to people with ruptured infrarenal AAAs. In relation to complex EVAR, the recommendation not to use it outside of RCTs will limit the use of a technically complex and expensive procedure in people for whom open surgery is a safe and suitable option.\n\nBecause the guideline recommends that fewer EVAR procedures should be performed for unruptured aneurysms (see the section on repairing unruptured aneurysms), surgical teams may have less opportunity to develop the skills they need to provide EVAR in emergency cases. The committee were mindful of this issue, but were convinced by the evidence showing that, overall, people with AAAs would be worse off if EVAR procedures were performed for unruptured aneurysms just to maintain EVAR expertise. Elective EVAR will still be available in certain circumstances and centralisation of aortic services may maintain expertise. However, neither training nor service models were in the scope of this guideline, so the committee did not review any evidence and were unable to make any specific recommendations in these areas.\n\nA lack of recommendations on goal-directed therapy will not impact on practice. Basic haemodynamic management is routinely performed during most surgical procedures, but goal-directed therapy is not widely adopted during AAA surgery.\n\nA lack of recommendations on tranexamic acid will have little impact on practice. Tranexamic acid is used in varying degrees across the NHS, but it is not standard practice for people with ruptured or symptomatic AAAs who are being transferred before surgery.\n\nReturn to recommendations\n\n# Anaesthesia and analgesia during ruptured aneurysm repair\n\n## Why the committee made the recommendation\n\nRecommendation 1.6.4\n\nNo evidence was identified on the optimal use of anaesthesia and analgesia in people having open surgical repair or EVAR of a ruptured AAA. The committee agreed, based on their knowledge and experience, that general anaesthesia alone is widely accepted as best practice for open surgical repair, so did not make a recommendation on this. The committee made a recommendation on the use of local infiltrative anaesthesia alone in people having EVAR for ruptured AAA because it was considered that increased awareness of this option was needed.\n\n## How the recommendation might affect practice\n\nThe committee agreed that the potential impact of this recommendation on practice is unclear, because it is difficult to predict the proportion of people for whom EVAR under local infiltrative anaesthesia might be an option. The main aim of this recommendation is to raise awareness of this option.\n\nReturn to recommendation\n\n# Abdominal compartment syndrome\n\n## Why the committee made the recommendations\n\nRecommendations 1.6.5 and 1.6.6\n\nThere was no evidence relating to preventing or managing abdominal compartment syndrome in people who are having AAA repair. The committee agreed it was important to raise awareness of this potentially life-threatening condition, and made recommendations to highlight that it can occur after both endovascular aneurysm repair and open surgical repair.\n\n## How the recommendations might affect practice\n\nThe recommendations will ensure that clinicians are aware of abdominal compartment syndrome in people who have undergone repair of ruptured AAA. This may result in better postoperative assessment and management.\n\nReturn to recommendations\n\n# Monitoring for complications after endovascular aneurysm repair\n\n## Why the committee made the recommendations\n\nRecommendations 1.7.1 to 1.7.5\n\nImaging surveillance is needed after EVAR, because there is a risk that people will develop complications from the procedure or need another operation. These risks are lower after open surgical repair, so surveillance is not standard practice and in this case the committee did not recommend it.\n\nThe committee noted that the frequency of EVAR surveillance is highly variable in practice. In the absence of evidence on how often imaging should be done, the committee agreed a recommendation to tailor surveillance to the perceived risk of complications. This should focus attention and resources on the people at greatest risk, and help to identify complications earlier.\n\nIn practice, identifying complications after EVAR usually involves sequential imaging, with ultrasound frequently used as the first-line test and other imaging modalities used to detect specific complications. Imaging modalities may be complimentary, and the clinical significance of some imaging findings remains unclear, which makes identifying a true reference standard difficult.\n\nContrast-enhanced CT angiography was widely used as a gold standard in the evidence that was reviewed. However, this has led to some abnormalities that are detected on other imaging modalities, but not on CT, being defined as false positives (for that modality, rather than as false negatives for CT). This may have introduced bias, and makes it difficult to rely on CT as a reference standard.\n\nThe evidence showed that colour duplex ultrasound was highly accurate at identifying changes in sac size when compared with contrast-enhanced CT angiography. Increases in sac size are often believed to indicate an endoleak even if no leak can be seen on the ultrasound. There was little evidence on graft kinking, but the committee agreed based on their experience that colour duplex ultrasound and CT angiography were equally as effective at detecting this type of complication.\n\nIn the evidence reviewed, contrast-enhanced ultrasound was the only imaging technique that had acceptable accuracy for directly identifying endoleaks when compared with contrast-enhanced CT angiography. Importantly, other imaging techniques had unacceptably high rates of false-negative results. For this reason, the committee agreed that in situations where the definitive exclusion (or identification) of endoleak is important (for example where endoleak is suspected) either contrast-enhanced CT angiography or contrast-enhanced ultrasound should be used. Contrast-enhanced ultrasound was not recommended for assessing other complications because the evidence for its use only covered endoleaks.\n\nThe committee agreed that it is particularly important not to falsely exclude an endoleak, so the sensitivity of a diagnostic test is more important than its specificity. While colour duplex ultrasound is highly accurate at identifying changes in sac size (which may indicate an endoleak), the available evidence shows that it has suboptimal sensitivity for directly detecting type I and III endoleaks. In addition, the accuracy of ultrasound was shown to be dependent on the operator, so its accuracy may be variable in practice. This variability in diagnostic accuracy, and resultant potential for harm if an endoleak is missed, led the committee to recommend that colour duplex ultrasound alone should not be used to confirm or exclude the presence of endoleaks.\n\n## How the recommendations might affect practice\n\nThere is variation in which imaging techniques are used for surveillance. Some centres use ultrasound only, and some use contrast-enhanced CT angiography and ultrasound. Colour duplex ultrasound is widely used, but contrast-enhanced ultrasound is not. These recommendations are not likely to alter surveillance regimens substantially because many centres use imaging tests in a complementary fashion, often relying on sac size as a trigger for further investigation if necessary. Sonographers will need training in administering contrast agents if contrast-enhanced ultrasound is to be more widely adopted.\n\nReturn to recommendations\n\n# Managing endoleaks after endovascular aneurysm repair\n\n## Why the committee made the recommendations\n\nRecommendations 1.8.1 to 1.8.3\n\nEndoleaks following EVAR are common. They can have a negative impact on patient prognosis and long-term quality of life, and further interventions are frequently needed to repair them. In the absence of evidence, the committee made recommendations based on their experience because:\n\nit is good practice to repair type I and III endoleaks and some type II endoleaks\n\nhealthcare professionals are not all aware that type II endoleaks without sac expansion can be managed conservatively\n\nthere are circumstances when sac expansion occurs without imaging evidence of a leak site (called type V endoleak), and these situations need further investigation.\n\n## How the recommendations might affect practice\n\nThe recommendations will have minimal impact on current practice because it is common practice to intervene for type I and type III endoleaks, and type II endoleaks if there is evidence of aneurysm sac expansion.\n\nReturn to recommendations", 'Context': 'Abdominal aortic aneurysms develop when the wall of the aorta in the abdomen weakens, causing it to bulge and form a balloon-like expansion. When the abdominal aorta reaches a diameter at least 1.5\xa0times the normal size, or greater than 3\xa0cm in total, it is called an abdominal aortic aneurysm (AAA).\n\nThe increased stress on the aortic wall may eventually cause the AAA to rupture (burst). The subsequent internal bleeding is frequently fatal before emergency repair can be attempted. When people have emergency repair for rupture, up to half will not survive to leave hospital.\n\nThere is a long period of growth before an AAA ruptures. The rate of growth may depend on a number of factors, including increasing age, smoking, blood pressure and a family history of aneurysm.\n\nMost AAAs are asymptomatic, and they are often diagnosed opportunistically during clinical examination or investigation for another condition. Because of this it is difficult to establish their prevalence. There is a national screening programme which enrols men at age 65 and suggests a prevalence of about 1.3% in this population. The prevalence is falling.\n\nThe prevalence of AAAs is approximately 6\xa0times lower in women, but the rate of aneurysm rupture is significantly higher. The guideline committee carefully considered the impact of their recommendations on women during guideline development.'}
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https://www.nice.org.uk/guidance/ng156
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This guideline covers diagnosing and managing abdominal aortic aneurysms. It aims to improve care by helping people who are at risk to get tested, specifying how often to monitor asymptomatic aneurysms, and identifying when aneurysm repair is needed and which procedure will work best.
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5202a74e990300cf365fd214ac7769fc154236dc
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nice
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Alemtuzumab for treating highly active relapsing remitting multiple sclerosis
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Alemtuzumab for treating highly active relapsing remitting multiple sclerosis
Evidence-based recommendations on alemtuzumab (Lemtrada) for treating highly active relapsing–remitting multiple sclerosis in adults.
# Guidance
Alemtuzumab is recommended as an option, within its marketing authorisation, for treating highly active relapsing–remitting multiple sclerosis in adults with:
highly active disease despite a full and adequate course of treatment with at least 1 disease-modifying therapy or
rapidly-evolving severe relapsing-remitting multiple sclerosis defined by 2 or more disabling relapses in 1 year, and with 1 or more gadolinium-enhancing lesions on brain MRI or a significant increase in T2 lesion load compared with a previous MRI.# The technology
Alemtuzumab (Lemtrada, Genzyme) is an antibody that binds to cells of the immune system (B and T cells), causing their destruction. The way in which alemtuzumab slows the decline of highly active relapsing–remitting multiple sclerosis is not fully understood. Alemtuzumab has a UK marketing authorisation 'as a single disease modifying therapy in adults with highly active relapsing remitting multiple sclerosis for the following patient groups:
patients with highly active disease despite a full and adequate course of treatment with at least 1 disease modifying therapy or
patients with rapidly evolving severe relapsing remitting multiple sclerosis defined by 2 or more disabling relapses in one year, and with 1 or more gadolinium enhancing lesions on brain MRI or a significant increase in T2 lesion load as compared to a previous recent MRI'.The recommended dosage of alemtuzumab is 12 mg/day administered by intravenous infusion for 2 treatment courses. The initial treatment course lasts 5 consecutive days, followed 12 months later by the second treatment course of 3 consecutive days.
For full details of adverse reactions and contraindications, see the summary of product characteristics.
The price of alemtuzumab is £7045 per 12 mg vial, which equates to £56,360 for the full course of treatment consisting of 5 daily consecutive 12 mg doses in year 1, followed by 3 daily consecutive 12 mg doses 12 months later in year 2. Costs may vary in different settings because of negotiated procurement discounts.# The manufacturer's submission
The Appraisal Committee's remit was to appraise the clinical and cost effectiveness of alemtuzumab within its licensed indication for treating active relapsing–remitting multiple sclerosis. The Appraisal Committee (section 7) considered evidence submitted by the manufacturer of alemtuzumab and a review of this submission by the Evidence Review Group (ERG; section 8).
# Clinical effectiveness
The manufacturer provided clinical-effectiveness evidence, identified by systematic review, from:
phase III randomised controlled clinical trials: CARE‑MS I (n=581, median follow-up of 2 years), and CARE‑MS II (n=1046, median follow-up of 2 years)
phase II randomised controlled clinical trial: CAMMS223 (n=334, maximum follow-up of 3 years extended by a follow-up period of 4 years from final alemtuzumab dose)
extension study: CAMMS03409 (n=1322, median follow-up of 7.1 years), which enrolled people with active relapsing–remitting multiple sclerosis from the CAMMS223, CARE‑MS I and CARE‑MS II trials. In this study, patients previously randomised to the control group in CAMMS223, CARE‑MS I and CARE‑MS II received alemtuzumab and patients previously randomised to alemtuzumab in CAMMS223, CARE‑MS I and CARE‑MS II received further treatment with alemtuzumab, as needed.In addition, the manufacturer submitted a meta-analysis of the above-listed trials and a mixed treatment comparison to compare alemtuzumab with other disease-modifying treatments for active relapsing–remitting multiple sclerosis (see sections 3.7-3.8).
CARE‑MS I, CARE‑MS II and CAMMS223 compared the effectiveness of 12 mg alemtuzumab (with an additional arm receiving 24 mg per infusion in CAMMS223 only) with subcutaneous interferon beta‑1a (Rebif, small initial doses, gradually increasing to 44 micrograms 3 times weekly). All 3 trials included sites in the UK. All 3 trials specified the number of previous relapses patients must have had before they could enrol. For CAMMS223 this was at least 2 relapses in the previous 2 years. For CARE‑MS I and CARE‑MS II this was at least 2 relapses within the previous 2 years, with at least 1 within the previous year. CARE‑MS I and CAMMS223 included patients with an Expanded Disability Status Scale (EDSS) score between 0 and 3 (in which 0 means no disability and no signs of impairment in any functional system and 3 means unimpaired walking, but either moderate disability in 1 functional system or mild disability in 3 or 4 functional systems). CARE‑MS II included patients with an EDSS score between 0 and 5 (in which 5 means disability severe enough to impair normal daily activities and the person's ability to work a full day without special provisions, but they are still able to walk for 200 metres without aid or rest). All patients in CARE‑MS II had to have previously received disease-modifying treatment with beta interferon or glatiramer acetate for 6 months in the preceding 10 years (the inclusion criteria also specified that more than 1 multiple sclerosis relapse had to have occurred while receiving these treatments), whereas patients in CARE‑MS I and CAMMS223 did not.
The co-primary outcomes of the 3 trials were time to the onset of sustained accumulation of disability (specified as lasting for 6 months for CARE‑MS I and CARE‑MS II) and relapse rate. In the trials, patients were assessed quarterly using the EDSS to determine disability, and were assessed as needed for suspected relapses. Sustained accumulation of disability was defined as an increase lasting for 6 months of at least 1.5 points for people with a baseline EDSS score of 0, or 1.0 point for people with a baseline EDSS score of 1.0 or more. A relapse was defined as new or worsening neurological symptoms attributable to relapsing–remitting multiple sclerosis, lasting at least 48 hours, without fever, after at least 30 days of clinical stability, with an objective change on neurological examination. Data from CAMMS223 were analysed by intention to treat, and adjusted for country and baseline EDSS score, as prespecified in the statistical plan. In CARE‑MS I and CARE‑MS II only patients who had received at least 1 dose of trial medication were included in the analysis (that is, a modified intention-to-treat analysis). In CARE-MS II the analysis was also limited to patients who had followed the trial protocol (excluding patients who had not met all inclusion criteria). The results were adjusted for region.
In CARE‑MS I 8% of people in the alemtuzumab treatment group had disability lasting for 6 months, compared with 11.1% in the Rebif group. There was no statistically significant difference in the rates of disability lasting for 6 months between people taking alemtuzumab and people taking Rebif (hazard ratio 0.70, 95% confidence interval 0.4 to 1.23; p=0.22). In CARE‑MS II 12.7% of people in the alemtuzumab treatment group had disability lasting for 6 months, compared with 21.1% in the Rebif group. This corresponded to a statistically significant improvement of 42% with alemtuzumab (HR 0.58, 95% CI 0.38 to 0.87; p=008). In CAMMS223 alemtuzumab statistically significantly reduced the risk of sustained accumulation of disability lasting for 6 months by 75% compared with Rebif (HR 0.25, 95% CI 0.11 to 0.57, p<0.001). A separate extended follow-up study of CAMMS223 showed that over 5 years, alemtuzumab statistically significantly reduced the risk of sustained accumulation of disability lasting for at least 6 months by 69% compared with Rebif (HR 0.31, 95% CI 0.16 to 0.60, p=0.0005).
Alemtuzumab statistically significantly reduced the relapse rate compared with Rebif: by 54.9% in CARE‑MS I (RR 0.45, 95% CI 0.32 to 0.63, p<0.0001), by 49.4% in CARE‑MS II (RR 0.51, 95% CI 0.39 to 0.65, p<0·0001) and by 69% in CAMMS223 (RR 0.31, 95% CI 0.18 to 0.52, p<0.001). The extended follow-up study of CAMMS223 showed that, over 5 years, alemtuzumab statistically significantly lowered the rate of relapse by 66% compared with Rebif (RR 0.34, 95% CI 0.20 to 0.57, p<0.0001).
The manufacturer presented data from CARE‑MS II and CAMMS223 (and its separate study extension) to compare alemtuzumab with Rebif in a subgroup of people with rapidly evolving severe relapsing–remitting multiple sclerosis (size of subpopulation not available). The manufacturer pooled the results of the 12‑mg and 24‑mg alemtuzumab arms of CAMMS223 because it considered that the results in each arm were sufficiently similar to allow this. The manufacturer stated that the analyses showed that the effectiveness of alemtuzumab compared with Rebif in the rapidly evolving severe relapsing–remitting multiple sclerosis subgroup was comparable to or greater than that seen in the overall trial populations. The reduction of risk in sustained accumulation of disability lasting at least 6 months was 51% in CARE‑MS II (no p value reported) and 65% (p=0.036) in the pooled group of CAMMS223. The analysis also indicated a statistically significant reduction in relapse rates for alemtuzumab compared with Rebif, of 56% (p=0.0018) in the rapidly evolving severe relapsing–remitting multiple sclerosis subgroup of CARE‑MS II and of 81% (p<0.0001) in the pooled dose group of CAMMS223.
The manufacturer presented a mixed treatment comparison that compared alemtuzumab with each of the treatments in the decision problem (Rebif, intramuscular interferon beta‑1a , interferon beta‑1b , glatiramer acetate, natalizumab and fingolimod). The manufacturer included 30 clinical trials identified in the systematic literature review, all of which recruited patients from the year 2000 onwards, and in which at least 80% of the patients had relapsing–remitting multiple sclerosis (the 'base-case mixed treatment comparison'). The manufacturer justified the year 2000 as an appropriate cut-off point because annualised relapse rates have fallen in recent years and because the diagnostic criteria used in multiple sclerosis trials have changed. The manufacturer provided a separate 'all years' analysis that, in addition, included trials recruiting patients before the year 2000. The outcomes in the base-case mixed treatment comparison were annualised relapse rate, proportion of patients who were relapse free, sustained accumulation of disability lasting for 3 months, sustained accumulation of disability lasting for 6 months, discontinuation of treatment rate and discontinuation of treatment rate because of adverse events. In the base-case mixed treatment comparison, alemtuzumab led to statistically significantly lower annualised relapse rates than the beta interferons and glatiramer acetate. For the 3‑month sustained accumulation of disability outcome, alemtuzumab was statistically significantly lower than Avonex, Betaferon and Rebif (44 micrograms); however, the difference between alemtuzumab and glatiramer acetate was not statistically significant. For the 6‑month sustained accumulation of disability outcome, alemtuzumab was statistically significantly lower than Rebif (44 micrograms). While the point estimates for alemtuzumab compared with glatiramer acetate favoured alemtuzumab, the difference was not statistically significant. The results of the mixed treatment comparison were considered confidential by the manufacturer and therefore cannot be reported here.
The manufacturer carried out 2 separate mixed treatment comparisons of alemtuzumab for the subgroups of patients with highly active relapsing-remitting multiple sclerosis despite beta interferon treatment (from CARE‑MS II) and rapidly evolving severe relapsing-remitting multiple sclerosis (from CARE‑MS I and II and CAMMS223). For the highly active relapsing-remitting multiple sclerosis despite beta interferon treatment subgroup, alemtuzumab had a lower annualised relapse rate than fingolimod; however, the difference was not statistically significant (HR 0.50, 95% CI 0.11 to 2.29). The 3‑month sustained accumulation of disability was lower with alemtuzumab than with fingolimod but the difference was not statistically significant (HR 0.65, 95% CI 0.11 to 3.72). For the rapidly evolving severe relapsing-remitting multiple sclerosis subgroup, alemtuzumab had a lower annualised relapse rate than natalizumab; however, the difference was not statistically significant (HR 0.69, 95% CI 0.11 to 4.53). The 6‑month sustained accumulation of disability was lower with alemtuzumab than with natalizumab, but the difference was not statistically significant (HR 0.78, 95% CI 0.06 to 10.83).
The manufacturer also presented a naïve indirect comparison of alemtuzumab compared with fingolimod and natalizumab for the subgroups of patients with highly active relapsing-remitting multiple sclerosis despite beta interferon therapy and patients with rapidly evolving severe relapsing-remitting multiple sclerosis respectively. The CARE MS-II study comparing alemtuzumab with active comparator (Rebif ) showed that alemtuzumab had a greater treatment effect on 3‑month sustained accumulation of disability in people with highly active relapsing-remitting multiple sclerosis despite beta interferon treatment (HR 0.61, 95% CI 0.37 to 1.01) than fingolimod compared with placebo had in the FREEDOM study (HR 0.73, 95% CI 0.29 to 1.84). Studies comparing alemtuzumab with Rebif showed that alemtuzumab had a similar treatment effect on 6‑month accumulation of disability in people with rapidly evolving severe relapsing-remitting multiple sclerosis (CAMMS223 , CARE MS-I and CARE MS-II ) to natalizumab compared with placebo in the AFFIRM study (HR 0.36, 95% CI 0.17 to 0.76).
In a pooled analysis of CARE‑MS I, CARE‑MS II and CAMMS223 results, most patients reported at least 1 adverse event, the majority of which were mild or moderate in severity. The most common adverse events were headache, rash, fever and multiple sclerosis relapse. The incidence of serious adverse events as reported at the end of the trials from the European Public Assessment Report (EPAR) was 18.3% in both the alemtuzumab and comparator arms. Independent investigators considered that the adverse events were related to alemtuzumab in 7.1% of all patients receiving 12 mg alemtuzumab and to Rebif in 1.6% of all patients receiving Rebif. The most frequently reported serious adverse events in the alemtuzumab 12 mg group were multiple sclerosis relapse (6.1%), pneumonia (0.4%), autoimmune thrombocytopenia (0.4%), gastroenteritis (0.4%), appendicitis (0.4%) and hives (0.4%). Four people developed idiopathic thrombocytopenic purpura. More thyroid-related adverse events were observed in the alemtuzumab arm of the trial (16.6%) than in the Rebif arm (5.2%). Thyroid-related adverse events were observed in 36.2% (at 4 years) and 44.7% (at 8 years) of patients in the alemtuzumab 12 mg/day group. The highest incidence of thyroid-related adverse events was observed between 24 and 42 months after the first treatment cycle. Other serious adverse events observed throughout the clinical trials included infections and renal disease. With the exception of thyroid disorders, administering more than 2 treatment cycles of alemtuzumab did not result in increased frequencies of common adverse events or clinically important events which had not already been observed. Eight people died during the clinical trials; 7 of these people had received alemtuzumab, and the EPAR states that the investigator judged that 3 deaths were possibly or likely to have been related to alemtuzumab treatment.
The manufacturer assessed health-related quality of life during the phase II and III trials using the Short-Form Health Survey (SF‑36), the Functional Assessment of Multiple Sclerosis (FAMS) and the EuroQoL‑5 Dimension-5 Level (EQ‑5D-5L) questionnaire. In CARE‑MS I and II, patients completed the SF‑36 at baseline, at month 12, at month 24, and at early discontinuation of treatment. In CARE‑MS I and II, the FAMS and EQ‑5D-5L were assessed at baseline and every 6 months thereafter until month 24 or early discontinuation of treatment. In CAMMS223, patients completed the SF‑36 every 6 months for 3 years, but not the FAMS or EQ-5D-5L. The manufacturer pooled the EQ-5D-5L utility scores from the CARE MS I and II trials in the alemtuzumab and Rebif (44 micrograms) arms at baseline and 24 months by EDSS score. The difference in mean utility values between patients with the same EDSS scores at baseline and at 24 months showed no consistent trend in either the alemtuzumab or the Rebif arms. The results were provided by the manufacturer as commercial in confidence.
# Cost effectiveness
To assess the cost effectiveness of alemtuzumab the manufacturer submitted a multi-state Markov model reflecting the course of multiple sclerosis and the effect of treatment with alemtuzumab or the comparators defined in the decision problem (that is, Rebif, Avonex, Betaferon, glatiramer acetate, natalizumab and fingolimod). The model incorporated health states for the type of multiple sclerosis (relapsing–remitting or secondary progressive) and for disease severity defined by the level of disability (EDSS scores ranging from 0 to 9 ). Patients with active relapsing–remitting multiple sclerosis entered the model at EDSS 0 up to EDSS 7 (an EDSS of 7 and above means patients have lost the ability to walk on their own). EDSS 10 represented death from multiple sclerosis. In each cycle, patients remained in the same state, progressed to a worse state (moving to a better state was not possible), transferred to a state reflecting secondary progressive multiple sclerosis, or died. The model assumed that when a patient progressed from relapsing–remitting multiple sclerosis to secondary progressive multiple sclerosis, their EDSS score increased by 1 point. The manufacturer chose a cycle length of 1 year, and a lifetime time horizon of 50 years. Patients entering the model had a mean age of 39.3 years, and there were approximately 3 times as many women as men. The analyses used an NHS and personal social services perspective and a 3.5% discount rate on costs and health effects. Most patients received only 2 courses of alemtuzumab, but the model included re-treatment for some patients in year 3, in years 6 to 9 and in year 10 or above (the manufacturer labelled the rates of re-treatment as commercial in confidence and so they cannot be presented here).
To estimate the rate of disease progression in people with relapsing–remitting multiple sclerosis, the manufacturer used a matrix to represent the natural history transition and disability progression in people who were not receiving disease-modifying therapies. The manufacturer chose the London Ontario dataset, a longitudinal observational study from 1989, to populate the natural history transition matrix. Since no data for patients with an EDSS state of 0 were available in this dataset, the manufacturer obtained transition probabilities for an EDSS 0 from the placebo arms of 2 trials (TOWER and TEMSO) that compared teriflunomide with placebo for treating multiple sclerosis. The manufacturer based the population entering the model on the average demographic profile of patients in the UK Risk Sharing Scheme, in which 85.8% have relapsing–remitting multiple sclerosis, the mean EDSS of patients with relapsing–remitting multiple sclerosis is 3.1, and the mean EDSS of patients with secondary progressive multiple sclerosis is 5.5.
To model the effect of treatment with alemtuzumab on relapsing–remitting multiple sclerosis, the manufacturer applied the hazard ratios for the outcome of disability sustained for 3 months compared with placebo from the base-case mixed treatment comparison (see section 3.7) to the natural history matrix. Separately, the manufacturer considered treatment effects on relapse rate and severity (whether or not the relapse leads to hospitalisation). In the base case, the manufacturer assumed that patients discontinue treatment when they convert from relapsing–remitting multiple sclerosis to secondary progressive multiple sclerosis, or progress to EDSS 7. After discontinuing treatment, patients were assumed to receive best supportive care only. The manufacturer's model assumed that no patient who received alemtuzumab ever discontinued treatment, while patients could discontinue comparator treatments (and subsequently receive best supportive care). The manufacturer also assumed that the treatment effect of alemtuzumab did not change over time (even during years when patients did not receive alemtuzumab) until a patient reached EDSS 7 or converted to secondary progressive multiple sclerosis. On entering EDSS 7 the benefits of alemtuzumab stopped, independent of the number of courses of alemtuzumab given. In each cycle patients could stop using comparator treatments, discontinue treatment after reaching EDSS 7, or experience relapse or adverse events. The probability of death was dependent on the EDSS state (the higher the EDSS score, the higher the risk of death), age and sex.
The manufacturer's model applied health state utility values to each of the EDSS states. Although the manufacturer collected EQ‑5D data in the CARE‑MS I and II trials, it did not use these data in the model as they were not available at the time of submission. Instead, the manufacturer obtained health state utility values from Orme et al. (2007), a UK survey of health-related quality of life in (EQ‑5D) in people with multiple sclerosis. Utility values decreased as EDSS scores increased, with the exception of the utility value for EDSS state 3, which was lower than EDSS 4. EDSS states 8 and 9 had negative utility values, indicating states that are considered to be worse than being dead. The manufacturer applied disutilities for a relapse, to caregivers, and for adverse events. The manufacturer obtained the value for the disutility of relapse from Orme et al. (2007), and the value for the disutility of relapse leading to hospitalisation from a US study (Prosser et al. 2003). To estimate disutility to caregivers, the manufacturer used values taken from Gani et al. (2008), and to estimate the time spent caring for the patient, the manufacturer used Orme et al. (2007). Disutility values applied for each adverse event were annualised based on the published literature. The manufacturer also took into account how long each adverse event lasted, and whether it was specific to treatment. The adverse events included infusion-associated reactions, bronchitis, herpes zoster, urinary tract infections, autoimmune thyroid-related adverse events, nephropathies, idiopathic thrombocytopenic purpura, other cytopenias and vomiting.
The model used NHS reference costs and the payment-by-results tariff to estimate the costs of administration, monitoring and adverse events associated with each treatment. The manufacturer assumed that monitoring of patients previously treated with alemtuzumab lasts for up to 12 years. The manufacturer derived some costs from the literature: health state costs (including direct medical costs and direct non-medical costs) from a UK study (Tyas et al. 2007), and the costs associated with relapse from a study from the Republic of Ireland (Dee et al. 2012). For a sensitivity analysis, the manufacturer used an alternative UK study (Karampampa et al. 2012) to derive health state costs, although the manufacturer provided only natural history costs aggregated for EDSS states 0–3, 4–6 and 7–9, rather than costs for individual EDSS states. The manufacturer validated the resource use and costs it applied in the model using clinical experts. The cost of one of the comparators, fingolimod, includes a simple discount patient access scheme agreed with the Department of Health. However, the manufacturer did not know how large the discount was, and therefore could not use it in its base-case analysis. Instead, the manufacturer explored different prices of fingolimod in sensitivity analyses, using a range of assumed discounts.
The manufacturer's submission presented the total life years gained, the total quality-adjusted life years (QALYs) and the total costs resulting from the economic model for alemtuzumab and Rebif (44 micrograms). Treatment with alemtuzumab was associated with 18.62 life years, which equated to 4.03 QALYs, at a total cost of £499,347. Treatment with Rebif (44 micrograms) was associated with 18.38 life years, which equated to 2.85 QALYs, at a total cost of £489,354.
The manufacturer conducted a fully incremental analysis, calculating the incremental QALY gains and costs for all treatment options and ordered by increasing costs. The treatments included alemtuzumab, glatiramer acetate, Rebif (22 micrograms), Rebif (44 micrograms), Avonex, and Betaferon. The manufacturer also included fingolimod and natalizumab in its incremental analysis, although it acknowledged that these drugs have marketing authorisations only for use in highly active relapsing-remitting multiple sclerosis despite beta interferon treatment and rapidly evolving severe relapsing–remitting multiple sclerosis. When compared in this incremental analysis, the probabilistic estimates of the incremental cost-effectiveness ratios (ICERs) suggested that:
alemtuzumab dominated Betaferon, fingolimod (without applying a patient access scheme discount), fingolimod (assuming a patient access scheme price of £13,000 per year), and natalizumab. (A treatment dominates other treatments when it is less expensive and more effective.)
Rebif (44 micrograms) and Rebif (22 micrograms) were extendedly dominated by alemtuzumab. (A treatment is extendedly dominated when its ICER is higher than that of the next, more effective, option when compared with a common baseline.)
The ICER for alemtuzumab compared with glatiramer acetate was £7017 per QALY gained. The manufacturer's deterministic results were similar with an ICER of £8924 per QALY gained for alemtuzumab compared with glatiramer acetate.
Using the results of the subgroup mixed treatment comparisons (see section 3.8), the manufacturer compared alemtuzumab with fingolimod and with natalizumab for the highly active relapsing-remitting multiple sclerosis despite beta interferon treatment and the rapidly evolving severe relapsing-remitting multiple sclerosis subgroups, respectively. For both analyses, alemtuzumab dominated the respective comparator.
The manufacturer conducted one‑way sensitivity analyses, which showed that the cost effectiveness of alemtuzumab was most sensitive to the hazard ratios reflecting the comparative effectiveness of alemtuzumab compared with placebo for sustained disability progression, disease costs, and the discontinuation rate of Rebif (44 micrograms). Alemtuzumab continued to dominate all comparators except glatiramer acetate, except when the manufacturer varied the hazard ratios for disability progression. When the manufacturer applied the upper limit of the 95% confidence interval around the sustained accumulation of disability hazard ratio for alemtuzumab from the manufacturer's mixed treatment comparison, the resulting ICER for alemtuzumab compared with Rebif (44 micrograms) was £1,200,973 per QALY gained. With the lower limit of the 95% confidence interval, alemtuzumab dominated Rebif (that is, had the lowest total treatment costs for the greatest clinical gain of all treatments in the analysis).
The manufacturer also tested how sensitive the results were to which mixed treatment comparison it used, by using the 'all years' data instead of the 'base-case' mixed treatment comparison and by only including trials in which 100% of patients had relapsing–remitting multiple sclerosis (rather than the base-case mixed treatment comparison, in which trials with at least 80% of patients with relapsing–remitting multiple sclerosis were included). When trials from 'all years' in which at least 80% of patients had relapsing–remitting multiple sclerosis were included, the deterministic ICER for alemtuzumab compared with glatiramer acetate increased from £8924 to £9982 per QALY gained. When the manufacturer included trials from all years in which the percentage of the population with relapsing–remitting multiple sclerosis was 100% the ICER for alemtuzumab compared with glatiramer acetate increased to £27,434 per QALY gained. When the manufacturer used the mixed treatment comparison including trials after the year 2000 in which 100% of patients had relapsing–remitting multiple sclerosis, the ICER for alemtuzumab compared with glatiramer acetate was £10,822 per QALY gained.
The manufacturer conducted a number of scenario analyses using Rebif (44 micrograms) as the comparator, but not glatiramer acetate, with the justification that Rebif (44 micrograms) was the standard treatment for active relapsing–remitting multiple sclerosis. In the best case scenario alemtuzumab dominated Rebif and in the worst case scenario the ICER for alemtuzumab compared with Rebif was £20,388 per QALY gained. The manufacturer developed other scenarios based on:
sourcing the baseline characteristics from the CARE‑MS trials rather than from the UK Risk Sharing Scheme (the ICER for alemtuzumab compared with Rebif was £869 per QALY gained)
using costs related to the natural history of multiple sclerosis from Karampampa et al. (2012) rather than Tyas et al. (2007) (alemtuzumab dominated Rebif)
using natural history transition probabilities assuming that the population only included people with active relapsing–remitting multiple sclerosis, instead of all people with relapsing–remitting multiple sclerosis (the ICER for alemtuzumab compared with Rebif was £8597 per QALY gained)
assuming long-term waning of treatment effect by 25% or 50% after year 5 for all treatments, instead of assuming that the beneficial effect of alemtuzumab does not wane (the ICERs for alemtuzumab compared with Rebif were £13,956 and £20,388 per QALY gained, respectively)
assuming that treatment with alemtuzumab does not influence the probability of relapses or hospitalisation (the ICER for alemtuzumab compared with Rebif was £14,517 per QALY gained)
using the trial data (pooled CARE‑MS I and CARE‑MS II) for the transition probabilities instead of using values sourced from the literature (alemtuzumab dominated Rebif).
# Evidence Review Group comments
The ERG reviewed the manufacturer's model and economic systematic review. The ERG commented that the structure of the economic model was appropriate for multiple sclerosis and consistent with previous economic evaluations of treatments for multiple sclerosis, and that the methods of analysis were appropriate and conformed to NICE methodological guidelines.
The ERG stated that the manufacturer systematically reviewed the literature to populate its transition matrix and reflect the natural history for disability progression for patients not receiving a disease-modifying treatment. The ERG did not find any data more appropriate than the London Ontario data identified by the manufacturer, but commented that the manufacturer did not fully explore the uncertainty around the natural history of multiple sclerosis. In light of previous technology appraisals, the ERG suggested that it would have been more appropriate to explore alternative sources of data.
The ERG evaluated the results of the economic model outputs as compared with published literature. The ERG noted that the manufacturer compared the results at the end of year 2, but no further. As there was no validation beyond 2 years, uncertainty remains as to the validity of longer-term outcomes.
The ERG stated that the manufacturer had performed appropriate structural sensitivity analyses, but had not conducted a sensitivity analysis that varied the rate of disease progression for patients receiving best supportive care only, or the rate of progression from relapsing–remitting multiple sclerosis to secondary progressive multiple sclerosis.
The ERG identified weaknesses and uncertainty in the manufacturer's economic analysis. The ERG stated that basing the starting model population on the UK Risk Sharing Scheme instead of the clinical trial populations introduced uncertainty into the model, because these populations did not have the same baseline characteristics, particularly with regard to the distribution of initial EDSS states. The ERG commented that the conversion rate used for patients moving from relapsing–remitting multiple sclerosis to secondary progressive multiple sclerosis in the model was too high, because it did not reflect the people receiving first-line treatment for relapsing–remitting multiple sclerosis. The ERG also stated that the London Ontario estimates for disease progression for patients not taking disease-modifying treatments did not allow EDSS scores to improve. Trial-based transition probabilities were available that allowed EDSS scores to improve, although the ERG commented that using the trial data could pose problems as it reflected a short period of time. The ERG explored the impact of changing these assumptions in their exploratory analyses.
# Exploratory sensitivity analyses undertaken by the Evidence Review Group
The ERG presented a 'preferred' base case that included alternative characteristics for the patient population, and a different progression rate from relapsing–remitting multiple sclerosis to secondary progressive multiple sclerosis. The ERG also conducted a series of sensitivity analyses to test uncertainties.
In all its exploratory analyses, the ERG compared alemtuzumab with Rebif (44 micrograms) (instead of glatiramer acetate as used in the manufacturer's fully incremental analysis). The ERG made this change because Rebif (44 micrograms) was the direct comparator in the clinical trials and was the most efficacious comparator in the manufacturer's mixed treatment comparison. Using the baseline characteristics for the populations in CARE‑MS I and CARE‑MS II, the ERG calculated that the ICER for alemtuzumab compared with Rebif (44 micrograms) would decrease from £8445 (manufacturer's base case comparing alemtuzumab with Rebif (44 micrograms) to £2869 per QALY gained. The ERG also applied a conversion rate of 15 years from relapsing–remitting multiple sclerosis to secondary progressive multiple sclerosis (instead of the 10–11 years used by the manufacturer), as used in Teriflunomide for treating active relapsing–remitting multiple sclerosis (NICE technology appraisal guidance 303). This had the effect of reducing the ICER to £3100 per QALY gained for alemtuzumab compared with Rebif (44 micrograms). The ERG's preferred approach combining these 2 changes resulted in alemtuzumab dominating (being less costly and more effective than) Rebif (44 micrograms), with a cost saving of £852 per QALY gained.
The ERG tested its preferred base case for alemtuzumab compared with Rebif (44 micrograms) in sensitivity analyses, including:
reducing by 50% the transition probabilities to more severe health states from the London Ontario dataset (alemtuzumab dominated Rebif )
using quality-of-life utility values (upper and lower confidence intervals from the Orme et al. 2007 data used in the manufacturer's model) (for both, alemtuzumab dominated Rebif )
using disease health state costs from Karampampa et al. (2012) and Biogen et al. (2007) (alemtuzumab dominated Rebif for Karampampa et al.; for Biogen et al., the ICER for alemtuzumab compared with Rebif was £4654 per QALY gained)
reducing the cost of a relapse that results in hospitalisation from £6146 to £3039 (the ICER for alemtuzumab compared with Rebif was £1013 per QALY gained)
applying a waning of treatment effect for alemtuzumab of 75% for year 10 and beyond, or 75% from year 6 to year 9 and 50% from year 10 and beyond (the ICERs for alemtuzumab compared with Rebif were £1815 and £7319 per QALY gained, respectively)
varying the proportion of patients receiving additional alemtuzumab treatment at year 3 (60%) and years 5 and beyond (the ICER for alemtuzumab compared with Rebif was £8336 per QALY gained)
applying the results from the 'all years' mixed treatment comparison (alemtuzumab dominated Rebif )
using the outcome of sustained accumulation of disability lasting for 6 months from the mixed treatment comparison (instead of 3 months) to calculate the disease transition probabilities (alemtuzumab dominated Rebif ).
The ERG also explored the cost effectiveness of alemtuzumab for the treatment‑naive and treatment‑experienced subgroups separately, using the ERG preferred base case, the relative risk for annualised rate of relapse, and a sustained accumulation of disability lasting 3 months for alemtuzumab. Using the treatment-naive group data from CARE‑MS I, the ERG's preferred base case (that is, where alemtuzumab dominated Rebif , see section 3.29) changed to an ICER of £6392 per QALY gained for alemtuzumab compared with Rebif (44 micrograms). When the ERG used the CAMMS223 data, alemtuzumab dominated Rebif (44 micrograms). Alemtuzumab also dominated Rebif (44 micrograms) when the ERG pooled data from the 2 trials. For the treatment-experienced group, using effectiveness data from CARE‑MS II, the ICER was £2854 per QALY gained for alemtuzumab compared with Rebif (44 micrograms).
The ERG also carried out exploratory analyses for the subgroup with highly active relapsing-remitting multiple sclerosis despite beta interferon treatment, and the subgroup with rapidly evolving severe relapsing–remitting multiple sclerosis. In these analyses the ERG used its preferred base case for a slower progression to secondary progressive multiple sclerosis for the rapidly evolving severe relapsing–remitting multiple sclerosis subgroup, and different patient characteristics for the highly active relapsing-remitting multiple sclerosis despite beta interferon treatment subgroup. These changes had only minimal effect on the model results, and alemtuzumab continued to dominate fingolimod and natalizumab.
# Manufacturer's response to the appraisal consultation document
The manufacturer provided a revised base case analysis using the Committee's preferred assumptions, as requested in the appraisal consultation document which did all of the following:
used sustained accumulation of disability lasting 6 months as the primary outcome measure of the mixed treatment comparison
used the 'all years' mixed treatment comparison adjusted for baseline relapse rates to estimate disease progression and withdrawal rates
used the intention-to-treat analyses developed for the CAMMS223, CARE‑MS I and CARE‑MS II trials adjusted for baseline Expanded Disability Status Scale (EDSS) only (unadjusted for country or region)
used the EQ-5D-5L utility scores pooled from the CARE MS I and II trials comparing alemtuzumab with Rebif (44 micrograms)
used data on the natural history and progression of disability from the placebo arms of the TOWER and TEMSO trials to allow for improvements in patients' EDSS states
incorporated the deaths observed in the trials into the model
assumed that the efficacy for alemtuzumab began waning at 3 or 5 years
used additional costs of other licensed treatments for active relapsing–remitting multiple sclerosis after failure of alemtuzumab
used a time-dependent rate of re-treatment for the costs of alemtuzumab
removed the mid-cycle correction for the costs of alemtuzumab
increased the number of monitoring and neurology visits for patients treated with alemtuzumab as well as visits for monitoring after restarting alemtuzumab treatment
used the lower health state costs used in the ERG's analyses
used costs associated with adverse effects of treatment including renal failure, renal transplantation, dialysis and death
used baseline characteristics from the alemtuzumab trials rather than from the UK Risk Sharing Scheme to populate the economic model.The manufacturer applied the Committee's preferences in individual analyses (see section 3.34) and also combined them into one analysis (see section 3.35).
In the manufacturer's individual analyses using the baseline characteristics of patients in the alemtuzumab trials in the model instead of the UK Risk Sharing Scheme, alemtuzumab dominated glatiramer acetate. For each of the other individual analyses, the resulting probabilistic ICERs for alemtuzumab compared with glatiramer acetate remained below £20,000 per QALY gained with the exception of the analyses exploring the impact of waning effectiveness of alemtuzumab and its comparators. For these analyses, the manufacturer presented 2 scenarios; the first assumed a decreasing efficacy for both alemtuzumab and the comparators over time, and the second assumed decreasing efficacy only for alemtuzumab. When the manufacturer assumed that the treatment effectiveness for both alemtuzumab and its comparators was reduced from 100% to 75% from year 3 to year 5 after treatment, and then to 50% from year 6 onward, the manufacturer's incremental analyses showed that glatiramer acetate dominated Avonex, Betaferon and Rebif (44 micrograms) and that the ICER for alemtuzumab compared with glatiramer acetate was £23,432 per QALY gained. When the manufacturer assumed that the effectiveness of alemtuzumab was reduced from 100% to 75% from year 3 to year 5, followed by a reduction to 50% from year 6 onward (while the efficacy of alemtuzumab's comparators remained unchanged) glatiramer acetate dominated Avonex, Betaferon and Rebif (44 micrograms) and the ICER for alemtuzumab compared with glatiramer acetate was £30,657 per QALY gained.
The manufacturer presented a fully incremental analysis combining each of the Committee's preferred assumptions including the 2 scenarios in which the effectiveness of treatments wanes over time. When the manufacturer assumed that the effectiveness for both alemtuzumab and its comparators was reduced from 100% to 75% from year 3 to year 5, followed by a reduction to 50% efficacy from year 6 onward, the manufacturer's incremental analyses showed that glatiramer acetate dominated Avonex, Betaferon and Rebif (44 micrograms) and that the ICER for alemtuzumab compared with glatiramer acetate was £13,636 per QALY gained. When the manufacturer assumed that the treatment effectiveness for alemtuzumab was reduced from 100% to 75% from year 3 to year 5, followed by a reduction to 50% efficacy from year 6 onward (while the efficacy of its comparators remained unchanged at 100%) glatiramer dominated Avonex, Betaferon and Rebif (44 micrograms) and the ICER for alemtuzumab compared with glatiramer acetate was £24,472 per QALY gained.
For the subgroup of rapidly evolving severe relapsing–remitting multiple sclerosis, when comparing alemtuzumab with natalizumab, the manufacturer used the Committee's preferred assumptions (see section 3.33) with the exception of using the results of the 'all years' mixed treatment comparison adjusted for baseline relapse rate because the manufacturer had not identified a relapse rate for natalizumab. When the manufacturer applied the Committee's assumptions individually, alemtuzumab dominated natalizumab for all but 1 scenario. In that scenario, the manufacturer assumed that the treatment effect for alemtuzumab waned beyond 3 years after treatment with alemtuzumab, while assuming that the treatment effect for natalizumab remained constant over the lifetime of the model. The ICER for this scenario was £236,172 per QALY gained. When the manufacturer combined all the Committee's preferred assumptions, alemtuzumab dominated natalizumab in the subgroup of people with rapidly evolving severe relapsing–remitting multiple sclerosis.
For the subgroup of patients with relapsing–remitting multiple sclerosis with high disease activity despite beta interferon treatment, when comparing alemtuzumab with fingolimod, the manufacturer used the Committee's preferred assumptions (see section 3.33) with the exception of 2 assumptions for which the manufacturer did not identify data. These 2 assumptions were sustained accumulation of disability lasting 6 months as a primary outcome measure in the mixed treatment comparison, and using the results of the 'all years' mixed treatment comparison adjusted for baseline relapse rate. When the manufacturer applied the Committee's assumptions individually, alemtuzumab dominated fingolimod in all scenarios. When the manufacturer combined all the Committee's assumptions, alemtuzumab continued to dominate fingolimod.
For the same subgroup, that is, patients with relapsing–remitting multiple sclerosis with high disease activity despite beta interferon treatment, and when comparing alemtuzumab with fingolimod, the manufacturer explored additional scenarios. The manufacturer combined all of the Committee's preferred assumptions (see section 3.33) and:
assumed that the hazard ratios from patients with relapsing–remitting multiple sclerosis with high disease activity despite beta interferon treatment in CARE MS II, which reflected the effectiveness of alemtuzumab compared with Rebif (44 micrograms) to delay disability (sustained accumulation of disability at 3 months) and annual relapse rates, were equivalent to what would have been expected had alemtuzumab been compared with placebo
incorporated these assumptions together with the hazard ratios from the subgroup of patients with relapsing–remitting multiple sclerosis with high disease activity despite beta interferon treatment in the FREEDOMS trial which compared fingolimod with placebo
assumed that the patient access scheme price for fingolimod (the details of which were not available to the manufacturer of alemtuzumab) was £13,000 and
applied either the utility values from CARE-MS I and II or those from the placebo arms of the TEMSO study (teriflunomide versus placebo) combined with the utility values reflecting relapses from Orme et al.The ICERs resulting from these analyses for alemtuzumab compared with fingolimod in patients with relapsing–remitting multiple sclerosis with high disease activity despite beta interferon treatment were £7,089 per QALY gained using the CARE-MS I and II trial utility results and £17,232 per QALY gained using the utility results from the placebo arms of the TEMSO study combined with the Orme study utility decrements.
# Evidence Review Group comments on the manufacturer's additional evidence
The ERG confirmed that the additional evidence presented by the manufacturer reflected the Committee's requests for additional analyses. The ERG confirmed that it could calculate the manufacturer's deterministic ICERs both in the individual analyses and in the Committee's preferred combined analysis but, owing to time constraints, it could only verify a sample of the probabilistic results presented by the manufacturer. The ERG noted that the manufacturer had incorrectly estimated the ICERs in its fully incremental analyses because the manufacturer compared the treatment with the next less costly treatment, even when the next less costly treatment was dominated.
The ERG reviewed the manufacturer's response to the ACD which focused on both subgroups reflecting patients with high disease activity. The ERG noted that while the manufacturer's mixed treatment comparison provided evidence of the effectiveness of alemtuzumab in these subgroups, there remained a number of uncertainties with these data: the evidence network depended on the teriflunomide trials which included either the overall relapsing-remitting multiple sclerosis population (TENERE) or a subgroup of previously-treated patients as a proxy for highly active relapsing-remitting multiple sclerosis despite beta interferon treatment (TEMSO and TOWER); inconsistencies in the definitions of the subgroups in each of the trials; differences between the patient populations included in the trials; and that the mixed treatment comparison was heavily dependent on indirect evidence to complete the evidence network.
The ERG conducted exploratory analyses that assumed that alemtuzumab and fingolimod were equally effective, and that alemtuzumab and natalizumab were equally effective. To do this, the ERG applied the hazard ratios for annual relapse rates and sustained accumulation of disability from the mixed treatment comparison for alemtuzumab compared with placebo and fingolimod and natalizumab each compared with placebo. The ERG applied hazard ratios for alemtuzumab to fingolimod and natalizumab (and vice versa) in the respective subgroups, and also applied the midpoint hazard ratio between alemtuzumab and either fingolimod or natalizumab. In the subgroup of high disease activity despite beta interferon treatment when comparing alemtuzumab with fingolimod, the resulting ICERs were £4,460, £14,788 and £8,942 per QALY gained, respectively. In the subgroup of rapidly evolving severe relapsing–remitting multiple sclerosis, alemtuzumab dominated natalizumab in each scenario.
Full details of all the evidence are in the manufacturer's original submission, the manufacturer's response to consultation, the ERG's original report, and the ERG's critique of the manufacturer's response to consultation.# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of alemtuzumab, having considered evidence on the nature of active relapsing–remitting multiple sclerosis and the value placed on the benefits of alemtuzumab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
The Committee heard from the clinical specialists and patient experts about the nature of the condition. It was aware that relapsing–remitting multiple sclerosis is a chronic, disabling, neurological condition that, as it progresses, is life altering and has a large negative impact on quality of life and activities of daily living. The Committee heard from clinical specialists that the currently available first-line treatments for active relapsing–remitting multiple sclerosis need to be injected weekly or several times per week and can be associated with unpleasant side effects (such as injection-site reactions, flu-like symptoms, fatigue and depression) and can significantly affect patients' emotional wellbeing. The Committee concluded that any delay in relapse and progression of disability or reduction in the frequency of treatment would have a positive impact on the lives of people with multiple sclerosis and their families.
The Committee considered the impact of treating active relapsing–remitting multiple sclerosis with alemtuzumab. The Committee was aware that patients in the UK may have participated in trials of alemtuzumab, or may have received alemtuzumab off-label before it was licensed for active relapsing–remitting multiple sclerosis (alemtuzumab had a previous marketing authorisation for B-cell chronic lymphocytic leukaemia, but the manufacturer has withdrawn the product for that indication). The Committee heard from a patient expert who received alemtuzumab for active relapsing–remitting multiple sclerosis in 2006 and 2007, and who has not experienced any relapses since, with her health being better now than at the time of diagnosis. She also preferred alemtuzumab's administration schedule (see section 2.1) to weekly or daily self-administered injections with beta interferons, which to her would have been a 'constant reminder' of her multiple sclerosis. She commented that the considerable impact on her family and their concern about relapse or accumulation of disability lessened once she had received alemtuzumab. The Committee concluded that alemtuzumab has the potential to benefit people with active relapsing–remitting multiple sclerosis and their families.
The Committee considered alemtuzumab's place in the treatment pathway for active relapsing–remitting multiple sclerosis. The Committee heard from the clinical specialists that alemtuzumab would be considered as a first-line treatment option, alongside beta interferons or glatiramer acetate, for people with active relapsing–remitting multiple sclerosis eligible for treatment under the Association for British Neurologists' guidelines. The Committee heard from the clinical specialists that, while effective therapies should ideally be offered early in disease, offering effective treatments later in disease is even more important because these patients have a higher risk for more severe complications. The Committee also heard that, while alemtuzumab's marketing authorisation permits its use as a first-line treatment, it is more likely to be offered to people for whom other disease-modifying treatments have not been effective. However, the Committee heard from the patient expert that a patient should not have to experience more severe symptoms before being offered alemtuzumab. One clinical specialist emphasised that alemtuzumab is 'not for everybody', and that clinicians would offer alemtuzumab to patients who, among other characteristics, would be likely to comply with the required monitoring for adverse effects, and that approaches exist to estimate the likely compliance with monitoring. The Committee concluded that alemtuzumab is a valuable treatment option for selected patients with varying types and stages of active relapsing–remitting multiple sclerosis.
The Committee considered whether neurologists would offer patients treatment with alemtuzumab beyond the 2 annual cycles stipulated in the marketing authorisation. The clinical specialists acknowledged that some patients need more than the 2 initial annual cycles, and that clinicians would consider offering further courses of alemtuzumab to patients whose disease had relapsed. One clinical specialist stated that people who have no relapses in the third year following first treatment, but who subsequently relapse, would be considered for retreatment. People who have relapses within the third year would not, however, be offered retreatment because clinicians would consider alemtuzumab to be no longer effective in this situation. The Committee concluded that some patients whose disease initially responds to alemtuzumab but later relapses may be treated with alemtuzumab beyond the 2 treatment courses described in the marketing authorisation.
The Committee considered the advantages and disadvantages of alemtuzumab treatment. The clinical specialists described advantages to alemtuzumab treatment, including that it is highly effective, does not cause the flu-like symptoms associated with beta interferons, and does not need to be discontinued by patients planning a pregnancy, although the Committee was aware that effective contraceptive measures should be taken when receiving alemtuzumab and for 4 months following a course of treatment according to the summary of product characteristics. This was seen as important, because multiple sclerosis affects women and men during the years when they are most likely to have children, and all other multiple sclerosis treatments, according to their summary of product characteristics, must be stopped for a person to have children. The clinical specialists explained that the main disadvantages of alemtuzumab treatment are the possible serious adverse effects observed during the trials, including idiopathic thrombocytopenic purpura, kidney disease or failure, thyroid disease and death. The clinical specialists stated that thyroid disease is the most common complication, affecting one-third of patients with multiple sclerosis treated with alemtuzumab. In response to a comment made by a consultee that patients treated with alemtuzumab were at risk for papillary thyroid cancer, a clinical specialist suggested that this could be related to increased detection following routine screening as required by the marketing authorisation for alemtuzumab. The clinical specialists and the manufacturer explained that patients need monthly platelet and white cell counts and quarterly assessment of thyroid and renal function for 4 years after the last treatment, and that patients are monitored even more often than this immediately after treatment with alemtuzumab. The clinical specialists stated that alemtuzumab permanently changes a person's immune system because it alters the numbers, proportions and properties of some lymphocyte subsets, and acknowledged that ongoing monthly monitoring might be an obstacle for some patients, particularly for those who feel well. The Committee expressed concern about the methods used to ensure that people treated with alemtuzumab would comply with monitoring requirements. The Committee heard from the clinical specialists that there are standard monitoring systems in place at the specialist centres that administer alemtuzumab and patients are contacted by a variety of methods if they miss a monthly monitoring visit. The Committee was aware that even when adverse events related to alemtuzumab were identified during regular monitoring, there could still be problems with follow-up actions when the results are received. The clinical specialists commented that idiopathic thrombocytopenic purpura associated with alemtuzumab responds to treatment with corticosteroids and immunoglobulin G, and patients would be unlikely to need treatment with thrombopoietin agonists. The clinical specialists and patient experts acknowledged the risk of renal disease for which some patients need renal replacement therapy but stated that people with active relapsing–remitting multiple sclerosis may be willing to accept the risks of serious adverse events associated with alemtuzumab treatment, because the potential benefits to quality of life are considerable. The clinical specialists acknowledged uncertainty about how prior treatment with alemtuzumab might change the adverse event profile of other monoclonal antibodies used for the treatment of multiple sclerosis, such as natalizumab. The Committee concluded that alemtuzumab is associated with significant benefits, but also significant harms, that some people with active relapsing–remitting multiple sclerosis are willing to accept the disadvantages of alemtuzumab treatment, and that adhering to the recommended monitoring schedule is important.
The Committee further considered the adverse effects associated with alemtuzumab. The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency acknowledged that alemtuzumab had been shown to be effective in people with active relapsing–remitting multiple sclerosis, but that there were serious safety concerns evidenced by the fact that 7 CHMP members had publicly disagreed with the majority decision. These dissenting members stated in the European Public Assessment Report for alemtuzumab that the benefits to risks balance could be considered acceptable in a limited indication in patients with relapsing–remitting multiple sclerosis with high disease activity defined by clinical and imaging features, but that they did not consider that the benefits outweighed the risks in a population with less active disease. The Committee took into account the view of a clinical specialist that the deaths that occurred during the clinical trials could have been avoided. It concluded that a clinical trial provides better opportunities for regular monitoring than could be achieved in clinical practice, and remained concerned about the deaths that were possibly related to alemtuzumab treatment.
The Committee discussed the information provided to patients for whom treatment with alemtuzumab is considered, and specifically the requirements for monitoring and risks associated with treatment with alemtuzumab. The Committee questioned whether those requirements and risks were being clearly communicated to patients considering alemtuzumab as a treatment option. The Committee heard from the clinical specialists that alemtuzumab would only be offered to people who were fully informed of the possible adverse effects of alemtuzumab and aware of the stringent monitoring requirements. The patient expert explained that she had been fully informed about the possible adverse effects and monitoring requirements for alemtuzumab before making the decision to enrol in the alemtuzumab trial and further information had been provided during the initial stages of treatment to help her recognise possible adverse reactions. The Committee was aware that the summary of product characteristics requires that a neurologist experienced in treating patients with multiple sclerosis supervises treatment with alemtuzumab, and states that specialists and equipment should be available to diagnose and manage the most frequent adverse reactions, especially autoimmune conditions and infections. The Committee was also aware that patients should be given a Patient Alert Card and Patient Guide and be informed about the risks of alemtuzumab. The Committee remained concerned that not all people offered alemtuzumab might understand the risks or comply with the monitoring requirements. The Committee concluded that there are monitoring processes in place based on evidence from patients who received alemtuzumab either in trial or clinical settings.
# Clinical effectiveness
The Committee considered the clinical effectiveness of alemtuzumab in the relapsing–remitting multiple sclerosis population in the 3 trials comparing it with Rebif (44 micrograms) (see section 3.2). On the basis of the improvements in sustained accumulation of disability at 6 months in the trials and in relapse rates, the Committee concluded that alemtuzumab is a more clinically effective treatment for active relapsing–remitting multiple sclerosis than Rebif (44 micrograms).
The Committee discussed whether it was appropriate for the manufacturer to have used the sustained accumulation of disability lasting 3 months rather than 6 months in its mixed treatment comparison and modelling for people with active relapsing–remitting multiple sclerosis, given that the CARE‑MS I and II trials included 6‑month sustained accumulation of disability as one of the co-primary endpoints (the other being annualised relapse rate). The Committee heard from the clinical specialists that patients may not have permanent disability progression after a relapse and that recovery may take up to 12 months, but on average people will recover within 3 or 4 months. The clinical specialists stated that sustained disability progression lasting for 6 months is a more appropriate outcome measure than disability progression lasting for 3 months. The Committee heard from the manufacturer that the main reason for why it initially chose to use the sustained accumulation of disability at 3 months in its mixed treatment comparison was that this would allow for comparison across trials that included 3‑month but not 6‑month disability. However the Committee understood that the 6‑month disability outcome was reported for all but 1 of the beta interferons. On the basis of clinicians' preference, the Committee concluded that it preferred sustained accumulation of disability lasting 6 months to be used as the primary outcome measure in the mixed treatment comparison.
The Committee discussed the manufacturer's mixed treatment comparison comparing alemtuzumab with other disease-modifying treatments for people with active relapsing–remitting multiple sclerosis. It noted that the manufacturer initially presented a base-case mixed treatment comparison excluding trials that recruited patients before the year 2000, and a separate 'all years' sensitivity analysis that included all trials (see section 3.7). The Committee acknowledged that earlier trials were excluded because of changes in diagnostic criteria, which resulted in part in changes in baseline relapse rates over time, but were concerned that important trials were excluded as a result of the cut-off date, including all trials comparing beta interferons with placebo. In addition, the Committee was not convinced that the difference in the baseline rate of relapse would modify the relative effectiveness of alemtuzumab compared with other disease-modifying drugs. It was aware that the manufacturer presented a revised mixed treatment comparison including trials from 'all years' and adjusted for baseline relapse in its response to the Appraisal Consultation Document. The Committee concluded that it is more appropriate for the mixed treatment comparison to include all available evidence, and that in this case adjusting the mixed treatment comparison for baseline relapse rates accounts for any differences in relapse rates between trials.
The Committee discussed the statistical analysis plan for the 3 alemtuzumab trials. The Committee noted that the statistical plan for CAMMS223 stipulated an intention-to-treat analysis adjusted for baseline Expanded Disability Status Scale (EDSS) score and country, which was reflected in the final publication. The Committee noted that in CAMMS223 and CARE‑MS II, the investigators used the per-protocol set to conduct the statistical analyses whereas in CARE‑MS I the full dataset was analysed, which included some patients who did not meet the specified inclusion criteria or who had not received treatment as specified in the clinical trial protocol. The Committee heard from a clinical specialist, and author of all 3 trials, that the results for the full analysis set were similar to those for the per-protocol set for CARE‑MS I. However, the Committee remained concerned about the pooling of trial results that had been analysed differently, and the fact that the manufacturer had not initially presented a sensitivity analysis demonstrating the impact this difference could have on the results of the mixed treatment comparison (and therefore on the economic modelling). The Committee concluded that it is more appropriate to include the per-protocol analyses set for all 3 trials, unadjusted for country or region and adjusted for baseline EDSS states only. However, it was aware that the manufacturer's revised mixed treatment comparison presented in its response to the appraisal consultation document included the results from intention-to-treat analyses of the CARE-MS I, CARE-MS II and CAMMS223 trials and concluded that in this case it had little impact on the results of the mixed treatment comparison.
The Committee considered the long-term efficacy of alemtuzumab. The clinical specialists acknowledged that there was uncertainty regarding the effectiveness of alemtuzumab in the long term and specifically for periods exceeding the duration of the follow-up studies to the clinical trials, which to date have followed some patients for a median of 7 years and a maximum of 12 years. The clinical specialists also stated that people who experience a relapse soon after treatment with alemtuzumab will probably be offered alternative treatment which, for severe disease, could include bone marrow transplantation. One clinical specialist noted that, in the trials, the number of people for whom alemtuzumab was no longer effective was small. The Committee concluded that, for some people, alemtuzumab might not provide long-term enduring effect and other treatments might be required.
The Committee considered the clinical effectiveness of alemtuzumab in people with rapidly evolving severe relapsing-remitting multiple sclerosis or highly active relapsing-remitting multiple sclerosis despite beta interferon treatment, for which the relevant comparators would be natalizumab and fingolimod respectively. The Committee heard from a clinical specialist that alemtuzumab was probably more effective than fingolimod, and probably equally effective to natalizumab. However, compared with natalizumab, alemtuzumab was probably safer in pregnancy and in people testing positive to John Cunningham virus, which can lead to progressive multifocal leukoencephalopathy. The Committee commented that the clinical effectiveness of alemtuzumab in the rapidly evolving severe relapsing-remitting multiple sclerosis or highly active relapsing-remitting multiple sclerosis despite beta interferon treatment subgroups was not robustly demonstrated. It was aware that no trials exist that directly compare alemtuzumab with either natalizumab or fingolimod. The Committee understood that the mixed treatment comparisons required a number of links to compare alemtuzumab with either natalizumab or fingolimod, and that different trials defined the subgroups differently, and both these factors increased uncertainty. The Committee noted that the results of the mixed treatment comparison had shown that alemtuzumab was associated with a lower annualised relapse rate and 3 month sustained accumulation of disability than fingolimod for the subgroup of highly active relapsing-remitting multiple sclerosis despite beta interferon treatment, although these differences were not statistically significant. The Committee also noted that alemtuzumab treatment led to lower annualised relapse rates and lower 6‑month sustained accumulation of disability than natalizumab for the subgroup of rapidly evolving severe relapsing-remitting multiple sclerosis, although the difference was not statistically significant. The Committee noted that the CARE MS-II study comparing alemtuzumab with Rebif (44 micrograms) showed that alemtuzumab had a greater absolute treatment effect on 3‑month sustained accumulation of disability in people with highly active relapsing-remitting multiple sclerosis despite beta interferon treatment than that of fingolimod compared with placebo in the FREEDOM study. The Committee also noted that in the CAMMS223, CARE MS-I and II studies (that compared alemtuzumab with Rebif ) alemtuzumab had a similar effect on 6‑month sustained accumulation of disability in people with rapidly evolving severe relapsing-remitting multiple sclerosis to that of natalizumab compared with placebo in the AFFIRM study. Acknowledging the uncertainty, the Committee was persuaded that alemtuzumab was at least as effective as fingolimod and natalizumab for people with highly active relapsing-remitting multiple sclerosis despite beta interferon treatment and rapidly evolving severe relapsing-remitting multiple sclerosis respectively.
# Cost effectiveness
The Committee considered the QALYs accumulated over the course of the modelled time horizon, and the consequences of assuming that people can only move to worse EDSS states (that is, a person's condition can deteriorate or stay the same but not improve) regardless of treatment. The Committee noted that for the full time horizon, a person who received treatment with alemtuzumab would accrue just over 4 QALYs despite accruing 18 life years (see section 3.17). It further noted that the modelled life years for the comparator (Rebif ) was also much higher than the corresponding number of modelled QALYs. The Committee considered this to be an implausibly low number of QALYs to be accrued by a person with multiple sclerosis over the course of their lifetime. It therefore reasoned that that the original economic model had poor face validity. The manufacturer could not explain the low total lifetime QALY values estimated within the model nor did it explore what might have caused the model to do this. The ERG commented that it was probably because the manufacturer had used the London Ontario data to define the natural history of disease in the absence of disease-modifying therapies, which only allowed a person to progress towards further disability on the EDSS. The Committee heard that the alemtuzumab trial data and other evidence provided by the patient expert and the clinical specialists suggested that people's EDSS states could improve. The Committee was aware that this would considerably affect the number of QALYs accrued by a modelled patient population over a lifetime. The Committee noted that EDSS states of 8 and above were associated with negative utility values, which would reduce lifetime QALYs accrued. The Committee commented that discounting alone was unlikely to explain the low number of lifetime QALYs accrued in the original economic model. The Committee concluded that it is appropriate for the economic modelling to allow patients with relapsing–remitting multiple sclerosis to move to lower as well as to higher EDSS states (that is, to allow for the condition to either improve or get worse) which is in line with what is seen in clinical practice for the lower EDSS states.
The Committee considered the health-related quality of life data used in the model. The Committee considered that the trials would provide the most appropriate source of quality of life data for the analysis, because the trial population best reflects the population that would receive the treatment if it were available in clinical practice. The Committee was concerned about the manufacturer's initial choice of values to reflect the disutility associated with some of the adverse effects. The clinical specialists agreed that, for example, it is not plausible that a patient with leukocytopenia would have no disutility. The Committee was also aware that a number of deaths were observed in the trials (see section 4.7) and noted that this needed to be reflected in the economic modelling. The Committee understood that in its response to the appraisal consultation document, the manufacturer had pooled EQ-5D-5L utility scores by EDSS state from CARE-MS I and CARE-MS II both at baseline and after 24 months of treatment and had accounted for the deaths observed in the trials in its economic modelling. The manufacturer explained that the difference in mean utility values between baseline and at 24 months in patients with the same EDSS scores did not show improved utility, as might have been expected. The Committee concluded that it is appropriate for the economic modelling to include the deaths observed in the trials and also the trial EQ-5D-5L data (which is more likely to capture the disutility of adverse events associated with alemtuzumab than the manufacturer's original approximations).
The Committee considered the manufacturer's assumption that the treatment effect from alemtuzumab would persist for many years after the last treatment. The Committee questioned whether a constant treatment effect was biologically plausible. In response, a clinical specialist stated that alemtuzumab permanently modifies a person's immune system, which may be why alemtuzumab's treatment effect might be life‑long. However, the clinical specialist stated that there were no data comparing immune markers in people whose disease does and does not progress after treatment with alemtuzumab. The clinical specialists also commented that the long-term benefit of alemtuzumab is unknown given the absence of long-term data, but that it would be reasonable to assume that alemtuzumab's treatment effect might start to decrease between 3 and 5 years after treatment but that this, too, was uncertain. The Committee concluded that the manufacturer's initial assumption of constant treatment effect throughout the course of a person's multiple sclerosis up to EDSS state 7 or secondary progressive multiple sclerosis was not supported by data, and that the clinical specialists had suggested a maximum of 5 years before waning occurs. The Committee concluded that because of the uncertainty about the long-term treatment effect from alemtuzumab it is appropriate to incorporate a 3- and 5‑year waning effect into the model, and it was satisfied that the manufacturer's revised economic analyses adequately explored the sensitivity of the ICER to several scenarios which assumed that the effectiveness of alemtuzumab and its comparators waned over time.
The Committee discussed re-treatment with alemtuzumab. It was aware from clinical specialists that, in CARE‑MS I, CARE‑MS II and CAMMS233, a further cycle of alemtuzumab was offered to patients if a relapse that lasted for at least 24 hours occurred after the second annual course of infusions. It also heard from clinical specialists that further treatments were considered likely in UK clinical practice. The Committee heard from the clinical specialists that, in the trials, the percentage of people who needed a third course was greater than the percentage who needed a fourth course, and that the trend of fewer people needing successive courses lasted up to 7 years (the median follow-up time for which data were available). The Committee considered that this indicated a time-dependent rate of re-treatment. The Committee concluded that it is appropriate to incorporate the time-dependent rate of re-treatment from the trials in the model and was satisfied that in its response to the Appraisal Consultation Document, the manufacturer had reflected this in its revised economic model.
The Committee considered the costs included in the economic model for alemtuzumab. The Committee noted that the manufacturer's original economic model included a mid-cycle correction, although alemtuzumab is given at the start of the cycle. The Committee was also concerned that the number of visits to neurologists included in the manufacturer's original economic model for people receiving alemtuzumab was low. Although the ERG increased the number of visits to neurologists (and the additional related costs) to 4 in year 1 and 2 in subsequent years, it did not take into account that people receiving 3 or more courses of alemtuzumab treatment would need 4 visits in the first year of restarting treatment. The Committee noted from the ERG exploratory analyses that using alternative health states costs had a large impact on the cost effectiveness of alemtuzumab (see section 3.30). The Committee commented that it would have been more appropriate for the manufacturer to incorporate the health state costs used by the ERG in their exploratory analyses (that only included direct 'medical' costs rather than both 'medical' and 'non-medical' costs) because this is more consistent with NICE's preferred methods as presented in its Guide to the methods of technology appraisal. It noted that the manufacturer did not initially include the costs associated with adverse effects of treatment including renal failure, renal transplantation, dialysis and death. The Committee concluded that it was satisfied that the manufacturer's revised analyses adequately addressed and explored all of these uncertainties associated with the costs included in the economic model.
The Committee discussed the data sources chosen by the manufacturer to reflect the baseline characteristics of patients with relapsing–remitting multiple sclerosis and the natural history of disease progression for patients not taking disease-modifying therapies. The Committee agreed that it was more appropriate for the manufacturer to use trial data to determine the initial EDSS distribution because this was representative of the patient population likely to be treated with alemtuzumab in the UK. The Committee was aware that the manufacturer of alemtuzumab also manufactures teriflunomide and has collected data in the TOWER and TEMSO trials, both of which include groups of patients randomised to placebo. It concluded that this dataset would more accurately reflect the natural history of disease (underlying progression without disease-modifying therapy) in people who would be treated with alemtuzumab in the UK. It concluded that it is appropriate to incorporate the baseline characteristics of patients in the alemtuzumab trials instead of using data from the UK Risk Sharing Scheme, and that it is appropriate to incorporate the rates of disease progression in the placebo group from the TOWER and TEMSO trials to reflect the natural history of the disease.
The Committee considered the manufacturer's revised base-case results submitted in response to consultation (see section 3.35). It was aware that for the active relapsing–remitting multiple sclerosis population, the manufacturer had incorporated all the Committee's preferred assumptions (see sections 3.33, 4.10–4.12 and 4.15–4.20). The Committee noted that when assuming that the effect of treatment decreased for alemtuzumab and not for the comparators, the ICER for alemtuzumab compared with glatiramer acetate was £24,500 per QALY gained and that if the model assumed that the effectiveness of both alemtuzumab and its comparators waned, the ICER for alemtuzumab compared with glatiramer acetate was £13,600 per QALY gained. The Committee concluded that alemtuzumab could be considered a cost-effective use of NHS resources for treating adults with active relapsing–remitting multiple sclerosis.
The Committee also considered the manufacturer's revised analyses for the subgroups characterised by highly active relapsing-remitting multiple sclerosis despite beta interferon treatment and rapidly evolving severe relapsing-remitting multiple sclerosis, submitted in response to consultation. The clinical specialists noted that the terms used to describe these subgroups of patients are not generally used in UK clinical practice. The Committee was aware that the manufacturer's mixed treatment comparisons for these subgroups had not generated statistically significantly effects for alemtuzumab compared with the relevant comparator (see section 4.14) and was associated with uncertainty. The Committee heard during consultation from the Association of British Neurologists that it would be impractical to recommend 'a potent drug with significant side effects for patients with modestly active disease but not patients whose future is most threatened by their disease'. The Committee also heard the clinical specialists confirm that it would be clinically counterintuitive to recommend alemtuzumab for the overall active relapsing–remitting multiple sclerosis population, but not recommend it for the highly active relapsing-remitting multiple sclerosis despite beta interferon treatment and the rapidly evolving severe relapsing-remitting multiple sclerosis subgroups for whom the need for treatment options was even greater. The Committee noted that the approach taken by the ERG assumed equal efficacy between alemtuzumab and fingolimod or natalizumab using a midpoint of the hazard ratios for treatment compared with placebo and applied it to the manufacturer's revised economic model. It agreed that this was a pragmatic way to determine the relative clinical and cost effectiveness of alemtuzumab in these subgroups given the uncertainty. The Committee noted that the most plausible ICER for patients with highly active relapsing-remitting multiple sclerosis despite beta interferon treatment was £8900 per QALY gained for alemtuzumab compared with fingolimod. The Committee noted that for patients with rapidly evolving severe relapsing-remitting multiple sclerosis, alemtuzumab dominated natalizumab (that is, less expensive and more effective). The Committee therefore concluded that alemtuzumab could be considered a cost-effective use of NHS resources for people with highly active relapsing-remitting multiple sclerosis despite beta interferon treatment and for people with rapidly evolving severe relapsing-remitting multiple sclerosis.
The Committee considered the manufacturer's assumptions about when people should receive disease-modifying therapies such as alemtuzumab and how this was incorporated into the manufacturer's economic model. The Committee noted that only patients with active relapsing–remitting multiple sclerosis in an EDSS state of 0 to 7 entered the model and that treatment with alemtuzumab would stop when a patient progresses to EDSS 7 or upon secondary progressive multiple sclerosis. It acknowledged that these assumptions were based on the Association of British Neurologists' guideline for prescribing of disease modifying treatments in multiple sclerosis. The Committee agreed that the manufacturer presented an economic model that supported the use of alemtuzumab in people with active relapsing–remitting multiple sclerosis in an EDSS state less than 7.
The Committee discussed whether alemtuzumab can be considered an innovative treatment, providing a step change in the treatment of active relapsing–remitting multiple sclerosis and providing benefit not accounted for in the modelling. The Committee heard from the clinical specialists and patient expert that alemtuzumab has been a revolutionary treatment for some people, allowing them to live their lives as they had before being diagnosed with multiple sclerosis. The clinical specialists believed that it was a step change because it delayed disease progression. The Committee noted that alemtuzumab did provide a step change in the treatment of active relapsing–remitting multiple sclerosis. However, the Committee considered that these benefits would already be captured through increased efficacy gains, both in survival gains and in quality of life gains. The Committee therefore concluded that no additional QALY gains should be attributed to alemtuzumab to account for these benefits.
# Summary of Appraisal Committee's key conclusions
TA312
Appraisal title: Alemtuzumab for treating relapsing–remitting multiple sclerosis
Section
Key conclusion
Alemtuzumab is recommended as an option, within its marketing authorisation, for treating highly active relapsing–remitting multiple sclerosis in adults with:
highly active disease despite a full and adequate course of treatment with at least 1 disease-modifying therapy or
rapidly-evolving severe relapsing-remitting multiple sclerosis defined by 2 or more disabling relapses in 1 year, and with 1 or more gadolinium-enhancing lesions on brain MRI or a significant increase in T2 lesion load compared with a previous MRI.
The Committee considered the manufacturer's revised base-case results submitted in response to consultation that incorporated all the Committee's preferred assumptions. The Committee concluded that the most plausible ICER for alemtuzumab compared with glatiramer acetate for people with active relapsing-remitting multiple sclerosis is likely to lie between £13,600 and £24,500 per QALY gained, and therefore alemtuzumab could be considered a cost-effective use of NHS resources for treating adults with active relapsing–remitting multiple sclerosis.
The Committee noted that the most plausible ICER for patients with highly active relapsing-remitting multiple sclerosis despite beta interferon treatment was £8900 per QALY gained for alemtuzumab compared with fingolimod. The Committee noted that for patients with rapidly evolving severe relapsing-remitting multiple sclerosis, alemtuzumab dominated natalizumab (that is, less expensive and more effective).
Current practice
Clinical need of patients, including the availability of alternative treatments
The Committee was aware that relapsing–remitting multiple sclerosis is a chronic, disabling, neurological condition that, as it progresses, is life altering and has a large negative impact on quality of life. Currently available first-line treatments for active relapsing–remitting multiple sclerosis need to be injected weekly or several times per week and can be associated with unpleasant side effects. The Committee concluded that any delay in relapse and progression of disability or reduction in the frequency of treatment would have a positive impact on the lives of people with multiple sclerosis and their families.
The Committee heard from the clinical specialists that, while therapies should ideally be offered early in disease, offering treatments later in disease is also important because these patients have a higher risk for more severe complications.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
The clinical specialists described advantages, including that it is highly effective, does not cause the flu-like symptoms, and does not need to be discontinued by patients planning a pregnancy, although the Committee was aware that effective contraceptive measures should be taken when receiving alemtuzumab and for 4 months following a course of treatment according to the summary of product characteristics.
The Committee heard from the clinical specialists and patient expert that alemtuzumab has been a revolutionary treatment for some people, allowing them to live their lives as they had before being diagnosed with multiple sclerosis.
What is the position of the treatment in the pathway of care for the condition?
The Committee heard from the clinical specialists that while alemtuzumab's marketing authorisation permits its use as a first-line treatment, it is more likely to be offered to people for whom other disease-modifying treatments have not been effective. One clinical specialist emphasised that alemtuzumab is 'not for everybody', and that clinicians would offer alemtuzumab to patients who, among other characteristics, would be likely to comply with the required monitoring. The Committee concluded that alemtuzumab is a valuable treatment option for selected patients with varying types and stages of active relapsing–remitting multiple sclerosis.
Adverse reactions
The clinical specialists explained that the main disadvantages of alemtuzumab treatment are the possible serious adverse effects, including idiopathic thrombocytopenic purpura, kidney disease or failure, thyroid disease and death. The Committee concluded that alemtuzumab is associated with significant benefits, but also significant harms, that some people with active relapsing–remitting multiple sclerosis are willing to accept the disadvantages of alemtuzumab treatment, and that adhering to the recommended monitoring schedule is important.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The Committee considered the clinical effectiveness of alemtuzumab in the relapsing–remitting multiple sclerosis population in the 3 trials comparing it with Rebif.
The Committee discussed the manufacturer's mixed treatment comparison comparing alemtuzumab with other disease-modifying treatments.
The Committee was aware that no trials exist that compare alemtuzumab with either natalizumab or fingolimod.
Relevance to general clinical practice in the NHS
The clinical specialists acknowledged that there was uncertainty regarding the effectiveness of alemtuzumab in the long term, and specifically for periods exceeding the duration of the follow-up studies to the clinical trials. The Committee concluded that for some people alemtuzumab might not provide long-term enduring effect and other treatments might be required.
Uncertainties generated by the evidence
The Committee concluded that it is more appropriate for the mixed treatment comparison to include all available evidence, and that adjusting for baseline relapse rates accounts for any differences between trials.
The Committee noted that in CAMMS223 and CARE‑MS II, the investigators used the per-protocol set to conduct the statistical analyses whereas in CARE‑MS I the full dataset was analysed, which included some patients who did not meet the specified inclusion criteria or who had not received treatment as specified in the clinical trial protocol. The Committee concluded that it is more appropriate to include the per-protocol analyses set for all 3 trials, adjusted for baseline EDSS states only.
The Committee commented that alemtuzumab's clinical effectiveness in the subgroups was not robust. It was aware that no trials exist that directly compare alemtuzumab with either natalizumab or fingolimod. The Committee understood that the mixed treatment comparisons required a number of links to compare alemtuzumab with either natalizumab or fingolimod, and that different trials defined the subgroups differently.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
Acknowledging the uncertainty, the Committee was persuaded that alemtuzumab was at least as effective as fingolimod and natalizumab for people with highly active relapsing-remitting multiple sclerosis despite beta interferon treatment and rapidly evolving severe relapsing-remitting multiple sclerosis respectively.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The Committee concluded that alemtuzumab is a clinically effective treatment in reducing relapse rates and has a beneficial impact on sustained accumulation of disability at 6 months compared with Rebif in people with active relapsing–remitting multiple sclerosis.
Evidence for cost effectiveness
Availability and nature of evidence
The Committee considered the manufacturer's revised base-case results submitted in response to consultation. It was aware the manufacturer had incorporated all the Committee's preferred assumptions.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The Committee heard that the alemtuzumab trial data and other evidence suggested that people's EDSS states could improve and concluded that it is appropriate for the economic modelling to allow patients to move to lower as well as to higher EDSS states.
The Committee considered that the trials provided the most appropriate source of quality of life data because the trial population best reflects the population that would receive the treatment in clinical practice. A number of deaths were observed in the trials and this needed to be reflected in the economic modelling.
The clinical specialists also commented that the long-term benefit of alemtuzumab is unknown given the absence of long-term data, but that it would be reasonable to assume that alemtuzumab's treatment effect might start to decrease between 3 and 5 years after treatment.
In the trials a further cycle of alemtuzumab was offered to patients if a relapse that lasted for at least 24 hours occurred after the second annual course of infusions, and the clinical specialists commented that further treatments were considered likely in clinical practice. The Committee concluded that it is appropriate to incorporate the time-dependent rate of re-treatment in the model.
The Committee concluded that it was more appropriate to remove the mid-cycle correction for the cost of alemtuzumab treatment, increase the number of monitoring and neurology visits to reflect any additional monitoring needed, only include health states costs that are likely to meet the NICE reference case and to include the costs associated with managing adverse effects in the economic modelling.
The Committee agreed that it was more appropriate for the manufacturer to use trial data to determine the initial EDSS distribution because this was representative of the patient population likely to be treated with alemtuzumab in the UK. The Committee was also aware that the manufacturer of alemtuzumab has collected data in patients randomised to placebo and concluded that this dataset would more accurately reflect the natural history of disease in people who would be treated with alemtuzumab in the UK.
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The manufacturer pooled EQ-5D-5L utility scores by EDSS state from CARE-MS I and CARE-MS II.
The Committee noted that alemtuzumab did provide a step change in the treatment of active relapsing–remitting multiple sclerosis. However, these benefits would already be captured through increased efficacy gains, both in survival gains and in quality of life gains.
Are there specific groups of people for whom the technology is particularly cost effective?
n/a
n/a
What are the key drivers of cost effectiveness?
The manufacturer's original assumption that the treatment effect from alemtuzumab would persist for many years after the last treatment. The Committee was satisfied that the manufacturer's revised economic analyses adequately explored the sensitivity of the ICER to several scenarios assuming that the effectiveness of alemtuzumab and its comparators waned over time.
Most likely cost-effectiveness estimate (given as an ICER)
The Committee concluded that the most plausible ICER for alemtuzumab compared with glatiramer acetate for people with active relapsing-remitting multiple sclerosis is likely to lie between £13,600 and £24,500 per QALY gained.
The Committee noted that the most plausible ICER for patients with highly active relapsing-remitting multiple sclerosis despite beta interferon treatment was £8900 per QALY gained for alemtuzumab compared with fingolimod. The Committee noted that for patients with rapidly evolving severe relapsing-remitting multiple sclerosis, alemtuzumab dominated natalizumab (that is, less expensive and more effective).
Additional factors taken into account
Patient access schemes (PPRS)
Not applicable
n/a
End-of-life considerations
Not applicable
n/a
Equalities considerations and social value judgements
No relevant equality considerations were raised during scoping or the appraisal.
n/a
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{'Guidance': 'Alemtuzumab is recommended as an option, within its marketing authorisation, for treating highly active relapsing–remitting multiple sclerosis in adults with:\n\nhighly active disease despite a full and adequate course of treatment with at least 1\xa0disease-modifying therapy or\n\nrapidly-evolving severe relapsing-remitting multiple sclerosis defined by 2 or more disabling relapses in 1\xa0year, and with\xa01 or more gadolinium-enhancing lesions on brain MRI or a significant increase in T2 lesion load compared with a previous MRI.', 'The technology': "Alemtuzumab (Lemtrada, Genzyme) is an antibody that binds to cells of the immune system (B and T cells), causing their destruction. The way in which alemtuzumab slows the decline of highly active relapsing–remitting multiple sclerosis is not fully understood. Alemtuzumab has a UK marketing authorisation 'as a single disease modifying therapy in adults with highly active relapsing remitting multiple sclerosis for the following patient groups:\n\npatients with highly active disease despite a full and adequate course of treatment with at least 1 disease modifying therapy or\n\npatients with rapidly evolving severe relapsing remitting multiple sclerosis defined by 2 or more disabling relapses in one year, and with 1 or more gadolinium enhancing lesions on brain MRI or a significant increase in T2 lesion load as compared to a previous recent MRI'.The recommended dosage of alemtuzumab is 12\xa0mg/day administered by intravenous infusion for 2\xa0treatment courses. The initial treatment course lasts 5 consecutive days, followed 12\xa0months later by the second treatment course of 3 consecutive days.\n\nFor full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nThe price of alemtuzumab is £7045 per 12\xa0mg vial, which equates to £56,360 for the full course of treatment consisting of 5 daily consecutive 12\xa0mg doses in year\xa01, followed by 3 daily consecutive 12\xa0mg doses 12\xa0months later in year\xa02. Costs may vary in different settings because of negotiated procurement discounts.", "The manufacturer's submission": "The Appraisal Committee's remit was to appraise the clinical and cost effectiveness of alemtuzumab within its licensed indication for treating active relapsing–remitting multiple sclerosis. The Appraisal Committee (section 7) considered evidence submitted by the manufacturer of alemtuzumab and a review of this submission by the Evidence Review Group (ERG; section 8).\n\n# Clinical effectiveness\n\nThe manufacturer provided clinical-effectiveness evidence, identified by systematic review, from:\n\nphase\xa0III randomised controlled clinical trials: CARE‑MS I (n=581, median follow-up of 2\xa0years), and CARE‑MS\xa0II (n=1046, median follow-up of 2\xa0years)\n\nphase\xa0II randomised controlled clinical trial: CAMMS223 (n=334, maximum follow-up of 3\xa0years extended by a follow-up period of 4\xa0years from final alemtuzumab dose)\n\nextension study: CAMMS03409 (n=1322, median follow-up of 7.1\xa0years), which enrolled people with active relapsing–remitting multiple sclerosis from the CAMMS223, CARE‑MS\xa0I and CARE‑MS\xa0II trials. In this study, patients previously randomised to the control group in CAMMS223, CARE‑MS\xa0I and CARE‑MS\xa0II received alemtuzumab and patients previously randomised to alemtuzumab in CAMMS223, CARE‑MS\xa0I and CARE‑MS\xa0II received further treatment with alemtuzumab, as needed.In addition, the manufacturer submitted a meta-analysis of the above-listed trials and a mixed treatment comparison to compare alemtuzumab with other disease-modifying treatments for active relapsing–remitting multiple sclerosis (see sections 3.7-3.8).\n\nCARE‑MS\xa0I, CARE‑MS\xa0II and CAMMS223 compared the effectiveness of 12\xa0mg alemtuzumab (with an additional arm receiving 24\xa0mg per infusion in CAMMS223 only) with subcutaneous interferon beta‑1a (Rebif, small initial doses, gradually increasing to 44\xa0micrograms 3\xa0times weekly). All 3 trials included sites in the UK. All 3 trials specified the number of previous relapses patients must have had before they could enrol. For CAMMS223 this was at least 2 relapses in the previous 2\xa0years. For CARE‑MS\xa0I and CARE‑MS\xa0II this was at least 2 relapses within the previous 2\xa0years, with at least 1 within the previous year. CARE‑MS\xa0I and CAMMS223 included patients with an Expanded Disability Status Scale (EDSS) score between 0 and 3 (in which 0 means no disability and no signs of impairment in any functional system and 3 means unimpaired walking, but either moderate disability in 1 functional system or mild disability in 3 or 4 functional systems). CARE‑MS\xa0II included patients with an EDSS score between 0 and 5 (in which 5 means disability severe enough to impair normal daily activities and the person's ability to work a full day without special provisions, but they are still able to walk for 200\xa0metres without aid or rest). All patients in CARE‑MS\xa0II had to have previously received disease-modifying treatment with beta interferon or glatiramer acetate for 6\xa0months in the preceding 10\xa0years (the inclusion criteria also specified that more than 1 multiple sclerosis relapse had to have occurred while receiving these treatments), whereas patients in CARE‑MS\xa0I and CAMMS223 did not.\n\nThe co-primary outcomes of the 3 trials were time to the onset of sustained accumulation of disability (specified as lasting for 6\xa0months for CARE‑MS\xa0I and CARE‑MS\xa0II) and relapse rate. In the trials, patients were assessed quarterly using the EDSS to determine disability, and were assessed as needed for suspected relapses. Sustained accumulation of disability was defined as an increase lasting for 6\xa0months of at least 1.5\xa0points for people with a baseline EDSS score of 0, or 1.0\xa0point for people with a baseline EDSS score of 1.0 or more. A relapse was defined as new or worsening neurological symptoms attributable to relapsing–remitting multiple sclerosis, lasting at least 48\xa0hours, without fever, after at least 30\xa0days of clinical stability, with an objective change on neurological examination. Data from CAMMS223 were analysed by intention to treat, and adjusted for country and baseline EDSS score, as prespecified in the statistical plan. In CARE‑MS\xa0I and CARE‑MS\xa0II only patients who had received at least 1 dose of trial medication were included in the analysis (that is, a modified intention-to-treat analysis). In CARE-MS\xa0II the analysis was also limited to patients who had followed the trial protocol (excluding patients who had not met all inclusion criteria). The results were adjusted for region.\n\nIn CARE‑MS\xa0I 8% of people in the alemtuzumab treatment group had disability lasting for 6\xa0months, compared with 11.1% in the Rebif group. There was no statistically significant difference in the rates of disability lasting for 6\xa0months between people taking alemtuzumab and people taking Rebif (hazard ratio [HR]\xa00.70, 95% confidence interval [CI]\xa00.4 to 1.23; p=0.22). In CARE‑MS\xa0II 12.7% of people in the alemtuzumab treatment group had disability lasting for 6\xa0months, compared with 21.1% in the Rebif group. This corresponded to a statistically significant improvement of 42% with alemtuzumab (HR\xa00.58, 95% CI 0.38 to 0.87; p=008). In CAMMS223 alemtuzumab statistically significantly reduced the risk of sustained accumulation of disability lasting for 6\xa0months by 75% compared with Rebif (HR\xa00.25, 95% CI\xa00.11 to 0.57, p<0.001). A separate extended follow-up study of CAMMS223 showed that over 5\xa0years, alemtuzumab statistically significantly reduced the risk of sustained accumulation of disability lasting for at least 6\xa0months by 69% compared with Rebif (HR\xa00.31, 95% CI\xa00.16 to 0.60, p=0.0005).\n\nAlemtuzumab statistically significantly reduced the relapse rate compared with Rebif: by 54.9% in CARE‑MS\xa0I (RR [rate ratio]\xa00.45, 95% CI\xa00.32 to 0.63, p<0.0001), by 49.4% in CARE‑MS\xa0II (RR\xa00.51, 95% CI\xa00.39 to 0.65, p<0·0001) and by 69% in CAMMS223 (RR\xa00.31, 95% CI\xa00.18 to 0.52, p<0.001). The extended follow-up study of CAMMS223 showed that, over 5\xa0years, alemtuzumab statistically significantly lowered the rate of relapse by 66% compared with Rebif (RR\xa00.34, 95% CI\xa00.20 to 0.57, p<0.0001).\n\nThe manufacturer presented data from CARE‑MS\xa0II and CAMMS223 (and its separate study extension) to compare alemtuzumab with Rebif in a subgroup of people with rapidly evolving severe relapsing–remitting multiple sclerosis (size of subpopulation not available). The manufacturer pooled the results of the 12‑mg and 24‑mg alemtuzumab arms of CAMMS223 because it considered that the results in each arm were sufficiently similar to allow this. The manufacturer stated that the analyses showed that the effectiveness of alemtuzumab compared with Rebif in the rapidly evolving severe relapsing–remitting multiple sclerosis subgroup was comparable to or greater than that seen in the overall trial populations. The reduction of risk in sustained accumulation of disability lasting at least 6\xa0months was 51% in CARE‑MS\xa0II (no p value reported) and 65% (p=0.036) in the pooled group of CAMMS223. The analysis also indicated a statistically significant reduction in relapse rates for alemtuzumab compared with Rebif, of 56% (p=0.0018) in the rapidly evolving severe relapsing–remitting multiple sclerosis subgroup of CARE‑MS\xa0II and of 81% (p<0.0001) in the pooled dose group of CAMMS223.\n\nThe manufacturer presented a mixed treatment comparison that compared alemtuzumab with each of the treatments in the decision problem (Rebif, intramuscular interferon beta‑1a [Avonex], interferon beta‑1b [Betaferon], glatiramer acetate, natalizumab and fingolimod). The manufacturer included 30 clinical trials identified in the systematic literature review, all of which recruited patients from the year 2000 onwards, and in which at least 80% of the patients had relapsing–remitting multiple sclerosis (the 'base-case mixed treatment comparison'). The manufacturer justified the year 2000 as an appropriate cut-off point because annualised relapse rates have fallen in recent years and because the diagnostic criteria used in multiple sclerosis trials have changed. The manufacturer provided a separate 'all years' analysis that, in addition, included trials recruiting patients before the year 2000. The outcomes in the base-case mixed treatment comparison were annualised relapse rate, proportion of patients who were relapse free, sustained accumulation of disability lasting for 3\xa0months, sustained accumulation of disability lasting for 6\xa0months, discontinuation of treatment rate and discontinuation of treatment rate because of adverse events. In the base-case mixed treatment comparison, alemtuzumab led to statistically significantly lower annualised relapse rates than the beta interferons and glatiramer acetate. For the 3‑month sustained accumulation of disability outcome, alemtuzumab was statistically significantly lower than Avonex, Betaferon and Rebif (44\xa0micrograms); however, the difference between alemtuzumab and glatiramer acetate was not statistically significant. For the 6‑month sustained accumulation of disability outcome, alemtuzumab was statistically significantly lower than Rebif (44\xa0micrograms). While the point estimates for alemtuzumab compared with glatiramer acetate favoured alemtuzumab, the difference was not statistically significant. The results of the mixed treatment comparison were considered confidential by the manufacturer and therefore cannot be reported here.\n\nThe manufacturer carried out 2 separate mixed treatment comparisons of alemtuzumab for the subgroups of patients with highly active relapsing-remitting multiple sclerosis despite beta interferon treatment (from CARE‑MS\xa0II) and rapidly evolving severe relapsing-remitting multiple sclerosis (from CARE‑MS\xa0I and II and CAMMS223). For the highly active relapsing-remitting multiple sclerosis despite beta interferon treatment subgroup, alemtuzumab had a lower annualised relapse rate than fingolimod; however, the difference was not statistically significant (HR\xa00.50, 95% CI\xa00.11 to 2.29). The 3‑month sustained accumulation of disability was lower with alemtuzumab than with fingolimod but the difference was not statistically significant (HR\xa00.65, 95% CI\xa00.11 to 3.72). For the rapidly evolving severe relapsing-remitting multiple sclerosis subgroup, alemtuzumab had a lower annualised relapse rate than natalizumab; however, the difference was not statistically significant (HR\xa00.69, 95% CI\xa00.11 to 4.53). The 6‑month sustained accumulation of disability was lower with alemtuzumab than with natalizumab, but the difference was not statistically significant (HR\xa00.78, 95% CI\xa00.06 to 10.83).\n\nThe manufacturer also presented a naïve indirect comparison of alemtuzumab compared with fingolimod and natalizumab for the subgroups of patients with highly active relapsing-remitting multiple sclerosis despite beta interferon therapy and patients with rapidly evolving severe relapsing-remitting multiple sclerosis respectively. The CARE MS-II study comparing alemtuzumab with active comparator (Rebif [44\xa0micrograms]) showed that alemtuzumab had a greater treatment effect on 3‑month sustained accumulation of disability in people with highly active relapsing-remitting multiple sclerosis despite beta interferon treatment (HR\xa00.61, 95% CI\xa00.37 to 1.01) than fingolimod compared with placebo had in the FREEDOM study (HR\xa00.73, 95% CI\xa00.29 to 1.84). Studies comparing alemtuzumab with Rebif showed that alemtuzumab had a similar treatment effect on 6‑month accumulation of disability in people with rapidly evolving severe relapsing-remitting multiple sclerosis (CAMMS223 [HR\xa00.3, 95% CI\xa00.13 to 0.69], CARE MS-I [HR\xa00.83, 95% CI\xa00.28 to 2.42] and CARE\xa0MS-II [HR\xa00.47, 95% CI\xa00.17 to 1.32]) to natalizumab compared with placebo in the AFFIRM study (HR\xa00.36, 95% CI\xa00.17 to 0.76).\n\nIn a pooled analysis of CARE‑MS\xa0I, CARE‑MS\xa0II and CAMMS223 results, most patients reported at least 1 adverse event, the majority of which were mild or moderate in severity. The most common adverse events were headache, rash, fever and multiple sclerosis relapse. The incidence of serious adverse events as reported at the end of the trials from the European Public Assessment Report (EPAR) was 18.3% in both the alemtuzumab and comparator arms. Independent investigators considered that the adverse events were related to alemtuzumab in 7.1% of all patients receiving 12\xa0mg alemtuzumab and to Rebif in 1.6% of all patients receiving Rebif. The most frequently reported serious adverse events in the alemtuzumab 12\xa0mg group were multiple sclerosis relapse (6.1%), pneumonia (0.4%), autoimmune thrombocytopenia (0.4%), gastroenteritis (0.4%), appendicitis (0.4%) and hives (0.4%). Four people developed idiopathic thrombocytopenic purpura. More thyroid-related adverse events were observed in the alemtuzumab arm of the trial (16.6%) than in the Rebif arm (5.2%). Thyroid-related adverse events were observed in 36.2% (at 4\xa0years) and 44.7% (at 8\xa0years) of patients in the alemtuzumab 12\xa0mg/day group. The highest incidence of thyroid-related adverse events was observed between 24 and 42\xa0months after the first treatment cycle. Other serious adverse events observed throughout the clinical trials included infections and renal disease. With the exception of thyroid disorders, administering more than 2 treatment cycles of alemtuzumab did not result in increased frequencies of common adverse events or clinically important events which had not already been observed. Eight people died during the clinical trials; 7 of these people had received alemtuzumab, and the EPAR states that the investigator judged that 3 deaths were possibly or likely to have been related to alemtuzumab treatment.\n\nThe manufacturer assessed health-related quality of life during the phase\xa0II and III trials using the Short-Form Health Survey (SF‑36), the Functional Assessment of Multiple Sclerosis (FAMS) and the EuroQoL‑5 Dimension-5 Level (EQ‑5D-5L) questionnaire. In CARE‑MS\xa0I and\xa0II, patients completed the SF‑36 at baseline, at month\xa012, at month\xa024, and at early discontinuation of treatment. In CARE‑MS\xa0I and\xa0II, the FAMS and EQ‑5D-5L were assessed at baseline and every 6\xa0months thereafter until month\xa024 or early discontinuation of treatment. In CAMMS223, patients completed the SF‑36 every 6\xa0months for 3\xa0years, but not the FAMS or EQ-5D-5L. The manufacturer pooled the EQ-5D-5L utility scores from the CARE MS I and II trials in the alemtuzumab and Rebif (44\xa0micrograms) arms at baseline and 24 months by EDSS score. The difference in mean utility values between patients with the same EDSS scores at baseline and at 24\xa0months showed no consistent trend in either the alemtuzumab or the Rebif arms. The results were provided by the manufacturer as commercial in confidence.\n\n# Cost effectiveness\n\nTo assess the cost effectiveness of alemtuzumab the manufacturer submitted a multi-state Markov model reflecting the course of multiple sclerosis and the effect of treatment with alemtuzumab or the comparators defined in the decision problem (that is, Rebif, Avonex, Betaferon, glatiramer acetate, natalizumab and fingolimod). The model incorporated health states for the type of multiple sclerosis (relapsing–remitting or secondary progressive) and for disease severity defined by the level of disability (EDSS scores ranging from 0 [normal neurological examination] to 9 [confined to bed]). Patients with active relapsing–remitting multiple sclerosis entered the model at EDSS 0 up to EDSS 7 (an EDSS of 7 and above means patients have lost the ability to walk on their own). EDSS 10 represented death from multiple sclerosis. In each cycle, patients remained in the same state, progressed to a worse state (moving to a better state was not possible), transferred to a state reflecting secondary progressive multiple sclerosis, or died. The model assumed that when a patient progressed from relapsing–remitting multiple sclerosis to secondary progressive multiple sclerosis, their EDSS score increased by 1\xa0point. The manufacturer chose a cycle length of 1\xa0year, and a lifetime time horizon of 50\xa0years. Patients entering the model had a mean age of 39.3\xa0years, and there were approximately 3 times as many women as men. The analyses used an NHS and personal social services perspective and a 3.5% discount rate on costs and health effects. Most patients received only 2 courses of alemtuzumab, but the model included re-treatment for some patients in year\xa03, in years\xa06 to 9 and in year\xa010 or above (the manufacturer labelled the rates of re-treatment as commercial in confidence and so they cannot be presented here).\n\nTo estimate the rate of disease progression in people with relapsing–remitting multiple sclerosis, the manufacturer used a matrix to represent the natural history transition and disability progression in people who were not receiving disease-modifying therapies. The manufacturer chose the London Ontario dataset, a longitudinal observational study from 1989, to populate the natural history transition matrix. Since no data for patients with an EDSS state of 0 were available in this dataset, the manufacturer obtained transition probabilities for an EDSS 0 from the placebo arms of 2 trials (TOWER and TEMSO) that compared teriflunomide with placebo for treating multiple sclerosis. The manufacturer based the population entering the model on the average demographic profile of patients in the UK Risk Sharing Scheme, in which 85.8% have relapsing–remitting multiple sclerosis, the mean EDSS of patients with relapsing–remitting multiple sclerosis is 3.1, and the mean EDSS of patients with secondary progressive multiple sclerosis is 5.5.\n\nTo model the effect of treatment with alemtuzumab on relapsing–remitting multiple sclerosis, the manufacturer applied the hazard ratios for the outcome of disability sustained for 3\xa0months compared with placebo from the base-case mixed treatment comparison (see section 3.7) to the natural history matrix. Separately, the manufacturer considered treatment effects on relapse rate and severity (whether or not the relapse leads to hospitalisation). In the base case, the manufacturer assumed that patients discontinue treatment when they convert from relapsing–remitting multiple sclerosis to secondary progressive multiple sclerosis, or progress to EDSS 7. After discontinuing treatment, patients were assumed to receive best supportive care only. The manufacturer's model assumed that no patient who received alemtuzumab ever discontinued treatment, while patients could discontinue comparator treatments (and subsequently receive best supportive care). The manufacturer also assumed that the treatment effect of alemtuzumab did not change over time (even during years when patients did not receive alemtuzumab) until a patient reached EDSS 7 or converted to secondary progressive multiple sclerosis. On entering EDSS 7 the benefits of alemtuzumab stopped, independent of the number of courses of alemtuzumab given. In each cycle patients could stop using comparator treatments, discontinue treatment after reaching EDSS 7, or experience relapse or adverse events. The probability of death was dependent on the EDSS state (the higher the EDSS score, the higher the risk of death), age and sex.\n\nThe manufacturer's model applied health state utility values to each of the EDSS states. Although the manufacturer collected EQ‑5D data in the CARE‑MS\xa0I and II trials, it did not use these data in the model as they were not available at the time of submission. Instead, the manufacturer obtained health state utility values from Orme et al. (2007), a UK survey of health-related quality of life in (EQ‑5D) in people with multiple sclerosis. Utility values decreased as EDSS scores increased, with the exception of the utility value for EDSS state 3, which was lower than EDSS 4. EDSS states 8 and 9 had negative utility values, indicating states that are considered to be worse than being dead. The manufacturer applied disutilities for a relapse, to caregivers, and for adverse events. The manufacturer obtained the value for the disutility of relapse from Orme et al. (2007), and the value for the disutility of relapse leading to hospitalisation from a US study (Prosser et al. 2003). To estimate disutility to caregivers, the manufacturer used values taken from Gani et al. (2008), and to estimate the time spent caring for the patient, the manufacturer used Orme et al. (2007). Disutility values applied for each adverse event were annualised based on the published literature. The manufacturer also took into account how long each adverse event lasted, and whether it was specific to treatment. The adverse events included infusion-associated reactions, bronchitis, herpes zoster, urinary tract infections, autoimmune thyroid-related adverse events, nephropathies, idiopathic thrombocytopenic purpura, other cytopenias and vomiting.\n\nThe model used NHS reference costs and the payment-by-results tariff to estimate the costs of administration, monitoring and adverse events associated with each treatment. The manufacturer assumed that monitoring of patients previously treated with alemtuzumab lasts for up to 12\xa0years. The manufacturer derived some costs from the literature: health state costs (including direct medical costs and direct non-medical costs) from a UK study (Tyas et al. 2007), and the costs associated with relapse from a study from the Republic of Ireland (Dee et al. 2012). For a sensitivity analysis, the manufacturer used an alternative UK study (Karampampa et al. 2012) to derive health state costs, although the manufacturer provided only natural history costs aggregated for EDSS states 0–3, 4–6 and 7–9, rather than costs for individual EDSS states. The manufacturer validated the resource use and costs it applied in the model using clinical experts. The cost of one of the comparators, fingolimod, includes a simple discount patient access scheme agreed with the Department of Health. However, the manufacturer did not know how large the discount was, and therefore could not use it in its base-case analysis. Instead, the manufacturer explored different prices of fingolimod in sensitivity analyses, using a range of assumed discounts.\n\nThe manufacturer's submission presented the total life years gained, the total quality-adjusted life years (QALYs) and the total costs resulting from the economic model for alemtuzumab and Rebif (44\xa0micrograms). Treatment with alemtuzumab was associated with 18.62\xa0life years, which equated to 4.03\xa0QALYs, at a total cost of £499,347. Treatment with Rebif (44\xa0micrograms) was associated with 18.38\xa0life years, which equated to 2.85\xa0QALYs, at a total cost of £489,354.\n\nThe manufacturer conducted a fully incremental analysis, calculating the incremental QALY gains and costs for all treatment options and ordered by increasing costs. The treatments included alemtuzumab, glatiramer acetate, Rebif (22\xa0micrograms), Rebif (44\xa0micrograms), Avonex, and Betaferon. The manufacturer also included fingolimod and natalizumab in its incremental analysis, although it acknowledged that these drugs have marketing authorisations only for use in highly active relapsing-remitting multiple sclerosis despite beta interferon treatment and rapidly evolving severe relapsing–remitting multiple sclerosis. When compared in this incremental analysis, the probabilistic estimates of the incremental cost-effectiveness ratios (ICERs) suggested that:\n\nalemtuzumab dominated Betaferon, fingolimod (without applying a patient access scheme discount), fingolimod (assuming a patient access scheme price of £13,000 per year), and natalizumab. (A treatment dominates other treatments when it is less expensive and more effective.)\n\nRebif (44\xa0micrograms) and Rebif (22\xa0micrograms) were extendedly dominated by alemtuzumab. (A treatment is extendedly dominated when its ICER is higher than that of the next, more effective, option when compared with a common baseline.)\n\nThe ICER for alemtuzumab compared with glatiramer acetate was £7017 per QALY gained. The manufacturer's deterministic results were similar with an ICER of £8924 per QALY gained for alemtuzumab compared with glatiramer acetate.\n\nUsing the results of the subgroup mixed treatment comparisons (see section 3.8), the manufacturer compared alemtuzumab with fingolimod and with natalizumab for the highly active relapsing-remitting multiple sclerosis despite beta interferon treatment and the rapidly evolving severe relapsing-remitting multiple sclerosis subgroups, respectively. For both analyses, alemtuzumab dominated the respective comparator.\n\nThe manufacturer conducted one‑way sensitivity analyses, which showed that the cost effectiveness of alemtuzumab was most sensitive to the hazard ratios reflecting the comparative effectiveness of alemtuzumab compared with placebo for sustained disability progression, disease costs, and the discontinuation rate of Rebif (44\xa0micrograms). Alemtuzumab continued to dominate all comparators except glatiramer acetate, except when the manufacturer varied the hazard ratios for disability progression. When the manufacturer applied the upper limit of the 95% confidence interval around the sustained accumulation of disability hazard ratio for alemtuzumab from the manufacturer's mixed treatment comparison, the resulting ICER for alemtuzumab compared with Rebif (44\xa0micrograms) was £1,200,973 per QALY gained. With the lower limit of the 95% confidence interval, alemtuzumab dominated Rebif (that is, had the lowest total treatment costs for the greatest clinical gain of all treatments in the analysis).\n\nThe manufacturer also tested how sensitive the results were to which mixed treatment comparison it used, by using the 'all years' data instead of the 'base-case' mixed treatment comparison and by only including trials in which 100% of patients had relapsing–remitting multiple sclerosis (rather than the base-case mixed treatment comparison, in which trials with at least 80% of patients with relapsing–remitting multiple sclerosis were included). When trials from 'all years' in which at least 80% of patients had relapsing–remitting multiple sclerosis were included, the deterministic ICER for alemtuzumab compared with glatiramer acetate increased from £8924 to £9982 per QALY gained. When the manufacturer included trials from all years in which the percentage of the population with relapsing–remitting multiple sclerosis was 100% the ICER for alemtuzumab compared with glatiramer acetate increased to £27,434 per QALY gained. When the manufacturer used the mixed treatment comparison including trials after the year 2000 in which 100% of patients had relapsing–remitting multiple sclerosis, the ICER for alemtuzumab compared with glatiramer acetate was £10,822 per QALY gained.\n\nThe manufacturer conducted a number of scenario analyses using Rebif (44\xa0micrograms) as the comparator, but not glatiramer acetate, with the justification that Rebif (44\xa0micrograms) was the standard treatment for active relapsing–remitting multiple sclerosis. In the best case scenario alemtuzumab dominated Rebif and in the worst case scenario the ICER for alemtuzumab compared with Rebif was £20,388 per QALY gained. The manufacturer developed other scenarios based on:\n\nsourcing the baseline characteristics from the CARE‑MS trials rather than from the UK Risk Sharing Scheme (the ICER for alemtuzumab compared with Rebif was £869 per QALY gained)\n\nusing costs related to the natural history of multiple sclerosis from Karampampa et al. (2012) rather than Tyas et al. (2007) (alemtuzumab dominated Rebif)\n\nusing natural history transition probabilities assuming that the population only included people with active relapsing–remitting multiple sclerosis, instead of all people with relapsing–remitting multiple sclerosis (the ICER for alemtuzumab compared with Rebif was £8597 per QALY gained)\n\nassuming long-term waning of treatment effect by 25% or 50% after year\xa05 for all treatments, instead of assuming that the beneficial effect of alemtuzumab does not wane (the ICERs for alemtuzumab compared with Rebif were £13,956 and £20,388 per QALY gained, respectively)\n\nassuming that treatment with alemtuzumab does not influence the probability of relapses or hospitalisation (the ICER for alemtuzumab compared with Rebif was £14,517 per QALY gained)\n\nusing the trial data (pooled CARE‑MS\xa0I and CARE‑MS\xa0II) for the transition probabilities instead of using values sourced from the literature (alemtuzumab dominated Rebif).\n\n# Evidence Review Group comments\n\nThe ERG reviewed the manufacturer's model and economic systematic review. The ERG commented that the structure of the economic model was appropriate for multiple sclerosis and consistent with previous economic evaluations of treatments for multiple sclerosis, and that the methods of analysis were appropriate and conformed to NICE methodological guidelines.\n\nThe ERG stated that the manufacturer systematically reviewed the literature to populate its transition matrix and reflect the natural history for disability progression for patients not receiving a disease-modifying treatment. The ERG did not find any data more appropriate than the London Ontario data identified by the manufacturer, but commented that the manufacturer did not fully explore the uncertainty around the natural history of multiple sclerosis. In light of previous technology appraisals, the ERG suggested that it would have been more appropriate to explore alternative sources of data.\n\nThe ERG evaluated the results of the economic model outputs as compared with published literature. The ERG noted that the manufacturer compared the results at the end of year\xa02, but no further. As there was no validation beyond 2\xa0years, uncertainty remains as to the validity of longer-term outcomes.\n\nThe ERG stated that the manufacturer had performed appropriate structural sensitivity analyses, but had not conducted a sensitivity analysis that varied the rate of disease progression for patients receiving best supportive care only, or the rate of progression from relapsing–remitting multiple sclerosis to secondary progressive multiple sclerosis.\n\nThe ERG identified weaknesses and uncertainty in the manufacturer's economic analysis. The ERG stated that basing the starting model population on the UK Risk Sharing Scheme instead of the clinical trial populations introduced uncertainty into the model, because these populations did not have the same baseline characteristics, particularly with regard to the distribution of initial EDSS states. The ERG commented that the conversion rate used for patients moving from relapsing–remitting multiple sclerosis to secondary progressive multiple sclerosis in the model was too high, because it did not reflect the people receiving first-line treatment for relapsing–remitting multiple sclerosis. The ERG also stated that the London Ontario estimates for disease progression for patients not taking disease-modifying treatments did not allow EDSS scores to improve. Trial-based transition probabilities were available that allowed EDSS scores to improve, although the ERG commented that using the trial data could pose problems as it reflected a short period of time. The ERG explored the impact of changing these assumptions in their exploratory analyses.\n\n# Exploratory sensitivity analyses undertaken by the Evidence Review Group\n\nThe ERG presented a 'preferred' base case that included alternative characteristics for the patient population, and a different progression rate from relapsing–remitting multiple sclerosis to secondary progressive multiple sclerosis. The ERG also conducted a series of sensitivity analyses to test uncertainties.\n\nIn all its exploratory analyses, the ERG compared alemtuzumab with Rebif (44\xa0micrograms) (instead of glatiramer acetate as used in the manufacturer's fully incremental analysis). The ERG made this change because Rebif (44\xa0micrograms) was the direct comparator in the clinical trials and was the most efficacious comparator in the manufacturer's mixed treatment comparison. Using the baseline characteristics for the populations in CARE‑MS\xa0I and CARE‑MS\xa0II, the ERG calculated that the ICER for alemtuzumab compared with Rebif (44\xa0micrograms) would decrease from £8445 (manufacturer's base case comparing alemtuzumab with Rebif (44\xa0micrograms) to £2869 per QALY gained. The ERG also applied a conversion rate of 15\xa0years from relapsing–remitting multiple sclerosis to secondary progressive multiple sclerosis (instead of the 10–11\xa0years used by the manufacturer), as used in Teriflunomide for treating active relapsing–remitting multiple sclerosis (NICE technology appraisal guidance 303). This had the effect of reducing the ICER to £3100 per QALY gained for alemtuzumab compared with Rebif (44\xa0micrograms). The ERG's preferred approach combining these 2 changes resulted in alemtuzumab dominating (being less costly and more effective than) Rebif (44\xa0micrograms), with a cost saving of £852 per QALY gained.\n\nThe ERG tested its preferred base case for alemtuzumab compared with Rebif (44\xa0micrograms) in sensitivity analyses, including:\n\nreducing by 50% the transition probabilities to more severe health states from the London Ontario dataset (alemtuzumab dominated Rebif [44\xa0micrograms])\n\nusing quality-of-life utility values (upper and lower confidence intervals from the Orme et al. 2007 data used in the manufacturer's model) (for both, alemtuzumab dominated Rebif [44\xa0micrograms])\n\nusing disease health state costs from Karampampa et al. (2012) and Biogen et al. (2007) (alemtuzumab dominated Rebif [44\xa0micrograms] for Karampampa et al.; for Biogen et al., the ICER for alemtuzumab compared with Rebif [44\xa0micrograms] was £4654 per QALY gained)\n\nreducing the cost of a relapse that results in hospitalisation from £6146 to £3039 (the ICER for alemtuzumab compared with Rebif [44\xa0micrograms] was £1013 per QALY gained)\n\napplying a waning of treatment effect for alemtuzumab of 75% for year\xa010 and beyond, or 75% from year\xa06 to year 9 and 50% from year\xa010 and beyond (the ICERs for alemtuzumab compared with Rebif [44\xa0micrograms] were £1815 and £7319 per QALY gained, respectively)\n\nvarying the proportion of patients receiving additional alemtuzumab treatment at year\xa03 (60%) and years\xa05 and beyond (the ICER for alemtuzumab compared with Rebif [44\xa0micrograms] was £8336 per QALY gained)\n\napplying the results from the 'all years' mixed treatment comparison (alemtuzumab dominated Rebif [44\xa0micrograms])\n\nusing the outcome of sustained accumulation of disability lasting for 6\xa0months from the mixed treatment comparison (instead of 3\xa0months) to calculate the disease transition probabilities (alemtuzumab dominated Rebif [44\xa0micrograms]).\n\nThe ERG also explored the cost effectiveness of alemtuzumab for the treatment‑naive and treatment‑experienced subgroups separately, using the ERG preferred base case, the relative risk for annualised rate of relapse, and a sustained accumulation of disability lasting 3\xa0months for alemtuzumab. Using the treatment-naive group data from CARE‑MS\xa0I, the ERG's preferred base case (that is, where alemtuzumab dominated Rebif [44\xa0micrograms], see section 3.29) changed to an ICER of £6392 per QALY gained for alemtuzumab compared with Rebif (44\xa0micrograms). When the ERG used the CAMMS223 data, alemtuzumab dominated Rebif (44\xa0micrograms). Alemtuzumab also dominated Rebif (44\xa0micrograms) when the ERG pooled data from the 2 trials. For the treatment-experienced group, using effectiveness data from CARE‑MS\xa0II, the ICER was £2854 per QALY gained for alemtuzumab compared with Rebif (44\xa0micrograms).\n\nThe ERG also carried out exploratory analyses for the subgroup with highly active relapsing-remitting multiple sclerosis despite beta interferon treatment, and the subgroup with rapidly evolving severe relapsing–remitting multiple sclerosis. In these analyses the ERG used its preferred base case for a slower progression to secondary progressive multiple sclerosis for the rapidly evolving severe relapsing–remitting multiple sclerosis subgroup, and different patient characteristics for the highly active relapsing-remitting multiple sclerosis despite beta interferon treatment subgroup. These changes had only minimal effect on the model results, and alemtuzumab continued to dominate fingolimod and natalizumab.\n\n# Manufacturer's response to the appraisal consultation document\n\nThe manufacturer provided a revised base case analysis using the Committee's preferred assumptions, as requested in the appraisal consultation document which did all of the following:\n\nused sustained accumulation of disability lasting 6\xa0months as the primary outcome measure of the mixed treatment comparison\n\nused the 'all years' mixed treatment comparison adjusted for baseline relapse rates to estimate disease progression and withdrawal rates\n\nused the intention-to-treat analyses developed for the CAMMS223, CARE‑MS\xa0I and CARE‑MS\xa0II trials adjusted for baseline Expanded Disability Status Scale (EDSS) only (unadjusted for country or region)\n\nused the EQ-5D-5L utility scores pooled from the CARE MS I and II trials comparing alemtuzumab with Rebif (44\xa0micrograms)\n\nused data on the natural history and progression of disability from the placebo arms of the TOWER and TEMSO trials to allow for improvements in patients' EDSS states\n\nincorporated the deaths observed in the trials into the model\n\nassumed that the efficacy for alemtuzumab began waning at 3 or 5\xa0years\n\nused additional costs of other licensed treatments for active relapsing–remitting multiple sclerosis after failure of alemtuzumab\n\nused a time-dependent rate of re-treatment for the costs of alemtuzumab\n\nremoved the mid-cycle correction for the costs of alemtuzumab\n\nincreased the number of monitoring and neurology visits for patients treated with alemtuzumab as well as visits for monitoring after restarting alemtuzumab treatment\n\nused the lower health state costs used in the ERG's analyses\n\nused costs associated with adverse effects of treatment including renal failure, renal transplantation, dialysis and death\n\nused baseline characteristics from the alemtuzumab trials rather than from the UK Risk Sharing Scheme to populate the economic model.The manufacturer applied the Committee's preferences in individual analyses (see section 3.34) and also combined them into one analysis (see section 3.35).\n\nIn the manufacturer's individual analyses using the baseline characteristics of patients in the alemtuzumab trials in the model instead of the UK Risk Sharing Scheme, alemtuzumab dominated glatiramer acetate. For each of the other individual analyses, the resulting probabilistic ICERs for alemtuzumab compared with glatiramer acetate remained below £20,000 per QALY gained with the exception of the analyses exploring the impact of waning effectiveness of alemtuzumab and its comparators. For these analyses, the manufacturer presented 2 scenarios; the first assumed a decreasing efficacy for both alemtuzumab and the comparators over time, and the second assumed decreasing efficacy only for alemtuzumab. When the manufacturer assumed that the treatment effectiveness for both alemtuzumab and its comparators was reduced from 100% to 75% from year\xa03 to year\xa05 after treatment, and then to 50% from year\xa06 onward, the manufacturer's incremental analyses showed that glatiramer acetate dominated Avonex, Betaferon and Rebif (44\xa0micrograms) and that the ICER for alemtuzumab compared with glatiramer acetate was £23,432 per QALY gained. When the manufacturer assumed that the effectiveness of alemtuzumab was reduced from 100% to 75% from year\xa03 to year\xa05, followed by a reduction to 50% from year\xa06 onward (while the efficacy of alemtuzumab's comparators remained unchanged) glatiramer acetate dominated Avonex, Betaferon and Rebif (44\xa0micrograms) and the ICER for alemtuzumab compared with glatiramer acetate was £30,657 per QALY gained.\n\nThe manufacturer presented a fully incremental analysis combining each of the Committee's preferred assumptions including the 2 scenarios in which the effectiveness of treatments wanes over time. When the manufacturer assumed that the effectiveness for both alemtuzumab and its comparators was reduced from 100% to 75% from year\xa03 to year\xa05, followed by a reduction to 50% efficacy from year\xa06 onward, the manufacturer's incremental analyses showed that glatiramer acetate dominated Avonex, Betaferon and Rebif (44\xa0micrograms) and that the ICER for alemtuzumab compared with glatiramer acetate was £13,636 per QALY gained. When the manufacturer assumed that the treatment effectiveness for alemtuzumab was reduced from 100% to 75% from year\xa03 to year\xa05, followed by a reduction to 50% efficacy from year\xa06 onward (while the efficacy of its comparators remained unchanged at 100%) glatiramer dominated Avonex, Betaferon and Rebif (44\xa0micrograms) and the ICER for alemtuzumab compared with glatiramer acetate was £24,472 per QALY gained.\n\nFor the subgroup of rapidly evolving severe relapsing–remitting multiple sclerosis, when comparing alemtuzumab with natalizumab, the manufacturer used the Committee's preferred assumptions (see section 3.33) with the exception of using the results of the 'all years' mixed treatment comparison adjusted for baseline relapse rate because the manufacturer had not identified a relapse rate for natalizumab. When the manufacturer applied the Committee's assumptions individually, alemtuzumab dominated natalizumab for all but 1 scenario. In that scenario, the manufacturer assumed that the treatment effect for alemtuzumab waned beyond 3\xa0years after treatment with alemtuzumab, while assuming that the treatment effect for natalizumab remained constant over the lifetime of the model. The ICER for this scenario was £236,172 per QALY gained. When the manufacturer combined all the Committee's preferred assumptions, alemtuzumab dominated natalizumab in the subgroup of people with rapidly evolving severe relapsing–remitting multiple sclerosis.\n\nFor the subgroup of patients with relapsing–remitting multiple sclerosis with high disease activity despite beta interferon treatment, when comparing alemtuzumab with fingolimod, the manufacturer used the Committee's preferred assumptions (see section 3.33) with the exception of 2 assumptions for which the manufacturer did not identify data. These 2 assumptions were sustained accumulation of disability lasting 6\xa0months as a primary outcome measure in the mixed treatment comparison, and using the results of the 'all years' mixed treatment comparison adjusted for baseline relapse rate. When the manufacturer applied the Committee's assumptions individually, alemtuzumab dominated fingolimod in all scenarios. When the manufacturer combined all the Committee's assumptions, alemtuzumab continued to dominate fingolimod.\n\nFor the same subgroup, that is, patients with relapsing–remitting multiple sclerosis with high disease activity despite beta interferon treatment, and when comparing alemtuzumab with fingolimod, the manufacturer explored additional scenarios. The manufacturer combined all of the Committee's preferred assumptions (see section 3.33) and:\n\nassumed that the hazard ratios from patients with relapsing–remitting multiple sclerosis with high disease activity despite beta interferon treatment in CARE MS II, which reflected the effectiveness of alemtuzumab compared with Rebif (44\xa0micrograms) to delay disability (sustained accumulation of disability at 3\xa0months) and annual relapse rates, were equivalent to what would have been expected had alemtuzumab been compared with placebo\n\nincorporated these assumptions together with the hazard ratios from the subgroup of patients with relapsing–remitting multiple sclerosis with high disease activity despite beta interferon treatment in the FREEDOMS trial which compared fingolimod with placebo\n\nassumed that the patient access scheme price for fingolimod (the details of which were not available to the manufacturer of alemtuzumab) was £13,000 and\n\napplied either the utility values from CARE-MS I and II or those from the placebo arms of the TEMSO study (teriflunomide versus placebo) combined with the utility values reflecting relapses from Orme et al.The ICERs resulting from these analyses for alemtuzumab compared with fingolimod in patients with relapsing–remitting multiple sclerosis with high disease activity despite beta interferon treatment were £7,089 per QALY gained using the CARE-MS I and II trial utility results and £17,232 per QALY gained using the utility results from the placebo arms of the TEMSO study combined with the Orme study utility decrements.\n\n# Evidence Review Group comments on the manufacturer's additional evidence\n\nThe ERG confirmed that the additional evidence presented by the manufacturer reflected the Committee's requests for additional analyses. The ERG confirmed that it could calculate the manufacturer's deterministic ICERs both in the individual analyses and in the Committee's preferred combined analysis but, owing to time constraints, it could only verify a sample of the probabilistic results presented by the manufacturer. The ERG noted that the manufacturer had incorrectly estimated the ICERs in its fully incremental analyses because the manufacturer compared the treatment with the next less costly treatment, even when the next less costly treatment was dominated.\n\nThe ERG reviewed the manufacturer's response to the ACD which focused on both subgroups reflecting patients with high disease activity. The ERG noted that while the manufacturer's mixed treatment comparison provided evidence of the effectiveness of alemtuzumab in these subgroups, there remained a number of uncertainties with these data: the evidence network depended on the teriflunomide trials which included either the overall relapsing-remitting multiple sclerosis population (TENERE) or a subgroup of previously-treated patients as a proxy for highly active relapsing-remitting multiple sclerosis despite beta interferon treatment (TEMSO and TOWER); inconsistencies in the definitions of the subgroups in each of the trials; differences between the patient populations included in the trials; and that the mixed treatment comparison was heavily dependent on indirect evidence to complete the evidence network.\n\nThe ERG conducted exploratory analyses that assumed that alemtuzumab and fingolimod were equally effective, and that alemtuzumab and natalizumab were equally effective. To do this, the ERG applied the hazard ratios for annual relapse rates and sustained accumulation of disability from the mixed treatment comparison for alemtuzumab compared with placebo and fingolimod and natalizumab each compared with placebo. The ERG applied hazard ratios for alemtuzumab to fingolimod and natalizumab (and vice versa) in the respective subgroups, and also applied the midpoint hazard ratio between alemtuzumab and either fingolimod or natalizumab. In the subgroup of high disease activity despite beta interferon treatment when comparing alemtuzumab with fingolimod, the resulting ICERs were £4,460, £14,788 and £8,942 per QALY gained, respectively. In the subgroup of rapidly evolving severe relapsing–remitting multiple sclerosis, alemtuzumab dominated natalizumab in each scenario.\n\nFull details of all the evidence are in the manufacturer's original submission, the manufacturer's response to consultation, the ERG's original report, and the ERG's critique of the manufacturer's response to consultation.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of alemtuzumab, having considered evidence on the nature of active relapsing–remitting multiple sclerosis and the value placed on the benefits of alemtuzumab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee heard from the clinical specialists and patient experts about the nature of the condition. It was aware that relapsing–remitting multiple sclerosis is a chronic, disabling, neurological condition that, as it progresses, is life altering and has a large negative impact on quality of life and activities of daily living. The Committee heard from clinical specialists that the currently available first-line treatments for active relapsing–remitting multiple sclerosis need to be injected weekly or several times per week and can be associated with unpleasant side effects (such as injection-site reactions, flu-like symptoms, fatigue and depression) and can significantly affect patients' emotional wellbeing. The Committee concluded that any delay in relapse and progression of disability or reduction in the frequency of treatment would have a positive impact on the lives of people with multiple sclerosis and their families.\n\nThe Committee considered the impact of treating active relapsing–remitting multiple sclerosis with alemtuzumab. The Committee was aware that patients in the UK may have participated in trials of alemtuzumab, or may have received alemtuzumab off-label before it was licensed for active relapsing–remitting multiple sclerosis (alemtuzumab had a previous marketing authorisation for B-cell chronic lymphocytic leukaemia, but the manufacturer has withdrawn the product for that indication). The Committee heard from a patient expert who received alemtuzumab for active relapsing–remitting multiple sclerosis in 2006 and 2007, and who has not experienced any relapses since, with her health being better now than at the time of diagnosis. She also preferred alemtuzumab's administration schedule (see section 2.1) to weekly or daily self-administered injections with beta interferons, which to her would have been a 'constant reminder' of her multiple sclerosis. She commented that the considerable impact on her family and their concern about relapse or accumulation of disability lessened once she had received alemtuzumab. The Committee concluded that alemtuzumab has the potential to benefit people with active relapsing–remitting multiple sclerosis and their families.\n\nThe Committee considered alemtuzumab's place in the treatment pathway for active relapsing–remitting multiple sclerosis. The Committee heard from the clinical specialists that alemtuzumab would be considered as a first-line treatment option, alongside beta interferons or glatiramer acetate, for people with active relapsing–remitting multiple sclerosis eligible for treatment under the Association for British Neurologists' guidelines. The Committee heard from the clinical specialists that, while effective therapies should ideally be offered early in disease, offering effective treatments later in disease is even more important because these patients have a higher risk for more severe complications. The Committee also heard that, while alemtuzumab's marketing authorisation permits its use as a first-line treatment, it is more likely to be offered to people for whom other disease-modifying treatments have not been effective. However, the Committee heard from the patient expert that a patient should not have to experience more severe symptoms before being offered alemtuzumab. One clinical specialist emphasised that alemtuzumab is 'not for everybody', and that clinicians would offer alemtuzumab to patients who, among other characteristics, would be likely to comply with the required monitoring for adverse effects, and that approaches exist to estimate the likely compliance with monitoring. The Committee concluded that alemtuzumab is a valuable treatment option for selected patients with varying types and stages of active relapsing–remitting multiple sclerosis.\n\nThe Committee considered whether neurologists would offer patients treatment with alemtuzumab beyond the 2 annual cycles stipulated in the marketing authorisation. The clinical specialists acknowledged that some patients need more than the 2 initial annual cycles, and that clinicians would consider offering further courses of alemtuzumab to patients whose disease had relapsed. One clinical specialist stated that people who have no relapses in the third year following first treatment, but who subsequently relapse, would be considered for retreatment. People who have relapses within the third year would not, however, be offered retreatment because clinicians would consider alemtuzumab to be no longer effective in this situation. The Committee concluded that some patients whose disease initially responds to alemtuzumab but later relapses may be treated with alemtuzumab beyond the 2\xa0treatment courses described in the marketing authorisation.\n\nThe Committee considered the advantages and disadvantages of alemtuzumab treatment. The clinical specialists described advantages to alemtuzumab treatment, including that it is highly effective, does not cause the flu-like symptoms associated with beta interferons, and does not need to be discontinued by patients planning a pregnancy, although the Committee was aware that effective contraceptive measures should be taken when receiving alemtuzumab and for 4\xa0months following a course of treatment according to the summary of product characteristics. This was seen as important, because multiple sclerosis affects women and men during the years when they are most likely to have children, and all other multiple sclerosis treatments, according to their summary of product characteristics, must be stopped for a person to have children. The clinical specialists explained that the main disadvantages of alemtuzumab treatment are the possible serious adverse effects observed during the trials, including idiopathic thrombocytopenic purpura, kidney disease or failure, thyroid disease and death. The clinical specialists stated that thyroid disease is the most common complication, affecting one-third of patients with multiple sclerosis treated with alemtuzumab. In response to a comment made by a consultee that patients treated with alemtuzumab were at risk for papillary thyroid cancer, a clinical specialist suggested that this could be related to increased detection following routine screening as required by the marketing authorisation for alemtuzumab. The clinical specialists and the manufacturer explained that patients need monthly platelet and white cell counts and quarterly assessment of thyroid and renal function for 4\xa0years after the last treatment, and that patients are monitored even more often than this immediately after treatment with alemtuzumab. The clinical specialists stated that alemtuzumab permanently changes a person's immune system because it alters the numbers, proportions and properties of some lymphocyte subsets, and acknowledged that ongoing monthly monitoring might be an obstacle for some patients, particularly for those who feel well. The Committee expressed concern about the methods used to ensure that people treated with alemtuzumab would comply with monitoring requirements. The Committee heard from the clinical specialists that there are standard monitoring systems in place at the specialist centres that administer alemtuzumab and patients are contacted by a variety of methods if they miss a monthly monitoring visit. The Committee was aware that even when adverse events related to alemtuzumab were identified during regular monitoring, there could still be problems with follow-up actions when the results are received. The clinical specialists commented that idiopathic thrombocytopenic purpura associated with alemtuzumab responds to treatment with corticosteroids and immunoglobulin\xa0G, and patients would be unlikely to need treatment with thrombopoietin agonists. The clinical specialists and patient experts acknowledged the risk of renal disease for which some patients need renal replacement therapy but stated that people with active relapsing–remitting multiple sclerosis may be willing to accept the risks of serious adverse events associated with alemtuzumab treatment, because the potential benefits to quality of life are considerable. The clinical specialists acknowledged uncertainty about how prior treatment with alemtuzumab might change the adverse event profile of other monoclonal antibodies used for the treatment of multiple sclerosis, such as natalizumab. The Committee concluded that alemtuzumab is associated with significant benefits, but also significant harms, that some people with active relapsing–remitting multiple sclerosis are willing to accept the disadvantages of alemtuzumab treatment, and that adhering to the recommended monitoring schedule is important.\n\nThe Committee further considered the adverse effects associated with alemtuzumab. The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency acknowledged that alemtuzumab had been shown to be effective in people with active relapsing–remitting multiple sclerosis, but that there were serious safety concerns evidenced by the fact that 7 CHMP members had publicly disagreed with the majority decision. These dissenting members stated in the European Public Assessment Report for alemtuzumab that the benefits to risks balance could be considered acceptable in a limited indication in patients with relapsing–remitting multiple sclerosis with high disease activity defined by clinical and imaging features, but that they did not consider that the benefits outweighed the risks in a population with less active disease. The Committee took into account the view of a clinical specialist that the deaths that occurred during the clinical trials could have been avoided. It concluded that a clinical trial provides better opportunities for regular monitoring than could be achieved in clinical practice, and remained concerned about the deaths that were possibly related to alemtuzumab treatment.\n\nThe Committee discussed the information provided to patients for whom treatment with alemtuzumab is considered, and specifically the requirements for monitoring and risks associated with treatment with alemtuzumab. The Committee questioned whether those requirements and risks were being clearly communicated to patients considering alemtuzumab as a treatment option. The Committee heard from the clinical specialists that alemtuzumab would only be offered to people who were fully informed of the possible adverse effects of alemtuzumab and aware of the stringent monitoring requirements. The patient expert explained that she had been fully informed about the possible adverse effects and monitoring requirements for alemtuzumab before making the decision to enrol in the alemtuzumab trial and further information had been provided during the initial stages of treatment to help her recognise possible adverse reactions. The Committee was aware that the summary of product characteristics requires that a neurologist experienced in treating patients with multiple sclerosis supervises treatment with alemtuzumab, and states that specialists and equipment should be available to diagnose and manage the most frequent adverse reactions, especially autoimmune conditions and infections. The Committee was also aware that patients should be given a Patient Alert Card and Patient Guide and be informed about the risks of alemtuzumab. The Committee remained concerned that not all people offered alemtuzumab might understand the risks or comply with the monitoring requirements. The Committee concluded that there are monitoring processes in place based on evidence from patients who received alemtuzumab either in trial or clinical settings.\n\n# Clinical effectiveness\n\nThe Committee considered the clinical effectiveness of alemtuzumab in the relapsing–remitting multiple sclerosis population in the 3 trials comparing it with Rebif (44\xa0micrograms) (see section 3.2). On the basis of the improvements in sustained accumulation of disability at 6\xa0months in the trials and in relapse rates, the Committee concluded that alemtuzumab is a more clinically effective treatment for active relapsing–remitting multiple sclerosis than Rebif (44\xa0micrograms).\n\nThe Committee discussed whether it was appropriate for the manufacturer to have used the sustained accumulation of disability lasting 3\xa0months rather than 6\xa0months in its mixed treatment comparison and modelling for people with active relapsing–remitting multiple sclerosis, given that the CARE‑MS\xa0I and II trials included 6‑month sustained accumulation of disability as one of the co-primary endpoints (the other being annualised relapse rate). The Committee heard from the clinical specialists that patients may not have permanent disability progression after a relapse and that recovery may take up to 12\xa0months, but on average people will recover within 3\xa0or 4\xa0months. The clinical specialists stated that sustained disability progression lasting for 6\xa0months is a more appropriate outcome measure than disability progression lasting for 3\xa0months. The Committee heard from the manufacturer that the main reason for why it initially chose to use the sustained accumulation of disability at 3\xa0months in its mixed treatment comparison was that this would allow for comparison across trials that included 3‑month but not 6‑month disability. However the Committee understood that the 6‑month disability outcome was reported for all but 1 of the beta interferons. On the basis of clinicians' preference, the Committee concluded that it preferred sustained accumulation of disability lasting 6\xa0months to be used as the primary outcome measure in the mixed treatment comparison.\n\nThe Committee discussed the manufacturer's mixed treatment comparison comparing alemtuzumab with other disease-modifying treatments for people with active relapsing–remitting multiple sclerosis. It noted that the manufacturer initially presented a base-case mixed treatment comparison excluding trials that recruited patients before the year 2000, and a separate 'all years' sensitivity analysis that included all trials (see section 3.7). The Committee acknowledged that earlier trials were excluded because of changes in diagnostic criteria, which resulted in part in changes in baseline relapse rates over time, but were concerned that important trials were excluded as a result of the cut-off date, including all trials comparing beta interferons with placebo. In addition, the Committee was not convinced that the difference in the baseline rate of relapse would modify the relative effectiveness of alemtuzumab compared with other disease-modifying drugs. It was aware that the manufacturer presented a revised mixed treatment comparison including trials from 'all years' and adjusted for baseline relapse in its response to the Appraisal Consultation Document. The Committee concluded that it is more appropriate for the mixed treatment comparison to include all available evidence, and that in this case adjusting the mixed treatment comparison for baseline relapse rates accounts for any differences in relapse rates between trials.\n\nThe Committee discussed the statistical analysis plan for the 3 alemtuzumab trials. The Committee noted that the statistical plan for CAMMS223 stipulated an intention-to-treat analysis adjusted for baseline Expanded Disability Status Scale (EDSS) score and country, which was reflected in the final publication. The Committee noted that in CAMMS223 and CARE‑MS\xa0II, the investigators used the per-protocol set to conduct the statistical analyses whereas in CARE‑MS\xa0I the full dataset was analysed, which included some patients who did not meet the specified inclusion criteria or who had not received treatment as specified in the clinical trial protocol. The Committee heard from a clinical specialist, and author of all 3 trials, that the results for the full analysis set were similar to those for the per-protocol set for CARE‑MS\xa0I. However, the Committee remained concerned about the pooling of trial results that had been analysed differently, and the fact that the manufacturer had not initially presented a sensitivity analysis demonstrating the impact this difference could have on the results of the mixed treatment comparison (and therefore on the economic modelling). The Committee concluded that it is more appropriate to include the per-protocol analyses set for all 3 trials, unadjusted for country or region and adjusted for baseline EDSS states only. However, it was aware that the manufacturer's revised mixed treatment comparison presented in its response to the appraisal consultation document included the results from intention-to-treat analyses of the CARE-MS I, CARE-MS II and CAMMS223 trials and concluded that in this case it had little impact on the results of the mixed treatment comparison.\n\nThe Committee considered the long-term efficacy of alemtuzumab. The clinical specialists acknowledged that there was uncertainty regarding the effectiveness of alemtuzumab in the long term and specifically for periods exceeding the duration of the follow-up studies to the clinical trials, which to date have followed some patients for a median of 7\xa0years and a maximum of 12\xa0years. The clinical specialists also stated that people who experience a relapse soon after treatment with alemtuzumab will probably be offered alternative treatment which, for severe disease, could include bone marrow transplantation. One clinical specialist noted that, in the trials, the number of people for whom alemtuzumab was no longer effective was small. The Committee concluded that, for some people, alemtuzumab might not provide long-term enduring effect and other treatments might be required.\n\nThe Committee considered the clinical effectiveness of alemtuzumab in people with rapidly evolving severe relapsing-remitting multiple sclerosis or highly active relapsing-remitting multiple sclerosis despite beta interferon treatment, for which the relevant comparators would be natalizumab and fingolimod respectively. The Committee heard from a clinical specialist that alemtuzumab was probably more effective than fingolimod, and probably equally effective to natalizumab. However, compared with natalizumab, alemtuzumab was probably safer in pregnancy and in people testing positive to John Cunningham virus, which can lead to progressive multifocal leukoencephalopathy. The Committee commented that the clinical effectiveness of alemtuzumab in the rapidly evolving severe relapsing-remitting multiple sclerosis or highly active relapsing-remitting multiple sclerosis despite beta interferon treatment subgroups was not robustly demonstrated. It was aware that no trials exist that directly compare alemtuzumab with either natalizumab or fingolimod. The Committee understood that the mixed treatment comparisons required a number of links to compare alemtuzumab with either natalizumab or fingolimod, and that different trials defined the subgroups differently, and both these factors increased uncertainty. The Committee noted that the results of the mixed treatment comparison had shown that alemtuzumab was associated with a lower annualised relapse rate and 3\xa0month sustained accumulation of disability than fingolimod for the subgroup of highly active relapsing-remitting multiple sclerosis despite beta interferon treatment, although these differences were not statistically significant. The Committee also noted that alemtuzumab treatment led to lower annualised relapse rates and lower 6‑month sustained accumulation of disability than natalizumab for the subgroup of rapidly evolving severe relapsing-remitting multiple sclerosis, although the difference was not statistically significant. The Committee noted that the CARE MS-II study comparing alemtuzumab with Rebif (44\xa0micrograms) showed that alemtuzumab had a greater absolute treatment effect on 3‑month sustained accumulation of disability in people with highly active relapsing-remitting multiple sclerosis despite beta interferon treatment than that of fingolimod compared with placebo in the FREEDOM study. The Committee also noted that in the CAMMS223, CARE MS-I and II studies (that compared alemtuzumab with Rebif [44\xa0micrograms]) alemtuzumab had a similar effect on 6‑month sustained accumulation of disability in people with rapidly evolving severe relapsing-remitting multiple sclerosis to that of natalizumab compared with placebo in the AFFIRM study. Acknowledging the uncertainty, the Committee was persuaded that alemtuzumab was at least as effective as fingolimod and natalizumab for people with highly active relapsing-remitting multiple sclerosis despite beta interferon treatment and rapidly evolving severe relapsing-remitting multiple sclerosis respectively.\n\n# Cost effectiveness\n\nThe Committee considered the QALYs accumulated over the course of the modelled time horizon, and the consequences of assuming that people can only move to worse EDSS states (that is, a person's condition can deteriorate or stay the same but not improve) regardless of treatment. The Committee noted that for the full time horizon, a person who received treatment with alemtuzumab would accrue just over 4\xa0QALYs despite accruing 18\xa0life years (see section 3.17). It further noted that the modelled life years for the comparator (Rebif [44\xa0micrograms]) was also much higher than the corresponding number of modelled QALYs. The Committee considered this to be an implausibly low number of QALYs to be accrued by a person with multiple sclerosis over the course of their lifetime. It therefore reasoned that that the original economic model had poor face validity. The manufacturer could not explain the low total lifetime QALY values estimated within the model nor did it explore what might have caused the model to do this. The ERG commented that it was probably because the manufacturer had used the London Ontario data to define the natural history of disease in the absence of disease-modifying therapies, which only allowed a person to progress towards further disability on the EDSS. The Committee heard that the alemtuzumab trial data and other evidence provided by the patient expert and the clinical specialists suggested that people's EDSS states could improve. The Committee was aware that this would considerably affect the number of QALYs accrued by a modelled patient population over a lifetime. The Committee noted that EDSS states of 8 and above were associated with negative utility values, which would reduce lifetime QALYs accrued. The Committee commented that discounting alone was unlikely to explain the low number of lifetime QALYs accrued in the original economic model. The Committee concluded that it is appropriate for the economic modelling to allow patients with relapsing–remitting multiple sclerosis to move to lower as well as to higher EDSS states (that is, to allow for the condition to either improve or get worse) which is in line with what is seen in clinical practice for the lower EDSS states.\n\nThe Committee considered the health-related quality of life data used in the model. The Committee considered that the trials would provide the most appropriate source of quality of life data for the analysis, because the trial population best reflects the population that would receive the treatment if it were available in clinical practice. The Committee was concerned about the manufacturer's initial choice of values to reflect the disutility associated with some of the adverse effects. The clinical specialists agreed that, for example, it is not plausible that a patient with leukocytopenia would have no disutility. The Committee was also aware that a number of deaths were observed in the trials (see section 4.7) and noted that this needed to be reflected in the economic modelling. The Committee understood that in its response to the appraisal consultation document, the manufacturer had pooled EQ-5D-5L utility scores by EDSS state from CARE-MS I and CARE-MS II both at baseline and after 24\xa0months of treatment and had accounted for the deaths observed in the trials in its economic modelling. The manufacturer explained that the difference in mean utility values between baseline and at 24\xa0months in patients with the same EDSS scores did not show improved utility, as might have been expected. The Committee concluded that it is appropriate for the economic modelling to include the deaths observed in the trials and also the trial EQ-5D-5L data (which is more likely to capture the disutility of adverse events associated with alemtuzumab than the manufacturer's original approximations).\n\nThe Committee considered the manufacturer's assumption that the treatment effect from alemtuzumab would persist for many years after the last treatment. The Committee questioned whether a constant treatment effect was biologically plausible. In response, a clinical specialist stated that alemtuzumab permanently modifies a person's immune system, which may be why alemtuzumab's treatment effect might be life‑long. However, the clinical specialist stated that there were no data comparing immune markers in people whose disease does and does not progress after treatment with alemtuzumab. The clinical specialists also commented that the long-term benefit of alemtuzumab is unknown given the absence of long-term data, but that it would be reasonable to assume that alemtuzumab's treatment effect might start to decrease between 3 and 5\xa0years after treatment but that this, too, was uncertain. The Committee concluded that the manufacturer's initial assumption of constant treatment effect throughout the course of a person's multiple sclerosis up to EDSS state 7 or secondary progressive multiple sclerosis was not supported by data, and that the clinical specialists had suggested a maximum of 5\xa0years before waning occurs. The Committee concluded that because of the uncertainty about the long-term treatment effect from alemtuzumab it is appropriate to incorporate a 3- and 5‑year waning effect into the model, and it was satisfied that the manufacturer's revised economic analyses adequately explored the sensitivity of the ICER to several scenarios which assumed that the effectiveness of alemtuzumab and its comparators waned over time.\n\nThe Committee discussed re-treatment with alemtuzumab. It was aware from clinical specialists that, in CARE‑MS\xa0I, CARE‑MS\xa0II and CAMMS233, a further cycle of alemtuzumab was offered to patients if a relapse that lasted for at least 24\xa0hours occurred after the second annual course of infusions. It also heard from clinical specialists that further treatments were considered likely in UK clinical practice. The Committee heard from the clinical specialists that, in the trials, the percentage of people who needed a third course was greater than the percentage who needed a fourth course, and that the trend of fewer people needing successive courses lasted up to 7\xa0years (the median follow-up time for which data were available). The Committee considered that this indicated a time-dependent rate of re-treatment. The Committee concluded that it is appropriate to incorporate the time-dependent rate of re-treatment from the trials in the model and was satisfied that in its response to the Appraisal Consultation Document, the manufacturer had reflected this in its revised economic model.\n\nThe Committee considered the costs included in the economic model for alemtuzumab. The Committee noted that the manufacturer's original economic model included a mid-cycle correction, although alemtuzumab is given at the start of the cycle. The Committee was also concerned that the number of visits to neurologists included in the manufacturer's original economic model for people receiving alemtuzumab was low. Although the ERG increased the number of visits to neurologists (and the additional related costs) to 4 in year\xa01 and 2 in subsequent years, it did not take into account that people receiving 3 or more courses of alemtuzumab treatment would need 4 visits in the first year of restarting treatment. The Committee noted from the ERG exploratory analyses that using alternative health states costs had a large impact on the cost effectiveness of alemtuzumab (see section\xa03.30). The Committee commented that it would have been more appropriate for the manufacturer to incorporate the health state costs used by the ERG in their exploratory analyses (that only included direct 'medical' costs rather than both 'medical' and 'non-medical' costs) because this is more consistent with NICE's preferred methods as presented in its Guide to the methods of technology appraisal. It noted that the manufacturer did not initially include the costs associated with adverse effects of treatment including renal failure, renal transplantation, dialysis and death. The Committee concluded that it was satisfied that the manufacturer's revised analyses adequately addressed and explored all of these uncertainties associated with the costs included in the economic model.\n\nThe Committee discussed the data sources chosen by the manufacturer to reflect the baseline characteristics of patients with relapsing–remitting multiple sclerosis and the natural history of disease progression for patients not taking disease-modifying therapies. The Committee agreed that it was more appropriate for the manufacturer to use trial data to determine the initial EDSS distribution because this was representative of the patient population likely to be treated with alemtuzumab in the UK. The Committee was aware that the manufacturer of alemtuzumab also manufactures teriflunomide and has collected data in the TOWER and TEMSO trials, both of which include groups of patients randomised to placebo. It concluded that this dataset would more accurately reflect the natural history of disease (underlying progression without disease-modifying therapy) in people who would be treated with alemtuzumab in the UK. It concluded that it is appropriate to incorporate the baseline characteristics of patients in the alemtuzumab trials instead of using data from the UK Risk Sharing Scheme, and that it is appropriate to incorporate the rates of disease progression in the placebo group from the TOWER and TEMSO trials to reflect the natural history of the disease.\n\nThe Committee considered the manufacturer's revised base-case results submitted in response to consultation (see section 3.35). It was aware that for the active relapsing–remitting multiple sclerosis population, the manufacturer had incorporated all the Committee's preferred assumptions (see sections 3.33, 4.10–4.12 and 4.15–4.20). The Committee noted that when assuming that the effect of treatment decreased for alemtuzumab and not for the comparators, the ICER for alemtuzumab compared with glatiramer acetate was £24,500 per QALY gained and that if the model assumed that the effectiveness of both alemtuzumab and its comparators waned, the ICER for alemtuzumab compared with glatiramer acetate was £13,600 per QALY gained. The Committee concluded that alemtuzumab could be considered a cost-effective use of NHS resources for treating adults with active relapsing–remitting multiple sclerosis.\n\nThe Committee also considered the manufacturer's revised analyses for the subgroups characterised by highly active relapsing-remitting multiple sclerosis despite beta interferon treatment and rapidly evolving severe relapsing-remitting multiple sclerosis, submitted in response to consultation. The clinical specialists noted that the terms used to describe these subgroups of patients are not generally used in UK clinical practice. The Committee was aware that the manufacturer's mixed treatment comparisons for these subgroups had not generated statistically significantly effects for alemtuzumab compared with the relevant comparator (see section 4.14) and was associated with uncertainty. The Committee heard during consultation from the Association of British Neurologists that it would be impractical to recommend 'a potent drug with significant side effects for patients with modestly active disease but not patients whose future is most threatened by their disease'. The Committee also heard the clinical specialists confirm that it would be clinically counterintuitive to recommend alemtuzumab for the overall active relapsing–remitting multiple sclerosis population, but not recommend it for the highly active relapsing-remitting multiple sclerosis despite beta interferon treatment and the rapidly evolving severe relapsing-remitting multiple sclerosis subgroups for whom the need for treatment options was even greater. The Committee noted that the approach taken by the ERG assumed equal efficacy between alemtuzumab and fingolimod or natalizumab using a midpoint of the hazard ratios for treatment compared with placebo and applied it to the manufacturer's revised economic model. It agreed that this was a pragmatic way to determine the relative clinical and cost effectiveness of alemtuzumab in these subgroups given the uncertainty. The Committee noted that the most plausible ICER for patients with highly active relapsing-remitting multiple sclerosis despite beta interferon treatment was £8900 per QALY gained for alemtuzumab compared with fingolimod. The Committee noted that for patients with rapidly evolving severe relapsing-remitting multiple sclerosis, alemtuzumab dominated natalizumab (that is, less expensive and more effective). The Committee therefore concluded that alemtuzumab could be considered a cost-effective use of NHS resources for people with highly active relapsing-remitting multiple sclerosis despite beta interferon treatment and for people with rapidly evolving severe relapsing-remitting multiple sclerosis.\n\nThe Committee considered the manufacturer's assumptions about when people should receive disease-modifying therapies such as alemtuzumab and how this was incorporated into the manufacturer's economic model. The Committee noted that only patients with active relapsing–remitting multiple sclerosis in an EDSS state of 0 to 7 entered the model and that treatment with alemtuzumab would stop when a patient progresses to EDSS 7 or upon secondary progressive multiple sclerosis. It acknowledged that these assumptions were based on the Association of British Neurologists' guideline for prescribing of disease modifying treatments in multiple sclerosis. The Committee agreed that the manufacturer presented an economic model that supported the use of alemtuzumab in people with active relapsing–remitting multiple sclerosis in an EDSS state less than 7.\n\nThe Committee discussed whether alemtuzumab can be considered an innovative treatment, providing a step change in the treatment of active relapsing–remitting multiple sclerosis and providing benefit not accounted for in the modelling. The Committee heard from the clinical specialists and patient expert that alemtuzumab has been a revolutionary treatment for some people, allowing them to live their lives as they had before being diagnosed with multiple sclerosis. The clinical specialists believed that it was a step change because it delayed disease progression. The Committee noted that alemtuzumab did provide a step change in the treatment of active relapsing–remitting multiple sclerosis. However, the Committee considered that these benefits would already be captured through increased efficacy gains, both in survival gains and in quality of life gains. The Committee therefore concluded that no additional QALY gains should be attributed to alemtuzumab to account for these benefits.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA312\n\nAppraisal title: Alemtuzumab for treating relapsing–remitting multiple sclerosis\n\nSection\n\nKey conclusion\n\nAlemtuzumab is recommended as an option, within its marketing authorisation, for treating highly active relapsing–remitting multiple sclerosis in adults with:\n\nhighly active disease despite a full and adequate course of treatment with at least 1 disease-modifying therapy or\n\nrapidly-evolving severe relapsing-remitting multiple sclerosis defined by 2 or more disabling relapses in 1 year, and with 1 or more gadolinium-enhancing lesions on brain MRI or a significant increase in T2 lesion load compared with a previous MRI.\n\nThe Committee considered the manufacturer's revised base-case results submitted in response to consultation that incorporated all the Committee's preferred assumptions. The Committee concluded that the most plausible ICER for alemtuzumab compared with glatiramer acetate for people with active relapsing-remitting multiple sclerosis is likely to lie between £13,600 and £24,500 per QALY gained, and therefore alemtuzumab could be considered a cost-effective use of NHS resources for treating adults with active relapsing–remitting multiple sclerosis.\n\nThe Committee noted that the most plausible ICER for patients with highly active relapsing-remitting multiple sclerosis despite beta interferon treatment was £8900 per QALY gained for alemtuzumab compared with fingolimod. The Committee noted that for patients with rapidly evolving severe relapsing-remitting multiple sclerosis, alemtuzumab dominated natalizumab (that is, less expensive and more effective).\n\n\n\n\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe Committee was aware that relapsing–remitting multiple sclerosis is a chronic, disabling, neurological condition that, as it progresses, is life altering and has a large negative impact on quality of life. Currently available first-line treatments for active relapsing–remitting multiple sclerosis need to be injected weekly or several times per week and can be associated with unpleasant side effects. The Committee concluded that any delay in relapse and progression of disability or reduction in the frequency of treatment would have a positive impact on the lives of people with multiple sclerosis and their families.\n\nThe Committee heard from the clinical specialists that, while therapies should ideally be offered early in disease, offering treatments later in disease is also important because these patients have a higher risk for more severe complications.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe clinical specialists described advantages, including that it is highly effective, does not cause the flu-like symptoms, and does not need to be discontinued by patients planning a pregnancy, although the Committee was aware that effective contraceptive measures should be taken when receiving alemtuzumab and for 4\xa0months following a course of treatment according to the summary of product characteristics.\n\nThe Committee heard from the clinical specialists and patient expert that alemtuzumab has been a revolutionary treatment for some people, allowing them to live their lives as they had before being diagnosed with multiple sclerosis.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe Committee heard from the clinical specialists that while alemtuzumab's marketing authorisation permits its use as a first-line treatment, it is more likely to be offered to people for whom other disease-modifying treatments have not been effective. One clinical specialist emphasised that alemtuzumab is 'not for everybody', and that clinicians would offer alemtuzumab to patients who, among other characteristics, would be likely to comply with the required monitoring. The Committee concluded that alemtuzumab is a valuable treatment option for selected patients with varying types and stages of active relapsing–remitting multiple sclerosis.\n\n\n\n\n\nAdverse reactions\n\nThe clinical specialists explained that the main disadvantages of alemtuzumab treatment are the possible serious adverse effects, including idiopathic thrombocytopenic purpura, kidney disease or failure, thyroid disease and death. The Committee concluded that alemtuzumab is associated with significant benefits, but also significant harms, that some people with active relapsing–remitting multiple sclerosis are willing to accept the disadvantages of alemtuzumab treatment, and that adhering to the recommended monitoring schedule is important.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe Committee considered the clinical effectiveness of alemtuzumab in the relapsing–remitting multiple sclerosis population in the 3 trials comparing it with Rebif.\n\nThe Committee discussed the manufacturer's mixed treatment comparison comparing alemtuzumab with other disease-modifying treatments.\n\nThe Committee was aware that no trials exist that compare alemtuzumab with either natalizumab or fingolimod.\n\n\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe clinical specialists acknowledged that there was uncertainty regarding the effectiveness of alemtuzumab in the long term, and specifically for periods exceeding the duration of the follow-up studies to the clinical trials. The Committee concluded that for some people alemtuzumab might not provide long-term enduring effect and other treatments might be required.\n\n\n\nUncertainties generated by the evidence\n\nThe Committee concluded that it is more appropriate for the mixed treatment comparison to include all available evidence, and that adjusting for baseline relapse rates accounts for any differences between trials.\n\nThe Committee noted that in CAMMS223 and CARE‑MS\xa0II, the investigators used the per-protocol set to conduct the statistical analyses whereas in CARE‑MS\xa0I the full dataset was analysed, which included some patients who did not meet the specified inclusion criteria or who had not received treatment as specified in the clinical trial protocol. The Committee concluded that it is more appropriate to include the per-protocol analyses set for all 3 trials, adjusted for baseline EDSS states only.\n\nThe Committee commented that alemtuzumab's clinical effectiveness in the subgroups was not robust. It was aware that no trials exist that directly compare alemtuzumab with either natalizumab or fingolimod. The Committee understood that the mixed treatment comparisons required a number of links to compare alemtuzumab with either natalizumab or fingolimod, and that different trials defined the subgroups differently.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nAcknowledging the uncertainty, the Committee was persuaded that alemtuzumab was at least as effective as fingolimod and natalizumab for people with highly active relapsing-remitting multiple sclerosis despite beta interferon treatment and rapidly evolving severe relapsing-remitting multiple sclerosis respectively.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee concluded that alemtuzumab is a clinically effective treatment in reducing relapse rates and has a beneficial impact on sustained accumulation of disability at 6\xa0months compared with Rebif in people with active relapsing–remitting multiple sclerosis.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe Committee considered the manufacturer's revised base-case results submitted in response to consultation. It was aware the manufacturer had incorporated all the Committee's preferred assumptions.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee heard that the alemtuzumab trial data and other evidence suggested that people's EDSS states could improve and concluded that it is appropriate for the economic modelling to allow patients to move to lower as well as to higher EDSS states.\n\nThe Committee considered that the trials provided the most appropriate source of quality of life data because the trial population best reflects the population that would receive the treatment in clinical practice. A number of deaths were observed in the trials and this needed to be reflected in the economic modelling.\n\nThe clinical specialists also commented that the long-term benefit of alemtuzumab is unknown given the absence of long-term data, but that it would be reasonable to assume that alemtuzumab's treatment effect might start to decrease between 3 and 5\xa0years after treatment.\n\nIn the trials a further cycle of alemtuzumab was offered to patients if a relapse that lasted for at least 24 hours occurred after the second annual course of infusions, and the clinical specialists commented that further treatments were considered likely in clinical practice. The Committee concluded that it is appropriate to incorporate the time-dependent rate of re-treatment in the model.\n\nThe Committee concluded that it was more appropriate to remove the mid-cycle correction for the cost of alemtuzumab treatment, increase the number of monitoring and neurology visits to reflect any additional monitoring needed, only include health states costs that are likely to meet the NICE reference case and to include the costs associated with managing adverse effects in the economic modelling.\n\nThe Committee agreed that it was more appropriate for the manufacturer to use trial data to determine the initial EDSS distribution because this was representative of the patient population likely to be treated with alemtuzumab in the UK. The Committee was also aware that the manufacturer of alemtuzumab has collected data in patients randomised to placebo and concluded that this dataset would more accurately reflect the natural history of disease in people who would be treated with alemtuzumab in the UK.\n\n\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe manufacturer pooled EQ-5D-5L utility scores by EDSS state from CARE-MS I and CARE-MS II.\n\nThe Committee noted that alemtuzumab did provide a step change in the treatment of active relapsing–remitting multiple sclerosis. However, these benefits would already be captured through increased efficacy gains, both in survival gains and in quality of life gains.\n\n\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nn/a\n\nn/a\n\nWhat are the key drivers of cost effectiveness?\n\nThe manufacturer's original assumption that the treatment effect from alemtuzumab would persist for many years after the last treatment. The Committee was satisfied that the manufacturer's revised economic analyses adequately explored the sensitivity of the ICER to several scenarios assuming that the effectiveness of alemtuzumab and its comparators waned over time.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe Committee concluded that the most plausible ICER for alemtuzumab compared with glatiramer acetate for people with active relapsing-remitting multiple sclerosis is likely to lie between £13,600 and £24,500 per QALY gained.\n\nThe Committee noted that the most plausible ICER for patients with highly active relapsing-remitting multiple sclerosis despite beta interferon treatment was £8900 per QALY gained for alemtuzumab compared with fingolimod. The Committee noted that for patients with rapidly evolving severe relapsing-remitting multiple sclerosis, alemtuzumab dominated natalizumab (that is, less expensive and more effective).\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nNot applicable\n\nn/a\n\nEnd-of-life considerations\n\nNot applicable\n\nn/a\n\nEqualities considerations and social value judgements\n\nNo relevant equality considerations were raised during scoping or the appraisal.\n\nn/a"}
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https://www.nice.org.uk/guidance/ta312
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Evidence-based recommendations on alemtuzumab (Lemtrada) for treating highly active relapsing–remitting multiple sclerosis in adults.
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bad479151e72f6d5e2f4cf3be395733a829670be
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nice
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Tinnitus: assessment and management
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Tinnitus: assessment and management
This guideline covers the assessment, investigation and management of tinnitus in primary, community and secondary care. It offers advice to healthcare professionals on supporting people presenting with tinnitus and on when to refer for specialist assessment and management.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
The recommendations in this guideline apply to all people (adults, children and young people) with tinnitus unless otherwise stated.
Tinnitus and hearing loss can co-exist. For adults with tinnitus and hearing loss this guideline should be read together with the NICE guideline on hearing loss in adults.
# Support and information for people with tinnitus
## Tinnitus support
At all stages of care:
Discuss with the person with tinnitus, and their family members or carers if appropriate, their experience of tinnitus, including its impact and any concerns.
Based on any identified needs, agree a management plan with the person, taking into account their preferences. The plan should include information about tinnitus and opportunities for discussion about different management options.
Discuss with the person the results of any recent assessments and their impact on the management plan.
With consent from the person or their parent or carer, as appropriate, share the management plan with relevant health, education and social care professionals.
For people with longstanding tinnitus who have delayed accessing care, aim to find out the reason for the delay and why they are accessing care now. This could involve, for example, asking questions about lifestyle factors or changes in health.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on support for people with tinnitus .
Full details of the evidence and the committee's discussion are in evidence review A: tinnitus support.
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## Information
Reassure the person with tinnitus, at first point of contact with a healthcare professional, that:
tinnitus is a common condition
it may resolve by itself
although it is commonly associated with hearing loss, it is not commonly associated with other underlying physical problems
there are a variety of management strategies that help many people live well with tinnitus.
Give information about tinnitus at all stages of care. The content should be tailored to the individual needs of the person, and their family members or carers if appropriate, and include information about:
what tinnitus is, what might have caused it, what might happen in the future
what can make tinnitus worse (for example, stress or exposure to loud noise)
safe listening practices (for example, noise protection)
the impact of tinnitus (for example, it can affect sleep, see the section on assessing how tinnitus affects sleep)
see investigations
self-help and coping strategies (for example, self-help books and relaxation strategies)
management options (see the section on management of tinnitus)
local and national support groups
-ther sources of information.
When providing information:
ensure it is available in appropriate formats such as verbal consultation, written information, leaflets and online in line with the NICE guideline on patient experience
take into account accessibility requirements for children, and people with hearing loss, cognitive impairment or visual impairment.
For a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on information for people with tinnitus .
Full details of the evidence and the committee's discussion are in evidence review B: patient information.
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# Referring people with tinnitus
Refer immediately to a crisis mental health management team for assessment people who have tinnitus associated with a high risk of suicide. If needed, provide a safe place while waiting for the assessment.
Refer immediately, in line with the NICE guideline on suspected neurological conditions, people with tinnitus associated with:
sudden onset of significant neurological symptoms or signs (for example, facial weakness), or
acute uncontrolled vestibular symptoms (for example, vertigo), or
suspected stroke (follow a local stroke referral pathway). For information about diagnosis and initial management of stroke, see the NICE guideline on stroke and transient ischaemic attack in over 16s.
Refer people to be seen within 24 hours, in line with the NICE guideline on hearing loss in adults, if they have tinnitus and have hearing loss that has developed suddenly (over a period of 3 days or less) in the past 30 days.
Recognise that assessment and management of the person's tinnitus may still need to continue following an immediate referral.
Refer people to be seen within 2 weeks for assessment and management if they have tinnitus associated with either of the following:
Distress affecting mental wellbeing (for example, distress that prevents them carrying out their usual daily activities) even after receiving tinnitus support at first point of contact with a healthcare professional (see the recommendation on all stages of care in tinnitus support). Refer in line with local pathways.
Hearing loss that developed suddenly more than 30 days ago or rapidly worsening hearing loss (over a period of 4 to 90 days). Refer in line with the NICE guideline on hearing loss in adults.
Refer people for tinnitus assessment and management in line with local pathways if they have any of the following:
tinnitus that bothers them despite having received tinnitus support at first point of contact with a healthcare professional (see the recommendation on all stages of care in tinnitus support)
persistent objective tinnitus
tinnitus associated with unilateral or asymmetric hearing loss.
Consider referring people for tinnitus assessment and management in line with local pathways if they have any of the following, in line with the NICE guideline on hearing loss in adults:
persistent pulsatile tinnitus
persistent unilateral tinnitus.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on referring people with tinnitus .
Full details of the evidence and the committee's discussion are in evidence reviews C-D: symptoms and features for urgent and non-urgent referral.
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# Assessing the impact of tinnitus using questionnaires
Consider using the Tinnitus Functional Index for adults to assess how tinnitus affects them.
If questionnaires cannot be used (for example, because of language issues or cognitive impairment) consider using other measures such as visual analogue scales.
Consider using an age- or ability-appropriate measure (such as a visual analogue scale) for children and young people to assess how tinnitus affects them.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on assessing tinnitus using questionnaires .
Full details of the evidence and the committee's discussion are in evidence review E: questionnaires to assess tinnitus.
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## Assessing how tinnitus affects quality of life
Discuss with the person with tinnitus, and their family members or carers if appropriate, how the condition affects their quality of life (home, social, leisure, work and school).
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on assessing how tinnitus affects quality of life .
Full details of the evidence and the committee's discussion are in evidence review G: assessing quality of life.
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## Assessing how tinnitus affects sleep
Ask people with tinnitus if they have problems sleeping because of tinnitus. If they do, consider screening with a questionnaire (such as the Insomnia Severity Index). Discuss the results with them and how this might inform their management plan.
For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on assessing sleep .
Full details of the evidence and the committee's discussion are in evidence review F: assessing psychological impact.
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## Assessing the psychological impact of tinnitus
Be alert at all stages of care to the impact of tinnitus on mental health and wellbeing in adults. If there are concerns, follow the recommendations in the NICE guideline on common mental health problems.
Consider using the tinnitus questionnaire (TQ) or mini-TQ alongside the Tinnitus Functional Index in adults with tinnitus if further assessment of the psychological effects of tinnitus is needed.
If there are concerns about depression or anxiety in adults, a healthcare professional competent in mental health assessment should:
carry out an assessment using a questionnaire (for example, those in the recommendations on assessment in the NICE guideline on common mental health problems), or an ability-appropriate measure
consider assessment using the Clinical Outcomes in Routine Evaluation – Outcome Measure
agree an action plan, if needed, in line with the recommendations on assessment in the NICE guideline on common mental health problems.
Be alert at all stages of care to the behavioural and psychological wellbeing of all children and young people presenting with tinnitus. Talk to them, and their family members or carers if appropriate, about how they feel.
If there are concerns about depression in children and young people, follow the recommendations in the NICE guideline on depression in children and young people.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on assessing the psychological impact of tinnitus .
Full details of the evidence and the committee's discussion are in evidence review F: assessing psychological impact.
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# Investigations
## Audiological assessment
Offer an audiological assessment to people with tinnitus. For recommendations on assessing and managing hearing loss in adults, see the NICE guideline on hearing loss in adults.
Consider tympanometry when middle-ear or Eustachian tube dysfunction, or other causes of conductive hearing loss contributing to tinnitus, are suspected.
Do not offer acoustic reflex testing or uncomfortable loudness levels/loudness discomfort levels testing as part of an investigation of tinnitus.
Do not offer otoacoustic emissions tests as part of an investigation of tinnitus unless the tinnitus is accompanied by other symptoms and signs.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on audiological assessment .
Full details of the evidence and the committee's discussion are in evidence review H: audiological assessment.
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## Psychoacoustic tests
Do not offer psychoacoustic tests, for example pitch and loudness matching, to assess tinnitus.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on psychoacoustic tests .
Full details of the evidence and the committee's discussion are in evidence review I: psychoacoustic measures.
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## Imaging
Offer MRI of internal auditory meati (IAM) to people with non-pulsatile tinnitus who have associated neurological, otological or head and neck signs and symptoms. If they are unable to have MRI (IAM), offer contrast-enhanced CT (IAM).
Consider MRI (IAM) for people with unilateral or asymmetrical non-pulsatile tinnitus who have no associated neurological, audiological, otological or head and neck signs and symptoms. If they are unable to have MRI (IAM), consider contrast-enhanced CT (IAM).
Do not offer imaging to people with symmetrical non-pulsatile tinnitus with no associated neurological, audiological, otological or head and neck signs and symptoms.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on non-pulsatile tinnitus .
Full details of the evidence and the committee's discussion are in evidence review J: imaging to investigate the cause of non-pulsatile tinnitus.
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Offer imaging to people with pulsatile tinnitus.
For people with synchronous pulsatile tinnitus, consider:
magnetic resonance angiogram or MRI of head, neck, temporal bone and IAM if clinical examination and audiological assessment are normal, or contrast-enhanced CT of head, neck, temporal bone and IAM if they cannot have magnetic resonance angiogram or MRI
contrast-enhanced CT of temporal bone if an osseous or middle-ear abnormality is suspected (for example, glomus tumour), followed by MRI if further investigation of soft tissue is required.
For people with non-synchronous pulsatile tinnitus (for example, caused by palatal myoclonus) consider MRI of the head, or if they cannot have MRI, contrast-enhanced CT of the head.
For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on pulsatile tinnitus .
Full details of the evidence and the committee's discussion are in evidence review K: imaging to investigate the cause of pulsatile tinnitus.
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# Management of tinnitus
## Amplification devices
Offer amplification devices to people with tinnitus who have a hearing loss that affects their ability to communicate. For adults, follow the recommendations on hearing aids in the NICE guideline on hearing loss in adults.
Consider amplification devices for people with tinnitus who have a hearing loss but do not have difficulties communicating.
Do not offer amplification devices to people with tinnitus but no hearing loss.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on amplification devices .
Full details of the evidence and the committee's discussion are in evidence review M: sound therapy and amplification devices.
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## Sound therapy
The committee were unable to make recommendations for practice in this area. They made a recommendation for research.
For a short explanation of why the committee made the recommendation for research, see the rationale section on sound therapy .
Full details of the evidence and the committee's discussion are in evidence review M: sound therapy and amplification devices.
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## Psychological therapies for people with tinnitus-related distress
Consider a stepped approach to treat tinnitus-related distress in adults whose tinnitus is still causing an impact on their emotional and social wellbeing, and day-to-day activities, despite having received tinnitus support. If a person does not benefit from the first psychological intervention they try or declines an intervention, offer an intervention from the next step in the following order:
digital tinnitus-related cognitive behavioural therapy (CBT) provided by psychologists
group-based tinnitus-related psychological interventions including mindfulness-based cognitive therapy (delivered by appropriately trained and supervised practitioners), acceptance and commitment therapy or CBT (delivered by psychologists)
individual tinnitus-related CBT (delivered by psychologists).
For a short explanation of why the committee made the recommendation and how it might affect practice, see the rationale and impact section on psychological therapies for people with tinnitus-related distress .
Full details of the evidence and the committee's discussion are in evidence review L: psychological therapies.
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## Betahistine
Do not offer betahistine to treat tinnitus.
For a short explanation of why the committee made the recommendation and how it might affect practice, see the rationale and impact section on betahistine .
Full details of the evidence and the committee's discussion are in evidence review N: betahistine.
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## Combining therapies
The committee were unable to make recommendations for practice in this area. They made a recommendation for research.
For a short explanation of why the committee made the recommendation for research, see the rationale section on combining therapies .
Full details of the evidence and the committee's discussion are in evidence review P: combinations of management strategies.
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## Neuromodulation
The committee were unable to make recommendations for practice in this area. They made a recommendation for research.
For a short explanation of why the committee made the recommendation for research, see the rationale section on neuromodulation .
Full details of the evidence and the committee's discussion are in evidence review O: neuromodulation.
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# Terms used in this guideline
This section defines terms that have been used in a particular way for this guideline.
## Digital tinnitus-related cognitive behavioural therapy
Digital CBT is a form of CBT delivered using digital technology, such as a computer, tablet or phone. Common components of digital tinnitus-related CBT are similar to those used in face-to-face CBT (for example, positive imagery and learning to identify and challenge unhelpful thoughts). People using digital CBT are more likely to have less direct contact with healthcare professionals during the intervention compared with face-to-face interventions.
## Objective tinnitus
Tinnitus that occurs as a result of noise generated in the ear that can be detected by the examiner. It is less common than subjective tinnitus.
## Refer immediately
To be seen by the specialist service within a few hours, or even more quickly if necessary.
## Tinnitus-related distress
Tinnitus that is having an impact on emotional and social wellbeing and day-to-day activities.
## Tinnitus support
A term used to describe a session that includes a 2-way process of information-giving and discussion to help the healthcare professional understand the difficulties and goals of the person with tinnitus. This discussion occurs between the person with tinnitus, and their family members or carers if appropriate, and the healthcare professional. A management plan is also jointly developed and the person is supported to continue with the plan or modify it as necessary. This process is sometimes known as tinnitus counselling.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Key recommendations for research
## Cognitive behavioural therapy for adults with tinnitus delivered by appropriately trained healthcare professionals other than psychologists
What is the clinical and cost effectiveness of cognitive behavioural therapy (CBT) for adults with tinnitus delivered by appropriately trained healthcare professionals other than psychologists (for example, audiologists)?
For a short explanation of why the committee made the recommendation for research, see the rationale and impact section on CBT for adults delivered by appropriately trained healthcare professionals .
Full details of the research recommendation are in evidence review L: psychological therapies.
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## Combination management strategy: sound therapy and tinnitus support
What is the clinical and cost effectiveness of a combination management strategy consisting of sound therapy and tinnitus support?
For a short explanation of why the committee made the recommendation for research, see the rationale section on combination management strategy .
Full details of the research recommendation are in evidence review P: combinations of management strategies.
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## Methods for assessing tinnitus in general practice
What is the optimal method for assessing tinnitus in general practice (including consultation questions, physical examinations and questionnaires)?
For a short explanation of why the committee made the recommendation for research, see the rationale and impact section on assessing tinnitus in general practice .
Full details of the research recommendation are in evidence review E: questionnaires to assess tinnitus.
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## Neuromodulation
What is the clinical, cost effectiveness and safety of neuromodulation interventions for treating tinnitus in adults?
For a short explanation of why the committee made the recommendation for research, see the rationale section on neuromodulation interventions .
Full details of the research recommendation are in evidence review O: neuromodulation.
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## Psychological therapies for children and young people
What is the clinical and cost effectiveness of psychological therapies for children and young people who have tinnitus-related distress?
For a short explanation of why the committee made the recommendation for research, see the rationale and impact section on psychological therapies for children and young people .
Full details of the research recommendation are in evidence review L: psychological therapies.
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# Other recommendations for research
## Tinnitus questionnaires for children and young people
What is the most clinically and cost-effective tinnitus questionnaire to assess tinnitus in children and young people?
Full details of the research recommendation are in evidence review E: questionnaires to assess tinnitus.
## Tinnitus questionnaires for people with a learning disability or cognitive impairment
What is the most clinically and cost-effective tinnitus questionnaire to assess tinnitus in people with a learning disability or cognitive impairment?
Full details of the research recommendation are in evidence review E: questionnaires to assess tinnitus.
## Tinnitus questionnaires for people who are d/Deaf or who have a severe-to-profound hearing loss
What is the most clinically and cost-effective tinnitus questionnaire to assess tinnitus in people who are d/Deaf or who have a severe-to-profound hearing loss?
Full details of the research recommendation are in evidence review E: questionnaires to assess tinnitus.
## Relaxation strategies for children, young people and adults
Are relaxation strategies clinically and cost effective for the management of tinnitus for children, young people and adults?
Full details of the research recommendation are in evidence review A: tinnitus support.
## Amplification devices for people who are d/Deaf or who have a severe-to-profound hearing loss
What is the clinical and cost effectiveness of amplification devices for people who are d/Deaf or who have a severe-to-profound hearing loss?
Full details of the research recommendation are in evidence review M: sound therapy and amplification devices.
## Psychological therapies for people who are d/Deaf or who have a severe-to-profound hearing loss
What is the clinical and cost effectiveness of psychological therapies for people who are d/Deaf or who have a severe-to-profound hearing loss and tinnitus-related distress?
Full details of the research recommendation are in evidence review L: psychological therapies.
## Amplification devices for people with tinnitus who have hearing loss but no perceived hearing difficulties
What is the clinical and cost effectiveness of fitting amplification devices(s) in people with tinnitus who have hearing loss but no perceived hearing difficulties?
Full details of the research recommendation are in evidence review M: sound therapy and amplification devices.# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.
# Support for people with tinnitus
Recommendations 1.1.1 and 1.1.2
## Why the committee made the recommendations
'Tinnitus support' was defined by the committee as a 2-way process of information giving and discussion to help the healthcare professional understand the difficulties and goals of the person with tinnitus. The evidence showed that similar interventions such as 'education counselling' gave some benefit in improving outcomes for people with tinnitus. Although the evidence was limited, the committee agreed that providing support to people with tinnitus and their family members or carers is essential, and ensures that the person's needs and preferences are taken into account. The committee recognised that the needs and concerns of children and young people with tinnitus can be different to those of their parents or carers, but these should be addressed, and appropriate support offered, for both groups.
The committee agreed that there should be a discussion between the healthcare professional and person with tinnitus about the results of recent assessments and their impact on their management plan. This will give the person the opportunity to ask questions and actively participate in the development of the plan. Sharing the management plan with the relevant health, education and social care professionals will help to further support the person with tinnitus.
It is important that healthcare professionals understand why people with longstanding tinnitus are accessing care at that point of contact, as this can inform the person's management plan. Asking the person prompting questions about lifestyle factors (for example, stress or change in mental wellbeing) or changes in health (for example, hearing loss) can help with this. The committee noted that tinnitus and its impact can change over time. Where tinnitus is troublesome, it can be helpful to review the factors affecting tinnitus and its impact, as the management plan may need to be revised. The committee acknowledged that in current practice the term 'tinnitus counselling' is used to describe a management strategy that may include elements of 'tinnitus support'.
The committee decided to not use the term 'tinnitus counselling' to describe this management strategy as there is inconsistency in how the term is used in current practice. For some healthcare professionals it can be a brief clinician-led talk with the intent to reassure that there is no significant pathology. Alternatively, it can be a longer interactive session focusing on the worries and concerns of the person with tinnitus. The committee's intention is for a standardised and improved level of care to be available to people with tinnitus, across the country, from the first point of contact with the healthcare system.
The committee also looked at evidence on relaxation strategies, although the amount of evidence was limited. They noted that the use of relaxation strategies for managing tinnitus is widespread but the strategies are insufficiently researched. Consequently, they made a research recommendation to assess relaxation strategies for the management of tinnitus.
## How the recommendations might affect practice
There is variation in how support for people with tinnitus is defined, what it should include, and how and when it is delivered. Implementing these recommendations should reduce this variation.
Return to recommendations
# Information for people with tinnitus
Recommendations 1.1.3 to 1.1.5
## Why the committee made the recommendations
There was limited evidence on what information should be provided to people with tinnitus, their family members and carers. However, the committee noted that patient information is an essential element of patient care in the NHS and should be provided at first point of contact with a healthcare professional.
The information should be tailored to individual needs to ensure that it is suitable and effective in informing the person's management plan. Where people with tinnitus encounter clinicians that tell them that nothing can be done and they have to live with it, this may worsen a person's perception of tinnitus and may impact on their mental wellbeing. A clinician's lack of awareness of the impact of tinnitus may also create barriers for onward referral. Therefore, the committee agreed it is important for clinicians to reassure people that tinnitus is common, and although it is commonly associated with hearing loss, it is not usually associated with an underlying physical health problem. In addition, many people find management strategies to help them live well with tinnitus.
Appropriate information provided in a timely manner to people first presenting with tinnitus will reduce distress and the likelihood of symptoms becoming debilitating. The information should take into account accessibility requirements – for example, be at the appropriate cognitive and linguistic level for children, and be in a suitable format for people who use British Sign Language or who have a visual or cognitive impairment.
## How the recommendations might affect practice
There is variation in the level of information provided to people with tinnitus, and in the content and format of the information. Implementing the recommendations should reduce this variation.
Return to recommendations
# Referring people with tinnitus
Recommendations 1.2.1 to 1.2.7
## Why the committee made the recommendations
No evidence was identified on which symptoms and features should warrant investigation or management. In the absence of evidence, the committee agreed that after clinical history and physical examinations, there are various symptoms and features associated with tinnitus that should prompt an immediate referral (to be seen within a few hours or even more quickly if necessary), referral to be seen within 24 hours, referral to be seen within 2 weeks, or non-urgent referral.
The categorisation of these symptoms and features is dependent on the potential consequence of not referring. For example, people who present to general practice with tinnitus and symptoms and features that include a high risk of suicide (for example, suicidal thoughts with an intended plan) should be referred to a crisis mental health management team immediately for assessment to preserve life. People presenting with tinnitus associated with a sudden onset of neurological symptoms should be seen within a few hours or more quickly if necessary after referral, as not referring can be life-threatening and increase morbidity.
The committee noted that it is important to recognise that assessment and management for tinnitus may still need to continue following immediate onward referral for other co-morbidities (for example, suspected stroke).
Immediate referrals should be made to ensure that underlying neurological causes can be diagnosed, and any treatment received, quickly. The treatment is then more likely to be successful. Two-week referrals should be made for people with tinnitus who have distress that is limiting daily activities, such as not being able to leave their house or not being able to go to work. The committee noted that this is a small subpopulation of people with tinnitus.
The committee agreed that the impact of tinnitus on a person's wellbeing and mental health is a critical component of any assessment of symptoms and features in all settings – for example, primary, community and secondary care. Providing tinnitus support for people after symptoms and features have been assessed can help reduce the impact of tinnitus on their mental health and any distress that limits their daily activities. If mental health concerns persist after this, referrals should be made.
The committee decided to not recommend specific referral locations because of variation in current practice and in tinnitus pathways in the UK. Common referral locations include audiology and ear, nose and throat services.
The categories of urgency and the timings for hearing loss associated with tinnitus are aligned with those in the NICE guideline on hearing loss in adults. The recommendations for referrals for persistent pulsatile tinnitus and persistent unilateral tinnitus were made in line with the NICE guideline on hearing loss in adults. However the committee noted that these types of tinnitus can be associated with vascular or neurological abnormalities. Onward referral for further investigations to detect these abnormalities may prevent the development of significant pathologies such as vestibular schwannoma.
The committee noted that children should be seen in a paediatric environment by healthcare professionals used to managing the needs of children and working in the children's support services (health, education and social care). In the absence of relevant specific guidelines for children, they also agreed that it was appropriate for the referral recommendations from the NICE guidelines on hearing loss in adults and stroke and transient ischaemic attack in over 16s to apply to children and young people as well as adults. The committee believed that the same clinical manifestations will be considered for referrals, regardless of age.
## How the recommendations might affect practice
These recommendations do not aim to change the number of referrals made but rather encourage more timely referrals. Services may need to change their protocols to accommodate 2‑week referrals. These timely referrals will improve patient safety and the appropriate implementation of treatment or management strategies. Timely and appropriate intervention will reduce distress and repeated requests or referrals for tinnitus support.
Return to recommendations
# Assessing the impact of tinnitus using questionnaires
Recommendations 1.3.1 to 1.3.3
## Why the committee made the recommendations
No evidence was identified on the clinical effectiveness of questionnaires used to assess the impact of tinnitus on a person. Questionnaires are not a substitute for a detailed clinical history. However, the committee noted the importance of using questionnaires and age-appropriate measures for assessment, which can help to inform management.
Questionnaires can provide a structured format for identifying and subjectively rating difficulties that a person with tinnitus may have. Areas that need intervention can be identified and changes that occurred as a result of the intervention can be measured. This information can be used on an individual level, and on a service level, to help ensure that appropriate resources are available.
A range of questionnaires are currently used to assess the impact of tinnitus in services across England. However, the questionnaires are typically designed to look at specific groups of people with tinnitus or specific problems associated with tinnitus. Therefore, their components may not reflect the range of needs of everyone with tinnitus. Most of the questionnaires are not designed to take account of change after intervention.
In the absence of evidence, the committee agreed that the most appropriate questionnaire that should be considered is the Tinnitus Functional Index. This provides the broadest assessment of the impact of tinnitus and incorporates a variety of components. It was also specifically designed to measure change.
The committee noted that questionnaires are not commonly used in general practice and there is also variation in how tinnitus is assessed in primary care. They thought it important that research is conducted to examine the optimal method for assessing tinnitus in general practice settings, as general practice is a gatekeeper for the further management of tinnitus (see research recommendation 3).
The committee agreed that it is crucial for healthcare professionals to discuss the results of assessments with the person. When answers to component questions are discussed with them, rather than solely focusing on overall scores, it can help people to fully engage with the management of their condition. In addition, using assessment methods such as questionnaires before and after an intervention can further inform management plans.
The committee agreed that if questionnaires cannot be used, visual analogue scales can be used to assess the impact of tinnitus. The committee noted that there are 2 types of questions in visual analogue scales that can be useful: how much does your tinnitus bother you and how much does the tinnitus interfere with what you do?
## How the recommendations might affect practice
A variety of methods are used in the UK to assess the impact of tinnitus, particularly with the use of different tinnitus questionnaires. Implementing the use of a common core questionnaire to assess tinnitus will lead to the standardisation of care across the UK and encourage best practice. It will also improve individual care if the components of the questionnaire are used meaningfully as part of the discussion about tinnitus and to signpost towards appropriate support.
As the questionnaires are expected to be completed outside the consultation room, there are little or no anticipated cost implications. Some resource time would be needed to discuss the results of the questionnaires with the person. But the committee noted that even in the absence of a questionnaire, a comprehensive assessment would require a clinician to ask about the topics covered in the questionnaire.
Return to recommendations
# Assessing how tinnitus affects quality of life
Recommendation 1.3.4
## Why the committee made the recommendation
No evidence was identified that evaluated the clinical effectiveness of questionnaires and interviews to assess quality of life in people with tinnitus. Questionnaires such as the Tinnitus Functional Index, which provide an overall assessment of tinnitus, include questions on assessing the impact of tinnitus on quality of life (for example, enjoyment of social activities and relationships with family and friends). The committee took this into account, together with the fact that quality-of-life questionnaires are not commonly used in current practice. They agreed that it was not necessary to recommend an additional questionnaire.
In clinical practice it is often when quality of life is affected that people with tinnitus seek help. The committee agreed, that as part of tinnitus support and clinical history taking, a discussion with the person is more useful than a questionnaire for understanding their experiences with tinnitus and its impact on their quality of life in different settings (such as home, social, leisure, work and school). These discussions could then inform their management plan.
## How the recommendation might affect practice
Implementing the recommendation will standardise clinical practice and encourage best practice. Additionally, it will help to increase the recognition of tinnitus-related difficulties and improve subsequent tinnitus management. There are no anticipated cost implications for implementing this recommendation.
Return to recommendations
# Assessing sleep and the psychological impact of tinnitus
Recommendations 1.3.5 to 1.3.10
## Why the committee made the recommendations
Insomnia is common in people with tinnitus, and this can have a psychological impact. The committee agreed that healthcare professionals should ask people with tinnitus if they have problems sleeping. In the absence of evidence evaluating questionnaires to assess the impact of tinnitus on sleep the committee recommended that an assessment using a questionnaire such as the Insomnia Severity Index could be useful when developing a management plan. The committee acknowledged that the Insomnia Severity Index is not commonly used in current practice but it is an appropriate measure and is freely available and easy to use. The questionnaire can also be used as a screening tool which can lead to a referral.
No evidence was identified that evaluated the clinical or cost effectiveness of questionnaires to assess the psychological impact of tinnitus. Tinnitus can cause depression or anxiety and can be exacerbated by depression or anxiety, leading to distress. This depression or anxiety sometimes needs to be treated before the person can begin to cope with tinnitus, to lessen the distress. Therefore, it is important to ask everyone if they feel anxious or depressed, in addition to asking about tinnitus.
In the absence of evidence, the committee agreed that the commonly used tinnitus questionnaire (TQ) and mini-TQ are appropriate questionnaires to use to further assess the psychological impact of tinnitus. The committee agreed that healthcare professionals should be alert to symptoms and signs of depression and anxiety, asking prompting questions as recommended in the NICE guideline on common mental health problems. Although the guideline is not specific to people with tinnitus, the committee agreed that healthcare professionals should refer to this guideline in the absence of any evidence for questionnaires that can be used to assess the psychological impact of tinnitus. The questionnaires recommended in the NICE guideline on common mental health problems are mainly used in mental health settings, but they can also be used in other services such as audiology. The committee agreed that although no evidence was identified that assessed the use of Clinical Outcomes in Routine Evaluation - Outcome Measure, it is particularly useful for assessing the psychological impact of tinnitus, where indications of depression and anxiety may be more subtle.
Depression in children and young people should be assessed and managed in line with the NICE guideline on depression in children and young people.
## How the recommendations might affect practice
The recommendations will standardise clinical practice in the UK and enhance patient safety. They will also increase the number of people with tinnitus who have assessments of their psychological wellbeing. Consequently, more people with depression and anxiety will have their condition managed appropriately. There are no anticipated cost implications for implementing these recommendations because these questionnaires are expected to be completed before the person enters the consultation room and interacts with the relevant clinician.
Return to recommendations
# Audiological assessment
Recommendations 1.4.1 to 1.4.4
## Why the committee made the recommendations
No clinical evidence was identified on audiological assessments for people with tinnitus. Tinnitus may co-exist with hearing loss, and some people with tinnitus may not be aware that they also have hearing loss. The hearing loss may have been gradual and some people may even attribute their hearing difficulties to their tinnitus. Therefore, the committee strongly believed that everyone referred to audiological, ear, nose and throat or audiovestibular medicine services should receive audiological assessments as a minimum to establish any hearing problems and to inform a management plan. Audiological assessments may need to be modified according to the person's age, level of development and cognitive ability.
Effective management of a hearing loss can reduce the audibility and impact of the tinnitus. The committee agreed that when middle-ear or Eustachian tube dysfunction or other causes of a conductive hearing loss are suspected, tympanometry should be considered. Tympanometry is a helpful supporting test in the assessment of hearing loss to help identify the nature of that hearing loss.
The committee agreed that, from their experiences, acoustic reflex testing and uncomfortable loudness levels/loudness discomfort levels (ULL/LDL) tests can be unnecessary, unpleasant and potentially harmful. They may exacerbate a person's tinnitus and increase distress. The results of these tests would not affect a person's management plan as the main focus of tinnitus management is to lessen the distress associated with tinnitus. The committee recognised that ULL tests can be useful for other purposes (for example, fitting hearing aids), but noted that they should be used with caution.
In addition, from the committee's experiences, it was agreed that although otoacoustic emissions tests are not unpleasant or harmful, the results are unlikely to affect a person's management plan. They should only be offered if tinnitus is accompanied by other symptoms and signs (for example, mild hearing loss or hearing being monitored for people on ototoxic medication).
## How the recommendations might affect practice
The committee thought that there would be little impact on practice as most healthcare professionals routinely use hearing assessments to establish hearing thresholds in people with tinnitus. Therefore, there would be no additional resource impact as a result of the recommendation on audiology assessment. Many also currently use tympanometry when needed, so this will not change current practice for most.
Some centres may be using acoustic reflexes, ULL/LDL tests and otoacoustic emissions routinely, and therefore stopping these may be a change to their practice and could result in modest cost savings.
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# Psychoacoustic tests
Recommendation 1.4.5
## Why the committee made the recommendation
No clinical evidence was identified on psychoacoustic tests, for example pitch and loudness matching, for people with tinnitus. The committee thought that undertaking psychoacoustic testing in addition to hearing assessments may increase distress for some and encourage people to focus on their tinnitus more. Continued focus on tinnitus can prevent a person from habituating to it. Many management strategies involve taking away the focus from tinnitus, and so psychoacoustic testing may counteract their effectiveness.
Psychoacoustic testing is mainly used as a tool in research rather than in clinical practice as the outcome of the test has no influence on the routine management of tinnitus. In addition, this testing was thought to carry an additional cost in terms of staff time, with little or no additional benefit, and even the potential for some harm. Therefore the committee agreed that it should not be used.
## How the recommendation might affect practice
The recommendation reflects current best practice where psychoacoustic measures are not commonly used. However, as some departments may be using this test, implementing the recommendation will mean that some staff time, otherwise spent on the tests, will be freed up.
These tests are not commonly used for children and therefore there will be no change in current practice for paediatric services.
Return to recommendations
# Imaging to investigate the cause of non-pulsatile tinnitus
Recommendations 1.4.6 to 1.4.8
## Why the committee made the recommendations
No evidence was identified on imaging to investigate the cause of non-pulsatile tinnitus. However, the committee agreed that scanning people with non-pulsatile tinnitus that is accompanied by neurological or head and neck signs and symptoms (for example, facial weakness, vertigo and asymmetric hearing loss) is best clinical practice. It is also important for detecting significant and potentially life-threatening central pathology, such as vestibular schwannoma compressing adjacent structures or brain tumours. Additionally, imaging people with non-pulsatile tinnitus can detect vascular arteriovenous malformations, which can also be life-threatening.
Imaging should also be considered where there is unilateral or asymmetrical non-pulsatile tinnitus without accompanying signs and symptoms, as it is more likely to be associated with an underlying significant pathology compared with symmetrical tinnitus. The committee agreed that no imaging should be conducted for bilateral non-pulsatile tinnitus in the absence of any associated signs and symptoms because the incidence of underlying pathology is very low.
MRI is more clinically effective at showing soft tissue structures and pathology than contrast-enhanced CT. In addition, CT scanning is associated with more harm than MRI because of risks from the radiation dose and the potential for adverse reaction to the contrast media. Therefore, the committee recommended MRI as the first choice. The committee noted that MRI is loud and some people may find that this noise affects their tinnitus. Radiology departments provide earplugs to help with this.
## How the recommendations might affect practice
The committee thought that, in current practice, some people with non-pulsatile unilateral tinnitus were being over tested (particularly for isolated bilateral non-pulsatile tinnitus), without proper assessment of neurological signs and symptoms beforehand. These recommendations will help to standardise clinical practice and encourage good clinical practice. They will also reassure clinicians and people with tinnitus that a scan may not always be necessary. There is the potential for some cost savings as the volume of unnecessary imaging is reduced.
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# Imaging to investigate the cause of pulsatile tinnitus
Recommendation 1.4.9
## Why the committee made the recommendation
No evidence was identified on imaging to investigate the cause of pulsatile tinnitus, so the committee used their knowledge and expertise to make a recommendation.
Scans are recommended on the basis of clinical manifestations and the ability of the scanning method to accurately detect pathology. Pulsatile tinnitus can have several different causes, some of which are serious. Possible causes include irregular blood vessels, high blood pressure, raised intracranial pressure, anaemia, atherosclerosis, paragangliomas, osseous pathology and glomus tumours. The underlying cause of the pulsatile tinnitus can be targeted for treatment, depending on the results of the scans.
MRI is more clinically effective at showing soft tissue structures and pathology than contrast-enhanced CT whereas CT is more effective at detecting osseous changes. CT scanning is associated with risks from the radiation dose and the potential for adverse reaction to the contrast media. Therefore, the committee recommended MRI as the first choice. The committee noted that MRI is loud and some people may find that this noise affects their tinnitus. Radiology departments provide earplugs to help with this.
## How the recommendation might affect practice
When investigating synchronous pulsatile tinnitus, it is current practice to carry out imaging of the ears, head and neck, but there is no consensus about whether an MRI or magnetic resonance angiogram or a CT scan with contrast is best. This recommendation aims to standardise and improve current practice.
When investigating non-synchronous pulsatile tinnitus, it is current practice to perform an MRI where other conditions, such as palatal myoclonus, are suspected to be the cause of tinnitus.
By directing clinicians to the most appropriate scanning method, there is a potential for some cost savings by reducing the unnecessary use of more expensive imaging techniques.
Return to recommendations
# Amplification devices
Recommendations 1.5.1 to 1.5.3
## Why the committee made the recommendations
There was limited evidence on using amplification devices for managing tinnitus. The committee noted that many people present with tinnitus without realising that they have a hearing loss. The committee agreed that adults with tinnitus and a hearing loss that affects their ability to communicate and hear should be offered an amplification device in line with the NICE guideline on hearing loss in adults. They agreed that in similar circumstances children and young people should also be offered an amplification device.
There was no evidence to support the use of amplification devices for people with tinnitus and a hearing loss that does not cause difficulties communicating. However, given that enhancing auditory input may improve the person's perception of tinnitus, the committee recommended that amplification devices be considered.
The committee recommended that people without a hearing loss should not be offered amplification devices as amplified sound may induce a hearing loss.
## How the recommendations might affect practice
Offering amplification devices to people with tinnitus and hearing loss that affects their ability to communicate is in line with current practice and many organisations will not need to change practice.
There is variation in practice on the use of amplification devices for people with tinnitus and hearing loss that does not cause difficulties in communicating, and some change in practice may be needed. Organisations may need to adapt their protocols to match the recommendations. Rarely people are offered hearing aids for tinnitus when they do not have a hearing loss. Amplification devices should not be offered in these situations and a small cost saving may be made.
Return to recommendations
# Sound therapy
## Why the committee were unable to make recommendations
There are many types of sound therapy used by people with tinnitus. There is, however, limited evidence available that assesses the clinical and cost effectiveness of these interventions in isolation. With the different types of sound therapy and insufficient evidence for any particular type, the committee were unable to make recommendations for practice.
The committee noted that although it is important to know the clinical effectiveness of sound therapies in isolation, it is important that tinnitus support is provided in combination with these interventions. They made a research recommendation on sound therapy in combination with tinnitus support.
Return to recommendations
# Psychological therapies for people with tinnitus-related distress
Recommendation 1.5.4
## Why the committee made the recommendation
The evidence suggests that cognitive behavioural therapy (CBT), mindfulness-based CBT and acceptance and commitment therapy (ACT) are effective interventions for managing tinnitus-related distress. CBT can be delivered in different formats such as digital (for example, internet based), group and individual face-to-face sessions.
The cost effectiveness of specific therapies is uncertain. However, economic analyses suggested that it would be less costly to use digital or group therapy first line, and individual therapy for people who are still distressed after their first-line psychological intervention.
Mindfulness-based cognitive therapy should be delivered by appropriately trained and supervised practitioners. The committee agreed that all psychological therapies should be supervised by psychologists.
The committee noted that with face-to-face psychological interventions (such as group CBT), people may sometimes not attend sessions. People may be more likely to complete the full intervention with digital CBT than with face-to-face sessions, as they would be able to participate according to their lifestyle, rather than having to travel to a session at a designated time. Digital CBT for tinnitus is currently only available in research, with evidence suggesting that it is clinically effective. While digital CBT is unavailable or when it is not suitable, group CBT should be used as the first-line psychological therapy. In current practice, the selection of group CBT or individual CBT is made on a case-by-case basis and mainly dependent on the availability of CBT services and individual preferences. The committee noted that some people may be hesitant about group CBT at first but may find it a more meaningful and positive experience.
CBT and ACT should be delivered by psychologists because this is considered important for achieving good patient outcomes. Taking into account the clinical and economic evidence, together with a lack of direct evidence of cost effectiveness, the committee agreed that a stepped approach for adults with tinnitus-related distress could be considered.
The committee noted that no evidence was identified that evaluated psychological therapies in children and young people. Access to psychological therapies for children and young people with tinnitus is currently limited. The committee agreed that further research is needed, and made a research recommendation on psychological therapies for children and young people.
## How the recommendation might affect practice
In some regions of the UK there is limited access to psychological therapies for people with tinnitus, with few healthcare professionals trained in delivering them. The committee noted that implementing the recommended psychological therapies will lead to a significant change in practice in regions where access is limited. However, to help providers in widening access to psychological therapies for people with tinnitus, the committee recommended that digital CBT be considered as a first-line intervention. This intervention would allow people with tinnitus to receive their treatment faster and help to reduce waiting lists. It is expected that some providers, working alongside clinicians (including psychologists) with experience in working with people with tinnitus, will take the initiative to adapt existing digital CBT tools available for other conditions.
The recommendation could result in cost savings for services that are currently offering individual-based psychological therapies as a first-line psychological treatment for tinnitus. This is because of the committee's view that these expensive interventions should only be used when other methods (digital CBT and group-based interventions) have been exhausted. Therefore, although some providers may incur additional expenditure as a result of implementing these recommendations, other providers might achieve cost savings. Furthermore, the committee recommended a number of different group-based psychological strategies as there is no clear evidence that 1 psychological intervention is more clinically effective than another. Providers can therefore adopt those interventions that are easiest to implement based on their existing staff and skills, and this would further minimise the resource impact.
As there is limited access to psychology services, the committee recommended that research is needed to assess the effectiveness of CBT delivered to people with tinnitus by appropriately trained and supervised healthcare practitioners other than psychologists (for example, audiologists; see research recommendation 1). This research could further help to widen access to psychological services as more clinicians would be available to provide the interventions listed in this recommendation.
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# Betahistine
Recommendation 1.5.5
## Why the committee made the recommendation
The committee noted that some people are occasionally prescribed betahistine to treat tinnitus, but it is not licensed for the treatment of tinnitus alone. Betahistine is licensed for treatment of Ménière's disease, of which tinnitus may be a symptom.
The evidence suggests that betahistine does not improve tinnitus symptoms and there is evidence of adverse effects. The committee agreed that betahistine should not be offered to treat tinnitus.
## How the recommendation might affect practice
As betahistine is occasionally prescribed to treat tinnitus, implementing this recommendation could lead to cost savings.
Return to recommendations
# Combining therapies
## Why the committee were unable to make recommendations
The evidence for combination strategies was limited, but indicated to the committee that tinnitus support alongside other management strategies was important. No recommendations on particular combinations of tinnitus management strategies were made. However, the recommendations on tinnitus support and management in this guideline specify that everyone should receive tinnitus support along with whatever strategy (for example, amplification devices and psychological therapies) has been chosen in their management plan.
The committee noted that there is limited evidence available for the use of sound therapy with tinnitus support. They made a research recommendation on the combination of sound therapy with tinnitus support.
The committee recognised that tinnitus retraining therapy (TRT) is a specific combination management strategy. They agreed that the original protocol for TRT does not allow people to be actively engaged in the development of their management plan. TRT is used in modified forms in current practice, generally in different formats to those described in the literature. In the evidence base identified in the associated evidence review, there is variation in how TRT is delivered, which makes it difficult to determine the most clinically effective form of TRT. The committee agreed that this evidence base does not reflect the TRT interventions that are typically delivered in current practice, and that a recommendation for TRT could not be made. Modified TRT, using the principles of tinnitus support, can be evaluated under the research recommendation made in the combination management strategies review.
Return to recommendations
# Neuromodulation
## Why the committee were unable to make recommendations
There is great variation in neuromodulation approaches reported for tinnitus. Insufficient robust evidence meant that the committee were unable to make any practice recommendations on the use of neuromodulation therapies. They made a recommendation for research on the use of neuromodulation therapies, and noted that evidence of the safety of these techniques for use in children and young people was needed before conducting extensive research of efficacy.
Return to recommendations# Context
Tinnitus is the perception of sounds in the ears or head that do not come from an outside source. It is a common condition, with similar prevalence rates in children young people and adults.
The NHS Joint Strategic Needs Assessment Guidance (2019) reports that '10% of the population will have tinnitus at some point and it will be moderately annoying in 2.8% of the population; severely annoying in 1.6%; and disrupting a person's ability to live a normal life in 0.5%'. It has also been estimated that 3% of adults might require a clinical intervention for tinnitus. The expectation is that a similar number of children will need clinical intervention for tinnitus.
Tinnitus can be associated with difficulty in concentrating and listening, and for some people it can be extremely distressing and have a significant impact on their mental wellbeing, family, work and social life. It is a heterogeneous condition that affects people differently both in its severity and its impact. Therefore, management of tinnitus is usually tailored according to the person's symptoms. Although there is no single effective treatment for tinnitus, there are a variety of approaches that may help people manage their tinnitus or the impact of their tinnitus.
Additionally, tinnitus is often associated with hearing loss. For example, 75% of people with hearing loss might experience tinnitus, while only 20% to 30% of people who report tinnitus have normal hearing.
Currently services across the UK vary in how accessible they are and the level of support offered for people with tinnitus. There is a lack of standardisation in assessment, referral and management approaches. This includes assessment of conditions underlying the tinnitus that need prompt, or even urgent, investigation and treatment by specialist services.
This guideline aims to improve care for people with tinnitus by providing advice to healthcare professionals on the assessment, investigation and management of tinnitus. It also offers advice on supporting people who are distressed by tinnitus and on when to refer for further assessment of their tinnitus and management.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThe recommendations in this guideline apply to all people (adults, children and young people) with tinnitus unless otherwise stated.\n\nTinnitus and hearing loss can co-exist. For adults with tinnitus and hearing loss this guideline should be read together with the NICE guideline on hearing loss in adults.\n\n# Support and information for people with tinnitus\n\n## Tinnitus support\n\nAt all stages of care:\n\nDiscuss with the person with tinnitus, and their family members or carers if appropriate, their experience of tinnitus, including its impact and any concerns.\n\nBased on any identified needs, agree a management plan with the person, taking into account their preferences. The plan should include information about tinnitus and opportunities for discussion about different management options.\n\nDiscuss with the person the results of any recent assessments and their impact on the management plan.\n\nWith consent from the person or their parent or carer, as appropriate, share the management plan with relevant health, education and social care professionals.\n\nFor people with longstanding tinnitus who have delayed accessing care, aim to find out the reason for the delay and why they are accessing care now. This could involve, for example, asking questions about lifestyle factors or changes in health.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on support for people with tinnitus\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: tinnitus support.\n\nLoading. Please wait.\n\n## Information\n\nReassure the person with tinnitus, at first point of contact with a healthcare professional, that:\n\ntinnitus is a common condition\n\nit may resolve by itself\n\nalthough it is commonly associated with hearing loss, it is not commonly associated with other underlying physical problems\n\nthere are a variety of management strategies that help many people live well with tinnitus.\n\nGive information about tinnitus at all stages of care. The content should be tailored to the individual needs of the person, and their family members or carers if appropriate, and include information about:\n\nwhat tinnitus is, what might have caused it, what might happen in the future\n\nwhat can make tinnitus worse (for example, stress or exposure to loud noise)\n\nsafe listening practices (for example, noise protection)\n\nthe impact of tinnitus (for example, it can affect sleep, see the section on assessing how tinnitus affects sleep)\n\nsee investigations\n\nself-help and coping strategies (for example, self-help books and relaxation strategies)\n\nmanagement options (see the section on management of tinnitus)\n\nlocal and national support groups\n\nother sources of information.\n\nWhen providing information:\n\nensure it is available in appropriate formats such as verbal consultation, written information, leaflets and online in line with the NICE guideline on patient experience\n\ntake into account accessibility requirements for children, and people with hearing loss, cognitive impairment or visual impairment.\n\nFor a short explanation of why the committee made the recommendations and how they might affect practice, see the rationale and impact section on information for people with tinnitus\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B: patient information.\n\nLoading. Please wait.\n\n# Referring people with tinnitus\n\nRefer immediately to a crisis mental health management team for assessment people who have tinnitus associated with a high risk of suicide. If needed, provide a safe place while waiting for the assessment.\n\nRefer immediately, in line with the NICE guideline on suspected neurological conditions, people with tinnitus associated with:\n\nsudden onset of significant neurological symptoms or signs (for example, facial weakness), or\n\nacute uncontrolled vestibular symptoms (for example, vertigo), or\n\nsuspected stroke (follow a local stroke referral pathway). For information about diagnosis and initial management of stroke, see the NICE guideline on stroke and transient ischaemic attack in over 16s.\n\nRefer people to be seen within 24\xa0hours, in line with the NICE guideline on hearing loss in adults, if they have tinnitus and have hearing loss that has developed suddenly (over a period of 3\xa0days or less) in the past 30\xa0days.\n\nRecognise that assessment and management of the person's tinnitus may still need to continue following an immediate referral.\n\nRefer people to be seen within 2\xa0weeks for assessment and management if they have tinnitus associated with either of the following:\n\nDistress affecting mental wellbeing (for example, distress that prevents them carrying out their usual daily activities) even after receiving tinnitus support at first point of contact with a healthcare professional (see the recommendation on all stages of care in tinnitus support). Refer in line with local pathways.\n\nHearing loss that developed suddenly more than 30\xa0days ago or rapidly worsening hearing loss (over a period of 4\xa0to 90\xa0days). Refer in line with the NICE guideline on hearing loss in adults.\n\nRefer people for tinnitus assessment and management in line with local pathways if they have any of the following:\n\ntinnitus that bothers them despite having received tinnitus support at first point of contact with a healthcare professional (see the recommendation on all stages of care in tinnitus support)\n\npersistent objective tinnitus\n\ntinnitus associated with unilateral or asymmetric hearing loss.\n\nConsider referring people for tinnitus assessment and management in line with local pathways if they have any of the following, in line with the NICE guideline on hearing loss in adults:\n\npersistent pulsatile tinnitus\n\npersistent unilateral tinnitus.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on referring people with tinnitus\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence reviews C-D: symptoms and features for urgent and non-urgent referral.\n\nLoading. Please wait.\n\n# Assessing the impact of tinnitus using questionnaires\n\nConsider using the Tinnitus Functional Index for adults to assess how tinnitus affects them.\n\nIf questionnaires cannot be used (for example, because of language issues or cognitive impairment) consider using other measures such as visual analogue scales.\n\nConsider using an age- or ability-appropriate measure (such as a visual analogue scale) for children and young people to assess how tinnitus affects them.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on assessing tinnitus using questionnaires\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review E: questionnaires to assess tinnitus.\n\nLoading. Please wait.\n\n## Assessing how tinnitus affects quality of life\n\nDiscuss with the person with tinnitus, and their family members or carers if appropriate, how the condition affects their quality of life (home, social, leisure, work and school).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on assessing how tinnitus affects quality of life\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review G: assessing quality of life.\n\nLoading. Please wait.\n\n## Assessing how tinnitus affects sleep\n\nAsk people with tinnitus if they have problems sleeping because of tinnitus. If they do, consider screening with a questionnaire (such as the Insomnia Severity Index). Discuss the results with them and how this might inform their management plan.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on assessing sleep\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review F: assessing psychological impact.\n\nLoading. Please wait.\n\n## Assessing the psychological impact of tinnitus\n\nBe alert at all stages of care to the impact of tinnitus on mental health and wellbeing in adults. If there are concerns, follow the recommendations in the NICE guideline on common mental health problems.\n\nConsider using the tinnitus questionnaire (TQ) or mini-TQ alongside the Tinnitus Functional Index in adults with tinnitus if further assessment of the psychological effects of tinnitus is needed.\n\nIf there are concerns about depression or anxiety in adults, a healthcare professional competent in mental health assessment should:\n\ncarry out an assessment using a questionnaire (for example, those in the recommendations on assessment in the NICE guideline on common mental health problems), or an ability-appropriate measure\n\nconsider assessment using the Clinical Outcomes in Routine Evaluation – Outcome Measure\n\nagree an action plan, if needed, in line with the recommendations on assessment in the NICE guideline on common mental health problems.\n\nBe alert at all stages of care to the behavioural and psychological wellbeing of all children and young people presenting with tinnitus. Talk to them, and their family members or carers if appropriate, about how they feel.\n\nIf there are concerns about depression in children and young people, follow the recommendations in the NICE guideline on depression in children and young people.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on assessing the psychological impact of tinnitus\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review F: assessing psychological impact.\n\nLoading. Please wait.\n\n# Investigations\n\n## Audiological assessment\n\nOffer an audiological assessment to people with tinnitus. For recommendations on assessing and managing hearing loss in adults, see the NICE guideline on hearing loss in adults.\n\nConsider tympanometry when middle-ear or Eustachian tube dysfunction, or other causes of conductive hearing loss contributing to tinnitus, are suspected.\n\nDo not offer acoustic reflex testing or uncomfortable loudness levels/loudness discomfort levels testing as part of an investigation of tinnitus.\n\nDo not offer otoacoustic emissions tests as part of an investigation of tinnitus unless the tinnitus is accompanied by other symptoms and signs.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on audiological assessment\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review H: audiological assessment.\n\nLoading. Please wait.\n\n## Psychoacoustic tests\n\nDo not offer psychoacoustic tests, for example pitch and loudness matching, to assess tinnitus.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on psychoacoustic tests\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review I: psychoacoustic measures.\n\nLoading. Please wait.\n\n## Imaging\n\nOffer MRI of internal auditory meati (IAM) to people with non-pulsatile tinnitus who have associated neurological, otological or head and neck signs and symptoms. If they are unable to have MRI (IAM), offer contrast-enhanced CT (IAM).\n\nConsider MRI (IAM) for people with unilateral or asymmetrical non-pulsatile tinnitus who have no associated neurological, audiological, otological or head and neck signs and symptoms. If they are unable to have MRI (IAM), consider contrast-enhanced CT (IAM).\n\nDo not offer imaging to people with symmetrical non-pulsatile tinnitus with no associated neurological, audiological, otological or head and neck signs and symptoms.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on non-pulsatile tinnitus\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review J: imaging to investigate the cause of non-pulsatile tinnitus.\n\nLoading. Please wait.\n\nOffer imaging to people with pulsatile tinnitus.\n\nFor people with synchronous pulsatile tinnitus, consider:\n\n\n\nmagnetic resonance angiogram or MRI of head, neck, temporal bone and IAM if clinical examination and audiological assessment are normal, or contrast-enhanced CT of head, neck, temporal bone and IAM if they cannot have magnetic resonance angiogram or MRI\n\ncontrast-enhanced CT of temporal bone if an osseous or middle-ear abnormality is suspected (for example, glomus tumour), followed by MRI if further investigation of soft tissue is required.\n\n\n\nFor people with non-synchronous pulsatile tinnitus (for example, caused by palatal myoclonus) consider MRI of the head, or if they cannot have MRI, contrast-enhanced CT of the head.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on pulsatile tinnitus\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review K: imaging to investigate the cause of pulsatile tinnitus.\n\nLoading. Please wait.\n\n# Management of tinnitus\n\n## Amplification devices\n\nOffer amplification devices to people with tinnitus who have a hearing loss that affects their ability to communicate. For adults, follow the recommendations on hearing aids in the NICE guideline on hearing loss in adults.\n\nConsider amplification devices for people with tinnitus who have a hearing loss but do not have difficulties communicating.\n\nDo not offer amplification devices to people with tinnitus but no hearing loss.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on amplification devices\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review M: sound therapy and amplification devices.\n\nLoading. Please wait.\n\n## Sound therapy\n\nThe committee were unable to make recommendations for practice in this area. They made a recommendation for research.\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on sound therapy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review M: sound therapy and amplification devices.\n\nLoading. Please wait.\n\n## Psychological therapies for people with tinnitus-related distress\n\nConsider a stepped approach to treat tinnitus-related distress in adults whose tinnitus is still causing an impact on their emotional and social wellbeing, and day-to-day activities, despite having received tinnitus support. If a person does not benefit from the first psychological intervention they try or declines an intervention, offer an intervention from the next step in the following order:\n\ndigital tinnitus-related cognitive behavioural therapy (CBT) provided by psychologists\n\ngroup-based tinnitus-related psychological interventions including mindfulness-based cognitive therapy (delivered by appropriately trained and supervised practitioners), acceptance and commitment therapy or CBT (delivered by psychologists)\n\nindividual tinnitus-related CBT (delivered by psychologists).\n\nFor a short explanation of why the committee made the recommendation and how it might affect practice, see the rationale and impact section on psychological therapies for people with tinnitus-related distress\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review L: psychological therapies.\n\nLoading. Please wait.\n\n## Betahistine\n\nDo not offer betahistine to treat tinnitus.\n\nFor a short explanation of why the committee made the recommendation and how it might affect practice, see the rationale and impact section on betahistine\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review N: betahistine.\n\nLoading. Please wait.\n\n## Combining therapies\n\nThe committee were unable to make recommendations for practice in this area. They made a recommendation for research.\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on combining therapies\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review P: combinations of management strategies.\n\nLoading. Please wait.\n\n## Neuromodulation\n\nThe committee were unable to make recommendations for practice in this area. They made a recommendation for research.\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on neuromodulation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review O: neuromodulation.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a particular way for this guideline.\n\n## Digital tinnitus-related cognitive behavioural therapy\n\nDigital CBT is a form of CBT delivered using digital technology, such as a computer, tablet or phone. Common components of digital tinnitus-related CBT are similar to those used in face-to-face CBT (for example, positive imagery and learning to identify and challenge unhelpful thoughts). People using digital CBT are more likely to have less direct contact with healthcare professionals during the intervention compared with face-to-face interventions.\n\n## Objective tinnitus\n\nTinnitus that occurs as a result of noise generated in the ear that can be detected by the examiner. It is less common than subjective tinnitus.\n\n## Refer immediately\n\nTo be seen by the specialist service within a few hours, or even more quickly if necessary.\n\n## Tinnitus-related distress\n\nTinnitus that is having an impact on emotional and social wellbeing and day-to-day activities.\n\n## Tinnitus support\n\nA term used to describe a session that includes a 2-way process of information-giving and discussion to help the healthcare professional understand the difficulties and goals of the person with tinnitus. This discussion occurs between the person with tinnitus, and their family members or carers if appropriate, and the healthcare professional. A management plan is also jointly developed and the person is supported to continue with the plan or modify it as necessary. This process is sometimes known as tinnitus counselling.", 'Recommendations for research': 'The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Cognitive behavioural therapy for adults with tinnitus delivered by appropriately trained healthcare professionals other than psychologists\n\nWhat is the clinical and cost effectiveness of cognitive behavioural therapy (CBT) for adults with tinnitus delivered by appropriately trained healthcare professionals other than psychologists (for example, audiologists)?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale and impact section on CBT for adults delivered by appropriately trained healthcare professionals\xa0.\n\nFull details of the research recommendation are in evidence review L: psychological therapies.\n\nLoading. Please wait.\n\n## Combination management strategy: sound therapy and tinnitus support\n\nWhat is the clinical and cost effectiveness of a combination management strategy consisting of sound therapy and tinnitus support?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on combination management strategy\xa0.\n\nFull details of the research recommendation are in evidence review P: combinations of management strategies.\n\nLoading. Please wait.\n\n## Methods for assessing tinnitus in general practice\n\nWhat is the optimal method for assessing tinnitus in general practice (including consultation questions, physical examinations and questionnaires)?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale and impact section on assessing tinnitus in general practice\xa0.\n\nFull details of the research recommendation are in evidence review E: questionnaires to assess tinnitus.\n\nLoading. Please wait.\n\n## Neuromodulation\n\nWhat is the clinical, cost effectiveness and safety of neuromodulation interventions for treating tinnitus in adults?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on neuromodulation interventions\xa0.\n\nFull details of the research recommendation are in evidence review O: neuromodulation.\n\nLoading. Please wait.\n\n## Psychological therapies for children and young people\n\nWhat is the clinical and cost effectiveness of psychological therapies for children and young people who have tinnitus-related distress?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale and impact section on psychological therapies for children and young people\xa0.\n\nFull details of the research recommendation are in evidence review L: psychological therapies.\n\nLoading. Please wait.\n\n# Other recommendations for research\n\n## Tinnitus questionnaires for children and young people\n\nWhat is the most clinically and cost-effective tinnitus questionnaire to assess tinnitus in children and young people?\n\nFull details of the research recommendation are in evidence review\xa0E: questionnaires to assess tinnitus.\n\n## Tinnitus questionnaires for people with a learning disability or cognitive impairment\n\nWhat is the most clinically and cost-effective tinnitus questionnaire to assess tinnitus in people with a learning disability or cognitive impairment?\n\nFull details of the research recommendation are in evidence review\xa0E: questionnaires to assess tinnitus.\n\n## Tinnitus questionnaires for people who are d/Deaf or who have a severe-to-profound hearing loss\n\nWhat is the most clinically and cost-effective tinnitus questionnaire to assess tinnitus in people who are d/Deaf or who have a severe-to-profound hearing loss?\n\nFull details of the research recommendation are in evidence review\xa0E: questionnaires to assess tinnitus.\n\n## Relaxation strategies for children, young people and adults\n\nAre relaxation strategies clinically and cost effective for the management of tinnitus for children, young people and adults?\n\nFull details of the research recommendation are in evidence review\xa0A: tinnitus support.\n\n## Amplification devices for people who are d/Deaf or who have a severe-to-profound hearing loss\n\nWhat is the clinical and cost effectiveness of amplification devices for people who are d/Deaf or who have a severe-to-profound hearing loss?\n\nFull details of the research recommendation are in evidence review\xa0M: sound therapy and amplification devices.\n\n## Psychological therapies for people who are d/Deaf or who have a severe-to-profound hearing loss\n\nWhat is the clinical and cost effectiveness of psychological therapies for people who are d/Deaf or who have a severe-to-profound hearing loss and tinnitus-related distress?\n\nFull details of the research recommendation are in evidence review\xa0L: psychological therapies.\n\n## Amplification devices for people with tinnitus who have hearing loss but no perceived hearing difficulties\n\nWhat is the clinical and cost effectiveness of fitting amplification devices(s) in people with tinnitus who have hearing loss but no perceived hearing difficulties?\n\nFull details of the research recommendation are in evidence review\xa0M: sound therapy and amplification devices.', 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.\n\n# Support for people with tinnitus\n\nRecommendations 1.1.1 and 1.1.2\n\n## Why the committee made the recommendations\n\n'Tinnitus support' was defined by the committee as a 2-way process of information giving and discussion to help the healthcare professional understand the difficulties and goals of the person with tinnitus. The evidence showed that similar interventions such as 'education counselling' gave some benefit in improving outcomes for people with tinnitus. Although the evidence was limited, the committee agreed that providing support to people with tinnitus and their family members or carers is essential, and ensures that the person's needs and preferences are taken into account. The committee recognised that the needs and concerns of children and young people with tinnitus can be different to those of their parents or carers, but these should be addressed, and appropriate support offered, for both groups.\n\nThe committee agreed that there should be a discussion between the healthcare professional and person with tinnitus about the results of recent assessments and their impact on their management plan. This will give the person the opportunity to ask questions and actively participate in the development of the plan. Sharing the management plan with the relevant health, education and social care professionals will help to further support the person with tinnitus.\n\nIt is important that healthcare professionals understand why people with longstanding tinnitus are accessing care at that point of contact, as this can inform the person's management plan. Asking the person prompting questions about lifestyle factors (for example, stress or change in mental wellbeing) or changes in health (for example, hearing loss) can help with this. The committee noted that tinnitus and its impact can change over time. Where tinnitus is troublesome, it can be helpful to review the factors affecting tinnitus and its impact, as the management plan may need to be revised. The committee acknowledged that in current practice the term 'tinnitus counselling' is used to describe a management strategy that may include elements of 'tinnitus support'.\n\nThe committee decided to not use the term 'tinnitus counselling' to describe this management strategy as there is inconsistency in how the term is used in current practice. For some healthcare professionals it can be a brief clinician-led talk with the intent to reassure that there is no significant pathology. Alternatively, it can be a longer interactive session focusing on the worries and concerns of the person with tinnitus. The committee's intention is for a standardised and improved level of care to be available to people with tinnitus, across the country, from the first point of contact with the healthcare system.\n\nThe committee also looked at evidence on relaxation strategies, although the amount of evidence was limited. They noted that the use of relaxation strategies for managing tinnitus is widespread but the strategies are insufficiently researched. Consequently, they made a research recommendation to assess relaxation strategies for the management of tinnitus.\n\n## How the recommendations might affect practice\n\nThere is variation in how support for people with tinnitus is defined, what it should include, and how and when it is delivered. Implementing these recommendations should reduce this variation.\n\nReturn to recommendations\n\n# Information for people with tinnitus\n\nRecommendations 1.1.3 to 1.1.5\n\n## Why the committee made the recommendations\n\nThere was limited evidence on what information should be provided to people with tinnitus, their family members and carers. However, the committee noted that patient information is an essential element of patient care in the NHS and should be provided at first point of contact with a healthcare professional.\n\nThe information should be tailored to individual needs to ensure that it is suitable and effective in informing the person's management plan. Where people with tinnitus encounter clinicians that tell them that nothing can be done and they have to live with it, this may worsen a person's perception of tinnitus and may impact on their mental wellbeing. A clinician's lack of awareness of the impact of tinnitus may also create barriers for onward referral. Therefore, the committee agreed it is important for clinicians to reassure people that tinnitus is common, and although it is commonly associated with hearing loss, it is not usually associated with an underlying physical health problem. In addition, many people find management strategies to help them live well with tinnitus.\n\nAppropriate information provided in a timely manner to people first presenting with tinnitus will reduce distress and the likelihood of symptoms becoming debilitating. The information should take into account accessibility requirements – for example, be at the appropriate cognitive and linguistic level for children, and be in a suitable format for people who use British Sign Language or who have a visual or cognitive impairment.\n\n## How the recommendations might affect practice\n\nThere is variation in the level of information provided to people with tinnitus, and in the content and format of the information. Implementing the recommendations should reduce this variation.\n\nReturn to recommendations\n\n# Referring people with tinnitus\n\nRecommendations 1.2.1 to 1.2.7\n\n## Why the committee made the recommendations\n\nNo evidence was identified on which symptoms and features should warrant investigation or management. In the absence of evidence, the committee agreed that after clinical history and physical examinations, there are various symptoms and features associated with tinnitus that should prompt an immediate referral (to be seen within a few hours or even more quickly if necessary), referral to be seen within 24\xa0hours, referral to be seen within 2\xa0weeks, or non-urgent referral.\n\nThe categorisation of these symptoms and features is dependent on the potential consequence of not referring. For example, people who present to general practice with tinnitus and symptoms and features that include a high risk of suicide (for example, suicidal thoughts with an intended plan) should be referred to a crisis mental health management team immediately for assessment to preserve life. People presenting with tinnitus associated with a sudden onset of neurological symptoms should be seen within a few hours or more quickly if necessary after referral, as not referring can be life-threatening and increase morbidity.\n\nThe committee noted that it is important to recognise that assessment and management for tinnitus may still need to continue following immediate onward referral for other co-morbidities (for example, suspected stroke).\n\nImmediate referrals should be made to ensure that underlying neurological causes can be diagnosed, and any treatment received, quickly. The treatment is then more likely to be successful. Two-week referrals should be made for people with tinnitus who have distress that is limiting daily activities, such as not being able to leave their house or not being able to go to work. The committee noted that this is a small subpopulation of people with tinnitus.\n\nThe committee agreed that the impact of tinnitus on a person's wellbeing and mental health is a critical component of any assessment of symptoms and features in all settings – for example, primary, community and secondary care. Providing tinnitus support for people after symptoms and features have been assessed can help reduce the impact of tinnitus on their mental health and any distress that limits their daily activities. If mental health concerns persist after this, referrals should be made.\n\nThe committee decided to not recommend specific referral locations because of variation in current practice and in tinnitus pathways in the UK. Common referral locations include audiology and ear, nose and throat services.\n\nThe categories of urgency and the timings for hearing loss associated with tinnitus are aligned with those in the NICE guideline on hearing loss in adults. The recommendations for referrals for persistent pulsatile tinnitus and persistent unilateral tinnitus were made in line with the NICE guideline on hearing loss in adults. However the committee noted that these types of tinnitus can be associated with vascular or neurological abnormalities. Onward referral for further investigations to detect these abnormalities may prevent the development of significant pathologies such as vestibular schwannoma.\n\nThe committee noted that children should be seen in a paediatric environment by healthcare professionals used to managing the needs of children and working in the children's support services (health, education and social care). In the absence of relevant specific guidelines for children, they also agreed that it was appropriate for the referral recommendations from the NICE guidelines on hearing loss in adults and stroke and transient ischaemic attack in over 16s to apply to children and young people as well as adults. The committee believed that the same clinical manifestations will be considered for referrals, regardless of age.\n\n## How the recommendations might affect practice\n\nThese recommendations do not aim to change the number of referrals made but rather encourage more timely referrals. Services may need to change their protocols to accommodate 2‑week referrals. These timely referrals will improve patient safety and the appropriate implementation of treatment or management strategies. Timely and appropriate intervention will reduce distress and repeated requests or referrals for tinnitus support.\n\nReturn to recommendations\n\n# Assessing the impact of tinnitus using questionnaires\n\nRecommendations 1.3.1 to 1.3.3\n\n## Why the committee made the recommendations\n\nNo evidence was identified on the clinical effectiveness of questionnaires used to assess the impact of tinnitus on a person. Questionnaires are not a substitute for a detailed clinical history. However, the committee noted the importance of using questionnaires and age-appropriate measures for assessment, which can help to inform management.\n\nQuestionnaires can provide a structured format for identifying and subjectively rating difficulties that a person with tinnitus may have. Areas that need intervention can be identified and changes that occurred as a result of the intervention can be measured. This information can be used on an individual level, and on a service level, to help ensure that appropriate resources are available.\n\nA range of questionnaires are currently used to assess the impact of tinnitus in services across England. However, the questionnaires are typically designed to look at specific groups of people with tinnitus or specific problems associated with tinnitus. Therefore, their components may not reflect the range of needs of everyone with tinnitus. Most of the questionnaires are not designed to take account of change after intervention.\n\nIn the absence of evidence, the committee agreed that the most appropriate questionnaire that should be considered is the Tinnitus Functional Index. This provides the broadest assessment of the impact of tinnitus and incorporates a variety of components. It was also specifically designed to measure change.\n\nThe committee noted that questionnaires are not commonly used in general practice and there is also variation in how tinnitus is assessed in primary care. They thought it important that research is conducted to examine the optimal method for assessing tinnitus in general practice settings, as general practice is a gatekeeper for the further management of tinnitus (see research recommendation 3).\n\nThe committee agreed that it is crucial for healthcare professionals to discuss the results of assessments with the person. When answers to component questions are discussed with them, rather than solely focusing on overall scores, it can help people to fully engage with the management of their condition. In addition, using assessment methods such as questionnaires before and after an intervention can further inform management plans.\n\nThe committee agreed that if questionnaires cannot be used, visual analogue scales can be used to assess the impact of tinnitus. The committee noted that there are 2\xa0types of questions in visual analogue scales that can be useful: how much does your tinnitus bother you and how much does the tinnitus interfere with what you do?\n\n## How the recommendations might affect practice\n\nA variety of methods are used in the UK to assess the impact of tinnitus, particularly with the use of different tinnitus questionnaires. Implementing the use of a common core questionnaire to assess tinnitus will lead to the standardisation of care across the UK and encourage best practice. It will also improve individual care if the components of the questionnaire are used meaningfully as part of the discussion about tinnitus and to signpost towards appropriate support.\n\nAs the questionnaires are expected to be completed outside the consultation room, there are little or no anticipated cost implications. Some resource time would be needed to discuss the results of the questionnaires with the person. But the committee noted that even in the absence of a questionnaire, a comprehensive assessment would require a clinician to ask about the topics covered in the questionnaire.\n\nReturn to recommendations\n\n# Assessing how tinnitus affects quality of life\n\nRecommendation 1.3.4\n\n## Why the committee made the recommendation\n\nNo evidence was identified that evaluated the clinical effectiveness of questionnaires and interviews to assess quality of life in people with tinnitus. Questionnaires such as the Tinnitus Functional Index, which provide an overall assessment of tinnitus, include questions on assessing the impact of tinnitus on quality of life (for example, enjoyment of social activities and relationships with family and friends). The committee took this into account, together with the fact that quality-of-life questionnaires are not commonly used in current practice. They agreed that it was not necessary to recommend an additional questionnaire.\n\nIn clinical practice it is often when quality of life is affected that people with tinnitus seek help. The committee agreed, that as part of tinnitus support and clinical history taking, a discussion with the person is more useful than a questionnaire for understanding their experiences with tinnitus and its impact on their quality of life in different settings (such as home, social, leisure, work and school). These discussions could then inform their management plan.\n\n## How the recommendation might affect practice\n\nImplementing the recommendation will standardise clinical practice and encourage best practice. Additionally, it will help to increase the recognition of tinnitus-related difficulties and improve subsequent tinnitus management. There are no anticipated cost implications for implementing this recommendation.\n\nReturn to recommendations\n\n# Assessing sleep and the psychological impact of tinnitus\n\nRecommendations 1.3.5 to 1.3.10\n\n## Why the committee made the recommendations\n\nInsomnia is common in people with tinnitus, and this can have a psychological impact. The committee agreed that healthcare professionals should ask people with tinnitus if they have problems sleeping. In the absence of evidence evaluating questionnaires to assess the impact of tinnitus on sleep the committee recommended that an assessment using a questionnaire such as the Insomnia Severity Index could be useful when developing a management plan. The committee acknowledged that the Insomnia Severity Index is not commonly used in current practice but it is an appropriate measure and is freely available and easy to use. The questionnaire can also be used as a screening tool which can lead to a referral.\n\nNo evidence was identified that evaluated the clinical or cost effectiveness of questionnaires to assess the psychological impact of tinnitus. Tinnitus can cause depression or anxiety and can be exacerbated by depression or anxiety, leading to distress. This depression or anxiety sometimes needs to be treated before the person can begin to cope with tinnitus, to lessen the distress. Therefore, it is important to ask everyone if they feel anxious or depressed, in addition to asking about tinnitus.\n\nIn the absence of evidence, the committee agreed that the commonly used tinnitus questionnaire (TQ) and mini-TQ are appropriate questionnaires to use to further assess the psychological impact of tinnitus. The committee agreed that healthcare professionals should be alert to symptoms and signs of depression and anxiety, asking prompting questions as recommended in the NICE guideline on common mental health problems. Although the guideline is not specific to people with tinnitus, the committee agreed that healthcare professionals should refer to this guideline in the absence of any evidence for questionnaires that can be used to assess the psychological impact of tinnitus. The questionnaires recommended in the NICE guideline on common mental health problems are mainly used in mental health settings, but they can also be used in other services such as audiology. The committee agreed that although no evidence was identified that assessed the use of Clinical Outcomes in Routine Evaluation - Outcome Measure, it is particularly useful for assessing the psychological impact of tinnitus, where indications of depression and anxiety may be more subtle.\n\nDepression in children and young people should be assessed and managed in line with the NICE guideline on depression in children and young people.\n\n## How the recommendations might affect practice\n\nThe recommendations will standardise clinical practice in the UK and enhance patient safety. They will also increase the number of people with tinnitus who have assessments of their psychological wellbeing. Consequently, more people with depression and anxiety will have their condition managed appropriately. There are no anticipated cost implications for implementing these recommendations because these questionnaires are expected to be completed before the person enters the consultation room and interacts with the relevant clinician.\n\nReturn to recommendations\n\n# Audiological assessment\n\nRecommendations 1.4.1 to 1.4.4\n\n## Why the committee made the recommendations\n\nNo clinical evidence was identified on audiological assessments for people with tinnitus. Tinnitus may co-exist with hearing loss, and some people with tinnitus may not be aware that they also have hearing loss. The hearing loss may have been gradual and some people may even attribute their hearing difficulties to their tinnitus. Therefore, the committee strongly believed that everyone referred to audiological, ear, nose and throat or audiovestibular medicine services should receive audiological assessments as a minimum to establish any hearing problems and to inform a management plan. Audiological assessments may need to be modified according to the person's age, level of development and cognitive ability.\n\nEffective management of a hearing loss can reduce the audibility and impact of the tinnitus. The committee agreed that when middle-ear or Eustachian tube dysfunction or other causes of a conductive hearing loss are suspected, tympanometry should be considered. Tympanometry is a helpful supporting test in the assessment of hearing loss to help identify the nature of that hearing loss.\n\nThe committee agreed that, from their experiences, acoustic reflex testing and uncomfortable loudness levels/loudness discomfort levels (ULL/LDL) tests can be unnecessary, unpleasant and potentially harmful. They may exacerbate a person's tinnitus and increase distress. The results of these tests would not affect a person's management plan as the main focus of tinnitus management is to lessen the distress associated with tinnitus. The committee recognised that ULL tests can be useful for other purposes (for example, fitting hearing aids), but noted that they should be used with caution.\n\nIn addition, from the committee's experiences, it was agreed that although otoacoustic emissions tests are not unpleasant or harmful, the results are unlikely to affect a person's management plan. They should only be offered if tinnitus is accompanied by other symptoms and signs (for example, mild hearing loss or hearing being monitored for people on ototoxic medication).\n\n## How the recommendations might affect practice\n\nThe committee thought that there would be little impact on practice as most healthcare professionals routinely use hearing assessments to establish hearing thresholds in people with tinnitus. Therefore, there would be no additional resource impact as a result of the recommendation on audiology assessment. Many also currently use tympanometry when needed, so this will not change current practice for most.\n\nSome centres may be using acoustic reflexes, ULL/LDL tests and otoacoustic emissions routinely, and therefore stopping these may be a change to their practice and could result in modest cost savings.\n\nReturn to recommendations\n\n# Psychoacoustic tests\n\nRecommendation 1.4.5\n\n## Why the committee made the recommendation\n\nNo clinical evidence was identified on psychoacoustic tests, for example pitch and loudness matching, for people with tinnitus. The committee thought that undertaking psychoacoustic testing in addition to hearing assessments may increase distress for some and encourage people to focus on their tinnitus more. Continued focus on tinnitus can prevent a person from habituating to it. Many management strategies involve taking away the focus from tinnitus, and so psychoacoustic testing may counteract their effectiveness.\n\nPsychoacoustic testing is mainly used as a tool in research rather than in clinical practice as the outcome of the test has no influence on the routine management of tinnitus. In addition, this testing was thought to carry an additional cost in terms of staff time, with little or no additional benefit, and even the potential for some harm. Therefore the committee agreed that it should not be used.\n\n## How the recommendation might affect practice\n\nThe recommendation reflects current best practice where psychoacoustic measures are not commonly used. However, as some departments may be using this test, implementing the recommendation will mean that some staff time, otherwise spent on the tests, will be freed up.\n\nThese tests are not commonly used for children and therefore there will be no change in current practice for paediatric services.\n\nReturn to recommendations\n\n# Imaging to investigate the cause of non-pulsatile tinnitus\n\nRecommendations 1.4.6 to 1.4.8\n\n## Why the committee made the recommendations\n\nNo evidence was identified on imaging to investigate the cause of non-pulsatile tinnitus. However, the committee agreed that scanning people with non-pulsatile tinnitus that is accompanied by neurological or head and neck signs and symptoms (for example, facial weakness, vertigo and asymmetric hearing loss) is best clinical practice. It is also important for detecting significant and potentially life-threatening central pathology, such as vestibular schwannoma compressing adjacent structures or brain tumours. Additionally, imaging people with non-pulsatile tinnitus can detect vascular arteriovenous malformations, which can also be life-threatening.\n\nImaging should also be considered where there is unilateral or asymmetrical non-pulsatile tinnitus without accompanying signs and symptoms, as it is more likely to be associated with an underlying significant pathology compared with symmetrical tinnitus. The committee agreed that no imaging should be conducted for bilateral non-pulsatile tinnitus in the absence of any associated signs and symptoms because the incidence of underlying pathology is very low.\n\nMRI is more clinically effective at showing soft tissue structures and pathology than contrast-enhanced CT. In addition, CT scanning is associated with more harm than MRI because of risks from the radiation dose and the potential for adverse reaction to the contrast media. Therefore, the committee recommended MRI as the first choice. The committee noted that MRI is loud and some people may find that this noise affects their tinnitus. Radiology departments provide earplugs to help with this.\n\n## How the recommendations might affect practice\n\nThe committee thought that, in current practice, some people with non-pulsatile unilateral tinnitus were being over tested (particularly for isolated bilateral non-pulsatile tinnitus), without proper assessment of neurological signs and symptoms beforehand. These recommendations will help to standardise clinical practice and encourage good clinical practice. They will also reassure clinicians and people with tinnitus that a scan may not always be necessary. There is the potential for some cost savings as the volume of unnecessary imaging is reduced.\n\nReturn to recommendations\n\n# Imaging to investigate the cause of pulsatile tinnitus\n\nRecommendation 1.4.9\n\n## Why the committee made the recommendation\n\nNo evidence was identified on imaging to investigate the cause of pulsatile tinnitus, so the committee used their knowledge and expertise to make a recommendation.\n\nScans are recommended on the basis of clinical manifestations and the ability of the scanning method to accurately detect pathology. Pulsatile tinnitus can have several different causes, some of which are serious. Possible causes include irregular blood vessels, high blood pressure, raised intracranial pressure, anaemia, atherosclerosis, paragangliomas, osseous pathology and glomus tumours. The underlying cause of the pulsatile tinnitus can be targeted for treatment, depending on the results of the scans.\n\nMRI is more clinically effective at showing soft tissue structures and pathology than contrast-enhanced CT whereas CT is more effective at detecting osseous changes. CT scanning is associated with risks from the radiation dose and the potential for adverse reaction to the contrast media. Therefore, the committee recommended MRI as the first choice. The committee noted that MRI is loud and some people may find that this noise affects their tinnitus. Radiology departments provide earplugs to help with this.\n\n## How the recommendation might affect practice\n\nWhen investigating synchronous pulsatile tinnitus, it is current practice to carry out imaging of the ears, head and neck, but there is no consensus about whether an MRI or magnetic resonance angiogram or a CT scan with contrast is best. This recommendation aims to standardise and improve current practice.\n\nWhen investigating non-synchronous pulsatile tinnitus, it is current practice to perform an MRI where other conditions, such as palatal myoclonus, are suspected to be the cause of tinnitus.\n\nBy directing clinicians to the most appropriate scanning method, there is a potential for some cost savings by reducing the unnecessary use of more expensive imaging techniques.\n\nReturn to recommendations\n\n# Amplification devices\n\nRecommendations 1.5.1 to 1.5.3\n\n## Why the committee made the recommendations\n\nThere was limited evidence on using amplification devices for managing tinnitus. The committee noted that many people present with tinnitus without realising that they have a hearing loss. The committee agreed that adults with tinnitus and a hearing loss that affects their ability to communicate and hear should be offered an amplification device in line with the NICE guideline on hearing loss in adults. They agreed that in similar circumstances children and young people should also be offered an amplification device.\n\nThere was no evidence to support the use of amplification devices for people with tinnitus and a hearing loss that does not cause difficulties communicating. However, given that enhancing auditory input may improve the person's perception of tinnitus, the committee recommended that amplification devices be considered.\n\nThe committee recommended that people without a hearing loss should not be offered amplification devices as amplified sound may induce a hearing loss.\n\n## How the recommendations might affect practice\n\nOffering amplification devices to people with tinnitus and hearing loss that affects their ability to communicate is in line with current practice and many organisations will not need to change practice.\n\nThere is variation in practice on the use of amplification devices for people with tinnitus and hearing loss that does not cause difficulties in communicating, and some change in practice may be needed. Organisations may need to adapt their protocols to match the recommendations. Rarely people are offered hearing aids for tinnitus when they do not have a hearing loss. Amplification devices should not be offered in these situations and a small cost saving may be made.\n\nReturn to recommendations\n\n# Sound therapy\n\n## Why the committee were unable to make recommendations\n\nThere are many types of sound therapy used by people with tinnitus. There is, however, limited evidence available that assesses the clinical and cost effectiveness of these interventions in isolation. With the different types of sound therapy and insufficient evidence for any particular type, the committee were unable to make recommendations for practice.\n\nThe committee noted that although it is important to know the clinical effectiveness of sound therapies in isolation, it is important that tinnitus support is provided in combination with these interventions. They made a research recommendation on sound therapy in combination with tinnitus support.\n\nReturn to recommendations\n\n# Psychological therapies for people with tinnitus-related distress\n\nRecommendation 1.5.4\n\n## Why the committee made the recommendation\n\nThe evidence suggests that cognitive behavioural therapy (CBT), mindfulness-based CBT and acceptance and commitment therapy (ACT) are effective interventions for managing tinnitus-related distress. CBT can be delivered in different formats such as digital (for example, internet based), group and individual face-to-face sessions.\n\nThe cost effectiveness of specific therapies is uncertain. However, economic analyses suggested that it would be less costly to use digital or group therapy first line, and individual therapy for people who are still distressed after their first-line psychological intervention.\n\nMindfulness-based cognitive therapy should be delivered by appropriately trained and supervised practitioners. The committee agreed that all psychological therapies should be supervised by psychologists.\n\nThe committee noted that with face-to-face psychological interventions (such as group CBT), people may sometimes not attend sessions. People may be more likely to complete the full intervention with digital CBT than with face-to-face sessions, as they would be able to participate according to their lifestyle, rather than having to travel to a session at a designated time. Digital CBT for tinnitus is currently only available in research, with evidence suggesting that it is clinically effective. While digital CBT is unavailable or when it is not suitable, group CBT should be used as the first-line psychological therapy. In current practice, the selection of group CBT or individual CBT is made on a case-by-case basis and mainly dependent on the availability of CBT services and individual preferences. The committee noted that some people may be hesitant about group CBT at first but may find it a more meaningful and positive experience.\n\nCBT and ACT should be delivered by psychologists because this is considered important for achieving good patient outcomes. Taking into account the clinical and economic evidence, together with a lack of direct evidence of cost effectiveness, the committee agreed that a stepped approach for adults with tinnitus-related distress could be considered.\n\nThe committee noted that no evidence was identified that evaluated psychological therapies in children and young people. Access to psychological therapies for children and young people with tinnitus is currently limited. The committee agreed that further research is needed, and made a research recommendation on psychological therapies for children and young people.\n\n## How the recommendation might affect practice\n\nIn some regions of the UK there is limited access to psychological therapies for people with tinnitus, with few healthcare professionals trained in delivering them. The committee noted that implementing the recommended psychological therapies will lead to a significant change in practice in regions where access is limited. However, to help providers in widening access to psychological therapies for people with tinnitus, the committee recommended that digital CBT be considered as a first-line intervention. This intervention would allow people with tinnitus to receive their treatment faster and help to reduce waiting lists. It is expected that some providers, working alongside clinicians (including psychologists) with experience in working with people with tinnitus, will take the initiative to adapt existing digital CBT tools available for other conditions.\n\nThe recommendation could result in cost savings for services that are currently offering individual-based psychological therapies as a first-line psychological treatment for tinnitus. This is because of the committee's view that these expensive interventions should only be used when other methods (digital CBT and group-based interventions) have been exhausted. Therefore, although some providers may incur additional expenditure as a result of implementing these recommendations, other providers might achieve cost savings. Furthermore, the committee recommended a number of different group-based psychological strategies as there is no clear evidence that 1 psychological intervention is more clinically effective than another. Providers can therefore adopt those interventions that are easiest to implement based on their existing staff and skills, and this would further minimise the resource impact.\n\nAs there is limited access to psychology services, the committee recommended that research is needed to assess the effectiveness of CBT delivered to people with tinnitus by appropriately trained and supervised healthcare practitioners other than psychologists (for example, audiologists; see research recommendation 1). This research could further help to widen access to psychological services as more clinicians would be available to provide the interventions listed in this recommendation.\n\nReturn to recommendations\n\n# Betahistine\n\nRecommendation 1.5.5\n\n## Why the committee made the recommendation\n\nThe committee noted that some people are occasionally prescribed betahistine to treat tinnitus, but it is not licensed for the treatment of tinnitus alone. Betahistine is licensed for treatment of Ménière's disease, of which tinnitus may be a symptom.\n\nThe evidence suggests that betahistine does not improve tinnitus symptoms and there is evidence of adverse effects. The committee agreed that betahistine should not be offered to treat tinnitus.\n\n## How the recommendation might affect practice\n\nAs betahistine is occasionally prescribed to treat tinnitus, implementing this recommendation could lead to cost savings.\n\nReturn to recommendations\n\n# Combining therapies\n\n## Why the committee were unable to make recommendations\n\nThe evidence for combination strategies was limited, but indicated to the committee that tinnitus support alongside other management strategies was important. No recommendations on particular combinations of tinnitus management strategies were made. However, the recommendations on tinnitus support and management in this guideline specify that everyone should receive tinnitus support along with whatever strategy (for example, amplification devices and psychological therapies) has been chosen in their management plan.\n\nThe committee noted that there is limited evidence available for the use of sound therapy with tinnitus support. They made a research recommendation on the combination of sound therapy with tinnitus support.\n\nThe committee recognised that tinnitus retraining therapy (TRT) is a specific combination management strategy. They agreed that the original protocol for TRT does not allow people to be actively engaged in the development of their management plan. TRT is used in modified forms in current practice, generally in different formats to those described in the literature. In the evidence base identified in the associated evidence review, there is variation in how TRT is delivered, which makes it difficult to determine the most clinically effective form of TRT. The committee agreed that this evidence base does not reflect the TRT interventions that are typically delivered in current practice, and that a recommendation for TRT could not be made. Modified TRT, using the principles of tinnitus support, can be evaluated under the research recommendation made in the combination management strategies review.\n\nReturn to recommendations\n\n# Neuromodulation\n\n## Why the committee were unable to make recommendations\n\nThere is great variation in neuromodulation approaches reported for tinnitus. Insufficient robust evidence meant that the committee were unable to make any practice recommendations on the use of neuromodulation therapies. They made a recommendation for research on the use of neuromodulation therapies, and noted that evidence of the safety of these techniques for use in children and young people was needed before conducting extensive research of efficacy.\n\nReturn to recommendations", 'Context': "Tinnitus is the perception of sounds in the ears or head that do not come from an outside source. It is a common condition, with similar prevalence rates in children young people and adults.\n\nThe NHS Joint Strategic Needs Assessment Guidance (2019) reports that '10% of the population will have tinnitus at some point and it will be moderately annoying in 2.8% of the population; severely annoying in 1.6%; and disrupting a person's ability to live a normal life in 0.5%'. It has also been estimated that 3% of adults might require a clinical intervention for tinnitus. The expectation is that a similar number of children will need clinical intervention for tinnitus.\n\nTinnitus can be associated with difficulty in concentrating and listening, and for some people it can be extremely distressing and have a significant impact on their mental wellbeing, family, work and social life. It is a heterogeneous condition that affects people differently both in its severity and its impact. Therefore, management of tinnitus is usually tailored according to the person's symptoms. Although there is no single effective treatment for tinnitus, there are a variety of approaches that may help people manage their tinnitus or the impact of their tinnitus.\n\nAdditionally, tinnitus is often associated with hearing loss. For example, 75% of people with hearing loss might experience tinnitus, while only 20% to 30% of people who report tinnitus have normal hearing.\n\nCurrently services across the UK vary in how accessible they are and the level of support offered for people with tinnitus. There is a lack of standardisation in assessment, referral and management approaches. This includes assessment of conditions underlying the tinnitus that need prompt, or even urgent, investigation and treatment by specialist services.\n\nThis guideline aims to improve care for people with tinnitus by providing advice to healthcare professionals on the assessment, investigation and management of tinnitus. It also offers advice on supporting people who are distressed by tinnitus and on when to refer for further assessment of their tinnitus and management."}
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https://www.nice.org.uk/guidance/ng155
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This guideline covers the assessment, investigation and management of tinnitus in primary, community and secondary care. It offers advice to healthcare professionals on supporting people presenting with tinnitus and on when to refer for specialist assessment and management.
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8bfb7e2185b7ae6b4f3bb2a1fcac5fc96334150c
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nice
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Bilateral cervicosacropexy (CESA) or vaginosacropexy (VASA) using mesh for pelvic organ prolapse
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Bilateral cervicosacropexy (CESA) or vaginosacropexy (VASA) using mesh for pelvic organ prolapse
Evidence-based recommendations on bilateral cervicosacropexy (CESA) or vaginosacropexy (VASA) using mesh for pelvic organ prolapse in adults. This involves replacing weakened or stretched ligaments that support the uterus and hold the pelvic organs in place with mesh tape.
# Recommendations
Evidence on the safety and efficacy of bilateral cervicosacropexy (CESA) or vaginosacropexy (VASA) using mesh for pelvic organ prolapse is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.
Further research should include randomised controlled trials, and report details of patient selection, technique, improvement in the prolapse, procedure-related adverse events and patient-reported outcome measures.# The condition, current treatments and procedure
# The condition
Pelvic organ prolapse is defined as symptomatic descent of 1 or more of: the anterior vaginal wall, the posterior vaginal wall, the cervix or uterus, or the apex of the vagina (vault or cuff). Symptoms include a vaginal bulge or sensation of something coming down, urinary, bowel and sexual symptoms, and pelvic and back pain. These symptoms affect women's quality of life.
# Current treatments
NICE's guideline on urinary incontinence and pelvic organ prolapse describes its management. Non-surgical management options include lifestyle modification, such as losing weight and minimising heavy lifting, topical oestrogen, pelvic floor muscle training and vaginal pessaries. Surgery may be needed when the prolapse is severe. Different surgical procedures are available using vaginal or abdominal (open, laparoscopic or robotic) approaches. Some procedures involve using mesh, the aim being to provide additional support.
# The procedure
Bilateral cervicosacropexy (CESA) or vaginosacropexy (VASA) for pelvic organ prolapse are mesh procedures, done through open or laparoscopic approaches using general anaesthesia. If the uterus is still in place, the first step of the procedure is a hysterectomy. A polyvinylidene fluoride (PVDF) mesh ligament-replacement structure is then placed within the peritoneal fold of both the left and right uterosacral ligaments. Anterior fixation of each PVDF structure is done by centrally suturing it to the cervix or vaginal vault with 3 or 4 interrupted, nonabsorbable polyester sutures. For posterior fixation, the PVDF structures are fixed to the left and right prevertebral fascia of the sacral vertebra at the level of S1 and S2, using a fixation device or sutures. The peritoneum above the cervix or vaginal vault is then closed to cover the PVDF structure. The aim is to support the pelvic organs in their correct position, and to improve symptoms associated with the prolapse.
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{'Recommendations': 'Evidence on the safety and efficacy of bilateral cervicosacropexy (CESA) or vaginosacropexy (VASA) using mesh for pelvic organ prolapse is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nFurther research should include randomised controlled trials, and report details of patient selection, technique, improvement in the prolapse, procedure-related adverse events and patient-reported outcome measures.', 'The condition, current treatments and procedure': "# The condition\n\nPelvic organ prolapse is defined as symptomatic descent of 1\xa0or more of: the anterior vaginal wall, the posterior vaginal wall, the cervix or uterus, or the apex of the vagina (vault or cuff). Symptoms include a vaginal bulge or sensation of something coming down, urinary, bowel and sexual symptoms, and pelvic and back pain. These symptoms affect women's quality of life.\n\n# Current treatments\n\nNICE's guideline on urinary incontinence and pelvic organ prolapse describes its management. Non-surgical management options include lifestyle modification, such as losing weight and minimising heavy lifting, topical oestrogen, pelvic floor muscle training and vaginal pessaries. Surgery may be needed when the prolapse is severe. Different surgical procedures are available using vaginal or abdominal (open, laparoscopic or robotic) approaches. Some procedures involve using mesh, the aim being to provide additional support.\n\n# The procedure\n\nBilateral cervicosacropexy (CESA) or vaginosacropexy (VASA) for pelvic organ prolapse are mesh procedures, done through open or laparoscopic approaches using general anaesthesia. If the uterus is still in place, the first step of the procedure is a hysterectomy. A polyvinylidene fluoride (PVDF) mesh ligament-replacement structure is then placed within the peritoneal fold of both the left and right uterosacral ligaments. Anterior fixation of each PVDF structure is done by centrally suturing it to the cervix or vaginal vault with 3\xa0or 4\xa0interrupted, nonabsorbable polyester sutures. For posterior fixation, the PVDF structures are fixed to the left and right prevertebral fascia of the sacral vertebra at the level of S1 and S2, using a fixation device or sutures. The peritoneum above the cervix or vaginal vault is then closed to cover the PVDF structure. The aim is to support the pelvic organs in their correct position, and to improve symptoms associated with the prolapse."}
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https://www.nice.org.uk/guidance/ipg669
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Evidence-based recommendations on bilateral cervicosacropexy (CESA) or vaginosacropexy (VASA) using mesh for pelvic organ prolapse in adults. This involves replacing weakened or stretched ligaments that support the uterus and hold the pelvic organs in place with mesh tape.
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4a3a09f6b13d96dab04029b79619da85abfd8a6f
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nice
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Cyanoacrylate glue occlusion for varicose veins
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Cyanoacrylate glue occlusion for varicose veins
Evidence-based recommendations on cyanoacrylate glue occlusion for varicose veins. This involves injecting medical glue (cyanoacrylate) into a vein to close it with the aim of improving symptoms.
# Recommendations
Evidence on the safety and efficacy of cyanoacrylate glue occlusion for varicose veins is adequate to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.
The procedure should only be done by clinicians with appropriate training in this procedure and experience in the use of venous ultrasound.# The condition, current treatments and procedure
# The condition
Varicose veins are a sign of underlying venous insufficiency. Primary valvular incompetence is the most common underlying cause of varicose veins. The saphenous veins are the most frequently affected vessels. Most people with varicose veins have no symptoms, but venous insufficiency may cause fatigue, heaviness, aching, throbbing, itching and cramps in the legs. Chronic venous insufficiency can lead to skin discoloration, inflammatory dermatitis and ulceration.
# Current treatments
NICE's guideline describes the diagnosis and management of varicose veins. Interventional treatment options include endothermal ablation (such as radiofrequency ablation and endovenous laser ablation therapy), foam sclerotherapy, mechanochemical ablation and surgery (usually stripping and ligation of the great and small saphenous veins, and phlebectomies).
# The procedure
Cyanoacrylate glue occlusion for varicose veins aims to close the veins by adherence then fibrosis of the lumen, without the need for tumescent anaesthesia and with reduced need for postoperative compression therapy.
The procedure is done using local anaesthesia. An introducer sheath is inserted into the distal great saphenous vein and, using ultrasound guidance, a delivery catheter is advanced into position before the saphenofemoral junction. The proximal vein is compressed, and medical glue is delivered in measured doses through the tip of the catheter to seal the vein.
This is repeated at different positions as the catheter is withdrawn, using ultrasound imaging to monitor the procedure. The procedure may also be done in a similar way for the small saphenous vein.
|
{'Recommendations': 'Evidence on the safety and efficacy of cyanoacrylate glue occlusion for varicose veins is adequate to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.\n\nThe procedure should only be done by clinicians with appropriate training in this procedure and experience in the use of venous ultrasound.', 'The condition, current treatments and procedure': "# The condition\n\nVaricose veins are a sign of underlying venous insufficiency. Primary valvular incompetence is the most common underlying cause of varicose veins. The saphenous veins are the most frequently affected vessels. Most people with varicose veins have no symptoms, but venous insufficiency may cause fatigue, heaviness, aching, throbbing, itching and cramps in the legs. Chronic venous insufficiency can lead to skin discoloration, inflammatory dermatitis and ulceration.\n\n# Current treatments\n\nNICE's guideline describes the diagnosis and management of varicose veins. Interventional treatment options include endothermal ablation (such as radiofrequency ablation and endovenous laser ablation therapy), foam sclerotherapy, mechanochemical ablation and surgery (usually stripping and ligation of the great and small saphenous veins, and phlebectomies).\n\n# The procedure\n\nCyanoacrylate glue occlusion for varicose veins aims to close the veins by adherence then fibrosis of the lumen, without the need for tumescent anaesthesia and with reduced need for postoperative compression therapy.\n\nThe procedure is done using local anaesthesia. An introducer sheath is inserted into the distal great saphenous vein and, using ultrasound guidance, a delivery catheter is advanced into position before the saphenofemoral junction. The proximal vein is compressed, and medical glue is delivered in measured doses through the tip of the catheter to seal the vein.\n\nThis is repeated at different positions as the catheter is withdrawn, using ultrasound imaging to monitor the procedure. The procedure may also be done in a similar way for the small saphenous vein."}
|
https://www.nice.org.uk/guidance/ipg670
|
Evidence-based recommendations on cyanoacrylate glue occlusion for varicose veins. This involves injecting medical glue (cyanoacrylate) into a vein to close it with the aim of improving symptoms.
|
7aa10cec0f2976bc1ad82d5b3d49f84d2f14b137
|
nice
|
MRI-guided laser interstitial thermal therapy for drug-resistant epilepsy
|
MRI-guided laser interstitial thermal therapy for drug-resistant epilepsy
Evidence-based recommendations on MRI-guided laser interstitial thermal therapy for drug-resistant epilepsy in adults and children. This involves inserting a laser into the area of the brain causing seizures.
# Recommendations
Evidence on the safety of MRI-guided laser interstitial thermal therapy for drug-resistant epilepsy shows there are serious but well-recognised safety concerns. Evidence on its efficacy is limited in quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.
Clinicians wishing to do MRI-guided laser interstitial thermal therapy for drug-resistant epilepsy should:
Inform the clinical governance leads in their NHS trusts.
Give patients and their parents or carers clear written information to support shared decision making, including NICE's information for the public.
Ensure that patients and their parents or carers understand the procedure's safety and efficacy, as well as any uncertainties about these.
Audit and review clinical outcomes of all patients having the procedure. NICE has identified relevant audit criteria and developed an audit tool (which is for use at local discretion).
Patient selection should be done by a multidisciplinary team experienced in managing drug-resistant epilepsy. This may include a neurologist, neurosurgeon, neurophysiologist, neuroradiologist and psychiatrist.
The procedure should only be done in specialist centres by clinicians with experience and specific training.
Further research could be in the form of randomised controlled trials, large case series or collaborative registries. It should report details of patient selection, including the size and site of the lesions being created, patient-reported outcomes and long-term follow up, particularly neurodevelopmental outcomes in children.# The condition, current treatments and procedure
# The condition
Epilepsy is a neurological condition characterised by episodes of abnormal electrical activity in the brain (recurrent seizures). The seizures can be focal or generalised.
# Current treatments
The main treatment for epilepsy is antiepileptic drugs taken to prevent or reduce the occurrence of seizures. However, many people with epilepsy have drug-resistant epilepsy, which is refractory to drug treatment (estimates vary between 20% and 40% of people with epilepsy). They have frequent seizures and are at risk of status epilepticus and sudden unexpected death in epilepsy. If drug treatment fails to control the epilepsy adequately, surgery may be considered. Surgical options include open surgical resection (such as lesionectomy, anterior temporal lobectomy or hemispherectomy) or disconnection (such as multiple subpial transection or corpus callosotomy), neuroablation (for example, with stereotactic radiosurgery, radiofrequency thermocoagulation or MRI-guided focused ultrasound) or neuromodulation (such as cranial nerve stimulation, deep-brain stimulation or closed-loop stimulation).
# The procedure
Preoperatively, an MRI scan is done to identify the part of the brain causing the seizures and to identify the entry location for the laser catheter. The procedure is usually done under general anaesthesia with the patient lying on an MRI couch. A small burr hole is made in the skull and a fine fibreoptic laser catheter is inserted into the target area under stereotactic guidance. Continuous real-time MRI scanning is done to allow visualisation of the exact target area to be ablated and the surrounding tissue, and to monitor the temperature in the brain during the procedure. Under computer guidance, laser energy is applied to the target area. The laser is switched off and removed when temperatures have reached levels sufficient to cause coagulation necrosis (usually 46°C to 60°C) and the target tissue has been ablated. After the procedure, an MRI is done to verify the location and volume of the tissue ablated. The aim is to precisely ablate the target tissue and to minimise damage to the surrounding area. MRI-guided laser interstitial thermal therapy has most commonly been used for patients with a well-defined epileptogenic focus, especially in the temporal lobe, but it can be used elsewhere in the brain.
|
{'Recommendations': "Evidence on the safety of MRI-guided laser interstitial thermal therapy for drug-resistant epilepsy shows there are serious but well-recognised safety concerns. Evidence on its efficacy is limited in quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wishing to do MRI-guided laser interstitial thermal therapy for drug-resistant epilepsy should:\n\nInform the clinical governance leads in their NHS trusts.\n\nGive patients and their parents or carers clear written information to support shared decision making, including NICE's information for the public.\n\nEnsure that patients and their parents or carers understand the procedure's safety and efficacy, as well as any uncertainties about these.\n\nAudit and review clinical outcomes of all patients having the procedure. NICE has identified relevant audit criteria and developed an audit tool (which is for use at local discretion).\n\nPatient selection should be done by a multidisciplinary team experienced in managing drug-resistant epilepsy. This may include a neurologist, neurosurgeon, neurophysiologist, neuroradiologist and psychiatrist.\n\nThe procedure should only be done in specialist centres by clinicians with experience and specific training.\n\nFurther research could be in the form of randomised controlled trials, large case series or collaborative registries. It should report details of patient selection, including the size and site of the lesions being created, patient-reported outcomes and long-term follow up, particularly neurodevelopmental outcomes in children.", 'The condition, current treatments and procedure': '# The condition\n\nEpilepsy is a neurological condition characterised by episodes of abnormal electrical activity in the brain (recurrent seizures). The seizures can be focal or generalised.\n\n# Current treatments\n\nThe main treatment for epilepsy is antiepileptic drugs taken to prevent or reduce the occurrence of seizures. However, many people with epilepsy have drug-resistant epilepsy, which is refractory to drug treatment (estimates vary between 20% and 40% of people with epilepsy). They have frequent seizures and are at risk of status epilepticus and sudden unexpected death in epilepsy. If drug treatment fails to control the epilepsy adequately, surgery may be considered. Surgical options include open surgical resection (such as lesionectomy, anterior temporal lobectomy or hemispherectomy) or disconnection (such as multiple subpial transection or corpus callosotomy), neuroablation (for example, with stereotactic radiosurgery, radiofrequency thermocoagulation or MRI-guided focused ultrasound) or neuromodulation (such as cranial nerve stimulation, deep-brain stimulation or closed-loop stimulation).\n\n# The procedure\n\nPreoperatively, an MRI scan is done to identify the part of the brain causing the seizures and to identify the entry location for the laser catheter. The procedure is usually done under general anaesthesia with the patient lying on an MRI couch. A small burr hole is made in the skull and a fine fibreoptic laser catheter is inserted into the target area under stereotactic guidance. Continuous real-time MRI scanning is done to allow visualisation of the exact target area to be ablated and the surrounding tissue, and to monitor the temperature in the brain during the procedure. Under computer guidance, laser energy is applied to the target area. The laser is switched off and removed when temperatures have reached levels sufficient to cause coagulation necrosis (usually 46°C to 60°C) and the target tissue has been ablated. After the procedure, an MRI is done to verify the location and volume of the tissue ablated. The aim is to precisely ablate the target tissue and to minimise damage to the surrounding area. MRI-guided laser interstitial thermal therapy has most commonly been used for patients with a well-defined epileptogenic focus, especially in the temporal lobe, but it can be used elsewhere in the brain.'}
|
https://www.nice.org.uk/guidance/ipg671
|
Evidence-based recommendations on MRI-guided laser interstitial thermal therapy for drug-resistant epilepsy in adults and children. This involves inserting a laser into the area of the brain causing seizures.
|
cad8b1b96c7844113990bbfdf6b98c7c388a843d
|
nice
|
Selective internal radiation therapy for unresectable colorectal metastases in the liver
|
Selective internal radiation therapy for unresectable colorectal metastases in the liver
Evidence-based recommendations on selective internal radiation therapy for unresectable colorectal metastases in the liver in adults. This involves injecting beads that emit radiation directly into the tumour.
# Recommendations
Evidence on the safety of selective internal radiation therapy (SIRT) for unresectable colorectal metastases in the liver shows there can be serious complications, but these are well recognised and infrequent.
In people who cannot tolerate chemotherapy or have liver metastases that are refractory to chemotherapy, there is evidence of efficacy but this is limited, particularly for important outcomes such as quality of life. Therefore, in these people, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.
In people who can have chemotherapy, evidence on overall survival and quality of life is inadequate in quality. Therefore, in these people, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.
Clinicians wishing to do SIRT for unresectable colorectal metastases in the liver, in people who cannot have chemotherapy or have liver metastases that are refractory to chemotherapy, should:
Inform the clinical governance leads in their NHS trusts.
Give patients clear written information to support shared decision making, including NICE's information for the public.
Ensure that patients understand the procedure's safety and efficacy, as well as any uncertainties about these.
Audit and review clinical outcomes of all patients having the procedure. Clinicians should enter details for all patients having SIRT for unresectable colorectal metastases in the liver onto a suitable register.
Patient selection should be done by a specialist hepatobiliary cancer multidisciplinary team that can offer the full range of treatment options for this condition.
This procedure should only be done by clinicians with specific training in SIRT including techniques to minimise the risk of damage to surrounding tissue.
Further research should report details of patient selection, whether the primary colorectal tumour arose in the left or right side of the colon, extrahepatic disease, and tumour‑to‑liver volume. Outcomes should include survival and quality of life.
NICE may update the guidance on publication of further evidence.# The condition, current treatments and procedure
# The condition
Around 30% to 50% of people with colorectal cancer have liver metastases at the time of presentation or develop them during the course of the disease.
# Current treatments
Treatment of liver (hepatic) metastases depends on their extent and location. For unresectable tumours, treatment options include thermal ablation techniques, chemotherapy, different types of arterial embolisation therapy and external beam radiotherapy.
# The procedure
Selective internal radiation therapy (SIRT; also known as radioembolisation) can be used as palliative treatment for unresectable colorectal metastases in the liver.
SIRT involves delivering microspheres containing radionuclides that emit beta radiation directly into the tumour. This aims to minimise the risk of radiation damage to surrounding healthy tissue. Using local anaesthesia and fluoroscopic guidance, the radioactive microspheres are injected into branches of the hepatic artery supplying the tumour. A percutaneous approach is used through the femoral or radial artery. The microspheres lodge in small arteries within and surrounding the tumour, releasing high doses of radiation directly into it. The procedure may be repeated depending on the response.
|
{'Recommendations': "Evidence on the safety of selective internal radiation therapy (SIRT) for unresectable colorectal metastases in the liver shows there can be serious complications, but these are well recognised and infrequent.\n\nIn people who cannot tolerate chemotherapy or have liver metastases that are refractory to chemotherapy, there is evidence of efficacy but this is limited, particularly for important outcomes such as quality of life. Therefore, in these people, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nIn people who can have chemotherapy, evidence on overall survival and quality of life is inadequate in quality. Therefore, in these people, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nClinicians wishing to do SIRT for unresectable colorectal metastases in the liver, in people who cannot have chemotherapy or have liver metastases that are refractory to chemotherapy, should:\n\nInform the clinical governance leads in their NHS trusts.\n\nGive patients clear written information to support shared decision making, including NICE's information for the public.\n\nEnsure that patients understand the procedure's safety and efficacy, as well as any uncertainties about these.\n\nAudit and review clinical outcomes of all patients having the procedure. Clinicians should enter details for all patients having SIRT for unresectable colorectal metastases in the liver onto a suitable register.\n\nPatient selection should be done by a specialist hepatobiliary cancer multidisciplinary team that can offer the full range of treatment options for this condition.\n\nThis procedure should only be done by clinicians with specific training in SIRT including techniques to minimise the risk of damage to surrounding tissue.\n\nFurther research should report details of patient selection, whether the primary colorectal tumour arose in the left or right side of the colon, extrahepatic disease, and tumour‑to‑liver volume. Outcomes should include survival and quality of life.\n\nNICE may update the guidance on publication of further evidence.", 'The condition, current treatments and procedure': '# The condition\n\nAround 30% to 50% of people with colorectal cancer have liver metastases at the time of presentation or develop them during the course of the disease.\n\n# Current treatments\n\nTreatment of liver (hepatic) metastases depends on their extent and location. For unresectable tumours, treatment options include thermal ablation techniques, chemotherapy, different types of arterial embolisation therapy and external beam radiotherapy.\n\n# The procedure\n\nSelective internal radiation therapy (SIRT; also known as radioembolisation) can be used as palliative treatment for unresectable colorectal metastases in the liver.\n\nSIRT involves delivering microspheres containing radionuclides that emit beta radiation directly into the tumour. This aims to minimise the risk of radiation damage to surrounding healthy tissue. Using local anaesthesia and fluoroscopic guidance, the radioactive microspheres are injected into branches of the hepatic artery supplying the tumour. A percutaneous approach is used through the femoral or radial artery. The microspheres lodge in small arteries within and surrounding the tumour, releasing high doses of radiation directly into it. The procedure may be repeated depending on the response.'}
|
https://www.nice.org.uk/guidance/ipg672
|
Evidence-based recommendations on selective internal radiation therapy for unresectable colorectal metastases in the liver in adults. This involves injecting beads that emit radiation directly into the tumour.
|
d681675f7f67a6a4a51474fea2760c3226657c02
|
nice
|
Impetigo: antimicrobial prescribing
|
Impetigo: antimicrobial prescribing
This guideline sets out an antimicrobial prescribing strategy for adults, young people and children aged 72 hours and over with impetigo. It aims to optimise antibiotic use and reduce antibiotic resistance.
# Recommendations
# Managing impetigo
## Advice to reduce the spread of impetigo
Advise people with impetigo, and their parents or carers if appropriate, about good hygiene measures to reduce the spread of impetigo to other areas of the body and to other people.
For a short explanation of why the committee made the recommendation, see the rationale section on advice to reduce the spread of impetigo .
Full details of the evidence and the committee's discussion are in evidence review.
Loading. Please wait.
## Initial treatment
Consider hydrogen peroxide 1% cream for people with localised non-bullous impetigo who are not systemically unwell or at high risk of complications (see recommendations on choice of antimicrobial). Although other topical antiseptics are available for treating superficial skin infections, no evidence was found for using them to treat impetigo.
If hydrogen peroxide 1% cream is unsuitable, offer a short course of a topical antibiotic for people with localised non-bullous impetigo who are not systemically unwell or at high risk of complications (see recommendations on choice of antimicrobial).
Offer a short course of a topical or oral antibiotic for people with widespread non‑bullous impetigo who are not systemically unwell or at high risk of complications (see recommendations on choice of antimicrobial). Take into account:
that topical and oral antibiotics are both effective at treating impetigo
the preferences of the person and, if appropriate, their parents or carers, including the practicalities of administration (particularly to large areas) and possible adverse effects
previous use of topical antibiotics because antimicrobial resistance can develop rapidly with extended or repeated use.
Offer a short course of an oral antibiotic for:
all people with bullous impetigo
people with non-bullous impetigo who are systemically unwell or at high risk of complications.See recommendations on choice of antimicrobial.
Do not offer combination treatment with a topical and oral antibiotic to treat impetigo.
For a short explanation of why the committee made these recommendations, see the rationale section on initial treatment .
Full details of the evidence and the committee's discussion are in evidence review.
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## Advice on treatment
Advise people with impetigo, and their parents or carers if appropriate, to seek medical help if symptoms worsen rapidly or significantly at any time, or have not improved after completing a course of treatment.
## Reassessment and further treatment
Reassess people with impetigo if their symptoms worsen rapidly or significantly at any time or have not improved after completing a course of treatment.
When reassessing people with impetigo, take account of:
-ther possible diagnoses, such as herpes simplex
any symptoms or signs suggesting a more serious illness or condition, such as cellulitis
previous antibiotic use, which may have led to resistant bacteria.
For people with impetigo that is worsening or has not improved after treatment with hydrogen peroxide 1% cream, offer:
a short course of a topical antibiotic if the impetigo remains localised or
a short course of a topical or oral antibiotic if the impetigo has become widespread (see the recommendation on widespread non-bullous impetigo).
For people with impetigo that is worsening or has not improved after completing a course of topical antibiotics:
-ffer a short course of an oral antibiotic (see the recommendations on choice of antimicrobial) and
consider sending a skin swab for microbiological testing.
For people with impetigo that is worsening or has not improved after completing a course of oral antibiotics, consider sending a skin swab for microbiological testing.
For people with impetigo that recurs frequently:
send a skin swab for microbiological testing and
consider taking a nasal swab and starting treatment for decolonisation.
If a skin swab has been sent for microbiological testing:
review the choice of antibiotic when results are available and
change the antibiotic according to results if symptoms are not improving, using a narrow-spectrum antibiotic if possible.
For a short explanation of why the committee made these recommendations, see the rationale section on reassessment and further treatment for impetigo .
Full details of the evidence and the committee's discussion are in evidence review.
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## Referral and seeking specialist advice
Refer to hospital:
people with impetigo and any symptoms or signs suggesting a more serious illness or condition (for example, cellulitis)
people with widespread impetigo who are immunocompromised.
Consider referral or seeking specialist advice for people with impetigo if they:
have bullous impetigo, particularly in babies (aged 1 year and under)
have impetigo that recurs frequently
are systemically unwell
are at high risk of complications.
For a short explanation of why the committee made these recommendations, see the rationale section on referral and seeking specialist advice for impetigo .
Full details of the evidence and the committee's discussion are in evidence review.
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# Choice of antimicrobial
When prescribing an antimicrobial for impetigo, take account of local antimicrobial resistance data when available and follow:
Table 1 for adults aged 18 years and over
Table 2 for children and young people under 18 years.
Treatment
Antimicrobial, dosage and course length
Topical antiseptic
Hydrogen peroxide 1%:
Apply two or three times a day for 5 days
First-choice topical antibiotic if hydrogen peroxide is unsuitable (for example, if impetigo is around eyes) or ineffective
Fusidic acid 2%:
Apply three times a day for 5 days
Alternative topical antibiotic if fusidic acid resistance is suspected or confirmed
Mupirocin 2%:
Apply three times a day for 5 days
First-choice oral antibiotic
Flucloxacillin:
mg four times a day for 5 days
Alternative oral antibiotic for penicillin allergy or if flucloxacillin is unsuitable (for people who are not pregnant)
Clarithromycin:
mg twice a day for 5 days (the dosage can be increased to 500 mg twice a day, if needed for severe infections)
Alternative oral antibiotic for penicillin allergy in pregnancy
Erythromycin:
mg to 500 mg four times a day for 5 days
Erythromycin is preferred if a macrolide is needed in pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. See the Medicines and Healthcare products Regulatory Agency (MHRA) Public Assessment Report on the safety of macrolide antibiotics in pregnancy.
If meticillin-resistant
Staphylococcus aureus
is suspected or confirmed
Consult a local microbiologist
See the BNF for appropriate use and dosing in specific populations, for example, in people with hepatic or renal impairment, and in pregnancy and breastfeeding.
A 5‑day course is usually appropriate but can be increased to 7 days based on clinical judgement, depending on the severity and number of lesions.
Other topical antiseptics besides hydrogen peroxide are available for superficial skin infections, but no evidence was found for these in impetigo
As with all antibiotics, extended or recurrent use of topical fusidic acid or mupirocin may increase the risk of developing antimicrobial resistance. See the BNF for more information.
Treatment
Antimicrobial, dosage and course length
Topical antiseptic
Hydrogen peroxide 1%:
Apply two or three times a day for 5 days
First-choice topical antibiotic if hydrogen peroxide is unsuitable (for example, if impetigo is around eyes) or ineffective
Fusidic acid 2%:
Apply three times a day for 5 days
Alternative topical antibiotic if fusidic acid resistance is suspected or confirmed
Mupirocin 2%:
Apply three times a day for 5 days
First-choice oral antibiotic
Flucloxacillin (oral solution or capsules):
month to 1 year, 62.5 mg to 125 mg four times a day for 5 days
years to 9 years, 125 mg to 250 mg four times a day for 5 days
years to 17 years, 250 mg to 500 mg four times a day for 5 days
Alternative oral antibiotic for penicillin allergy or if flucloxacillin is unsuitable (for people who are not pregnant; for example, if an oral solution is unpalatable and the child is unable to swallow capsules)
Clarithromycin:
month to 11 years:
under 8 kg, 7.5 mg/kg twice a day for 5 days
kg to 11 kg, 62.5 mg twice a day for 5 days
kg to 19 kg, 125 mg twice a day for 5 days
kg to 29 kg, 187.5 mg twice a day for 5 days
kg to 40 kg, 250 mg twice a day for 5 days
years to 17 years, 250 mg twice a day for 5 days (the dosage can be increased to 500 mg twice a day, if needed for severe infections)
Alternative oral antibiotic for penicillin allergy in pregnancy
Erythromycin:
years to 17 years, 250 mg to 500 mg four times a day for 5 days
Erythromycin is preferred if a macrolide is needed in pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. See the Medicines and Healthcare products Regulatory Agency (MHRA) Public Assessment Report on the safety of macrolide antibiotics in pregnancy.
If meticillin-resistant
Staphylococcus aureus
is suspected or confirmed
Consult a local microbiologist
See the BNF for Children for appropriate use and dosing in specific populations, for example, in people with hepatic or renal impairment, and in pregnancy and breastfeeding. Dosing in some age groups may be off-label.
The age bands apply to children of average size and, in practice, the prescriber will use the age bands with other factors such as the severity of the condition being treated and the child's size in relation to the average size of children of the same age.
A 5‑day course is usually appropriate but can be increased to 7 days based on clinical judgement, depending on the severity and number of lesions.
Other topical antiseptics besides hydrogen peroxide are available for superficial skin infections, but no evidence was found for these in impetigo.
Licenses for mupirocin use in infants vary between products. See individual summaries of product characteristics for details.
As with all antibiotics, extended or recurrent use of topical fusidic acid or mupirocin may increase the risk of developing antimicrobial resistance. See the BNF for Children for more information.
If flucloxacillin oral solution is not tolerated because of poor palatability, consider capsules (see the Medicines for Children leaflet on helping your child to swallow tablets).
For a short explanation of why the committee made this recommendation, see the rationale section on choice of antimicrobial for impetigo .
Full details of the evidence and the committee's discussion are in evidence review.
Loading. Please wait.
# Terms used in the guideline
## Non-bullous impetigo
Impetigo characterised by thin-walled vesicles or pustules that rupture quickly, forming a golden-brown crust.
## Bullous impetigo
Impetigo characterised by the presence of fluid-filled vesicles and blisters often with a diameter of over 1 cm that rupture, leaving a thin, flat, yellow-brown crust.
## Decolonisation
Use of topical treatments (antiseptic body wash, nasal ointment or a combination of both) and personal hygiene measures to remove the bacteria causing the infection from the body.# Recommendation for research
The guideline committee has made the following recommendation for research.
# Antiseptics compared with antibiotics for impetigo
For which people with impetigo are antiseptics as effective as antibiotics?
For a short explanation of why the committee made the recommendation for research, see the rationales .
Full details of the evidence and the committee's discussion are in the evidence review.
Loading. Please wait.# Rationales
The recommendations in this guideline are based on the evidence identified and the experience of the committee.
# Advice to reduce the spread of impetigo
## Why the committee made the recommendation
Recommendation 1.1.1
The committee agreed, based on its experience, that good hygiene measures help reduce the spread of impetigo, both to other areas of the body and to other people. The committee noted that resources are available with further information (see the management of impetigo in NICE's clinical knowledge summary on impetigo).
Return to the recommendations
# Initial treatment
## Why the committee made the recommendations
Recommendations 1.1.2 to 1.1.6
The evidence showed that impetigo was cured or improved with a placebo in some people. However, impetigo is highly infectious, and the committee agreed that treatment is important to limit the spread of infection and the worsening of symptoms, and to hasten recovery. A faster recovery is also likely to mean less time off school, nursery or work.
It was not clear in the evidence reviewed if impetigo was localised or widespread. The committee agreed that different treatment options are appropriate for impetigo based on the type and extent of the infection. It agreed that clinical judgement should be used to determine whether impetigo is localised or widespread.
The evidence suggested that hydrogen peroxide 1% cream (a topical antiseptic) is as effective as a topical antibiotic for treating impetigo. Impetigo was cured or improved in a large proportion of people using hydrogen peroxide. The committee noted this evidence came from 1 randomised controlled trial. Based on its experience, the committee agreed that the risk of adverse effects from hydrogen peroxide at 1% concentration, such as irritation and skin bleaching, are minimal. They also agreed that the significance of this is especially low when compared with the risk of adverse effects associated with topical antibiotics, such as rapid development of antimicrobial resistance.
The committee was aware that the use of hydrogen peroxide 1% cream for impetigo is a change in practice and health professionals may not be familiar with its use. It noted that some other topical antiseptics are licensed for superficial skin infections, which may be cheaper and more widely available. However, no evidence was identified for treating impetigo with other topical antiseptics, so the committee could not make a recommendation for their use. Based on the available evidence, the committee agreed that the long-term benefits of good antimicrobial stewardship, in combination with the low risk of adverse events compared with using a topical antibiotic, outweighed the additional cost of hydrogen peroxide 1% cream.
Overall, the evidence showed that a topical antibiotic was as effective as an oral antibiotic for curing or improving impetigo. Based on the evidence and its experience, the committee agreed that topical antibiotics would cause fewer adverse effects than oral antibiotics, and that applying a topical antibiotic is usually straightforward for localised impetigo. The committee discussed its experience of antimicrobial resistance with topical antibiotics compared with oral antibiotics. It agreed that the likely increased risk of resistance with topical antibiotics applied to a localised area of impetigo for a short duration was outweighed by the increased risk of adverse events with oral antibiotics. The committee therefore agreed that if hydrogen peroxide 1% cream is unsuitable, for example, because impetigo is around the eyes, a topical antibiotic should be offered for people who are not systemically unwell or at high risk of complications.
Based on its experience, the committee agreed that people with widespread non-bullous impetigo should be offered a short course of either a topical or an oral antibiotic. They discussed that the choice of topical or oral use would be an individualised clinical decision, taking local antimicrobial resistance data into account alongside patient preference, practicalities of administration, possible adverse effects and previous use.
The committee discussed that effectively applying a cream may be difficult over larger skin areas. It agreed that an oral antibiotic may be a better option for some people with widespread non-bullous impetigo, despite the higher risk of adverse events, and that the decision should be based on a discussion of the person's preferences and the balance of risks and benefits. Antimicrobial resistance can develop rapidly with the use of topical antibiotics, and the committee agreed that repeated doses or extended use of the same topical antibiotic should be avoided.
The evidence on treating bullous impetigo was limited to a small study in newborn babies. From its experience, the committee discussed that the presence of bullae may mean that a topical antibiotic is unable to reach the infected area. Therefore, it agreed that an oral antibiotic is needed to target the infection adequately.
No evidence was identified for treating people who are systemically unwell or at higher risk of complications. Based on its experience of current practice, and because of the high risk of harm if topical application of antibiotic is inadequate, the committee agreed that this population should be offered an oral antibiotic. People at higher risk of complications can include, for example, people who are immunocompromised or have coexisting skin conditions.
The evidence suggested that combination treatment with an oral and topical antibiotic was no more effective than a topical antibiotic alone. The committee agreed that combination treatment should be discouraged because of the increased risk of adverse events and antimicrobial resistance.
The committee agreed that further research is needed to more clearly show which populations would benefit from antiseptic treatment. A research recommendation was developed to encourage more research in this area, which may contribute to future antibiotic-sparing recommendations and help reduce the risk of resistance and adverse events with antibiotics.
For more detail see the summary of the evidence on antimicrobials.
Return to the recommendations
# Reassessment and further treatment
## Why the committee made the recommendations
Recommendations 1.1.8 to 1.1.14
No evidence was identified for reassessing people with impetigo if initial treatment is unsuccessful. Therefore, the committee agreed on good practice points for this population based on consensus.
Based on its experience and the evidence for initial treatment, the committee agreed that a short course of a topical antibiotic should be offered for localised non-bullous impetigo if hydrogen peroxide 1% cream is ineffective. If impetigo becomes widespread after treatment, a short course of a topical or oral antibiotic should be offered, in line with the recommendation for initial treatment for widespread non-bullous impetigo. Although there is no evidence that oral antibiotics are more effective than topical antibiotics, the committee agreed that an oral antibiotic is more likely to target all areas of infection and that there is a risk of inadequate application of topical antibiotics. Based on its experience, the committee decided that an oral antibiotic should be an option if a topical antibiotic is unsuccessful. It also agreed that microbiological testing of an area of infected skin may help to guide antimicrobial prescribing.
For people with impetigo that recurs frequently, the committee agreed that a skin swab should be sent for microbiological testing to determine antimicrobial susceptibility. A nasal swab should also be considered if nasal carriage of Staphylococcus aureus is suspected. A nasal or skin (or combination) decolonisation regimen should be considered, based on clinical judgement and microbiological test results, in order to remove the bacteria causing recurrence of infection. The committee recognised that family decolonisation may be appropriate in some cases but did not make a recommendation because this decision should be based on specialist advice.
The committee agreed on good practice for antimicrobial stewardship when reviewing the results of microbiological tests. This includes changing to a narrow-spectrum antibiotic or continuing with a narrow-spectrum antibiotic that has shown resistance in microbiological tests if symptoms are already improving.
Return to the recommendations
# Referral and seeking specialist advice
## Why the committee made the recommendations
Recommendations 1.1.15 to 1.1.16
Based on its experience, the committee agreed that people who may have a more serious illness or condition or are immunocompromised with widespread impetigo need further assessment and treatment in hospital. Sometimes impetigo is difficult to treat (for example, bullous impetigo or impetigo that recurs frequently) and the committee agreed that referral or specialist advice should be an option.
Return to the recommendations
# Choice of antimicrobial
## Why the committee made the recommendation
Recommendation 1.2.1
The evidence suggested that hydrogen peroxide 1% cream is effective and based on its experience, the committee agreed that a short course of treatment is associated with a low risk of adverse events. There was no evidence identified for other topical antiseptics.
The evidence showed that fusidic acid is as effective as other topical antibiotics and is associated with fewer adverse events. Based on this evidence, current practice and its experience, the committee agreed that the first-choice topical antibiotic in adults, young people and children with non-bullous impetigo when hydrogen peroxide 1% cream is unsuitable (including when impetigo is widespread) is fusidic acid 2% (either as a cream or an ointment). Based on its experience, the committee agreed that fusidic acid resistance rates are higher than for some other antibiotics. However, the evidence showed fewer skin reactions with fusidic acid compared with mupirocin. The committee agreed that the risk of antimicrobial resistance should be considered when offering an antibiotic, but that this risk is likely to be low in people with a first episode of impetigo.
The alternative topical antibiotic in adults, young people and children with non-bullous impetigo (when a topical antiseptic is unsuitable or has been ineffective) and fusidic acid resistance is suspected or confirmed is mupirocin 2% (either as a cream or an ointment). The committee based this on its experience and knowledge of current practice, evidence that mupirocin is as effective as other topical antibiotics for treatment of impetigo and its experience that mupirocin resistance rates are low.
National antimicrobial resistance data from Public Health England's voluntary surveillance reports on Staphylococcus aureus showed resistance rates for meticillin-susceptible Staphylococcus aureus (MSSA) bloodstream infection of 13% for fusidic acid and less than 1% for mupirocin in 2018. The equivalent rates for meticillin-resistant Staphylococcus aureus (MRSA) bloodstream infection were 25% and 3%. However, the committee discussed that resistance rates in blood isolates may not be a good indicator of resistance rates in skin isolates, which can vary greatly from person to person, based on their history of antibiotic use, and between localities.
There was some evidence showing that topical ozenoxacin is more effective than placebo for treating impetigo. However, because the evidence did not compare topical ozenoxacin with another antibiotic, the committee could not make recommendations for its use. It was also noted that topical ozenoxacin is not currently available in the UK.
Based on its experience and knowledge of current practice, the committee agreed that the first-choice oral antibiotic in adults, young people and children is flucloxacillin. This is a relatively narrow-spectrum penicillin that is effective against Staphylococcus aureus and Streptococcus pyogenes. The committee recognised that some children may not be able to tolerate flucloxacillin solution or swallow capsules. For these children, the alternative oral antibiotic is suitable.
The alternative oral antibiotic in adults, young people and children with penicillin allergy or if flucloxacillin is unsuitable is clarithromycin. In pregnancy, erythromycin was recommended if there is true penicillin allergy. The committee agreed that these antibiotics are effective against the common pathogens that cause impetigo, and the evidence indicated that macrolides are as effective as penicillins for treating impetigo.
The committee discussed the MHRA Public Assessment Report on the safety of macrolide antibiotics in pregnancy. This found that the available evidence is insufficient to confirm with certainty whether there is a small increased risk of birth defects or miscarriage when macrolides are taken in early pregnancy. They agreed with the UK Teratology Information Service monograph on the use of macrolides in pregnancy. They decided that there should be an informed discussion of the potential benefits and harms of treatment. Then, after such a discussion, macrolides can be used if there is a compelling clinical need and there are no suitable alternatives with adequate pregnancy safety data. Erythromycin is the preferred choice if a macrolide is needed during pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. This is because there is more documented experience of its use than for other macrolides.
The committee discussed that in its experience, MRSA infection in impetigo is rare and that appropriate antibiotic choice may depend on local antimicrobial resistance rates. Therefore, the committee agreed that for people with suspected or confirmed MRSA, a local microbiologist should be consulted.
There was very little evidence on dosage and course length. Therefore, the recommendations were based on committee experience of current practice and the BNF. The committee also agreed that the shortest course that is likely to be effective should be prescribed to reduce the risk of antimicrobial resistance and adverse effects. All doses are given as in the BNF. Based on its experience that lower doses are not clinically effective due to poor oral bioavailability, the committee agreed that the higher dose for flucloxacillin recommended in the BNF is appropriate for treating impetigo in adults. The committee agreed that dose ranges are appropriate for children as the appropriate dose may vary depending on the age and weight of the child.
From its experience, the committee agreed that 5 days of treatment would be sufficient for treating most people with impetigo, and this is consistent with current practice. However, the committee was aware that some people may need a longer course because of the severity or number of lesions, so agreed that this could be up to 7 days, based on clinical judgement. The committee noted current BNF advice that topical fusidic acid and mupirocin should not be used for longer than 10 days.
For more details see the summary of the evidence on choice of antibiotic.
Return to the recommendations# Context
Impetigo is a contagious, bacterial infection of the superficial layers of the skin. The most common bacterial pathogen is Staphylococcus aureus, although infection with Streptococcus pyogenes or a combination of both pathogens is also seen. Impetigo affects all age groups; however it is most common in young children.# Summary of the evidence
This is a summary of the evidence, for full details see the evidence review.
# Antimicrobials
## Efficacy of topical antibiotics
The following topical antibiotics were shown to be more effective than placebo for the outcome of cure or improvement:
mupirocin in adults, young people and children
fusidic acid in children
-zenoxacin in children.
## Efficacy of oral antibiotics
Phenoxymethylpenicillin was not statistically significantly different compared with placebo in children for the outcome of cure or improvement.
## Topical antibiotics compared with antiseptics, steroids or antifungals
There were no statistically significant differences in clinical effectiveness of the following comparisons for the outcome of cure or improvement:
topical antibiotic (fusidic acid) compared with a topical antiseptic (hydrogen peroxide 1%) in children
topical antibiotic (gentamicin) compared with a topical steroid (betamethasone valerate; age not reported)
topical antibiotic (gentamicin) plus a topical steroid (betamethasone valerate) compared with a topical steroid (betamethasone valerate; age not reported)
topical antibiotic (mupirocin) compared with a topical antifungal (terbinafine) in children.
## Safety of antibiotics
There were no statistically significant differences in adverse effects for the following comparisons:
topical mupirocin and placebo in adults, young people and children
topical fusidic acid and disinfectants in children
topical mupirocin and antifungals in children.
No safety or tolerability data were reported for the other comparisons.
The evidence for the efficacy and safety of antimicrobials is based on 1 systematic review and meta-analysis of randomised controlled trials (RCTs; Koning et al. 2012) and 1 pooled-analysis of 2 RCTs (Hebert et al. 2018).
# Choice of antibiotics
## Topical antibiotics
There were no statistically significant differences in the clinical effectiveness of the following topical antibiotic comparisons for the outcome of cure or improvement:
topical mupirocin compared with topical fusidic acid in adults, young people and children
topical mupirocin compared with topical neomycin in children and young people
topical mupirocin compared with topical polymyxin B plus neomycin (population not reported).
Some differences were seen for cure or improvement for other topical antibiotic comparisons:
topical fusidic acid was more effective than topical neomycin plus bacitracin in children
topical gentamicin was more effective than topical neomycin in adults, young people and children.
There were no statistically significant differences in adverse effects between topical mupirocin compared with topical polymyxin B plus neomycin (age not reported).
The incidence of skin rash was increased with topical mupirocin compared with topical fusidic acid in adults, young people and children.
No safety or tolerability data were reported for the other comparisons.
## Oral antibiotics
There were no statistically significant differences in the clinical effectiveness of the following oral antibiotic comparisons for the outcome of cure or improvement:
-ral macrolides compared with oral penicillins in adults, young people and children
-ral erythromycin compared with oral amoxicillin in children
-ral azithromycin compared with oral erythromycin in adults, young people and children
-ral cefalexin compared with oral cefadroxil in children and young people
-ral cefalexin compared with oral erythromycin in children or oral azithromycin in adults
-ral cefaclor compared with oral azithromycin or oral co-amoxiclav in children
-ral cefadroxil compared with oral flucloxacillin in adults, young people and children.
Some differences were seen for cure or improvement for other antibiotic comparisons:
-ral erythromycin was more effective than phenoxymethylpenicillin in children
-ral co-amoxiclav was more effective than oral amoxicillin in children and young people
-ral cefalexin was more effective than oral phenoxymethylpenicillin in children.
There were no statistically significant differences in adverse effects for the following oral antibiotic comparisons:
-ral co-amoxiclav compared with oral amoxicillin in children and young people
-ral cefalexin compared with oral azithromycin in adults
-ral cefaclor compared with oral azithromycin in children
-ral cefaclor compared with co-amoxiclav in children.
Some differences were seen in adverse effects for other oral antibiotic comparisons:
there were more incidences of diarrhoea in children taking oral erythromycin compared with oral amoxicillin
there were more incidences of stomach ache, rash, fever or vomiting but fewer incidents of diarrhoea in adults, young people and children taking oral cefadroxil compared with oral flucloxacillin.
No safety or tolerability data were reported for the other comparisons.
## Dual antibiotics
There were no statistically significant differences in the clinical effectiveness of the following antibiotic comparisons in children for the outcome of cure or improvement:
-ral cefdinir plus topical tetracycline compared with topical tetracycline
-ral minomycin plus topical tetracycline compared with topical tetracycline
-ral fosfomycin plus topical tetracycline compared with topical tetracycline.
The evidence for choice of antibiotics is based on 1 systematic review and meta-analysis of RCTs (Koning et al. 2012).
# Course length
## Shorter course antibiotics compared with longer course antibiotics
A 3-day course of oral co-trimoxazole was not statistically significantly different compared with a 5-day course of oral co-trimoxazole for treatment success in children.
The evidence for course length of antibiotics is based on 1 non-inferiority RCT (Bowen et al. 2014).
# Route of administration
## Topical antibiotics compared with oral antibiotics
There were no statistically significant differences in the clinical effectiveness of the following antibiotic comparisons for the outcome of cure or improvement:
topical mupirocin compared with oral erythromycin in adults, young people and children
topical mupirocin compared with oral cefalexin in children with impetigo, or in adults, young people and children with secondary impetigo
topical mupirocin compared with oral ampicillin (age not reported)
topical fusidic acid compared with oral erythromycin in newborn babies (aged 3 days to 14 days) with bullous impetigo
topical chloramphenicol compared with oral erythromycin in newborn babies (aged 3 days to 14 days) with bullous impetigo.
Oral erythromycin was more effective than topical neomycin plus bacitracin for the outcome of cure or improvement in newborn babies (aged 3 days to 14 days) with bullous impetigo.
Topical mupirocin was not statistically significantly different compared with oral cefalexin for adverse effects in children.
Topical mupirocin was associated with fewer gastrointestinal adverse events than oral erythromycin in adults, young people and children.
No safety or tolerability data were reported for the other comparisons.
## Intramuscular antibiotics compared with oral antibiotics
Intramuscular ceftriaxone was not statistically significantly different compared with oral cefadroxil for cure in children.
Oral co-amoxiclav was non-inferior to intramuscular benzylpenicillin for treatment success in children.
Intramuscular benzylpenicillin was associated with more adverse events than co-trimoxazole in children.
The evidence for route of administration of antibiotics is based on 1 systematic review and meta-analysis of RCTs (Koning et al. 2012), and 2 RCTs (Al-Samman et al. 2014 and Bowen et al. 2014).# Other considerations
# Medicines safety
As with all antibiotics, extended or recurrent use of topical fusidic acid or mupirocin may increase the risk of developing antimicrobial resistance. See the BNF for more information.
About 10% of the general population claim to have a penicillin allergy; this is often because of a skin rash that occurred while taking a course of penicillin as a child. Fewer than 10% of people who think they are allergic to penicillin are truly allergic. See the NICE guideline on drug allergy: diagnosis and management for more information.
People with a history of immediate hypersensitivity to penicillins may also react to cephalosporins and other beta‑lactam antibiotics (BNF, November 2019).
Macrolides should be used with caution in people with a predisposition to QT interval prolongation (BNF, November 2019).
See the summaries of product characteristics for information on contraindications, cautions, drug interactions and adverse effects of individual medicines.
# Medicines adherence
Medicines adherence may be a problem for some people taking antibiotics that need frequent dosing or longer treatment duration (see the NICE guideline on medicines adherence).
# Resource implications
Recommended antibiotics are available as generic formulations. See the Drug Tariff for costs.
The incremental cost of hydrogen peroxide 1% cream is estimated to be around £3.50 more per person, when compared with current treatment options for people with localised non-bullous impetigo who are not systemically unwell or at risk of complications. We expect the population that will be eligible for this treatment will not be greater than around 125,000 people per year, with the biggest incidence occurring in children.
See the evidence review for more information.
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{'Recommendations': "# Managing impetigo\n\n## Advice to reduce the spread of impetigo\n\nAdvise people with impetigo, and their parents or carers if appropriate, about good hygiene measures to reduce the spread of impetigo to other areas of the body and to other people.\n\nFor a short explanation of why the committee made the recommendation, see the rationale section on advice to reduce the spread of impetigo\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review.\n\nLoading. Please wait.\n\n## Initial treatment\n\nConsider hydrogen peroxide 1% cream for people with localised non-bullous impetigo who are not systemically unwell or at high risk of complications (see recommendations on choice of antimicrobial). Although other topical antiseptics are available for treating superficial skin infections, no evidence was found for using them to treat impetigo.\n\nIf hydrogen peroxide 1% cream is unsuitable, offer a short course of a topical antibiotic for people with localised non-bullous impetigo who are not systemically unwell or at high risk of complications (see recommendations on choice of antimicrobial).\n\nOffer a short course of a topical or oral antibiotic for people with widespread non‑bullous impetigo who are not systemically unwell or at high risk of complications (see recommendations on choice of antimicrobial). Take into account:\n\nthat topical and oral antibiotics are both effective at treating impetigo\n\nthe preferences of the person and, if appropriate, their parents or carers, including the practicalities of administration (particularly to large areas) and possible adverse effects\n\nprevious use of topical antibiotics because antimicrobial resistance can develop rapidly with extended or repeated use.\n\nOffer a short course of an oral antibiotic for:\n\nall people with bullous impetigo\n\npeople with non-bullous impetigo who are systemically unwell or at high risk of complications.See recommendations on choice of antimicrobial.\n\nDo not offer combination treatment with a topical and oral antibiotic to treat impetigo.\n\nFor a short explanation of why the committee made these recommendations, see the rationale section on initial treatment\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review.\n\nLoading. Please wait.\n\n## Advice on treatment\n\nAdvise people with impetigo, and their parents or carers if appropriate, to seek medical help if symptoms worsen rapidly or significantly at any time, or have not improved after completing a course of treatment.\n\n## Reassessment and further treatment\n\nReassess people with impetigo if their symptoms worsen rapidly or significantly at any time or have not improved after completing a course of treatment.\n\nWhen reassessing people with impetigo, take account of:\n\nother possible diagnoses, such as herpes simplex\n\nany symptoms or signs suggesting a more serious illness or condition, such as cellulitis\n\nprevious antibiotic use, which may have led to resistant bacteria.\n\nFor people with impetigo that is worsening or has not improved after treatment with hydrogen peroxide 1% cream, offer:\n\na short course of a topical antibiotic if the impetigo remains localised or\n\na short course of a topical or oral antibiotic if the impetigo has become widespread (see the recommendation on widespread non-bullous impetigo).\n\nFor people with impetigo that is worsening or has not improved after completing a course of topical antibiotics:\n\noffer a short course of an oral antibiotic (see the recommendations on choice of antimicrobial) and\n\nconsider sending a skin swab for microbiological testing.\n\nFor people with impetigo that is worsening or has not improved after completing a course of oral antibiotics, consider sending a skin swab for microbiological testing.\n\nFor people with impetigo that recurs frequently:\n\nsend a skin swab for microbiological testing and\n\nconsider taking a nasal swab and starting treatment for decolonisation.\n\nIf a skin swab has been sent for microbiological testing:\n\nreview the choice of antibiotic when results are available and\n\nchange the antibiotic according to results if symptoms are not improving, using a narrow-spectrum antibiotic if possible.\n\nFor a short explanation of why the committee made these recommendations, see the rationale section on reassessment and further treatment for impetigo\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review.\n\nLoading. Please wait.\n\n## Referral and seeking specialist advice\n\nRefer to hospital:\n\npeople with impetigo and any symptoms or signs suggesting a more serious illness or condition (for example, cellulitis)\n\npeople with widespread impetigo who are immunocompromised.\n\nConsider referral or seeking specialist advice for people with impetigo if they:\n\nhave bullous impetigo, particularly in babies (aged 1 year and under)\n\nhave impetigo that recurs frequently\n\nare systemically unwell\n\nare at high risk of complications.\n\nFor a short explanation of why the committee made these recommendations, see the rationale section on referral and seeking specialist advice for impetigo\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review.\n\nLoading. Please wait.\n\n# Choice of antimicrobial\n\nWhen prescribing an antimicrobial for impetigo, take account of local antimicrobial resistance data when available and follow:\n\nTable\xa01 for adults aged 18\xa0years and over\n\nTable\xa02 for children and young people under 18\xa0years.\n\nTreatment\n\nAntimicrobial, dosage and course length\n\nTopical antiseptic\n\nHydrogen peroxide 1%:\n\nApply two or three times a day for 5\xa0days\n\nFirst-choice topical antibiotic if hydrogen peroxide is unsuitable (for example, if impetigo is around eyes) or ineffective\n\nFusidic acid 2%:\n\nApply three times a day for 5\xa0days\n\nAlternative topical antibiotic if fusidic acid resistance is suspected or confirmed\n\nMupirocin 2%:\n\nApply three times a day for 5\xa0days\n\nFirst-choice oral antibiotic\n\nFlucloxacillin:\n\nmg four times a day for 5\xa0days\n\nAlternative oral antibiotic for penicillin allergy or if flucloxacillin is unsuitable (for people who are not pregnant)\n\nClarithromycin:\n\nmg twice a day for 5\xa0days (the dosage can be increased to 500\xa0mg twice a day, if needed for severe infections)\n\nAlternative oral antibiotic for penicillin allergy in pregnancy\n\nErythromycin:\n\nmg to 500\xa0mg four times a day for 5\xa0days\n\nErythromycin is preferred if a macrolide is needed in pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. See the Medicines and Healthcare products Regulatory Agency (MHRA) Public Assessment Report on the safety of macrolide antibiotics in pregnancy.\n\nIf meticillin-resistant \n \n Staphylococcus aureus\n \n is suspected or confirmed\n\nConsult a local microbiologist\n\nSee the BNF for appropriate use and dosing in specific populations, for example, in people with hepatic or renal impairment, and in pregnancy and breastfeeding.\n\nA 5‑day course is usually appropriate but can be increased to 7\xa0days based on clinical judgement, depending on the severity and number of lesions.\n\nOther topical antiseptics besides hydrogen peroxide are available for superficial skin infections, but no evidence was found for these in impetigo\n\nAs with all antibiotics, extended or recurrent use of topical fusidic acid or mupirocin may increase the risk of developing antimicrobial resistance. See the BNF for more information.\n\nTreatment\n\nAntimicrobial, dosage and course length\n\nTopical antiseptic\n\nHydrogen peroxide 1%:\n\nApply two or three times a day for 5\xa0days\n\nFirst-choice topical antibiotic if hydrogen peroxide is unsuitable (for example, if impetigo is around eyes) or ineffective\n\nFusidic acid 2%:\n\nApply three times a day for 5\xa0days\n\nAlternative topical antibiotic if fusidic acid resistance is suspected or confirmed\n\nMupirocin 2%:\n\nApply three times a day for 5\xa0days\n\nFirst-choice oral antibiotic\n\nFlucloxacillin (oral solution or capsules):\n\nmonth to 1\xa0year, 62.5\xa0mg to 125\xa0mg four times a day for 5\xa0days\n\nyears to 9\xa0years, 125\xa0mg to 250\xa0mg four times a day for 5\xa0days\n\nyears to 17\xa0years, 250\xa0mg to 500\u202fmg four times a day for 5\xa0days\n\nAlternative oral antibiotic for penicillin allergy or if flucloxacillin is unsuitable (for people who are not pregnant; for example, if an oral solution is unpalatable and the child is unable to swallow capsules)\n\nClarithromycin:\n\nmonth to 11\xa0years:\n\nunder 8\xa0kg, 7.5\xa0mg/kg twice a day for 5\xa0days\n\nkg to 11\xa0kg, 62.5\xa0mg twice a day for 5\xa0days\n\nkg to 19\xa0kg, 125\xa0mg twice a day for 5\xa0days\n\nkg to 29\xa0kg, 187.5\xa0mg twice a day for 5\xa0days\n\nkg to 40\xa0kg, 250\xa0mg twice a day for 5\xa0days\n\nyears to 17\xa0years, 250\xa0mg twice a day for 5\xa0days (the dosage can be increased to 500\xa0mg twice a day, if needed for severe infections)\n\nAlternative oral antibiotic for penicillin allergy in pregnancy\n\nErythromycin:\n\nyears to 17\xa0years, 250\xa0mg to 500\xa0mg four times a day for 5\xa0days\n\nErythromycin is preferred if a macrolide is needed in pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. See the Medicines and Healthcare products Regulatory Agency (MHRA) Public Assessment Report on the safety of macrolide antibiotics in pregnancy.\n\nIf meticillin-resistant \n \n Staphylococcus aureus\n \n is suspected or confirmed\n\nConsult a local microbiologist\n\nSee the BNF for Children for appropriate use and dosing in specific populations, for example, in people with hepatic or renal impairment, and in pregnancy and breastfeeding. Dosing in some age groups may be off-label.\n\nThe age bands apply to children of average size and, in practice, the prescriber will use the age bands with other factors such as the severity of the condition being treated and the child's size in relation to the average size of children of the same age.\n\nA 5‑day course is usually appropriate but can be increased to 7\xa0days based on clinical judgement, depending on the severity and number of lesions.\n\nOther topical antiseptics besides hydrogen peroxide are available for superficial skin infections, but no evidence was found for these in impetigo.\n\nLicenses for mupirocin use in infants vary between products. See individual summaries of product characteristics for details.\n\nAs with all antibiotics, extended or recurrent use of topical fusidic acid or mupirocin may increase the risk of developing antimicrobial resistance. See the BNF for Children for more information.\n\nIf flucloxacillin oral solution is not tolerated because of poor palatability, consider capsules (see the Medicines for Children leaflet on helping your child to swallow tablets).\n\nFor a short explanation of why the committee made this recommendation, see the rationale section on choice of antimicrobial for impetigo\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review.\n\nLoading. Please wait.\n\n# Terms used in the guideline\n\n## Non-bullous impetigo\n\nImpetigo characterised by thin-walled vesicles or pustules that rupture quickly, forming a golden-brown crust.\n\n## Bullous impetigo\n\nImpetigo characterised by the presence of fluid-filled vesicles and blisters often with a diameter of over 1\xa0cm that rupture, leaving a thin, flat, yellow-brown crust.\n\n## Decolonisation\n\nUse of topical treatments (antiseptic body wash, nasal ointment or a combination of both) and personal hygiene measures to remove the bacteria causing the infection from the body.", 'Recommendation for research': "The guideline committee has made the following recommendation for research.\n\n# Antiseptics compared with antibiotics for impetigo\n\nFor which people with impetigo are antiseptics as effective as antibiotics?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationales\xa0.\n\nFull details of the evidence and the committee's discussion are in the evidence review.\n\nLoading. Please wait.", 'Rationales': "The recommendations in this guideline are based on the evidence identified and the experience of the committee.\n\n# Advice to reduce the spread of impetigo\n\n## Why the committee made the recommendation\n\nRecommendation 1.1.1\n\nThe committee agreed, based on its experience, that good hygiene measures help reduce the spread of impetigo, both to other areas of the body and to other people. The committee noted that resources are available with further information (see the management of impetigo in NICE's clinical knowledge summary on impetigo).\n\nReturn to the recommendations\n\n# Initial treatment\n\n## Why the committee made the recommendations\n\nRecommendations 1.1.2 to 1.1.6\n\nThe evidence showed that impetigo was cured or improved with a placebo in some people. However, impetigo is highly infectious, and the committee agreed that treatment is important to limit the spread of infection and the worsening of symptoms, and to hasten recovery. A faster recovery is also likely to mean less time off school, nursery or work.\n\nIt was not clear in the evidence reviewed if impetigo was localised or widespread. The committee agreed that different treatment options are appropriate for impetigo based on the type and extent of the infection. It agreed that clinical judgement should be used to determine whether impetigo is localised or widespread.\n\nThe evidence suggested that hydrogen peroxide 1% cream (a topical antiseptic) is as effective as a topical antibiotic for treating impetigo. Impetigo was cured or improved in a large proportion of people using hydrogen peroxide. The committee noted this evidence came from 1 randomised controlled trial. Based on its experience, the committee agreed that the risk of adverse effects from hydrogen peroxide at 1% concentration, such as irritation and skin bleaching, are minimal. They also agreed that the significance of this is especially low when compared with the risk of adverse effects associated with topical antibiotics, such as rapid development of antimicrobial resistance.\n\nThe committee was aware that the use of hydrogen peroxide 1% cream for impetigo is a change in practice and health professionals may not be familiar with its use. It noted that some other topical antiseptics are licensed for superficial skin infections, which may be cheaper and more widely available. However, no evidence was identified for treating impetigo with other topical antiseptics, so the committee could not make a recommendation for their use. Based on the available evidence, the committee agreed that the long-term benefits of good antimicrobial stewardship, in combination with the low risk of adverse events compared with using a topical antibiotic, outweighed the additional cost of hydrogen peroxide 1% cream.\n\nOverall, the evidence showed that a topical antibiotic was as effective as an oral antibiotic for curing or improving impetigo. Based on the evidence and its experience, the committee agreed that topical antibiotics would cause fewer adverse effects than oral antibiotics, and that applying a topical antibiotic is usually straightforward for localised impetigo. The committee discussed its experience of antimicrobial resistance with topical antibiotics compared with oral antibiotics. It agreed that the likely increased risk of resistance with topical antibiotics applied to a localised area of impetigo for a short duration was outweighed by the increased risk of adverse events with oral antibiotics. The committee therefore agreed that if hydrogen peroxide 1% cream is unsuitable, for example, because impetigo is around the eyes, a topical antibiotic should be offered for people who are not systemically unwell or at high risk of complications.\n\nBased on its experience, the committee agreed that people with widespread non-bullous impetigo should be offered a short course of either a topical or an oral antibiotic. They discussed that the choice of topical or oral use would be an individualised clinical decision, taking local antimicrobial resistance data into account alongside patient preference, practicalities of administration, possible adverse effects and previous use.\n\nThe committee discussed that effectively applying a cream may be difficult over larger skin areas. It agreed that an oral antibiotic may be a better option for some people with widespread non-bullous impetigo, despite the higher risk of adverse events, and that the decision should be based on a discussion of the person's preferences and the balance of risks and benefits. Antimicrobial resistance can develop rapidly with the use of topical antibiotics, and the committee agreed that repeated doses or extended use of the same topical antibiotic should be avoided.\n\nThe evidence on treating bullous impetigo was limited to a small study in newborn babies. From its experience, the committee discussed that the presence of bullae may mean that a topical antibiotic is unable to reach the infected area. Therefore, it agreed that an oral antibiotic is needed to target the infection adequately.\n\nNo evidence was identified for treating people who are systemically unwell or at higher risk of complications. Based on its experience of current practice, and because of the high risk of harm if topical application of antibiotic is inadequate, the committee agreed that this population should be offered an oral antibiotic. People at higher risk of complications can include, for example, people who are immunocompromised or have coexisting skin conditions.\n\nThe evidence suggested that combination treatment with an oral and topical antibiotic was no more effective than a topical antibiotic alone. The committee agreed that combination treatment should be discouraged because of the increased risk of adverse events and antimicrobial resistance.\n\nThe committee agreed that further research is needed to more clearly show which populations would benefit from antiseptic treatment. A research recommendation was developed to encourage more research in this area, which may contribute to future antibiotic-sparing recommendations and help reduce the risk of resistance and adverse events with antibiotics.\n\nFor more detail see the summary of the evidence on antimicrobials.\n\nReturn to the recommendations\n\n# Reassessment and further treatment\n\n## Why the committee made the recommendations\n\nRecommendations 1.1.8 to 1.1.14\n\nNo evidence was identified for reassessing people with impetigo if initial treatment is unsuccessful. Therefore, the committee agreed on good practice points for this population based on consensus.\n\nBased on its experience and the evidence for initial treatment, the committee agreed that a short course of a topical antibiotic should be offered for localised non-bullous impetigo if hydrogen peroxide 1% cream is ineffective. If impetigo becomes widespread after treatment, a short course of a topical or oral antibiotic should be offered, in line with the recommendation for initial treatment for widespread non-bullous impetigo. Although there is no evidence that oral antibiotics are more effective than topical antibiotics, the committee agreed that an oral antibiotic is more likely to target all areas of infection and that there is a risk of inadequate application of topical antibiotics. Based on its experience, the committee decided that an oral antibiotic should be an option if a topical antibiotic is unsuccessful. It also agreed that microbiological testing of an area of infected skin may help to guide antimicrobial prescribing.\n\nFor people with impetigo that recurs frequently, the committee agreed that a skin swab should be sent for microbiological testing to determine antimicrobial susceptibility. A nasal swab should also be considered if nasal carriage of Staphylococcus aureus is suspected. A nasal or skin (or combination) decolonisation regimen should be considered, based on clinical judgement and microbiological test results, in order to remove the bacteria causing recurrence of infection. The committee recognised that family decolonisation may be appropriate in some cases but did not make a recommendation because this decision should be based on specialist advice.\n\nThe committee agreed on good practice for antimicrobial stewardship when reviewing the results of microbiological tests. This includes changing to a narrow-spectrum antibiotic or continuing with a narrow-spectrum antibiotic that has shown resistance in microbiological tests if symptoms are already improving.\n\nReturn to the recommendations\n\n# Referral and seeking specialist advice\n\n## Why the committee made the recommendations\n\nRecommendations 1.1.15 to 1.1.16\n\nBased on its experience, the committee agreed that people who may have a more serious illness or condition or are immunocompromised with widespread impetigo need further assessment and treatment in hospital. Sometimes impetigo is difficult to treat (for example, bullous impetigo or impetigo that recurs frequently) and the committee agreed that referral or specialist advice should be an option.\n\nReturn to the recommendations\n\n# Choice of antimicrobial\n\n## Why the committee made the recommendation\n\nRecommendation 1.2.1\n\nThe evidence suggested that hydrogen peroxide 1% cream is effective and based on its experience, the committee agreed that a short course of treatment is associated with a low risk of adverse events. There was no evidence identified for other topical antiseptics.\n\nThe evidence showed that fusidic acid is as effective as other topical antibiotics and is associated with fewer adverse events. Based on this evidence, current practice and its experience, the committee agreed that the first-choice topical antibiotic in adults, young people and children with non-bullous impetigo when hydrogen peroxide 1% cream is unsuitable (including when impetigo is widespread) is fusidic acid 2% (either as a cream or an ointment). Based on its experience, the committee agreed that fusidic acid resistance rates are higher than for some other antibiotics. However, the evidence showed fewer skin reactions with fusidic acid compared with mupirocin. The committee agreed that the risk of antimicrobial resistance should be considered when offering an antibiotic, but that this risk is likely to be low in people with a first episode of impetigo.\n\nThe alternative topical antibiotic in adults, young people and children with non-bullous impetigo (when a topical antiseptic is unsuitable or has been ineffective) and fusidic acid resistance is suspected or confirmed is mupirocin\xa02% (either as a cream or an ointment). The committee based this on its experience and knowledge of current practice, evidence that mupirocin is as effective as other topical antibiotics for treatment of impetigo and its experience that mupirocin resistance rates are low.\n\nNational antimicrobial resistance data from Public Health England's voluntary surveillance reports on Staphylococcus aureus showed resistance rates for meticillin-susceptible Staphylococcus aureus (MSSA) bloodstream infection of 13% for fusidic acid and less than 1% for mupirocin in 2018. The equivalent rates for meticillin-resistant Staphylococcus aureus (MRSA) bloodstream infection were 25% and 3%. However, the committee discussed that resistance rates in blood isolates may not be a good indicator of resistance rates in skin isolates, which can vary greatly from person to person, based on their history of antibiotic use, and between localities.\n\nThere was some evidence showing that topical ozenoxacin is more effective than placebo for treating impetigo. However, because the evidence did not compare topical ozenoxacin with another antibiotic, the committee could not make recommendations for its use. It was also noted that topical ozenoxacin is not currently available in the UK.\n\nBased on its experience and knowledge of current practice, the committee agreed that the first-choice oral antibiotic in adults, young people and children is flucloxacillin. This is a relatively narrow-spectrum penicillin that is effective against Staphylococcus aureus and Streptococcus pyogenes. The committee recognised that some children may not be able to tolerate flucloxacillin solution or swallow capsules. For these children, the alternative oral antibiotic is suitable.\n\nThe alternative oral antibiotic in adults, young people and children with penicillin allergy or if flucloxacillin is unsuitable is clarithromycin. In pregnancy, erythromycin was recommended if there is true penicillin allergy. The committee agreed that these antibiotics are effective against the common pathogens that cause impetigo, and the evidence indicated that macrolides are as effective as penicillins for treating impetigo.\n\nThe committee discussed the MHRA Public Assessment Report on the safety of macrolide antibiotics in pregnancy. This found that the available evidence is insufficient to confirm with certainty whether there is a small increased risk of birth defects or miscarriage when macrolides are taken in early pregnancy. They agreed with the UK Teratology Information Service monograph on the use of macrolides in pregnancy. They decided that there should be an informed discussion of the potential benefits and harms of treatment. Then, after such a discussion, macrolides can be used if there is a compelling clinical need and there are no suitable alternatives with adequate pregnancy safety data. Erythromycin is the preferred choice if a macrolide is needed during pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. This is because there is more documented experience of its use than for other macrolides.\n\nThe committee discussed that in its experience, MRSA infection in impetigo is rare and that appropriate antibiotic choice may depend on local antimicrobial resistance rates. Therefore, the committee agreed that for people with suspected or confirmed MRSA, a local microbiologist should be consulted.\n\nThere was very little evidence on dosage and course length. Therefore, the recommendations were based on committee experience of current practice and the BNF. The committee also agreed that the shortest course that is likely to be effective should be prescribed to reduce the risk of antimicrobial resistance and adverse effects. All doses are given as in the BNF. Based on its experience that lower doses are not clinically effective due to poor oral bioavailability, the committee agreed that the higher dose for flucloxacillin recommended in the BNF is appropriate for treating impetigo in adults. The committee agreed that dose ranges are appropriate for children as the appropriate dose may vary depending on the age and weight of the child.\n\nFrom its experience, the committee agreed that 5\xa0days of treatment would be sufficient for treating most people with impetigo, and this is consistent with current practice. However, the committee was aware that some people may need a longer course because of the severity or number of lesions, so agreed that this could be up to 7\xa0days, based on clinical judgement. The committee noted current BNF advice that topical fusidic acid and mupirocin should not be used for longer than 10\xa0days.\n\nFor more details see the summary of the evidence on choice of antibiotic.\n\nReturn to the recommendations", 'Context': 'Impetigo is a contagious, bacterial infection of the superficial layers of the skin. The most common bacterial pathogen is Staphylococcus aureus, although infection with Streptococcus pyogenes or a combination of both pathogens is also seen. Impetigo affects all age groups; however it is most common in young children.', 'Summary of the evidence': 'This is a summary of the evidence, for full details see the evidence review.\n\n# Antimicrobials\n\n## Efficacy of topical antibiotics\n\nThe following topical antibiotics were shown to be more effective than placebo for the outcome of cure or improvement:\n\nmupirocin in adults, young people and children\n\nfusidic acid in children\n\nozenoxacin in children.\n\n## Efficacy of oral antibiotics\n\nPhenoxymethylpenicillin was not statistically significantly different compared with placebo in children for the outcome of cure or improvement.\n\n## Topical antibiotics compared with antiseptics, steroids or antifungals\n\nThere were no statistically significant differences in clinical effectiveness of the following comparisons for the outcome of cure or improvement:\n\ntopical antibiotic (fusidic acid) compared with a topical antiseptic (hydrogen peroxide 1%) in children\n\ntopical antibiotic (gentamicin) compared with a topical steroid (betamethasone valerate; age not reported)\n\ntopical antibiotic (gentamicin) plus a topical steroid (betamethasone valerate) compared with a topical steroid (betamethasone valerate; age not reported)\n\ntopical antibiotic (mupirocin) compared with a topical antifungal (terbinafine) in children.\n\n## Safety of antibiotics\n\nThere were no statistically significant differences in adverse effects for the following comparisons:\n\ntopical mupirocin and placebo in adults, young people and children\n\ntopical fusidic acid and disinfectants in children\n\ntopical mupirocin and antifungals in children.\n\nNo safety or tolerability data were reported for the other comparisons.\n\nThe evidence for the efficacy and safety of antimicrobials is based on 1 systematic review and meta-analysis of randomised controlled trials (RCTs; Koning et al. 2012) and 1 pooled-analysis of 2 RCTs (Hebert et al. 2018).\n\n# Choice of antibiotics\n\n## Topical antibiotics\n\nThere were no statistically significant differences in the clinical effectiveness of the following topical antibiotic comparisons for the outcome of cure or improvement:\n\ntopical mupirocin compared with topical fusidic acid in adults, young people and children\n\ntopical mupirocin compared with topical neomycin in children and young people\n\ntopical mupirocin compared with topical polymyxin B plus neomycin (population not reported).\n\nSome differences were seen for cure or improvement for other topical antibiotic comparisons:\n\ntopical fusidic acid was more effective than topical neomycin plus bacitracin in children\n\ntopical gentamicin was more effective than topical neomycin in adults, young people and children.\n\nThere were no statistically significant differences in adverse effects between topical mupirocin compared with topical polymyxin B plus neomycin (age not reported).\n\nThe incidence of skin rash was increased with topical mupirocin compared with topical fusidic acid in adults, young people and children.\n\nNo safety or tolerability data were reported for the other comparisons.\n\n## Oral antibiotics\n\nThere were no statistically significant differences in the clinical effectiveness of the following oral antibiotic comparisons for the outcome of cure or improvement:\n\noral macrolides compared with oral penicillins in adults, young people and children\n\noral erythromycin compared with oral amoxicillin in children\n\noral azithromycin compared with oral erythromycin in adults, young people and children\n\noral cefalexin compared with oral cefadroxil in children and young people\n\noral cefalexin compared with oral erythromycin in children or oral azithromycin in adults\n\noral cefaclor compared with oral azithromycin or oral co-amoxiclav in children\n\noral cefadroxil compared with oral flucloxacillin in adults, young people and children.\n\nSome differences were seen for cure or improvement for other antibiotic comparisons:\n\noral erythromycin was more effective than phenoxymethylpenicillin in children\n\noral co-amoxiclav was more effective than oral amoxicillin in children and young people\n\noral cefalexin was more effective than oral phenoxymethylpenicillin in children.\n\nThere were no statistically significant differences in adverse effects for the following oral antibiotic comparisons:\n\noral co-amoxiclav compared with oral amoxicillin in children and young people\n\noral cefalexin compared with oral azithromycin in adults\n\noral cefaclor compared with oral azithromycin in children\n\noral cefaclor compared with co-amoxiclav in children.\n\nSome differences were seen in adverse effects for other oral antibiotic comparisons:\n\nthere were more incidences of diarrhoea in children taking oral erythromycin compared with oral amoxicillin\n\nthere were more incidences of stomach ache, rash, fever or vomiting but fewer incidents of diarrhoea in adults, young people and children taking oral cefadroxil compared with oral flucloxacillin.\n\nNo safety or tolerability data were reported for the other comparisons.\n\n## Dual antibiotics\n\nThere were no statistically significant differences in the clinical effectiveness of the following antibiotic comparisons in children for the outcome of cure or improvement:\n\noral cefdinir plus topical tetracycline compared with topical tetracycline\n\noral minomycin plus topical tetracycline compared with topical tetracycline\n\noral fosfomycin plus topical tetracycline compared with topical tetracycline.\n\nThe evidence for choice of antibiotics is based on 1 systematic review and meta-analysis of RCTs (Koning et al. 2012).\n\n# Course length\n\n## Shorter course antibiotics compared with longer course antibiotics\n\nA 3-day course of oral co-trimoxazole was not statistically significantly different compared with a 5-day course of oral co-trimoxazole for treatment success in children.\n\nThe evidence for course length of antibiotics is based on 1 non-inferiority RCT (Bowen et al. 2014).\n\n# Route of administration\n\n## Topical antibiotics compared with oral antibiotics\n\nThere were no statistically significant differences in the clinical effectiveness of the following antibiotic comparisons for the outcome of cure or improvement:\n\ntopical mupirocin compared with oral erythromycin in adults, young people and children\n\ntopical mupirocin compared with oral cefalexin in children with impetigo, or in adults, young people and children with secondary impetigo\n\ntopical mupirocin compared with oral ampicillin (age not reported)\n\ntopical fusidic acid compared with oral erythromycin in newborn babies (aged 3\xa0days to 14\xa0days) with bullous impetigo\n\ntopical chloramphenicol compared with oral erythromycin in newborn babies (aged 3\xa0days to 14\xa0days) with bullous impetigo.\n\nOral erythromycin was more effective than topical neomycin plus bacitracin for the outcome of cure or improvement in newborn babies (aged 3\xa0days to 14\xa0days) with bullous impetigo.\n\nTopical mupirocin was not statistically significantly different compared with oral cefalexin for adverse effects in children.\n\nTopical mupirocin was associated with fewer gastrointestinal adverse events than oral erythromycin in adults, young people and children.\n\nNo safety or tolerability data were reported for the other comparisons.\n\n## Intramuscular antibiotics compared with oral antibiotics\n\nIntramuscular ceftriaxone was not statistically significantly different compared with oral cefadroxil for cure in children.\n\nOral co-amoxiclav was non-inferior to intramuscular benzylpenicillin for treatment success in children.\n\nIntramuscular benzylpenicillin was associated with more adverse events than co-trimoxazole in children.\n\nThe evidence for route of administration of antibiotics is based on 1 systematic review and meta-analysis of RCTs (Koning et al. 2012), and 2 RCTs (Al-Samman et al. 2014 and Bowen et al. 2014).', 'Other considerations': '# Medicines safety\n\nAs with all antibiotics, extended or recurrent use of topical fusidic acid or mupirocin may increase the risk of developing antimicrobial resistance. See the BNF for more information.\n\nAbout 10% of the general population claim to have a penicillin allergy; this is often because of a skin rash that occurred while taking a course of penicillin as a child. Fewer than 10% of people who think they are allergic to penicillin are truly allergic. See the NICE guideline on drug allergy: diagnosis and management for more information.\n\nPeople with a history of immediate hypersensitivity to penicillins may also react to cephalosporins and other beta‑lactam antibiotics (BNF, November 2019).\n\nMacrolides should be used with caution in people with a predisposition to QT interval prolongation (BNF, November 2019).\n\nSee the summaries of product characteristics for information on contraindications, cautions, drug interactions and adverse effects of individual medicines.\n\n# Medicines adherence\n\nMedicines adherence may be a problem for some people taking antibiotics that need frequent dosing or longer treatment duration (see the NICE guideline on medicines adherence).\n\n# Resource implications\n\nRecommended antibiotics are available as generic formulations. See the Drug Tariff for costs.\n\nThe incremental cost of hydrogen peroxide 1% cream is estimated to be around £3.50 more per person, when compared with current treatment options for people with localised non-bullous impetigo who are not systemically unwell or at risk of complications. We expect the population that will be eligible for this treatment will not be greater than around 125,000 people per year, with the biggest incidence occurring in children.\n\nSee the evidence review for more information.'}
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https://www.nice.org.uk/guidance/ng153
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This guideline sets out an antimicrobial prescribing strategy for adults, young people and children aged 72 hours and over with impetigo. It aims to optimise antibiotic use and reduce antibiotic resistance.
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e1fa48859da8376c0aa4cab2cafece85f2993ba3
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nice
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Neonatal parenteral nutrition
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Neonatal parenteral nutrition
This guideline covers parenteral nutrition (intravenous feeding) for babies born preterm, up to 28 days after their due birth date and babies born at term, up to 28 days after their birth. Parenteral nutrition is often needed by preterm babies, critically ill babies, and babies who need surgery.
# Recommendations
Parents and carers have the right to be involved in planning and making decisions about their baby's health and care, and to be given information and support to enable them to do this, as set out in the NHS constitution and summarised in making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Indications for, and timing of, neonatal parenteral nutrition
## Indications for starting neonatal parenteral nutrition
For preterm babies born before 31+0 weeks, start neonatal parenteral nutrition.
For preterm babies born at or after 31+0 weeks, start parenteral nutrition if sufficient progress is not made with enteral feeding in the first 72 hours after birth.
Start parenteral nutrition for preterm and term babies who are unlikely to establish sufficient enteral feeding, for example, babies with:
a congenital gut disorder
a critical illness such as sepsis.
## Indications for starting neonatal parenteral nutrition if enteral feeds are stopped
For preterm babies on enteral feeds, start parenteral nutrition if:
enteral feeds have to be stopped and it is unlikely they will be restarted within 48 hours
enteral feeds have been stopped for more than 24 hours and there is unlikely to be sufficient progress with enteral feeding within a further 48 hours.
For term babies on enteral feeds, start parenteral nutrition if:
enteral feeds have to be stopped and it is unlikely they will be restarted within 72 hours
enteral feeds have been stopped for more than 48 hours and there is unlikely to be sufficient progress with enteral feeding within a further 48 hours.
## Timing of starting neonatal parenteral nutrition
When a preterm or term baby meets the indications for parenteral nutrition, start it as soon as possible, and within 8 hours at the latest.
For a short explanation of why the committee made the recommendations on indications for, and timing of, neonatal parenteral nutrition, and how they might affect practice, see rationale and impact .
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# Administration of neonatal parenteral nutrition
## Venous access
Use a central venous catheter to give neonatal parenteral nutrition. Only consider using peripheral venous access to give neonatal parenteral nutrition if:
it would avoid a delay in starting parenteral nutrition
short-term use of peripheral venous access is anticipated, for example, less than 5 days
it would avoid interruptions in giving parenteral nutrition
central venous access is impractical.
Only consider surgical insertion of a central venous catheter if:
non-surgical insertion is not possible
long-term parenteral nutrition is anticipated, for example, in short bowel syndrome.
For a short explanation of why the committee made the recommendations on venous access for neonatal parenteral nutrition and how they might affect practice, see rationale and impact .
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## Protection from light
Protect the bags, syringes and infusion sets of both aqueous and lipid parenteral nutrition solutions from light.
For a short explanation of why the committee made the recommendation on protection from light and how it might affect practice, and why the committee were unable to make recommendations about filtration, see rationale and impact .
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# Energy needs of babies on neonatal parenteral nutrition
For preterm and term babies who need total neonatal parenteral nutrition, deliver energy as follows:
If starting parenteral nutrition in the first 4 days after birth:
give a starting range of 40 to 60 kcal/kg/day
gradually increase (for example, over 4 days) to a maintenance range of 75 to 120 kcal/kg/day.
If starting parenteral nutrition more than 4 days after birth:
give a range of 75 to 120 kcal/kg/day.
For preterm and term babies who are on enteral feeds in addition to neonatal parenteral nutrition, reduce the amount of energy that is given parenterally as enteral feeds increase.
## Term babies who are critically ill or have just had surgery
For term babies who are critically ill or have just had surgery, consider giving parenteral energy at the lower end of the starting range in recommendation 1.3.1, and gradually increase to the intended maintenance intake.
For a short explanation of why the committee made the recommendations on the energy needs of babies on neonatal parenteral nutrition and how they might affect practice, see rationale and impact .
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# Neonatal parenteral nutrition volume
Standardised neonatal parenteral nutrition ('standardised bags') should be formulated in concentrated solutions to help ensure that the nutritive element of intravenous fluids is included within the total fluid allowance.
For a short explanation of why the committee made the recommendation on neonatal parenteral nutrition volume and how it might affect practice, see rationale and impact .
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# Constituents of neonatal parenteral nutrition
## Glucose
For preterm and term babies, give glucose as follows:
If starting parenteral nutrition in the first 4 days after birth:
give a starting range of 6 to 9 g/kg/day
gradually increase (for example, over 4 days) to a maintenance range of 9 to 16 g/kg/day.
If starting parenteral nutrition more than 4 days after birth:
give a range of 9 to 16 g/kg/day.
For a short explanation of why the committee made the recommendation on glucose and how it might affect practice, see rationale and impact .
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## Amino acids
For preterm babies, give amino acids as follows:
If starting parenteral nutrition in the first 4 days after birth:
give a starting range of 1.5 to 2 g/kg/day
gradually increase (for example, over 4 days) to a maintenance range of 3 to 4 g/kg/day.
If starting parenteral nutrition more than 4 days after birth:
give a range of 3 to 4 g/kg/day.
For term babies, give amino acids as follows:
If starting parenteral nutrition in the first 4 days after birth:
give a starting range of 1 to 2 g/kg/day
gradually increase (for example, over 4 days) to a maintenance range of 2.5 to 3 g/kg/day.
If starting parenteral nutrition more than 4 days after birth:
give a range of 2.5 to 3 g/kg/day.
For a short explanation of why the committee made the recommendations on amino acids and how they might affect practice, see rationale and impact .
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## Lipids and lipid emulsions
For preterm and term babies, give lipids as follows:
If starting parenteral nutrition in the first 4 days after birth:
give a starting range of 1 to 2 g/kg/day
gradually increase (for example, in daily increments of 0.5 to 1 g/kg/day) to a maintenance range of 3 to 4 g/kg/day.
If starting parenteral nutrition more than 4 days after birth:
give a range of 3 to 4 g/kg/day.
For preterm and term babies with parenteral nutrition-associated liver disease, consider giving a composite lipid emulsion rather than a pure soy lipid emulsion.
For a short explanation of why the committee made the recommendations on lipids and lipid emulsions and how they might affect practice, see rationale and impact .
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## Ratios of non-nitrogen energy to nitrogen, and carbohydrates to lipids
When giving neonatal parenteral nutrition to preterm or term babies:
use the values for each individual component in recommendations 1.5.1 to 1.5.4
provide non-nitrogen energy as 60% to 75% carbohydrate and 25% to 40% lipid
use a non-nitrogen energy to nitrogen ratio in a range of 20 to 30 kcal of non-nitrogen energy per gram of amino acids (this equates to 23 to 34 kcal of total energy per gram of amino acid).
When altering the amount of neonatal parenteral nutrition, maintain the non-nitrogen energy to nitrogen ratio, and the carbohydrate to lipid ratio, to keep within the ranges of ratios specified in recommendation 1.5.6.
For a short explanation of why the committee made the recommendations on ratios of non-nitrogen to nitrogen energy, and carbohydrates to lipids, and how they might affect practice, and why the committee were unable to make recommendations about ratios of phosphate to amino acids, see rationale and impact .
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## Iron
Do not give intravenous parenteral iron supplements to preterm or term babies on neonatal parenteral nutrition who are younger than 28 days.
For preterm babies on neonatal parenteral nutrition who are 28 days or older, monitor for iron deficiency and treat if necessary (see recommendation 1.7.11).
For a short explanation of why the committee made the recommendations on iron and how they might affect practice, see rationale and impact .
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## Acetate
For a short explanation of why the committee were unable to make recommendations about acetate, see rationale .
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## Calcium
For preterm and term babies, give calcium as follows:
If starting parenteral nutrition in the first 48 hours after birth:
give a starting range of 0.8 to 1 mmol/kg/day
increase to a maintenance range of 1.5 to 2 mmol/kg/day after 48 hours.
If starting parenteral nutrition more than 48 hours after birth, give a range of 1.5 to 2 mmol/kg/day.
## Phosphate
For preterm and term babies, give phosphate as follows:
If starting parenteral nutrition in the first 48 hours after birth:
give 1 mmol/kg/day
increase to a maintenance dosage of 2 mmol/kg/day after 48 hours.
If starting parenteral nutrition more than 48 hours after birth, give 2 mmol/kg/day.
Give a higher dosage of phosphate if indicated by serum phosphate monitoring.
Be aware that preterm babies may be at increased risk of phosphate deficit requiring additional phosphate supplementation.
## Ratio of calcium to phosphate
Use a calcium to phosphate ratio of between 0.75:1 and 1:1 for preterm and term babies on neonatal parenteral nutrition.
For a short explanation of why the committee made the recommendations on calcium, phosphate, and the ratio of calcium to phosphate, and how they might affect practice, see rationale and impact .
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## Other constituents of neonatal parenteral nutrition – general principles
Give daily intravenous fat-soluble and water-soluble vitamins ideally from the outset, but as soon as possible after starting parenteral nutrition, to maintain standard daily requirements.
Give fat-soluble and water-soluble vitamins in the intravenous lipid emulsion to improve their stability.
Give sodium and potassium in parenteral nutrition to maintain standard daily requirements, adjusted as necessary for the individual baby.
Be aware that even if the parenteral nutrition solution contains sodium and potassium, additional supplements of these electrolytes can be given using a separate intravenous infusion.
Give magnesium in parenteral nutrition ideally from the outset, but as soon as possible after starting parenteral nutrition.
Give daily intravenous trace elements ideally from the outset, but as soon as possible after starting parenteral nutrition.
For a short explanation of why the committee made the recommendations on general principles of other constituents of neonatal parenteral nutrition, and how they might affect practice, see rationale and impact .
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# Standardised neonatal parenteral nutrition formulations ('standardised bags')
When starting neonatal parenteral nutrition for preterm and term babies, use a standardised neonatal parenteral nutrition formulation ('standardised bag').Note that this might be an off-label use as not all parenteral nutrition formulations have a UK marketing authorisation for this indication. See prescribing medicines for more information.
Standardised bags should:
be formulated to allow delivery of parenteral nutrition as recommended in the sections on neonatal parenteral nutrition volume and constituents of neonatal parenteral nutrition
be prepared following nationally agreed quality standards.
Continue with a standardised bag unless an individualised parenteral nutrition formulation is indicated, for example, if the baby has:
complex disorders associated with a fluid and electrolyte imbalance
renal failure.
For a short explanation of why the committee made the recommendations on standardised neonatal parenteral nutrition formulations ('standardised bags') and how they might affect practice, see rationale and impact .
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# Monitoring neonatal parenteral nutrition
When taking blood samples to monitor the preterm or term baby's neonatal parenteral nutrition:
collect the minimum blood volume needed for the tests
use a protocol agreed with the local clinical laboratory to retrieve as much information as possible from the sample
coordinate the timing of blood tests to minimise the number of blood samples needed.
## Blood glucose
Measure the blood glucose level:
to 2 hours after first starting parenteral nutrition
to 2 hours after each change of parenteral nutrition bag (usually every 24 or 48 hours).
Measure blood glucose more frequently if:
the preterm or term baby has previously had hypoglycaemia or hyperglycaemia
the dosage of intravenous glucose has been changed
there are clinical reasons for concern, for example, sepsis or seizures.
## Blood pH, potassium, chloride and calcium
Measure the blood pH, potassium, chloride and calcium levels:
daily when starting and increasing parenteral nutrition
twice weekly after reaching a maintenance parenteral nutrition.
Measure blood pH, potassium, chloride or calcium more frequently if:
the preterm or term baby has previously had levels of these components outside the normal range
the dosages of intravenous potassium, chloride or calcium have been changed
there are clinical reasons for concern, for example, in critically ill babies.
## Serum triglycerides
Measure serum triglycerides:
daily while increasing the parenteral nutrition lipid dosage
weekly after reaching a maintenance intravenous lipid dosage.
Measure serum triglycerides more frequently, but not more than once a day, if:
the level is elevated
the preterm or term baby is at risk of hypertriglyceridaemia, for example, if the baby is critically ill or has a lipaemic blood sample.
Be aware that ongoing serum triglyceride monitoring may not be needed for stable preterm or term babies transitioning from parenteral nutrition to enteral nutrition.
## Serum or plasma phosphate
Measure the serum or plasma phosphate level:
daily while increasing the parenteral nutrition phosphate dosage
weekly after reaching a maintenance intravenous phosphate dosage.
Consider measuring serum or plasma phosphate more frequently:
if the level has been outside the normal range
if there are clinical reasons for concern, for example, metabolic bone disease
for preterm babies born at less than 32+0 weeks.
## Iron status
Measure ferritin, iron and transferrin saturation if a preterm baby is on parenteral nutrition for more than 28 days.
## Liver function
Measure liver function weekly in preterm and term babies on parenteral nutrition.
Measure liver function more frequently than weekly if there are clinical concerns or previous liver function test levels outside the normal range.
For a short explanation of why the committee made the recommendations on monitoring neonatal parenteral nutrition and how they might affect practice, see rationale and impact .
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# Stopping neonatal parenteral nutrition
For all babies, take into account the following when deciding when to stop parenteral nutrition:
the baby's tolerance of enteral feeds
the amount of nutrition being delivered by enteral feeds (volume and composition)
the relative contribution of parenteral nutrition and enteral nutrition to the baby's total nutritional requirement
the likely benefit of the nutritional intake compared with the risk of venous catheter sepsis
the individual baby's particular circumstances, for example, a baby with complex needs such as short bowel syndrome, increased stoma losses or slow growth, may need long-term parenteral nutrition.
For preterm babies born before 28+0 weeks, consider stopping parenteral nutrition within 24 hours once the enteral feed volume is 140 to 150 ml/kg/day, taking into account the factors in recommendation 1.8.1.
For preterm babies born at or after 28+0 weeks and term babies, consider stopping parenteral nutrition within 24 hours if the enteral feed volume tolerated is 120 to 140 ml/kg/day, taking into account the factors in recommendation 1.8.1.
For a short explanation of why the committee made the recommendations on stopping neonatal parenteral nutrition and how they might affect practice, see rationale and impact .
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# Service design
Neonatal parenteral nutrition services should be supported by a specialist multidisciplinary team. Such teams could be based locally or within a clinical network.
The neonatal parenteral nutrition multidisciplinary team should include a consultant neonatologist or paediatrician with a special interest in neonatology, a neonatal pharmacist and a neonatal dietitian, and should have access to the following:
a neonatal nurse
a paediatric gastroenterologist
an expert in clinical biochemistry.
The neonatal parenteral nutrition multidisciplinary team should be responsible for:
governance, including:
agreeing policies and protocols for the neonatal parenteral nutrition service
ensuring that policies and protocols for neonatal parenteral nutrition are followed and audited
monitoring clinical outcomes
supporting delivery of parenteral nutrition, including:
providing clinical advice
providing enhanced multidisciplinary team input for preterm and term babies with complex needs, for example, babies with short bowel syndrome who may need long-term parenteral nutrition.
For a short explanation of why the committee made the recommendations on service design and how they might affect services, see rationale and impact .
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# Information and support for parents and carers
Ask parents and carers of babies on parenteral nutrition how and when they would like to receive information and updates, and how much information they would like about their baby's care.
Topics to discuss with parents or carers include:
why their baby needs parenteral nutrition
what parenteral nutrition involves
the importance of good nutrition for newborn babies
how long their baby is likely to need parenteral nutrition for
common concerns, for example, central venous catheter placement, the risk of catheter-related infections, taking blood samples, and whether they can hold and care for their baby
simultaneous enteral feeding, unless this is not possible
how their baby's progress will be monitored
how their baby will be weaned off parenteral nutrition.
Give information to parents or carers that:
is tailored to their baby's circumstances
meets their needs and preferences
is up to date, relevant and consistent between healthcare professionals
is available in suitable formats (written and spoken, with information available to take away). For more guidance on communication (including different formats and languages), providing information, and shared decision making, see the NICE guidelines on patient experience in adult NHS services, babies, children and young people's experience of healthcare and shared decision making.
Provide regular opportunities and time for parents and carers of babies on parenteral nutrition to discuss their baby's care, ask questions about the information they have been given, and discuss concerns.
For a short explanation of why the committee made the recommendations on information and support for parents and carers of babies on neonatal parenteral nutrition and how they might affect practice, see rationale and impact .
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# Terms used in this guideline
This section defines terms that have been used in a particular way for this guideline.
## Composite lipid emulsion
A lipid emulsion that is derived from more than 1 source, for example, it might include 2 or more of soy oil, medium chain triglycerides, olive oil or fish oil.
## Individualised parenteral nutrition formulations
Aqueous and lipid parenteral nutrition solutions that meet the nutritional requirements of an individual baby. The solutions are not pre-formulated and have to be prescribed and made up each time they are needed, on an individual basis for each baby. Electrolytes can be added, and macronutrients or micronutrients can be adjusted as necessary.
## Nominal group consensus method
This is a structured method focusing on the opinions of individuals within a group to reach a consensus. Because of the focus on individuals, it is referred to as a 'nominal group' technique. It involves anonymous voting with an opportunity to provide comments. Options with low agreement are eliminated and options with high agreement are retained. Using the comments that individuals provide, options with medium agreement are revised and then considered in a second round.
## Osmolality or osmolarity
Measurement of the number of dissolved particles present in a solution to indicate fluid concentration. It is defined as the number of osmoles of solute per kilogram of solvent (osmolality), or the number of osmoles of solute per litre of solution (osmolarity).
## Preterm
A baby born before 37+0 weeks. This can be subdivided further:
extremely preterm: babies born at less than 28+0 weeks
very preterm: babies born at between 28+0 and 31+6 weeks
moderate to late preterm: babies born at between 32+0 and 36+6 weeks.
## Standardised neonatal parenteral nutrition formulations ('standardised bags')
Standardised bags contain pre-formulated aqueous and lipid parenteral nutrition solutions made to a set composition that is not varied. They are ready to use and aim to meet the nutritional and clinical needs of a defined group of babies. Additional intravenous infusions are sometimes used to meet more individualised fluid or electrolyte requirements.
Standardised bags are prescribed as part of a standardised parenteral nutrition regimen: a choice of standardised bags that are given at the appropriate volume to meet the nutritional and clinical needs of a defined group of babies.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Key recommendations for research
## Information and support
What are the information and support needs of parents and carers with babies on parenteral nutrition?
For a short explanation of why the committee made the research recommendation on information and support, see rationale and impact .
Full details of the research recommendation are in evidence review I: information and support.
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## Ratios of non-nitrogen energy to nitrogen
What is the optimal ratio of non-nitrogen energy to nitrogen in parenteral nutrition for preterm and term babies?
For a short explanation of why the committee made the research recommendation on the ratio of non-nitrogen energy to nitrogen in parenteral nutrition, see rationale and impact .
Full details of the research recommendation are in evidence review D7: ratio of non-nitrogen energy to nitrogen.
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## Timing of starting neonatal parenteral nutrition
What is the optimal timeframe for starting parenteral nutrition in term babies who are critically ill or require surgery?
For a short explanation of why the committee made the research recommendation on the timing of starting neonatal parenteral nutrition, see rationale and impact .
Full details of the research recommendation are in evidence review A2: optimal timeframe to start parenteral nutrition.
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## Venous access
What overall osmolality (or concentration of calcium and glucose/dextrose) in parenteral nutrition can determine whether to administer centrally or peripherally?
For a short explanation of why the committee made the research recommendation on using osmolality to determine whether to administer centrally or peripherally, see rationale and impact .
Full details of the research recommendation are in evidence review B: venous access.
Loading. Please wait.# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect services. They link to details of the evidence and a full description of the committee's discussion.
# Indications for, and timing of, neonatal parenteral nutrition
Recommendations 1.1.1 to 1.1.6
## Why the committee made the recommendations
There was no evidence on the indications for neonatal parenteral nutrition, and limited evidence about the timeframe in which it should be provided, so the committee used their knowledge and experience to make the recommendations.
The committee agreed that all preterm babies born before 31+0 weeks should receive parenteral nutrition from birth until they transition to enteral feeds. Even though there was no specific evidence for this, the committee agreed that there is a risk of significant deficits in nutrition and short-term and long-term adverse events if babies born before 31+0 weeks are not supported by parenteral nutrition from birth.
For preterm babies born at or after 31+0 weeks, it needs to be established whether sufficient progress is made with enteral feeding within the first 72 hours after the birth. The committee decided not to be prescriptive about 'sufficient', to reflect the clinical judgements that healthcare professionals would make depending on each baby's individual circumstances and condition, and because enteral nutrition was not reviewed as part of this guideline. If babies have difficulties tolerating enteral feeds during this time, parenteral nutrition should be provided without delay. The committee was aware of evidence that this group of moderately preterm babies is at increased risk of long-term neurodevelopmental problems, and that optimal early nutrition may reduce the risk.
The committee discussed the influence of gestational age and birthweight on gut maturity and the baby's ability to tolerate enteral feeds. Although weight is closely linked to age, the committee had concerns that including more than 1 parameter may lead to uncertainty in deciding when to start parenteral nutrition, so they based the recommendations solely on gestational age at birth.
Critically ill term babies (with, for example, sepsis), and babies with congenital disorders, may be unlikely to make progress on enteral feeding. The committee agreed that this would be a clinical judgement, depending on each baby's circumstances and condition. They agreed that a delay could have long-term consequences and recommended parenteral feeding for these babies.
The committee agreed the timings based on their knowledge and experience, and because preterm babies have limited stores and the potential for accumulating deficits. For term babies, the committee based the recommendation on current practice and their knowledge of the more replete nutritional stores of a baby born at term.
There was evidence to show that, for preterm babies, there are some benefits to starting parenteral nutrition early. However, the definition of 'early' varied in the evidence (ranging from 2 hours to 36 hours without very clear descriptions of the enteral feeding regimen), and there was no consistent pattern of findings. There was evidence for critically ill term babies that compared starting parenteral nutrition early (within 24 hours) with starting it after 1 week. There were some benefits in delaying parenteral nutrition but the committee had reservations about the evidence because the study was relatively small, the parenteral nutrition regimens used were not consistent across the different study sites and the intervention may not have been appropriate because parenteral nutrition would not normally be started on day 1 for critically ill term babies due to restricted fluid volumes and strain on organ systems. The timeframe for starting parenteral nutrition is therefore based on what the committee believe is achievable and safe.
The committee agreed that starting parenteral nutrition within 8 hours of the decision being made to provide it would reduce the risks of a nutritional deficit developing for the smallest babies (born at less than 31+0 weeks). In addition, the committee noted that this timeframe would allow for placement of central lines if needed.
The committee also discussed the timeframe for critically ill babies, but there was not enough evidence to make a separate recommendation. From their knowledge and experience, they were aware that without parenteral nutrition, preterm babies will develop a nutritional deficit more rapidly than term babies who have greater nutritional reserves; therefore, they agreed that it may take longer to decide whether parenteral nutrition in term babies is needed.
However, once the decision is made that parenteral nutrition is needed, it should be started within 8 hours, regardless of whether babies are term or preterm.
The committee recognised the need for further research to inform the timing of starting parenteral nutrition for term babies who are critically ill or require surgery.
## How the recommendations might affect practice
The committee agreed that the recommendations would improve consistency of care across neonatal units, and ensure that the nutritional needs of vulnerable babies are met. Hospitals providing care for babies for whom parenteral nutrition is indicated would have to provide access to parenteral nutrition. If a hospital does not have access to neonatal parenteral nutrition, babies would need to be transferred to a unit that could provide it.
Early provision may be more costly because parenteral nutrition and staff would need to be available out-of-hours (including during weekends) to administer parenteral nutrition within the first 8 hours. However, costs can be reduced by using standardised parenteral nutrition bags, as recommended in the section on standardised neonatal parenteral nutrition formulations ('standardised bags'), which can be stored and be readily accessible. The committee believe that there should be no reason why neonatal units cannot stock standardised bags because they have a long enough shelf life to enable storage, as long as a system of stock rotation is in place. The committee also agreed that the costs of early administration would be offset by the positive impact of early optimal nutrition.
Full details of the evidence and the committee's discussion are in:
evidence review A1: predictors of enteral feeding success
evidence review A2: optimal timeframe to start parenteral nutrition.
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Return to research recommendation
# Administration of neonatal parenteral nutrition
Recommendations 1.2.1 to 1.2.3
## Why the committee made the recommendations
There was some evidence that included a comparison of fluid concentrations (as measured by osmolality or osmolarity, which depends on the level of calcium and glucose within the same amount of fluid) for peripheral venous lines. This evidence included delivering peripheral parenteral nutrition at concentrations of up to 1,425 mOsm/l. However, the committee agreed that it was not possible to recommend a specific safe concentration for parenteral nutrition delivered peripherally because of the wide range of concentrations used in the different groups in the study. Furthermore, there was no evidence that compared centrally with peripherally inserted catheters for any given level of concentration of parenteral nutrition. Therefore, the committee made their recommendations using the available evidence, as well as their knowledge and experience.
The committee discussed the risks and benefits associated with centrally and peripherally inserted catheters. The committee acknowledged that there is variation in clinical practice, and some units routinely use peripherally inserted catheters, whereas others prefer centrally inserted catheters and avoid using peripherally inserted catheters.
The committee agreed that centrally inserted catheters should normally be the preferred option for delivering neonatal parenteral nutrition. This is because centrally inserted catheters have a longer lifespan, and the central vein is bigger and has a lower risk of thrombophlebitis. However, they also agreed that peripherally inserted catheters can be used safely (which was supported by the evidence) when use of a peripheral line will be short term, and should be used when parenteral nutrition would otherwise be delayed or interrupted (for example, because there is no one available to insert a central venous catheter, a central venous catheter has stopped working and needs to be removed, or there are concerns about line infection). The committee did not define how long parenteral nutrition can be delayed before peripheral venous access should be considered, because this decision will be based on clinical judgement. Ideally, delays should not exceed the 8 hours specified in recommendation 1.1.6, but healthcare professionals will need to consider the risks and benefits of inserting a peripheral line if it is anticipated that a central venous catheter would be inserted soon.
The benefits and risks of surgically inserted central catheters were also discussed by the committee, and recommendations were made that these should only be used in exceptional circumstances when non-surgical insertion is not possible, or it is expected that parenteral nutrition would be needed for a long time.
Because of the limited evidence, the committee decided to prioritise this topic for further research. This is important because peripheral lines (although not the preferred choice of the committee) are generally easier to insert, and are very commonly used for a number of indications on neonatal units. However, they have a shorter life span and therefore would need to be changed more frequently. Because the infusions run into a smaller peripheral vein, there is a greater risk of the infusion causing direct damage to the vein. This is particularly true if there is a higher concentration (as measured by osmolality or osmolarity, depending on the unit of measurement) of the parenteral nutrition infusion fluid, for example, a formulation with a higher dextrose load.
Photo-degradation and oxidation are processes that do not lend themselves to comparative clinical studies (because of safety risks if the integrity of the solution is compromised) that are commonly used as evidence in NICE guidelines, so the committee made the recommendation based on a formal nominal group consensus method and their knowledge and experience.
The committee discussed photo-degradation and oxidation of parenteral nutrition solutions (including aqueous and lipid components), which can be managed by protecting both the infusion set (tubing) and bag from light. The committee discussed whether to recommend protecting just the bag, or the bag, the tubing and syringe. They recognised that it is simple to cover the bag, and this is already done in current practice. The committee agreed that, although some units would need to use a different type of infusion set, it is best practice to also protect the infusion set and syringe of both aqueous and lipid parenteral nutrition solutions from light, in line with European Medicines Agency and Medicines and Healthcare products Regulatory Agency guidance that states 'for administration to neonates and children below 2 years of age, parenteral nutrition products containing amino acids and/or lipids should be protected from light (containers and administration sets)'.
The committee acknowledged that adding a terminal filter to the infusion set makes giving parenteral nutrition significantly more expensive. They discussed that adding filters can remove particulate matter, fungi, bacteria and endotoxins depending on the size of the filter. However, making up parenteral nutrition in aseptic units and using bags instead of syringes reduces the risk of bacterial contamination. Breaking a line to change the filter when running lipid from a bag was thought to pose more of an infection risk than changing the bag and filter frequently (every 48 hours). Given these uncertainties around benefits and harms, as well as additional costs, the committee were not able to make a recommendation related to filtration.
## How the recommendations might affect practice
The recommendations reinforce current best practice. The recommendations may affect clinical practice by reducing the current delay that some units experience when siting a central line for giving parenteral nutrition, because peripherally inserted catheters may now be used as a short-term alternative.
Any likely changes in practice and costs associated with light-protected bags and light-protected tubing will be outweighed by the benefits associated with preserving the integrity of the parenteral nutrition solution.
Full details of the evidence and the committee's discussion are in evidence review B: venous access and evidence review J: general principles.
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Return to research recommendation
# Energy needs of babies on neonatal parenteral nutrition
Recommendations 1.3.1 to 1.3.3
## Why the committee made the recommendations
There was limited evidence on the energy needs for babies on parenteral nutrition, so the committee used their knowledge and experience to give a starting and maintenance range, and an example of how this should be increased gradually. The committee discussed the number of days over which energy intake should increase to reach the intended maintenance level, and agreed to align this with the recommendations on lipid, glucose and amino acid increases.
The committee agreed that babies who start parenteral nutrition in the first 4 days after birth should have a starting range and increase up to a maintenance range over approximately 4 days. This timeframe was primarily selected because neonatal metabolic adaptation occurs in the early days of life, enabling the baby to metabolise the nutrients delivered. In addition, fluid volume allowances are commonly increased over the first few days of life and this allows increasing amounts of nutrition to be given parenterally.
For babies who start parenteral nutrition more than 4 days after birth, early metabolic adaptation is likely to have taken place. The fluid allowances will have already increased, so this allows parenteral nutrition to be started using maintenance ranges.
The energy requirements were taken from the committee's knowledge, informed (to a limited extent) by the evidence, and cross-referenced to the energy delivered by the combined constituent components (in the section on constituents of neonatal parenteral nutrition).
The committee agreed that giving energy at the lower range may be more appropriate for term babies who are critically ill or have just had surgery because the energy stores of term babies tend to be more replete. However, in critically ill preterm babies, who have limited nutritional stores, prioritising nutritional intake may be more important.
## How the recommendations might affect practice
The committee agreed that the recommendations would improve consistency of care across neonatal units and would not incur extra costs or increase resource use. Providing the appropriate nutritional intake may avoid additional costs associated with nutritional deficit or providing excess energy.
Full details of the evidence and the committee's discussion are in evidence review C: energy needs.
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# Neonatal parenteral nutrition volume
Recommendation 1.4.1
## Why the committee made the recommendation
The recommendation on parenteral nutrition fluid volume was not developed by the usual NICE guideline systematic review process. The committee agreed the recommendation using a formal nominal group consensus method as well as their knowledge and experience.
The total fluid requirement for preterm and term babies is a complex topic, and was outside the scope of this guideline. Nevertheless, it is an important factor in providing neonatal parenteral nutrition. In some situations, the total fluid allowance may be restricted, or a significant proportion of the allowance might be required for other purposes (for example, other intravenous drug infusions). The committee recognised that this could result in difficulties in giving the required amount of parenteral nutrition. In order to minimise this risk, the committee agreed that standardised neonatal parenteral nutrition formulations ('standardised bags') should use the smallest fluid volume possible (see the section on standardised neonatal nutrition formulations). Concentrating parenteral nutrition in this way will facilitate the provision of nutritional requirements within the total fluid allowance.
## How the recommendation might affect practice
The committee agreed that the recommendation will reinforce current best practice.
Full details of the evidence and the committee's discussion are in evidence review J: general principles.
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# Constituents of neonatal parenteral nutrition – glucose
Recommendation 1.5.1
## Why the committee made the recommendation
The evidence on glucose was difficult to interpret and draw any conclusions from. Only 1 study has been conducted that varied glucose intake without also varying other constituents (such as amino acids and lipids), so it is difficult to see what effect different levels of glucose intake have. Because of this, the committee used their knowledge and experience of physiological and metabolic requirements, and took into account the glucose doses used in the studies as well as current practice and international guidelines, when making their recommendation.
The committee decided that the maintenance range should be given for babies who start parenteral nutrition more than 4 days after birth. This is consistent with the approximate 4 days by which a maintenance dosage would be reached in babies starting parenteral nutrition from birth, because tolerance would increase during the first few days of life.
## How the recommendation might affect practice
The committee agreed that the recommendation will reinforce current best practice.
Full details of the evidence and the committee's discussion are in evidence review D1: glucose.
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# Constituents of neonatal parenteral nutrition – amino acids
Recommendations 1.5.2 and 1.5.3
## Why the committee made the recommendations
There was a lot of evidence related to amino acid intake. However, the evidence was uncertain, for example, because the studies involved small numbers of babies and the results were inconsistent, so the committee also used their knowledge and experience of current practice to make the recommendations.
For preterm babies, 1.5 g/kg/day was chosen as the lower starting dose threshold, because less than this can result in a negative nitrogen balance. The committee did not look for evidence on how different amino acid doses affect nitrogen balance, but used their knowledge of metabolic studies, which are widely used to estimate the minimum amount of amino acids needed to prevent negative nitrogen balance. The upper starting dose threshold of 2 g/kg/day was selected because there was evidence of better growth at a starting dose of 2 g/kg/day of amino acids compared with less than 2 g/kg/day, but these benefits did not persist at higher amino acid starting doses (3 g/kg/day).
Studies using different maximal amino acid intakes were considered in the evidence review, and informed the recommended maintenance range. There was some evidence that a maximal amino acid intake of 3 g/kg/day or more compared with less than 3 g/kg/day improved growth outcomes, but there was no evidence of reduced sepsis or neurodevelopmental problems. There was some evidence of appropriate growth at a maximal intake of 2.7 g/kg/day, but this was supported by early (within the first 24 hours) and progressive enteral feeding. Some babies receiving neonatal parenteral nutrition will be on no or minimal enteral feeds, or will be unable to increase enteral feeding in a timely manner. This, combined with the weak evidence of improved growth at 3 g/kg/day or more, meant that 3 g/kg/day was selected as the lower end of the maintenance range. However, the committee were split on this point so a majority decision was taken.
The committee agreed, based on their expertise, that it was important to provide an upper limit for amino acid intake because of possible adverse events such as acidosis, high serum urea, hypercalcaemia or hypophosphatemia, hypokalaemia and re‑feeding syndrome. The maximal amino acid intake in the studies reviewed was 4 g/kg/day. The committee looked for adverse effects across all the studies in the evidence review, including those using maximal amounts of over 3.5 g/kg/day, and found no evidence of harm. However, the committee were concerned that the absence of evidence of harm is not the same as evidence of absence. It was noted that higher amino acid intakes need to be supported by sufficient non-nitrogen energy. The committee followed the evidence in agreeing an upper maintenance range limit of 4 g/kg/day. They suggested being more vigilant for adverse effects when using the top half of this maintenance range.
Babies on enteral feeds will receive macronutrients from milk in addition to those from parenteral nutrition. The committee acknowledged that for those babies on enteral feeds, the proportional decrease in parenteral nutrition as enteral intake increases will decrease the delivery of amino acids from parenteral nutrition, thus alleviating risks of excessive amino acid delivery. However, they noted that the enteral feeding regimen was outside the scope of this guideline, so did not recommend different ratios for babies on enteral feeds.
Most of the studies gradually increased amino acid intake over a number of days to reach a target dose. However, there was not enough consistent evidence to specify the number of days over which intake should be increased. The committee recommended 4 days, based on informal consensus agreement, using their knowledge and experience. In addition, the committee agreed that this is approximately how long it would take to reach the maintenance range if incrementing from the starting range at rates similar to those used in the included studies. This also matched the recommendations made for glucose and lipids, which is important because nitrogen to non-nitrogen ratios need to be maintained within the range specified in the guideline.
There was no evidence about amino acids for term babies, so the committee recommended a lower starting and maintenance dose based on their own expert consensus and knowledge of nitrogen balance studies. These studies show that term babies lose less protein than preterm babies, and suggest the amount of amino acids needed to achieve similar weight gain to term babies on milk feeds.
There was no evidence for babies who did not start parenteral nutrition from birth. The committee agreed, based on their expertise, that babies starting parental nutrition more than 4 days after birth would be able to tolerate the maintenance dosage of amino acids.
## How the recommendations might affect practice
The committee noted that the recommendations will reduce variation in practice.
Full details of the evidence and the committee's discussion are in evidence review D2: amino acids.
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# Constituents of neonatal parenteral nutrition – lipids and lipid emulsions
Recommendations 1.5.4 and 1.5.5
## Why the committee made the recommendations
The evidence was uncertain (there was an inconsistent pattern of benefit and harm), so the committee also used their knowledge and experience of current practice to make the recommendations by informal consensus.
There was evidence of both benefit and harm when giving lipids compared with no lipids, but the committee agreed that the benefits of giving lipids outweighed possible risks. There was evidence that giving lipids in the ranges provided in the studies was not associated with any harm in the short term. In addition, there was evidence that higher doses may reduce retinopathy of prematurity and necrotising enterocolitis compared with lower doses. The committee concluded that the ranges in the studies were safe and effective.
In relation to how the target dose is reached, the evidence showed that slowly increasing lipids from a low starting dose to a target dose may be associated with a reduced risk of retinopathy of prematurity and hypertriglyceridaemia, compared with starting at a higher dose and rapidly increasing to the same target dose. The committee agreed to use similar parameters in the recommendations. Based on their knowledge of doses of lipids exceeding those used in the studies and the risk of problems such as hypertriglyceridemia, the committee recommended an upper limit for the maintenance dose.
The committee recommended that in babies with parenteral nutrition-associated liver disease, consideration be given to changing from a pure soy lipid emulsion (if that is being used) to a composite lipid emulsion. The committee discussed some evidence suggesting that there was more resolution of parenteral nutrition-associated liver disease or cholestasis with fish oil-containing lipid emulsions compared with pure soy lipid emulsions. However, the committee noted that there were limitations in the design of some studies and uncertainty in the measurement, which made this evidence very weak. There was also some evidence of a benefit with pure fish oil, but the committee were aware that there is a risk of essential fatty acid deficiency with pure fish oil. They therefore decided that even though this evidence to support the efficacy of composite lipid emulsions is not compelling, it could be trialled because these babies are at risk of developing progressive liver disease and liver failure. The available evidence was from preterm and late preterm babies. However, the recommendation was extended to cover term babies based on expertise from the committee that late preterm and term babies often have the same treatment, and similar benefits would be likely for term babies.
The committee did not make recommendations for babies with surgical conditions because there was no evidence of advantage of any type of lipid emulsion over other lipid formulations. Recommendations were not made for babies without parenteral nutrition-associated liver disease, including those at high risk, because there was not conclusive evidence of either benefit or harm.
## How the recommendations might affect practice
The committee agreed that the recommendations will reinforce and standardise current best practice.
Full details of the evidence and the committee's discussion are in:
evidence review D3: lipids
evidence review D4: lipid emulsions.
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# Constituents of neonatal parenteral nutrition – ratios of non-nitrogen energy to nitrogen, and carbohydrates to lipids
Recommendations 1.5.6 and 1.5.7
## Why the committee made the recommendations
There was limited evidence, and the evidence did not provide sufficient data to inform optimal ratios. The committee used their knowledge and experience to agree ratios, taking into account the available evidence and current practice.
When the amount of parenteral nutrition is changing (for example, when transitioning onto enteral feeding), there is a risk of negative outcomes associated with too low or too high ratios. Too low a ratio (non-nitrogen energy to nitrogen below 20 kcal per gram) could cause oxidation of amino acids and high blood urea. Too high a ratio (non-nitrogen energy to nitrogen above 30 kcal per gram) could result in deposition of excess body fat, which is associated with metabolic ill health in later life (for example, risk of cardiovascular disease, diabetes and obesity-related conditions). Because of these risks, the committee recommended keeping the ratios the same when changing the amount of parenteral nutrition.
The evidence supported the need to give babies enough energy to ensure the nitrogen provided is retained.
Because of the limited evidence, the committee decided to prioritise this topic for further research. This is important because insufficient non-nitrogen energy (carbohydrates and lipids) leads to nitrogen (protein) being used for non-growth purposes so is not available to generate new tissues. An excess of non-nitrogen energy can lead to increased adiposity and may cause hyperglycaemia or hypertriglyceridemia. Having more evidence about the optimal ratio of non-nitrogen energy to nitrogen in parenteral nutrition is therefore needed.
There was limited evidence, so the committee used their knowledge and experience to agree the ratio, taking into account the available evidence and current practice. One study provided lipids in a range from 18% to 40% (meaning that the other 82% to 60% of non-nitrogen energy was made up of glucose), with better growth associated with 40% lipid intake.
The committee also discussed the recommendations developed for glucose and lipid dosages (recommendations 1.5.1 and 1.5.4). They agreed that it should be clear to those prescribing parenteral nutrition that when calculating the relative amounts of carbohydrate and lipid, the recommended dosages of each of these components should not be exceeded.
The committee decided not to recommend the lower end of the lipid range (18%) that was used in the evidence because that would lead to a high glucose intake, for which the risk of hyperglycaemia was considered to be too high. Therefore, the committee agreed that a lower level of 25% lipid is needed to limit the risk of hyperglycaemia, and to provide sufficient essential fatty acids and fat-soluble vitamins. The committee agreed, based on their knowledge and experience, that there should be an upper limit of 40% fat. Even though there is no evidence available to firmly state the risks of higher lipid provision, the committee agreed 40% would be safe and not risk fatty liver or raised triglyceride levels.
The recommended ranges aim to provide sufficient lipid energy to optimise growth, provide essential fatty acids and fat-soluble vitamins, and minimise the risk of hyperglycaemia. However, it is important not to give too much lipid because this could risk high triglyceride levels, fatty liver and increased fat deposition.
## Why the committee did not make a recommendation on ratios of phosphate to amino acids
The evidence on the relative amounts of amino acids and phosphate to be given in parenteral nutrition was limited.
The committee agreed that the phosphate to amino acid ratios derived from following the phosphate and amino acid recommendations (1.5.11, 1.5.2 and 1.5.3) in this guideline are appropriate. However, because the evidence was limited and did not provide enough detail on the exact amount of phosphate needed per gram of amino acid, the committee decided not to make a recommendation on specific relative amounts.
## How the recommendations might affect practice
The committee agreed that the recommendations reflect current best practice and should have little impact on practice. They should reduce any variation across units.
Full details of the evidence and the committee's discussion are in:
evidence review D7: ratio of non-nitrogen energy to nitrogen
evidence review D8: ratio of carbohydrates to lipids
evidence review D10: ratio of phosphate to amino acids.
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Return to research recommendation
# Constituents of neonatal parenteral nutrition – iron
Recommendations 1.5.8 and 1.5.9
## Why the committee made the recommendations
There was limited evidence about intravenous iron supplementation for babies younger than 28 days. The evidence did not show a substantial benefit or harm. The committee recognised that usual clinical practice in the UK is not to include intravenous iron in the parenteral nutrition regimen for babies younger than 28 days, and agreed that there was not enough new evidence to change current practice. In addition, preterm babies often have blood transfusions that can result in unpredictable amounts of iron. The committee discussed the potential for iron overload and toxicity, and used their expertise and experience to recommend that early supplementation should not be used.
The committee agreed that healthcare professionals may need to reconsider iron supplementation for preterm babies who are 28 days or older based on monitoring for iron deficiency.
## How the recommendations might affect practice
The recommendations reflect current practice, so should not result in any changes.
Full details of the evidence and the committee's discussion are in evidence review D5: iron.
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# Constituents of neonatal parenteral nutrition – acetate
## Why the committee decided not to make a recommendation
There was some evidence that using acetate in parenteral nutrition reduces the risk of hyperchloraemia, but there was no evidence about the amount of acetate needed. The evidence did not explain how chloride had been provided and the committee were unconvinced that the interventions used in the studies reflect current practice. The committee agreed that using the right balance of parenteral nutrition components and the use of standardised bags would avoid an excess of chloride and the need to add acetate.
The committee acknowledged that parenteral nutrition is not the only source of chloride (for example, some trace elements are in the form of chloride salts), so an imbalance may need to be addressed by adding acetate to reduce the risk of metabolic acidosis secondary to hyperchloraemia. The committee discussed that there is variation in clinical practice about the use of acetate but agreed that the evidence was not strong enough to make any recommendations about acetate.
Full details of the evidence and the committee's discussion are in evidence review D6: acetate.
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# Constituents of neonatal parenteral nutrition – calcium and phosphate
Recommendations 1.5.10 to 1.5.13
## Why the committee made the recommendations
Evidence was limited, and there was inconsistency in the definitions of high and low levels or concentrations of calcium and phosphate across the included studies, so the committee also used their knowledge and experience to make the recommendations.
Although the evidence that was reviewed focused on relative amounts, the committee decided that recommendations for absolute values were also needed because the amounts of calcium and phosphate in the evidence reviewed were lower than those currently given in UK clinical practice. However, the evidence also showed that higher amounts of calcium and phosphate were beneficial in reducing the incidence of rickets, fractures and hypercalciuria, and increasing bone mineral density. This guided the committee to agree that higher amounts of calcium and phosphate are preferable for preterm and term babies. They decided that a decision about the absolute amounts would then determine the ratio between these constituents rather than the other way around.
The committee made recommendations for an initial and maintenance dosage and dosage range of calcium and phosphate that overlap, which means that this would lead to a ratio between of 0.75:1 and 1:1. The committee recommended total amounts and a ratio of calcium to phosphate according to the timing of when babies would start parenteral nutrition after birth (before or after the first 48 hours) rather than whether or not they are preterm or term. This is because of body fluid adjustments in the first days of life. A too low or too high amount of calcium and phosphate and the ratio between them will result in suboptimal bone mineralisation and urinary losses. They noted that preterm babies may need more calcium and phosphate, based on their knowledge, fetal accretion studies and potential urinary phosphate losses. However, they decided not to make different recommendations for preterm or term babies because blood monitoring will indicate whether this is needed.
The committee also agreed to be more prescriptive in recommending absolute amounts of phosphate by restricting the dose to set amounts instead of a range. This was because of practical considerations: in most current parenteral preparations, 2 mmol of sodium would be administered for every 1 mmol of phosphate, and higher sodium intakes would not be recommended within the first 48 hours, before the expected postnatal diuresis. More flexibility could be applied in the amount of calcium given to babies because calcium would not alter other electrolyte delivery. The amounts of both calcium and phosphate would also be restricted by stability issues, but the committee noted that the amounts recommended could be achieved within these restrictions.
## How the recommendations might affect practice
The recommendations on phosphate and calcium are largely in line with existing guidance and reflect current best practice. There is variation in practice so the recommendations should ensure consistency of care across different care settings.
Full details of the evidence and the committee's discussion are in evidence review D9: ratio of calcium to phosphate.
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# Other constituents of neonatal parenteral nutrition – general principles
Recommendations 1.5.14 to 1.5.19
## Why the committee made the recommendations
The recommendations were not developed by the usual NICE guideline systematic review process. The committee agreed the recommendations' evidence statements using a formal nominal group consensus method, and based the recommendations on their knowledge and experience.
The committee agreed that vitamins are an essential part of a baby's nutritional needs, and discussed whether vitamins should be provided daily. Babies gain most of their vitamin reserves from their mother in the third trimester of pregnancy, so babies born preterm are relatively vitamin deficient. The committee decided that daily vitamins would improve the vitamin accretion rate and represent best clinical practice. The committee agreed that the recommendation would apply to term babies, because term babies who need parenteral nutrition are likely to have surgical problems or to be critically unwell, so will not establish enteral feeding rapidly. In addition, there was no consensus about making a separate recommendation for term babies. Although the committee acknowledged that some initial or 'starter' parenteral nutrition preparations may not contain vitamins, they stressed that starting parenteral nutrition should not be delayed.
Putting fat- and water-soluble vitamins in the lipid emulsion improves their stability but shortens the shelf life of the lipid emulsion. However, the committee decided that ensuring vitamin stability was important and putting the vitamins in the lipid emulsion was therefore recommended. The committee noted that modern parenteral nutrition preparations generally have longer shelf lives, and so this was a smaller concern than in the past.
Serum sodium and potassium levels can change frequently in babies on neonatal units, and these changes may not be related to parenteral nutrition. How often sodium and potassium levels need to be checked depends on multiple factors and will be decided by the local clinical team based on the overall clinical situation. Sodium and potassium supplementation, in addition to that already contained in parenteral nutrition in phosphate (which is often given as sodium glycerophosphate), can be given using an additional intravenous infusion. This allows standardised parenteral nutrition bags to contain sufficient sodium and potassium to cover usual daily maintenance requirements but allows adjustments to sodium and potassium delivery to cover additional requirements without having to interfere with the parenteral nutrition.
The committee agreed that magnesium is an essential component of parenteral nutrition because of its important role in skeletal development and in nervous system and muscle membranes. Although the committee noted that magnesium may not be immediately available in some initial or 'starter' parenteral nutrition preparations, they stressed that parenteral nutrition should not be delayed, and magnesium should be added as soon as possible after starting parenteral nutrition.
The committee agreed that trace elements are an essential component of parenteral nutrition. Although the committee noted that trace elements may not be immediately available in some initial or 'starter' parenteral nutrition preparations, they stressed that parenteral nutrition should not be delayed and trace elements should be added as soon as possible after starting parenteral nutrition.
## How the recommendations might affect practice
The committee agreed that the recommendation will reinforce current best practice.
Full details of the evidence and the committee's discussion are in evidence review J: general principles.
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# Standardised neonatal parenteral nutrition formulation ('standardised bags')
Recommendations 1.6.1 to 1.6.3
## Why the committee made the recommendations
There was limited evidence on whether healthcare professionals should use parenteral nutrition formulations that are standardised ('standardised bags') or individualised. The committee used the limited evidence, and their knowledge and experience, to make the recommendations.
The committee agreed that healthcare professionals should use standardised bags routinely because:
standardised bags are immediately available when needed, and suitable for most babies
they help to minimise prescribing errors and clinical variation
they can improve compliance with national recommendations on quality control of parenteral nutrition manufacturing, dispensing, prescribing and administration, because they must comply with nationally agreed quality standards (in line with the Royal Pharmaceutical Society and NHS Pharmaceutical Quality Assurance Committee standards for the quality assurance of aseptic preparation services)
they have lower acquisition costs.
Individualised bags are not immediately available on a neonatal unit and are more complex to prescribe. The committee agreed that without good evidence to support the use of individualised bags, the additional complexity and cost is not justified.
Although the committee agreed that standardised bags should be used routinely and continued once started, individualised parenteral nutrition may be needed for babies with complex needs, for example, babies with a fluid imbalance.
Standardisation of parenteral nutrition is a concept which means that its effectiveness depends on optimal content for the average baby and its safety is related to the process of standardisation. Although there was some evidence suggesting that growth-related outcomes favoured an individualised approach, these findings were largely dependent on the specifics of what was in the standardised bag being trialled (which for most studies was not what would currently be recommended). The committee therefore agreed that, to be effective formulations, the standardised bags would be made up using the constituents outlined in the section on constituents of neonatal parenteral nutrition to provide optimal nutrition.
## How the recommendations might affect practice
The committee agreed that the recommendations will lead to greater consistency in clinical practice and improve safety through compliance with national recommendations for parenteral nutrition manufacturing, dispensing, prescribing and administration.
Full details of the evidence and the committee's discussion are in evidence review E: standardised neonatal parenteral nutrition formulations.
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# Monitoring neonatal parenteral nutrition
Recommendations 1.7.1 to 1.7.13
## Why the committee made the recommendations
There was no evidence so the committee used their knowledge and experience to make the recommendations.
The committee agreed that regular blood monitoring is needed to detect potential abnormalities and inform the baby's care. They agreed that the frequency of blood sampling needs to take into account the clinical stability of the baby, the amount of blood taken, and should also strike a balance between minimising distress to the baby (and parents) and obtaining enough information to guide clinical care. To minimise distress resulting from repeated monitoring, the committee emphasised the need to retrieve as much information as possible from 1 sample, so they recommended combining testing wherever possible and agreeing with the laboratory the best ways to coordinate this. The committee agreed that taking minimal blood volumes would be best for the baby, and that this could be achieved by liaising with the laboratory.
The committee recommended minimum frequencies for monitoring parameters, but they also described situations when increased monitoring may be needed (for example, when there is a change in the composition of parenteral nutrition or when the baby is unstable). They also recommended more frequent monitoring when babies had previous abnormal levels of a particular constituent. However, the committee did not want to be too prescriptive about the level of abnormality or how recently this occurred to allow for a degree of clinical judgement tailored to the needs of each baby.
The committee agreed that glucose should be monitored when starting parenteral nutrition and at every change of the bag, for safety reasons, because the time when a bag is changed would be a critical time where hypoglycaemia or hyperglycaemia could occur. After that, monitoring should depend on the stability of the baby – that is, an unstable glucose level should be monitored more frequently because of the risks associated with hyperglycaemia or hypoglycaemia.
The committee agreed that blood pH, potassium, chloride and calcium would usually need to be monitored when starting and when increasing parenteral nutrition. Blood pH is important for a number of reasons, for example, chloride levels cannot be interpreted without knowing the pH, and it is also informative when titrating acetate. Serum sodium is considered in the section on other constituents of neonatal parenteral nutrition – general principles.
The committee discussed the variability in monitoring triglycerides in clinical practice, where some neonatal units monitor more or less frequently, and some neonatal units do not monitor triglycerides at all. The committee agreed that recommendations would be useful to improve consistency across clinical practice. They agreed that triglycerides should be monitored when increasing dosages of lipid, because they were aware of evidence that suggests that around 10% of babies do not tolerate recommended intakes of lipids. Monitoring should continue when the maintenance dosage is reached. The committee agreed that when a baby is at risk of hypertriglyceridaemia, for example if the baby is critically ill, triglycerides should be monitored to ensure the safety of the baby.
The committee agreed that phosphate would initially require daily monitoring because amino acid intake affects phosphate levels and amino acid intake is changed every day for the first 4 days of parenteral nutrition.
The committee decided that after the maintenance dosage is reached, weekly monitoring would be safe. More frequent monitoring would be needed if there are concerns about recent abnormal levels or phosphate levels and bone development, and for preterm babies born at less than 32+0 weeks (because preterm babies are at risk of metabolic bone disease of prematurity where their bones become very brittle as a result of insufficient mineralisation).
The committee agreed that a number of different factors could affect iron status in babies on parenteral nutrition for longer than 28 days, including the number of transfusions administered as well as the amount of enteral nutrition achieved. It is therefore important to measure ferritin, and iron and transferrin saturations for babies who remain on parenteral nutrition after this time. The committee acknowledged that these measurements should be interpreted with caution in unstable babies because they are acute phase reactants and can be elevated as a result of infective or inflammatory conditions.
Abnormal liver function tests could indicate the onset of parenteral nutrition-associated liver disease, so the committee agreed it was important to carry out regular liver function tests for babies on parenteral nutrition.
## How the recommendations might affect practice
Because there is no current consensus on the monitoring of lipids, these recommendations may change clinical practice. All other recommendations reflect current practice, so the committee agreed there would be no change in practice.
Full details of the evidence and the committee's discussion are in evidence review F: monitoring neonatal parenteral nutrition.
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# Stopping neonatal parenteral nutrition
Recommendations 1.8.1 to 1.8.3
## Why the committee made the recommendations
There was some evidence indicating better growth with stopping parenteral nutrition at a higher volume of enteral feeds (140 ml/kg/day). However, there were some inconsistencies between different studies, so the committee also used their knowledge and experience to make the recommendations. The committee based the ranges on the baby's age because the balance between prioritising nutritional intake and minimising the risk of line sepsis may differ depending on the size of the baby. The committee agreed that there were other factors apart from the volume of enteral feeds that should be considered for all babies before stopping parenteral nutrition (for example, tolerance and amount of enteral feeds delivered as well as the clinical situation).
The lower limit for stopping parenteral nutrition in extremely preterm babies was taken from the evidence, but the upper limit was based on the committee's knowledge and experience. In clinical practice, enteral feeds are not normally fortified at 140 ml/kg/day (as was done in the available evidence), so stopping at this point may risk nutritional deficits, so the committee recommended an upper threshold of 150 ml/kg/day. This may be considered the threshold at which the risks of continuing parenteral nutrition outweigh the benefits. The thresholds for stopping parental nutrition in babies born at or after 28+0 weeks were based on the committee's expertise. The energy stores of older preterm babies and term babies are more replete than those of extremely preterm babies, allowing parenteral nutrition to be stopped at a lower volume.
However, the committee highlighted that stopping parenteral nutrition, even when these ranges are reached, should only be made once the other considerations (in recommendation 1.8.1) have been taken into account.
## How the recommendations might affect practice
The committee agreed that the recommendations would reduce variation in clinical practice. For some services, these recommendations may result in a longer duration of parenteral nutrition, which would have associated costs. However, for other services, these recommendations would result in providing parenteral nutrition for a shorter duration and may produce cost savings.
The committee discussed whether the recommendations could result in smaller volumes of parenteral nutrition being prescribed during the transition from parenteral to enteral nutrition, and that these small volumes would not be an efficient use of costs or resources. However, the committee agreed this could be mitigated by giving consideration to residual prescribed volumes of parenteral nutrition when making the decision to stop parenteral nutrition.
Full details of the evidence and the committee's discussion are in evidence review G: stopping parenteral nutrition.
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# Service design
Recommendations 1.9.1 to 1.9.3
## Why the committee made the recommendations
There was some evidence that multidisciplinary team services improve outcomes in newborn babies. However, there were many limitations relating to the evidence, and none of the studies were conducted in the UK. The committee made recommendations that they considered would provide optimum care for babies on parenteral nutrition, using the limited evidence (relating to the clinical role of multidisciplinary teams), and their knowledge of current clinical practice reports in the public domain (particularly related to the team's role in service governance).
The committee acknowledged that inadequacies in the provision of neonatal parenteral nutrition had been highlighted in a 2011 report from the Paediatric Chief Pharmacists Group, Improving practice and reducing risk in the provision of parenteral nutrition for neonates and children, which highlighted the need for improvements in practice
To address these shortcomings and ensure the safety of babies receiving parenteral nutrition, the committee agreed that neonatal parenteral nutrition services should be overseen and supported by a multidisciplinary team with expertise in neonatal parenteral nutrition. The committee specified the membership of the team to ensure that there is expertise in the clinical, prescribing and nutritional core components of neonatal parenteral nutrition (a consultant neonatologist or paediatrician with a special interest in neonatology, as well as a neonatal pharmacist and dietitian). The committee also recognised that access to other roles may be required, such as neonatal nursing, paediatric gastroenterology or expertise in clinical biochemistry to cover specific clinical or specialist areas of parenteral nutrition. The committee listed these different professionals, but agreed that all those listed would not need to see every baby routinely within the unit. The committee decided that an oversight or support team could be available at a local level or within a clinical network to ensure that every unit has access to these professionals when needed.
The committee agreed that enhanced multidisciplinary team input (for assessment and management) may be needed for preterm and term babies with complex needs, for example, babies with short gut who need parenteral nutrition for long time periods and who therefore have an increased risk of complications. This may involve more frequent meetings between multidisciplinary team members, and may also mean that other specialists are included in the multidisciplinary team, for example, a gastroenterologist. The committee did not want to be prescriptive about which professionals should be in the 'enhanced' multidisciplinary team because this would depend on the needs of each baby.
## How the recommendations might affect services
The committee noted that there is currently variation in practice regarding the availability of specialists who are included within multidisciplinary teams, but agreed that these professionals would be available somewhere within a network of care. Arranging and formalising this access may require extra resources. However, babies with complex needs would invariably be seen by professionals from multiple disciplines, so this would not be a change in practice. The recommendations therefore would reduce variation and reinforce current best practice.
Full details of the evidence and the committee's discussion are in evidence review H: service design.
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# Information and support for parents and carers of babies who need neonatal parenteral nutrition
Recommendations 1.10.1 to 1.10.4
## Why the committee made the recommendations
There was no evidence so the committee used their knowledge and experience to make the recommendations.
Good nutrition underpins good neonatal care, so the committee agreed that giving parents and carers information about parenteral nutrition is important.
The committee recognised that having a baby in a neonatal unit is a challenging and stressful situation, and agreed that the best approach to working with parents and carers is a collaborative one. This should involve giving parents and carers information tailored to their needs, and helping them to feel involved in their baby's care.
The committee noted that principles of good information sharing and communication, as well as encouraging shared decision making, are covered in the NICE clinical guideline on patient experience in adult NHS services.
Given that there was no evidence, the committee made a recommendation for further research. This is important because having a baby in a neonatal unit can be a stressful and difficult time for parents and carers. Information and support can help parents manage these circumstances and help them feel involved and part of their baby's care, which can improve outcomes. Given that the number of babies needing parenteral nutrition is likely to increase as prematurity survival rates improve, understanding what information and support parents need will help to support good outcomes.
## How the recommendations might affect practice
The committee agreed there is variation in practice. These recommendations should improve consistency in how healthcare professionals support parents and carers, and ensure that they are given timely, consistent and appropriate information about parenteral nutrition.
Full details of the evidence and the committee's discussion are in evidence review I: information and support.
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Return to research recommendation# Context
Parenteral nutrition refers to intravenous feeding, a technique for providing nutrition to those who are unable to tolerate adequate enteral nutrition (orally or through an enteral tube). It is frequently needed by preterm babies while they establish enteral feeds, critically ill babies, and babies with gastrointestinal disorders who need surgery.
Inadequate nutrition, particularly in preterm babies, can have short-term and long-term health effects, including longer stays in the neonatal unit, an increased risk of infection, and worsened developmental outcomes. There is also evidence that inappropriate nutritional management soon after birth is linked to the development of metabolic syndrome in adults.
Approximately 95,000 babies born in the UK each year need neonatal care (National Neonatal Audit Programme 2016). Parenteral nutrition is widely used in neonatal care. It has become common practice to start it in preterm babies within the first few hours of life, and also to support term babies who are critically ill.
Parenteral nutrition contains nutrients such as glucose, electrolytes, amino acids, lipids, minerals, trace elements and vitamins. It may complement enteral feeding or, in some situations, replace it.
The National Confidential Enquiry into Patient Outcome and Death enquiry into the care of hospital patients receiving parenteral nutrition (2010) reviewed 264 cases of neonatal parenteral nutrition. It found that 73% of cases represented less than 'good practice', 40% had metabolic complications, 40% did not meet nutritional needs, and in 28% the start of parenteral nutrition was delayed. In 37%, the first parenteral nutrition provided was considered inadequate for the patient's needs.
Parenteral nutrition is normally formulated in an aseptic pharmacy unit. It can be in standardised or individualised forms. Prescribing is complex and open to error. Simplified, standardised regimens may reduce this risk, and may reduce costs.
In current practice, virtually all babies born before 31+0 weeks who weigh less than 1.5 kg need parenteral nutrition for a period that depends on gestation, birthweight and other morbidities. Postnatal growth failure is common in babies born before 31+0 weeks. It is associated with an increased need for respiratory support and increased risk of infection. It is also a risk factor for neurocognitive impairment. Optimal use of parenteral nutrition could potentially avoid postnatal growth failure.
Parenteral nutrition is expensive: for a large tertiary neonatal unit, it costs approximately £175,000 a year.
Given the wide variation in practice, safety concerns and costs, this guideline is needed to ensure that the provision of parenteral nutrition for babies is consistent across units and provides optimal care.
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{'Recommendations': "Parents and carers have the right to be involved in planning and making decisions about their baby's health and care, and to be given information and support to enable them to do this, as set out in the NHS constitution and summarised in making decisions about your care.\n\nMaking decisions using NICE guidelines\xa0explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Indications for, and timing of, neonatal parenteral nutrition\n\n## Indications for starting neonatal parenteral nutrition\n\nFor preterm babies born before 31+0\xa0weeks, start neonatal parenteral nutrition.\n\nFor preterm babies born at or after 31+0\xa0weeks, start parenteral nutrition if sufficient progress is not made with enteral feeding in the first 72\xa0hours after birth.\n\nStart parenteral nutrition for preterm and term babies who are unlikely to establish sufficient enteral feeding, for example, babies with:\n\na congenital gut disorder\n\na critical illness such as sepsis.\n\n## Indications for starting neonatal parenteral nutrition if enteral feeds are stopped\n\nFor preterm babies on enteral feeds, start parenteral nutrition if:\n\nenteral feeds have to be stopped and it is unlikely they will be restarted within 48\xa0hours\n\nenteral feeds have been stopped for more than 24\xa0hours and there is unlikely to be sufficient progress with enteral feeding within a further 48\xa0hours.\n\nFor term babies on enteral feeds, start parenteral nutrition if:\n\nenteral feeds have to be stopped and it is unlikely they will be restarted within 72\xa0hours\n\nenteral feeds have been stopped for more than 48\xa0hours and there is unlikely to be sufficient progress with enteral feeding within a further 48\xa0hours.\n\n## Timing of starting neonatal parenteral nutrition\n\nWhen a preterm or term baby meets the indications for parenteral nutrition, start it as soon as possible, and within 8\xa0hours at the latest.\n\nFor a short explanation of why the committee made the recommendations on indications for, and timing of, neonatal parenteral nutrition, and how they might affect practice, see rationale and impact\xa0.\n\nLoading. Please wait.\n\n# Administration of neonatal parenteral nutrition\n\n## Venous access\n\nUse a central venous catheter to give neonatal parenteral nutrition. Only consider using peripheral venous access to give neonatal parenteral nutrition if:\n\nit would avoid a delay in starting parenteral nutrition\n\nshort-term use of peripheral venous access is anticipated, for example, less than 5\xa0days\n\nit would avoid interruptions in giving parenteral nutrition\n\ncentral venous access is impractical.\n\nOnly consider surgical insertion of a central venous catheter if:\n\nnon-surgical insertion is not possible\n\nlong-term parenteral nutrition is anticipated, for example, in short bowel syndrome.\n\nFor a short explanation of why the committee made the recommendations on venous access for neonatal parenteral nutrition and how they might affect practice, see rationale and impact\xa0.\n\nLoading. Please wait.\n\n## Protection from light\n\nProtect the bags, syringes and infusion sets of both aqueous and lipid parenteral nutrition solutions from light.\n\nFor a short explanation of why the committee made the recommendation on protection from light and how it might affect practice, and why the committee were unable to make recommendations about filtration, see rationale and impact\xa0.\n\nLoading. Please wait.\n\n# Energy needs of babies on neonatal parenteral nutrition\n\nFor preterm and term babies who need total neonatal parenteral nutrition, deliver energy as follows:\n\nIf starting parenteral nutrition in the first 4\xa0days after birth:\n\n\n\ngive a starting range of 40\xa0to 60\xa0kcal/kg/day\n\ngradually increase (for example, over 4\xa0days) to a maintenance range of 75\xa0to 120\xa0kcal/kg/day.\n\n\n\nIf starting parenteral nutrition more than 4\xa0days after birth:\n\n\n\ngive a range of 75\xa0to 120\xa0kcal/kg/day.\n\n\n\nFor preterm and term babies who are on enteral feeds in addition to neonatal parenteral nutrition, reduce the amount of energy that is given parenterally as enteral feeds increase.\n\n## Term babies who are critically ill or have just had surgery\n\nFor term babies who are critically ill or have just had surgery, consider giving parenteral energy at the lower end of the starting range in recommendation\xa01.3.1, and gradually increase to the intended maintenance intake.\n\nFor a short explanation of why the committee made the recommendations on the energy needs of babies on neonatal parenteral nutrition and how they might affect practice, see rationale and impact\xa0.\n\nLoading. Please wait.\n\n# Neonatal parenteral nutrition volume\n\nStandardised neonatal parenteral nutrition ('standardised bags') should be formulated in concentrated solutions to help ensure that the nutritive element of intravenous fluids is included within the total fluid allowance.\n\nFor a short explanation of why the committee made the recommendation on neonatal parenteral nutrition volume and how it might affect practice, see rationale and impact\xa0.\n\nLoading. Please wait.\n\n# Constituents of neonatal parenteral nutrition\n\n## Glucose\n\nFor preterm and term babies, give glucose as follows:\n\nIf starting parenteral nutrition in the first 4\xa0days after birth:\n\n\n\ngive a starting range of 6\xa0to 9\xa0g/kg/day\n\ngradually increase (for example, over 4\xa0days) to a maintenance range of 9\xa0to 16\xa0g/kg/day.\n\n\n\nIf starting parenteral nutrition more than 4\xa0days after birth:\n\n\n\ngive a range of 9\xa0to 16\xa0g/kg/day.\n\n\n\nFor a short explanation of why the committee made the recommendation on glucose and how it might affect practice, see rationale and impact\xa0.\n\nLoading. Please wait.\n\n## Amino acids\n\nFor preterm babies, give amino acids as follows:\n\nIf starting parenteral nutrition in the first 4\xa0days after birth:\n\n\n\ngive a starting range of 1.5\xa0to 2\xa0g/kg/day\n\ngradually increase (for example, over 4\xa0days) to a maintenance range of 3\xa0to 4\xa0g/kg/day.\n\n\n\nIf starting parenteral nutrition more than 4\xa0days after birth:\n\n\n\ngive a range of 3\xa0to 4\xa0g/kg/day.\n\n\n\nFor term babies, give amino acids as follows:\n\nIf starting parenteral nutrition in the first 4\xa0days after birth:\n\n\n\ngive a starting range of 1\xa0to 2\xa0g/kg/day\n\ngradually increase (for example, over 4\xa0days) to a maintenance range of 2.5\xa0to 3\xa0g/kg/day.\n\n\n\nIf starting parenteral nutrition more than 4\xa0days after birth:\n\n\n\ngive a range of 2.5\xa0to 3\xa0g/kg/day.\n\n\n\nFor a short explanation of why the committee made the recommendations on amino acids and how they might affect practice, see rationale and impact\xa0.\n\nLoading. Please wait.\n\n## Lipids and lipid emulsions\n\nFor preterm and term babies, give lipids as follows:\n\nIf starting parenteral nutrition in the first 4\xa0days after birth:\n\n\n\ngive a starting range of 1\xa0to 2\xa0g/kg/day\n\ngradually increase (for example, in daily increments of 0.5\xa0to 1\xa0g/kg/day) to a maintenance range of 3\xa0to 4\xa0g/kg/day.\n\n\n\nIf starting parenteral nutrition more than 4\xa0days after birth:\n\n\n\ngive a range of 3\xa0to 4\xa0g/kg/day.\n\n\n\nFor preterm and term babies with parenteral nutrition-associated liver disease, consider giving a composite lipid emulsion rather than a pure soy lipid emulsion.\n\nFor a short explanation of why the committee made the recommendations on lipids and lipid emulsions and how they might affect practice, see rationale and impact\xa0.\n\nLoading. Please wait.\n\n## Ratios of non-nitrogen energy to nitrogen, and carbohydrates to lipids\n\nWhen giving neonatal parenteral nutrition to preterm or term babies:\n\nuse the values for each individual component in recommendations\xa01.5.1 to\xa01.5.4\n\nprovide non-nitrogen energy as 60% to 75% carbohydrate and 25% to 40% lipid\n\nuse a non-nitrogen energy to nitrogen ratio in a range of 20\xa0to 30\xa0kcal of non-nitrogen energy per gram of amino acids (this equates to 23\xa0to 34\xa0kcal of total energy per gram of amino acid).\n\nWhen altering the amount of neonatal parenteral nutrition, maintain the non-nitrogen energy to nitrogen ratio, and the carbohydrate to lipid ratio, to keep within the ranges of ratios specified in recommendation\xa01.5.6.\n\nFor a short explanation of why the committee made the recommendations on ratios of non-nitrogen to nitrogen energy, and carbohydrates to lipids, and how they might affect practice, and why the committee were unable to make recommendations about ratios of phosphate to amino acids, see rationale and impact\xa0.\n\nLoading. Please wait.\n\n## Iron\n\nDo not give intravenous parenteral iron supplements to preterm or term babies on neonatal parenteral nutrition who are younger than 28\xa0days.\n\nFor preterm babies on neonatal parenteral nutrition who are 28\xa0days or older, monitor for iron deficiency and treat if necessary (see recommendation\xa01.7.11).\n\nFor a short explanation of why the committee made the recommendations on iron and how they might affect practice, see rationale and impact\xa0.\n\nLoading. Please wait.\n\n## Acetate\n\nFor a short explanation of why the committee were unable to make recommendations about acetate, see rationale\xa0.\n\nLoading. Please wait.\n\n## Calcium\n\nFor preterm and term babies, give calcium as follows:\n\nIf starting parenteral nutrition in the first 48\xa0hours after birth:\n\n\n\ngive a starting range of 0.8\xa0to 1\xa0mmol/kg/day\n\nincrease to a maintenance range of 1.5\xa0to 2\xa0mmol/kg/day after 48\xa0hours.\n\n\n\nIf starting parenteral nutrition more than 48\xa0hours after birth, give a range of 1.5\xa0to 2\xa0mmol/kg/day.\n\n## Phosphate\n\nFor preterm and term babies, give phosphate as follows:\n\nIf starting parenteral nutrition in the first 48\xa0hours after birth:\n\n\n\ngive 1\xa0mmol/kg/day\n\nincrease to a maintenance dosage of 2\xa0mmol/kg/day after 48\xa0hours.\n\n\n\nIf starting parenteral nutrition more than 48\xa0hours after birth, give 2\xa0mmol/kg/day.\n\nGive a higher dosage of phosphate if indicated by serum phosphate monitoring.\n\nBe aware that preterm babies may be at increased risk of phosphate deficit requiring additional phosphate supplementation.\n\n## Ratio of calcium to phosphate\n\nUse a calcium to phosphate ratio of between 0.75:1 and 1:1 for preterm and term babies on neonatal parenteral nutrition.\n\nFor a short explanation of why the committee made the recommendations on calcium, phosphate, and the ratio of calcium to phosphate, and how they might affect practice, see rationale and impact\xa0.\n\nLoading. Please wait.\n\n## Other constituents of neonatal parenteral nutrition – general principles\n\nGive daily intravenous fat-soluble and water-soluble vitamins ideally from the outset, but as soon as possible after starting parenteral nutrition, to maintain standard daily requirements.\n\nGive fat-soluble and water-soluble vitamins in the intravenous lipid emulsion to improve their stability.\n\nGive sodium and potassium in parenteral nutrition to maintain standard daily requirements, adjusted as necessary for the individual baby.\n\nBe aware that even if the parenteral nutrition solution contains sodium and potassium, additional supplements of these electrolytes can be given using a separate intravenous infusion.\n\nGive magnesium in parenteral nutrition ideally from the outset, but as soon as possible after starting parenteral nutrition.\n\nGive daily intravenous trace elements ideally from the outset, but as soon as possible after starting parenteral nutrition.\n\nFor a short explanation of why the committee made the recommendations on general principles of other constituents of neonatal parenteral nutrition, and how they might affect practice, see rationale and impact\xa0.\n\nLoading. Please wait.\n\n# Standardised neonatal parenteral nutrition formulations ('standardised bags')\n\nWhen starting neonatal parenteral nutrition for preterm and term babies, use a standardised neonatal parenteral nutrition formulation ('standardised bag').Note that this might be an off-label use as not all parenteral nutrition formulations have a UK marketing authorisation for this indication. See prescribing medicines for more information.\n\nStandardised bags should:\n\nbe formulated to allow delivery of parenteral nutrition as recommended in the sections on neonatal parenteral nutrition volume and constituents of neonatal parenteral nutrition\n\nbe prepared following nationally agreed quality standards.\n\nContinue with a standardised bag unless an individualised parenteral nutrition formulation is indicated, for example, if the baby has:\n\ncomplex disorders associated with a fluid and electrolyte imbalance\n\nrenal failure.\n\nFor a short explanation of why the committee made the recommendations on standardised neonatal parenteral nutrition formulations ('standardised bags') and how they might affect practice, see rationale and impact\xa0.\n\nLoading. Please wait.\n\n# Monitoring neonatal parenteral nutrition\n\nWhen taking blood samples to monitor the preterm or term baby's neonatal parenteral nutrition:\n\ncollect the minimum blood volume needed for the tests\n\nuse a protocol agreed with the local clinical laboratory to retrieve as much information as possible from the sample\n\ncoordinate the timing of blood tests to minimise the number of blood samples needed.\n\n## Blood glucose\n\nMeasure the blood glucose level:\n\nto 2\xa0hours after first starting parenteral nutrition\n\nto 2\xa0hours after each change of parenteral nutrition bag (usually every 24\xa0or 48\xa0hours).\n\nMeasure blood glucose more frequently if:\n\nthe preterm or term baby has previously had hypoglycaemia or hyperglycaemia\n\nthe dosage of intravenous glucose has been changed\n\nthere are clinical reasons for concern, for example, sepsis or seizures.\n\n## Blood pH, potassium, chloride and calcium\n\nMeasure the blood pH, potassium, chloride and calcium levels:\n\ndaily when starting and increasing parenteral nutrition\n\ntwice weekly after reaching a maintenance parenteral nutrition.\n\nMeasure blood pH, potassium, chloride or calcium more frequently if:\n\nthe preterm or term baby has previously had levels of these components outside the normal range\n\nthe dosages of intravenous potassium, chloride or calcium have been changed\n\nthere are clinical reasons for concern, for example, in critically ill babies.\n\n## Serum triglycerides\n\nMeasure serum triglycerides:\n\ndaily while increasing the parenteral nutrition lipid dosage\n\nweekly after reaching a maintenance intravenous lipid dosage.\n\nMeasure serum triglycerides more frequently, but not more than once a day, if:\n\nthe level is elevated\n\nthe preterm or term baby is at risk of hypertriglyceridaemia, for example, if the baby is critically ill or has a lipaemic blood sample.\n\nBe aware that ongoing serum triglyceride monitoring may not be needed for stable preterm or term babies transitioning from parenteral nutrition to enteral nutrition.\n\n## Serum or plasma phosphate\n\nMeasure the serum or plasma phosphate level:\n\ndaily while increasing the parenteral nutrition phosphate dosage\n\nweekly after reaching a maintenance intravenous phosphate dosage.\n\nConsider measuring serum or plasma phosphate more frequently:\n\nif the level has been outside the normal range\n\nif there are clinical reasons for concern, for example, metabolic bone disease\n\nfor preterm babies born at less than 32+0\xa0weeks.\n\n## Iron status\n\nMeasure ferritin, iron and transferrin saturation if a preterm baby is on parenteral nutrition for more than 28\xa0days.\n\n## Liver function\n\nMeasure liver function weekly in preterm and term babies on parenteral nutrition.\n\nMeasure liver function more frequently than weekly if there are clinical concerns or previous liver function test levels outside the normal range.\n\nFor a short explanation of why the committee made the recommendations on monitoring neonatal parenteral nutrition and how they might affect practice, see rationale and impact\xa0.\n\nLoading. Please wait.\n\n# Stopping neonatal parenteral nutrition\n\nFor all babies, take into account the following when deciding when to stop parenteral nutrition:\n\nthe baby's tolerance of enteral feeds\n\nthe amount of nutrition being delivered by enteral feeds (volume and composition)\n\nthe relative contribution of parenteral nutrition and enteral nutrition to the baby's total nutritional requirement\n\nthe likely benefit of the nutritional intake compared with the risk of venous catheter sepsis\n\nthe individual baby's particular circumstances, for example, a baby with complex needs such as short bowel syndrome, increased stoma losses or slow growth, may need long-term parenteral nutrition.\n\nFor preterm babies born before 28+0\xa0weeks, consider stopping parenteral nutrition within 24\xa0hours once the enteral feed volume is 140\xa0to 150\xa0ml/kg/day, taking into account the factors in recommendation\xa01.8.1.\n\nFor preterm babies born at or after 28+0\xa0weeks and term babies, consider stopping parenteral nutrition within 24\xa0hours if the enteral feed volume tolerated is 120\xa0to 140\xa0ml/kg/day, taking into account the factors in recommendation\xa01.8.1.\n\nFor a short explanation of why the committee made the recommendations on stopping neonatal parenteral nutrition and how they might affect practice, see rationale and impact\xa0.\n\nLoading. Please wait.\n\n# Service design\n\nNeonatal parenteral nutrition services should be supported by a specialist multidisciplinary team. Such teams could be based locally or within a clinical network.\n\nThe neonatal parenteral nutrition multidisciplinary team should include a consultant neonatologist or paediatrician with a special interest in neonatology, a neonatal pharmacist and a neonatal dietitian, and should have access to the following:\n\na neonatal nurse\n\na paediatric gastroenterologist\n\nan expert in clinical biochemistry.\n\nThe neonatal parenteral nutrition multidisciplinary team should be responsible for:\n\ngovernance, including:\n\n\n\nagreeing policies and protocols for the neonatal parenteral nutrition service\n\nensuring that policies and protocols for neonatal parenteral nutrition are followed and audited\n\nmonitoring clinical outcomes\n\n\n\nsupporting delivery of parenteral nutrition, including:\n\n\n\nproviding clinical advice\n\nproviding enhanced multidisciplinary team input for preterm and term babies with complex needs, for example, babies with short bowel syndrome who may need long-term parenteral nutrition.\n\n\n\nFor a short explanation of why the committee made the recommendations on service design and how they might affect services, see rationale and impact\xa0.\n\nLoading. Please wait.\n\n# Information and support for parents and carers\n\nAsk parents and carers of babies on parenteral nutrition how and when they would like to receive information and updates, and how much information they would like about their baby's care.\n\nTopics to discuss with parents or carers include:\n\nwhy their baby needs parenteral nutrition\n\nwhat parenteral nutrition involves\n\nthe importance of good nutrition for newborn babies\n\nhow long their baby is likely to need parenteral nutrition for\n\ncommon concerns, for example, central venous catheter placement, the risk of catheter-related infections, taking blood samples, and whether they can hold and care for their baby\n\nsimultaneous enteral feeding, unless this is not possible\n\nhow their baby's progress will be monitored\n\nhow their baby will be weaned off parenteral nutrition.\n\nGive information to parents or carers that:\n\nis tailored to their baby's circumstances\n\nmeets their needs and preferences\n\nis up to date, relevant and consistent between healthcare professionals\n\nis available in suitable formats (written and spoken, with information available to take away). For more guidance on communication (including different formats and languages), providing information, and shared decision making, see the NICE guidelines on patient experience in adult NHS services, babies, children and young people's experience of healthcare and shared decision making.\n\nProvide regular opportunities and time for parents and carers of babies on parenteral nutrition to discuss their baby's care, ask questions about the information they have been given, and discuss concerns.\n\nFor a short explanation of why the committee made the recommendations on information and support for parents and carers of babies on neonatal parenteral nutrition and how they might affect practice, see rationale and impact\xa0.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a particular way for this guideline.\n\n## Composite lipid emulsion\n\nA lipid emulsion that is derived from more than 1\xa0source, for example, it might include 2\xa0or more of soy oil, medium chain triglycerides, olive oil or fish oil.\n\n## Individualised parenteral nutrition formulations\n\nAqueous and lipid parenteral nutrition solutions that meet the nutritional requirements of an individual baby. The solutions are not pre-formulated and have to be prescribed and made up each time they are needed, on an individual basis for each baby. Electrolytes can be added, and macronutrients or micronutrients can be adjusted as necessary.\n\n## Nominal group consensus method\n\nThis is a structured method focusing on the opinions of individuals within a group to reach a consensus. Because of the focus on individuals, it is referred to as a 'nominal group' technique. It involves anonymous voting with an opportunity to provide comments. Options with low agreement are eliminated and options with high agreement are retained. Using the comments that individuals provide, options with medium agreement are revised and then considered in a second round.\n\n## Osmolality or osmolarity\n\nMeasurement of the number of dissolved particles present in a solution to indicate fluid concentration. It is defined as the number of osmoles of solute per kilogram of solvent (osmolality), or the number of osmoles of solute per litre of solution (osmolarity).\n\n## Preterm\n\nA baby born before 37+0\xa0weeks. This can be subdivided further:\n\nextremely preterm: babies born at less than 28+0\xa0weeks\n\nvery preterm: babies born at between 28+0 and 31+6\xa0weeks\n\nmoderate to late preterm: babies born at between 32+0 and 36+6\xa0weeks.\n\n## Standardised neonatal parenteral nutrition formulations ('standardised bags')\n\nStandardised bags contain pre-formulated aqueous and lipid parenteral nutrition solutions made to a set composition that is not varied. They are ready to use and aim to meet the nutritional and clinical needs of a defined group of babies. Additional intravenous infusions are sometimes used to meet more individualised fluid or electrolyte requirements.\n\nStandardised bags are prescribed as part of a standardised parenteral nutrition regimen: a choice of standardised bags that are given at the appropriate volume to meet the nutritional and clinical needs of a defined group of babies.", 'Recommendations for research': 'The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Information and support\n\nWhat are the information and support needs of parents and carers with babies on parenteral nutrition?\n\nFor a short explanation of why the committee made the research recommendation on information and support, see rationale and impact\xa0.\n\nFull details of the research recommendation are in evidence review\xa0I: information and support.\n\nLoading. Please wait.\n\n## Ratios of non-nitrogen energy to nitrogen\n\nWhat is the optimal ratio of non-nitrogen energy to nitrogen in parenteral nutrition for preterm and term babies?\n\nFor a short explanation of why the committee made the research recommendation on the ratio of non-nitrogen energy to nitrogen in parenteral nutrition, see rationale and impact\xa0.\n\nFull details of the research recommendation are in evidence review\xa0D7: ratio of non-nitrogen energy to nitrogen.\n\nLoading. Please wait.\n\n## Timing of starting neonatal parenteral nutrition\n\nWhat is the optimal timeframe for starting parenteral nutrition in term babies who are critically ill or require surgery?\n\nFor a short explanation of why the committee made the research recommendation on the timing of starting neonatal parenteral nutrition, see rationale and impact\xa0.\n\nFull details of the research recommendation are in evidence review\xa0A2: optimal timeframe to start parenteral nutrition.\n\nLoading. Please wait.\n\n## Venous access\n\nWhat overall osmolality (or concentration of calcium and glucose/dextrose) in parenteral nutrition can determine whether to administer centrally or peripherally?\n\nFor a short explanation of why the committee made the research recommendation on using osmolality to determine whether to administer centrally or peripherally, see rationale and impact\xa0.\n\nFull details of the research recommendation are in evidence review\xa0B: venous access.\n\nLoading. Please wait.', 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect services. They link to details of the evidence and a full description of the committee's discussion.\n\n# Indications for, and timing of, neonatal parenteral nutrition\n\nRecommendations 1.1.1 to 1.1.6\n\n## Why the committee made the recommendations\n\nThere was no evidence on the indications for neonatal parenteral nutrition, and limited evidence about the timeframe in which it should be provided, so the committee used their knowledge and experience to make the recommendations.\n\nThe committee agreed that all preterm babies born before 31+0\xa0weeks should receive parenteral nutrition from birth until they transition to enteral feeds. Even though there was no specific evidence for this, the committee agreed that there is a risk of significant deficits in nutrition and short-term and long-term adverse events if babies born before 31+0\xa0weeks are not supported by parenteral nutrition from birth.\n\nFor preterm babies born at or after 31+0\xa0weeks, it needs to be established whether sufficient progress is made with enteral feeding within the first 72\xa0hours after the birth. The committee decided not to be prescriptive about 'sufficient', to reflect the clinical judgements that healthcare professionals would make depending on each baby's individual circumstances and condition, and because enteral nutrition was not reviewed as part of this guideline. If babies have difficulties tolerating enteral feeds during this time, parenteral nutrition should be provided without delay. The committee was aware of evidence that this group of moderately preterm babies is at increased risk of long-term neurodevelopmental problems, and that optimal early nutrition may reduce the risk.\n\nThe committee discussed the influence of gestational age and birthweight on gut maturity and the baby's ability to tolerate enteral feeds. Although weight is closely linked to age, the committee had concerns that including more than 1\xa0parameter may lead to uncertainty in deciding when to start parenteral nutrition, so they based the recommendations solely on gestational age at birth.\n\nCritically ill term babies (with, for example, sepsis), and babies with congenital disorders, may be unlikely to make progress on enteral feeding. The committee agreed that this would be a clinical judgement, depending on each baby's circumstances and condition. They agreed that a delay could have long-term consequences and recommended parenteral feeding for these babies.\n\nThe committee agreed the timings based on their knowledge and experience, and because preterm babies have limited stores and the potential for accumulating deficits. For term babies, the committee based the recommendation on current practice and their knowledge of the more replete nutritional stores of a baby born at term.\n\nThere was evidence to show that, for preterm babies, there are some benefits to starting parenteral nutrition early. However, the definition of 'early' varied in the evidence (ranging from 2\xa0hours to 36\xa0hours without very clear descriptions of the enteral feeding regimen), and there was no consistent pattern of findings. There was evidence for critically ill term babies that compared starting parenteral nutrition early (within 24\xa0hours) with starting it after 1\xa0week. There were some benefits in delaying parenteral nutrition but the committee had reservations about the evidence because the study was relatively small, the parenteral nutrition regimens used were not consistent across the different study sites and the intervention may not have been appropriate because parenteral nutrition would not normally be started on day\xa01 for critically ill term babies due to restricted fluid volumes and strain on organ systems. The timeframe for starting parenteral nutrition is therefore based on what the committee believe is achievable and safe.\n\nThe committee agreed that starting parenteral nutrition within 8\xa0hours of the decision being made to provide it would reduce the risks of a nutritional deficit developing for the smallest babies (born at less than 31+0\xa0weeks). In addition, the committee noted that this timeframe would allow for placement of central lines if needed.\n\nThe committee also discussed the timeframe for critically ill babies, but there was not enough evidence to make a separate recommendation. From their knowledge and experience, they were aware that without parenteral nutrition, preterm babies will develop a nutritional deficit more rapidly than term babies who have greater nutritional reserves; therefore, they agreed that it may take longer to decide whether parenteral nutrition in term babies is needed.\n\nHowever, once the decision is made that parenteral nutrition is needed, it should be started within 8\xa0hours, regardless of whether babies are term or preterm.\n\nThe committee recognised the need for further research to inform the timing of starting parenteral nutrition for term babies who are critically ill or require surgery.\n\n## How the recommendations might affect practice\n\nThe committee agreed that the recommendations would improve consistency of care across neonatal units, and ensure that the nutritional needs of vulnerable babies are met. Hospitals providing care for babies for whom parenteral nutrition is indicated would have to provide access to parenteral nutrition. If a hospital does not have access to neonatal parenteral nutrition, babies would need to be transferred to a unit that could provide it.\n\nEarly provision may be more costly because parenteral nutrition and staff would need to be available out-of-hours (including during weekends) to administer parenteral nutrition within the first 8\xa0hours. However, costs can be reduced by using standardised parenteral nutrition bags, as recommended in the section on standardised neonatal parenteral nutrition formulations ('standardised bags'), which can be stored and be readily accessible. The committee believe that there should be no reason why neonatal units cannot stock standardised bags because they have a long enough shelf life to enable storage, as long as a system of stock rotation is in place. The committee also agreed that the costs of early administration would be offset by the positive impact of early optimal nutrition.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0A1: predictors of enteral feeding success\n\nevidence review\xa0A2: optimal timeframe to start parenteral nutrition.\n\nReturn to recommendations\n\nReturn to research recommendation\n\n# Administration of neonatal parenteral nutrition\n\nRecommendations 1.2.1 to 1.2.3\n\n## Why the committee made the recommendations\n\nThere was some evidence that included a comparison of fluid concentrations (as measured by osmolality or osmolarity, which depends on the level of calcium and glucose within the same amount of fluid) for peripheral venous lines. This evidence included delivering peripheral parenteral nutrition at concentrations of up to 1,425\xa0mOsm/l. However, the committee agreed that it was not possible to recommend a specific safe concentration for parenteral nutrition delivered peripherally because of the wide range of concentrations used in the different groups in the study. Furthermore, there was no evidence that compared centrally with peripherally inserted catheters for any given level of concentration of parenteral nutrition. Therefore, the committee made their recommendations using the available evidence, as well as their knowledge and experience.\n\nThe committee discussed the risks and benefits associated with centrally and peripherally inserted catheters. The committee acknowledged that there is variation in clinical practice, and some units routinely use peripherally inserted catheters, whereas others prefer centrally inserted catheters and avoid using peripherally inserted catheters.\n\nThe committee agreed that centrally inserted catheters should normally be the preferred option for delivering neonatal parenteral nutrition. This is because centrally inserted catheters have a longer lifespan, and the central vein is bigger and has a lower risk of thrombophlebitis. However, they also agreed that peripherally inserted catheters can be used safely (which was supported by the evidence) when use of a peripheral line will be short term, and should be used when parenteral nutrition would otherwise be delayed or interrupted (for example, because there is no one available to insert a central venous catheter, a central venous catheter has stopped working and needs to be removed, or there are concerns about line infection). The committee did not define how long parenteral nutrition can be delayed before peripheral venous access should be considered, because this decision will be based on clinical judgement. Ideally, delays should not exceed the 8\xa0hours specified in recommendation\xa01.1.6, but healthcare professionals will need to consider the risks and benefits of inserting a peripheral line if it is anticipated that a central venous catheter would be inserted soon.\n\nThe benefits and risks of surgically inserted central catheters were also discussed by the committee, and recommendations were made that these should only be used in exceptional circumstances when non-surgical insertion is not possible, or it is expected that parenteral nutrition would be needed for a long time.\n\nBecause of the limited evidence, the committee decided to prioritise this topic for further research. This is important because peripheral lines (although not the preferred choice of the committee) are generally easier to insert, and are very commonly used for a number of indications on neonatal units. However, they have a shorter life span and therefore would need to be changed more frequently. Because the infusions run into a smaller peripheral vein, there is a greater risk of the infusion causing direct damage to the vein. This is particularly true if there is a higher concentration (as measured by osmolality or osmolarity, depending on the unit of measurement) of the parenteral nutrition infusion fluid, for example, a formulation with a higher dextrose load.\n\nPhoto-degradation and oxidation are processes that do not lend themselves to comparative clinical studies (because of safety risks if the integrity of the solution is compromised) that are commonly used as evidence in NICE guidelines, so the committee made the recommendation based on a formal nominal group consensus method and their knowledge and experience.\n\nThe committee discussed photo-degradation and oxidation of parenteral nutrition solutions (including aqueous and lipid components), which can be managed by protecting both the infusion set (tubing) and bag from light. The committee discussed whether to recommend protecting just the bag, or the bag, the tubing and syringe. They recognised that it is simple to cover the bag, and this is already done in current practice. The committee agreed that, although some units would need to use a different type of infusion set, it is best practice to also protect the infusion set and syringe of both aqueous and lipid parenteral nutrition solutions from light, in line with European Medicines Agency and Medicines and Healthcare products Regulatory Agency guidance that states 'for administration to neonates and children below 2\xa0years of age, parenteral nutrition products containing amino acids and/or lipids should be protected from light (containers and administration sets)'.\n\nThe committee acknowledged that adding a terminal filter to the infusion set makes giving parenteral nutrition significantly more expensive. They discussed that adding filters can remove particulate matter, fungi, bacteria and endotoxins depending on the size of the filter. However, making up parenteral nutrition in aseptic units and using bags instead of syringes reduces the risk of bacterial contamination. Breaking a line to change the filter when running lipid from a bag was thought to pose more of an infection risk than changing the bag and filter frequently (every 48\xa0hours). Given these uncertainties around benefits and harms, as well as additional costs, the committee were not able to make a recommendation related to filtration.\n\n## How the recommendations might affect practice\n\nThe recommendations reinforce current best practice. The recommendations may affect clinical practice by reducing the current delay that some units experience when siting a central line for giving parenteral nutrition, because peripherally inserted catheters may now be used as a short-term alternative.\n\nAny likely changes in practice and costs associated with light-protected bags and light-protected tubing will be outweighed by the benefits associated with preserving the integrity of the parenteral nutrition solution.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: venous access and evidence review\xa0J: general principles.\n\nReturn to recommendations\n\nReturn to research recommendation\n\n# Energy needs of babies on neonatal parenteral nutrition\n\nRecommendations 1.3.1 to 1.3.3\n\n## Why the committee made the recommendations\n\nThere was limited evidence on the energy needs for babies on parenteral nutrition, so the committee used their knowledge and experience to give a starting and maintenance range, and an example of how this should be increased gradually. The committee discussed the number of days over which energy intake should increase to reach the intended maintenance level, and agreed to align this with the recommendations on lipid, glucose and amino acid increases.\n\nThe committee agreed that babies who start parenteral nutrition in the first 4\xa0days after birth should have a starting range and increase up to a maintenance range over approximately 4\xa0days. This timeframe was primarily selected because neonatal metabolic adaptation occurs in the early days of life, enabling the baby to metabolise the nutrients delivered. In addition, fluid volume allowances are commonly increased over the first few days of life and this allows increasing amounts of nutrition to be given parenterally.\n\nFor babies who start parenteral nutrition more than 4\xa0days after birth, early metabolic adaptation is likely to have taken place. The fluid allowances will have already increased, so this allows parenteral nutrition to be started using maintenance ranges.\n\nThe energy requirements were taken from the committee's knowledge, informed (to a limited extent) by the evidence, and cross-referenced to the energy delivered by the combined constituent components (in the section on constituents of neonatal parenteral nutrition).\n\nThe committee agreed that giving energy at the lower range may be more appropriate for term babies who are critically ill or have just had surgery because the energy stores of term babies tend to be more replete. However, in critically ill preterm babies, who have limited nutritional stores, prioritising nutritional intake may be more important.\n\n## How the recommendations might affect practice\n\nThe committee agreed that the recommendations would improve consistency of care across neonatal units and would not incur extra costs or increase resource use. Providing the appropriate nutritional intake may avoid additional costs associated with nutritional deficit or providing excess energy.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: energy needs.\n\nReturn to recommendations\n\n# Neonatal parenteral nutrition volume\n\nRecommendation 1.4.1\n\n## Why the committee made the recommendation\n\nThe recommendation on parenteral nutrition fluid volume was not developed by the usual NICE guideline systematic review process. The committee agreed the recommendation using a formal nominal group consensus method as well as their knowledge and experience.\n\nThe total fluid requirement for preterm and term babies is a complex topic, and was outside the scope of this guideline. Nevertheless, it is an important factor in providing neonatal parenteral nutrition. In some situations, the total fluid allowance may be restricted, or a significant proportion of the allowance might be required for other purposes (for example, other intravenous drug infusions). The committee recognised that this could result in difficulties in giving the required amount of parenteral nutrition. In order to minimise this risk, the committee agreed that standardised neonatal parenteral nutrition formulations ('standardised bags') should use the smallest fluid volume possible (see the section on standardised neonatal nutrition formulations). Concentrating parenteral nutrition in this way will facilitate the provision of nutritional requirements within the total fluid allowance.\n\n## How the recommendation might affect practice\n\nThe committee agreed that the recommendation will reinforce current best practice.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0J: general principles.\n\nReturn to recommendations\n\n# Constituents of neonatal parenteral nutrition – glucose\n\nRecommendation 1.5.1\n\n## Why the committee made the recommendation\n\nThe evidence on glucose was difficult to interpret and draw any conclusions from. Only 1\xa0study has been conducted that varied glucose intake without also varying other constituents (such as amino acids and lipids), so it is difficult to see what effect different levels of glucose intake have. Because of this, the committee used their knowledge and experience of physiological and metabolic requirements, and took into account the glucose doses used in the studies as well as current practice and international guidelines, when making their recommendation.\n\nThe committee decided that the maintenance range should be given for babies who start parenteral nutrition more than 4\xa0days after birth. This is consistent with the approximate 4\xa0days by which a maintenance dosage would be reached in babies starting parenteral nutrition from birth, because tolerance would increase during the first few days of life.\n\n## How the recommendation might affect practice\n\nThe committee agreed that the recommendation will reinforce current best practice.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D1: glucose.\n\nReturn to recommendations\n\n# Constituents of neonatal parenteral nutrition – amino acids\n\nRecommendations 1.5.2 and 1.5.3\n\n## Why the committee made the recommendations\n\nThere was a lot of evidence related to amino acid intake. However, the evidence was uncertain, for example, because the studies involved small numbers of babies and the results were inconsistent, so the committee also used their knowledge and experience of current practice to make the recommendations.\n\nFor preterm babies, 1.5\xa0g/kg/day was chosen as the lower starting dose threshold, because less than this can result in a negative nitrogen balance. The committee did not look for evidence on how different amino acid doses affect nitrogen balance, but used their knowledge of metabolic studies, which are widely used to estimate the minimum amount of amino acids needed to prevent negative nitrogen balance. The upper starting dose threshold of 2\xa0g/kg/day was selected because there was evidence of better growth at a starting dose of 2\xa0g/kg/day of amino acids compared with less than 2\xa0g/kg/day, but these benefits did not persist at higher amino acid starting doses (3\xa0g/kg/day).\n\nStudies using different maximal amino acid intakes were considered in the evidence review, and informed the recommended maintenance range. There was some evidence that a maximal amino acid intake of 3\xa0g/kg/day or more compared with less than 3\xa0g/kg/day improved growth outcomes, but there was no evidence of reduced sepsis or neurodevelopmental problems. There was some evidence of appropriate growth at a maximal intake of 2.7\xa0g/kg/day, but this was supported by early (within the first 24\xa0hours) and progressive enteral feeding. Some babies receiving neonatal parenteral nutrition will be on no or minimal enteral feeds, or will be unable to increase enteral feeding in a timely manner. This, combined with the weak evidence of improved growth at 3\xa0g/kg/day or more, meant that 3\xa0g/kg/day was selected as the lower end of the maintenance range. However, the committee were split on this point so a majority decision was taken.\n\nThe committee agreed, based on their expertise, that it was important to provide an upper limit for amino acid intake because of possible adverse events such as acidosis, high serum urea, hypercalcaemia or hypophosphatemia, hypokalaemia and re‑feeding syndrome. The maximal amino acid intake in the studies reviewed was 4\xa0g/kg/day. The committee looked for adverse effects across all the studies in the evidence review, including those using maximal amounts of over 3.5\xa0g/kg/day, and found no evidence of harm. However, the committee were concerned that the absence of evidence of harm is not the same as evidence of absence. It was noted that higher amino acid intakes need to be supported by sufficient non-nitrogen energy. The committee followed the evidence in agreeing an upper maintenance range limit of 4\xa0g/kg/day. They suggested being more vigilant for adverse effects when using the top half of this maintenance range.\n\nBabies on enteral feeds will receive macronutrients from milk in addition to those from parenteral nutrition. The committee acknowledged that for those babies on enteral feeds, the proportional decrease in parenteral nutrition as enteral intake increases will decrease the delivery of amino acids from parenteral nutrition, thus alleviating risks of excessive amino acid delivery. However, they noted that the enteral feeding regimen was outside the scope of this guideline, so did not recommend different ratios for babies on enteral feeds.\n\nMost of the studies gradually increased amino acid intake over a number of days to reach a target dose. However, there was not enough consistent evidence to specify the number of days over which intake should be increased. The committee recommended 4\xa0days, based on informal consensus agreement, using their knowledge and experience. In addition, the committee agreed that this is approximately how long it would take to reach the maintenance range if incrementing from the starting range at rates similar to those used in the included studies. This also matched the recommendations made for glucose and lipids, which is important because nitrogen to non-nitrogen ratios need to be maintained within the range specified in the guideline.\n\nThere was no evidence about amino acids for term babies, so the committee recommended a lower starting and maintenance dose based on their own expert consensus and knowledge of nitrogen balance studies. These studies show that term babies lose less protein than preterm babies, and suggest the amount of amino acids needed to achieve similar weight gain to term babies on milk feeds.\n\nThere was no evidence for babies who did not start parenteral nutrition from birth. The committee agreed, based on their expertise, that babies starting parental nutrition more than 4\xa0days after birth would be able to tolerate the maintenance dosage of amino acids.\n\n## How the recommendations might affect practice\n\nThe committee noted that the recommendations will reduce variation in practice.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D2: amino acids.\n\nReturn to recommendations\n\n# Constituents of neonatal parenteral nutrition – lipids and lipid emulsions\n\nRecommendations 1.5.4 and 1.5.5\n\n## Why the committee made the recommendations\n\nThe evidence was uncertain (there was an inconsistent pattern of benefit and harm), so the committee also used their knowledge and experience of current practice to make the recommendations by informal consensus.\n\nThere was evidence of both benefit and harm when giving lipids compared with no lipids, but the committee agreed that the benefits of giving lipids outweighed possible risks. There was evidence that giving lipids in the ranges provided in the studies was not associated with any harm in the short term. In addition, there was evidence that higher doses may reduce retinopathy of prematurity and necrotising enterocolitis compared with lower doses. The committee concluded that the ranges in the studies were safe and effective.\n\nIn relation to how the target dose is reached, the evidence showed that slowly increasing lipids from a low starting dose to a target dose may be associated with a reduced risk of retinopathy of prematurity and hypertriglyceridaemia, compared with starting at a higher dose and rapidly increasing to the same target dose. The committee agreed to use similar parameters in the recommendations. Based on their knowledge of doses of lipids exceeding those used in the studies and the risk of problems such as hypertriglyceridemia, the committee recommended an upper limit for the maintenance dose.\n\nThe committee recommended that in babies with parenteral nutrition-associated liver disease, consideration be given to changing from a pure soy lipid emulsion (if that is being used) to a composite lipid emulsion. The committee discussed some evidence suggesting that there was more resolution of parenteral nutrition-associated liver disease or cholestasis with fish oil-containing lipid emulsions compared with pure soy lipid emulsions. However, the committee noted that there were limitations in the design of some studies and uncertainty in the measurement, which made this evidence very weak. There was also some evidence of a benefit with pure fish oil, but the committee were aware that there is a risk of essential fatty acid deficiency with pure fish oil. They therefore decided that even though this evidence to support the efficacy of composite lipid emulsions is not compelling, it could be trialled because these babies are at risk of developing progressive liver disease and liver failure. The available evidence was from preterm and late preterm babies. However, the recommendation was extended to cover term babies based on expertise from the committee that late preterm and term babies often have the same treatment, and similar benefits would be likely for term babies.\n\nThe committee did not make recommendations for babies with surgical conditions because there was no evidence of advantage of any type of lipid emulsion over other lipid formulations. Recommendations were not made for babies without parenteral nutrition-associated liver disease, including those at high risk, because there was not conclusive evidence of either benefit or harm.\n\n## How the recommendations might affect practice\n\nThe committee agreed that the recommendations will reinforce and standardise current best practice.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0D3: lipids\n\nevidence review\xa0D4: lipid emulsions.\n\nReturn to recommendations\n\n# Constituents of neonatal parenteral nutrition – ratios of non-nitrogen energy to nitrogen, and carbohydrates to lipids\n\nRecommendations 1.5.6 and 1.5.7\n\n## Why the committee made the recommendations\n\nThere was limited evidence, and the evidence did not provide sufficient data to inform optimal ratios. The committee used their knowledge and experience to agree ratios, taking into account the available evidence and current practice.\n\nWhen the amount of parenteral nutrition is changing (for example, when transitioning onto enteral feeding), there is a risk of negative outcomes associated with too low or too high ratios. Too low a ratio (non-nitrogen energy to nitrogen below 20\xa0kcal per gram) could cause oxidation of amino acids and high blood urea. Too high a ratio (non-nitrogen energy to nitrogen above 30\xa0kcal per gram) could result in deposition of excess body fat, which is associated with metabolic ill health in later life (for example, risk of cardiovascular disease, diabetes and obesity-related conditions). Because of these risks, the committee recommended keeping the ratios the same when changing the amount of parenteral nutrition.\n\nThe evidence supported the need to give babies enough energy to ensure the nitrogen provided is retained.\n\nBecause of the limited evidence, the committee decided to prioritise this topic for further research. This is important because insufficient non-nitrogen energy (carbohydrates and lipids) leads to nitrogen (protein) being used for non-growth purposes so is not available to generate new tissues. An excess of non-nitrogen energy can lead to increased adiposity and may cause hyperglycaemia or hypertriglyceridemia. Having more evidence about the optimal ratio of non-nitrogen energy to nitrogen in parenteral nutrition is therefore needed.\n\nThere was limited evidence, so the committee used their knowledge and experience to agree the ratio, taking into account the available evidence and current practice. One study provided lipids in a range from 18% to 40% (meaning that the other 82% to 60% of non-nitrogen energy was made up of glucose), with better growth associated with 40% lipid intake.\n\nThe committee also discussed the recommendations developed for glucose and lipid dosages (recommendations\xa01.5.1 and\xa01.5.4). They agreed that it should be clear to those prescribing parenteral nutrition that when calculating the relative amounts of carbohydrate and lipid, the recommended dosages of each of these components should not be exceeded.\n\nThe committee decided not to recommend the lower end of the lipid range (18%) that was used in the evidence because that would lead to a high glucose intake, for which the risk of hyperglycaemia was considered to be too high. Therefore, the committee agreed that a lower level of 25% lipid is needed to limit the risk of hyperglycaemia, and to provide sufficient essential fatty acids and fat-soluble vitamins. The committee agreed, based on their knowledge and experience, that there should be an upper limit of 40% fat. Even though there is no evidence available to firmly state the risks of higher lipid provision, the committee agreed 40% would be safe and not risk fatty liver or raised triglyceride levels.\n\nThe recommended ranges aim to provide sufficient lipid energy to optimise growth, provide essential fatty acids and fat-soluble vitamins, and minimise the risk of hyperglycaemia. However, it is important not to give too much lipid because this could risk high triglyceride levels, fatty liver and increased fat deposition.\n\n## Why the committee did not make a recommendation on ratios of phosphate to amino acids\n\nThe evidence on the relative amounts of amino acids and phosphate to be given in parenteral nutrition was limited.\n\nThe committee agreed that the phosphate to amino acid ratios derived from following the phosphate and amino acid recommendations (1.5.11, 1.5.2 and 1.5.3) in this guideline are appropriate. However, because the evidence was limited and did not provide enough detail on the exact amount of phosphate needed per gram of amino acid, the committee decided not to make a recommendation on specific relative amounts.\n\n## How the recommendations might affect practice\n\nThe committee agreed that the recommendations reflect current best practice and should have little impact on practice. They should reduce any variation across units.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0D7: ratio of non-nitrogen energy to nitrogen\n\nevidence review\xa0D8: ratio of carbohydrates to lipids\n\nevidence review\xa0D10: ratio of phosphate to amino acids.\n\nReturn to recommendations\n\nReturn to research recommendation\n\n# Constituents of neonatal parenteral nutrition – iron\n\nRecommendations 1.5.8 and 1.5.9\n\n## Why the committee made the recommendations\n\nThere was limited evidence about intravenous iron supplementation for babies younger than 28\xa0days. The evidence did not show a substantial benefit or harm. The committee recognised that usual clinical practice in the UK is not to include intravenous iron in the parenteral nutrition regimen for babies younger than 28\xa0days, and agreed that there was not enough new evidence to change current practice. In addition, preterm babies often have blood transfusions that can result in unpredictable amounts of iron. The committee discussed the potential for iron overload and toxicity, and used their expertise and experience to recommend that early supplementation should not be used.\n\nThe committee agreed that healthcare professionals may need to reconsider iron supplementation for preterm babies who are 28\xa0days or older based on monitoring for iron deficiency.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current practice, so should not result in any changes.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D5: iron.\n\nReturn to recommendations\n\n# Constituents of neonatal parenteral nutrition – acetate\n\n## Why the committee decided not to make a recommendation\n\nThere was some evidence that using acetate in parenteral nutrition reduces the risk of hyperchloraemia, but there was no evidence about the amount of acetate needed. The evidence did not explain how chloride had been provided and the committee were unconvinced that the interventions used in the studies reflect current practice. The committee agreed that using the right balance of parenteral nutrition components and the use of standardised bags would avoid an excess of chloride and the need to add acetate.\n\nThe committee acknowledged that parenteral nutrition is not the only source of chloride (for example, some trace elements are in the form of chloride salts), so an imbalance may need to be addressed by adding acetate to reduce the risk of metabolic acidosis secondary to hyperchloraemia. The committee discussed that there is variation in clinical practice about the use of acetate but agreed that the evidence was not strong enough to make any recommendations about acetate.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D6: acetate.\n\nReturn to recommendations\n\n# Constituents of neonatal parenteral nutrition – calcium and phosphate\n\nRecommendations 1.5.10 to 1.5.13\n\n## Why the committee made the recommendations\n\nEvidence was limited, and there was inconsistency in the definitions of high and low levels or concentrations of calcium and phosphate across the included studies, so the committee also used their knowledge and experience to make the recommendations.\n\nAlthough the evidence that was reviewed focused on relative amounts, the committee decided that recommendations for absolute values were also needed because the amounts of calcium and phosphate in the evidence reviewed were lower than those currently given in UK clinical practice. However, the evidence also showed that higher amounts of calcium and phosphate were beneficial in reducing the incidence of rickets, fractures and hypercalciuria, and increasing bone mineral density. This guided the committee to agree that higher amounts of calcium and phosphate are preferable for preterm and term babies. They decided that a decision about the absolute amounts would then determine the ratio between these constituents rather than the other way around.\n\nThe committee made recommendations for an initial and maintenance dosage and dosage range of calcium and phosphate that overlap, which means that this would lead to a ratio between of 0.75:1 and 1:1. The committee recommended total amounts and a ratio of calcium to phosphate according to the timing of when babies would start parenteral nutrition after birth (before or after the first 48\xa0hours) rather than whether or not they are preterm or term. This is because of body fluid adjustments in the first days of life. A too low or too high amount of calcium and phosphate and the ratio between them will result in suboptimal bone mineralisation and urinary losses. They noted that preterm babies may need more calcium and phosphate, based on their knowledge, fetal accretion studies and potential urinary phosphate losses. However, they decided not to make different recommendations for preterm or term babies because blood monitoring will indicate whether this is needed.\n\nThe committee also agreed to be more prescriptive in recommending absolute amounts of phosphate by restricting the dose to set amounts instead of a range. This was because of practical considerations: in most current parenteral preparations, 2\xa0mmol of sodium would be administered for every 1\xa0mmol of phosphate, and higher sodium intakes would not be recommended within the first 48\xa0hours, before the expected postnatal diuresis. More flexibility could be applied in the amount of calcium given to babies because calcium would not alter other electrolyte delivery. The amounts of both calcium and phosphate would also be restricted by stability issues, but the committee noted that the amounts recommended could be achieved within these restrictions.\n\n## How the recommendations might affect practice\n\nThe recommendations on phosphate and calcium are largely in line with existing guidance and reflect current best practice. There is variation in practice so the recommendations should ensure consistency of care across different care settings.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D9: ratio of calcium to phosphate.\n\nReturn to recommendations\n\n# Other constituents of neonatal parenteral nutrition – general principles\n\nRecommendations 1.5.14 to 1.5.19\n\n## Why the committee made the recommendations\n\nThe recommendations were not developed by the usual NICE guideline systematic review process. The committee agreed the recommendations' evidence statements using a formal nominal group consensus method, and based the recommendations on their knowledge and experience.\n\nThe committee agreed that vitamins are an essential part of a baby's nutritional needs, and discussed whether vitamins should be provided daily. Babies gain most of their vitamin reserves from their mother in the third trimester of pregnancy, so babies born preterm are relatively vitamin deficient. The committee decided that daily vitamins would improve the vitamin accretion rate and represent best clinical practice. The committee agreed that the recommendation would apply to term babies, because term babies who need parenteral nutrition are likely to have surgical problems or to be critically unwell, so will not establish enteral feeding rapidly. In addition, there was no consensus about making a separate recommendation for term babies. Although the committee acknowledged that some initial or 'starter' parenteral nutrition preparations may not contain vitamins, they stressed that starting parenteral nutrition should not be delayed.\n\nPutting fat- and water-soluble vitamins in the lipid emulsion improves their stability but shortens the shelf life of the lipid emulsion. However, the committee decided that ensuring vitamin stability was important and putting the vitamins in the lipid emulsion was therefore recommended. The committee noted that modern parenteral nutrition preparations generally have longer shelf lives, and so this was a smaller concern than in the past.\n\nSerum sodium and potassium levels can change frequently in babies on neonatal units, and these changes may not be related to parenteral nutrition. How often sodium and potassium levels need to be checked depends on multiple factors and will be decided by the local clinical team based on the overall clinical situation. Sodium and potassium supplementation, in addition to that already contained in parenteral nutrition in phosphate (which is often given as sodium glycerophosphate), can be given using an additional intravenous infusion. This allows standardised parenteral nutrition bags to contain sufficient sodium and potassium to cover usual daily maintenance requirements but allows adjustments to sodium and potassium delivery to cover additional requirements without having to interfere with the parenteral nutrition.\n\nThe committee agreed that magnesium is an essential component of parenteral nutrition because of its important role in skeletal development and in nervous system and muscle membranes. Although the committee noted that magnesium may not be immediately available in some initial or 'starter' parenteral nutrition preparations, they stressed that parenteral nutrition should not be delayed, and magnesium should be added as soon as possible after starting parenteral nutrition.\n\nThe committee agreed that trace elements are an essential component of parenteral nutrition. Although the committee noted that trace elements may not be immediately available in some initial or 'starter' parenteral nutrition preparations, they stressed that parenteral nutrition should not be delayed and trace elements should be added as soon as possible after starting parenteral nutrition.\n\n## How the recommendations might affect practice\n\nThe committee agreed that the recommendation will reinforce current best practice.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0J: general principles.\n\nReturn to recommendations\n\n# Standardised neonatal parenteral nutrition formulation ('standardised bags')\n\nRecommendations 1.6.1 to 1.6.3\n\n## Why the committee made the recommendations\n\nThere was limited evidence on whether healthcare professionals should use parenteral nutrition formulations that are standardised ('standardised bags') or individualised. The committee used the limited evidence, and their knowledge and experience, to make the recommendations.\n\nThe committee agreed that healthcare professionals should use standardised bags routinely because:\n\nstandardised bags are immediately available when needed, and suitable for most babies\n\nthey help to minimise prescribing errors and clinical variation\n\nthey can improve compliance with national recommendations on quality control of parenteral nutrition manufacturing, dispensing, prescribing and administration, because they must comply with nationally agreed quality standards (in line with the Royal Pharmaceutical Society and NHS Pharmaceutical Quality Assurance Committee standards for the quality assurance of aseptic preparation services)\n\nthey have lower acquisition costs.\n\nIndividualised bags are not immediately available on a neonatal unit and are more complex to prescribe. The committee agreed that without good evidence to support the use of individualised bags, the additional complexity and cost is not justified.\n\nAlthough the committee agreed that standardised bags should be used routinely and continued once started, individualised parenteral nutrition may be needed for babies with complex needs, for example, babies with a fluid imbalance.\n\nStandardisation of parenteral nutrition is a concept which means that its effectiveness depends on optimal content for the average baby and its safety is related to the process of standardisation. Although there was some evidence suggesting that growth-related outcomes favoured an individualised approach, these findings were largely dependent on the specifics of what was in the standardised bag being trialled (which for most studies was not what would currently be recommended). The committee therefore agreed that, to be effective formulations, the standardised bags would be made up using the constituents outlined in the section on constituents of neonatal parenteral nutrition to provide optimal nutrition.\n\n## How the recommendations might affect practice\n\nThe committee agreed that the recommendations will lead to greater consistency in clinical practice and improve safety through compliance with national recommendations for parenteral nutrition manufacturing, dispensing, prescribing and administration.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: standardised neonatal parenteral nutrition formulations.\n\nReturn to recommendations\n\n# Monitoring neonatal parenteral nutrition\n\nRecommendations 1.7.1 to 1.7.13\n\n## Why the committee made the recommendations\n\nThere was no evidence so the committee used their knowledge and experience to make the recommendations.\n\nThe committee agreed that regular blood monitoring is needed to detect potential abnormalities and inform the baby's care. They agreed that the frequency of blood sampling needs to take into account the clinical stability of the baby, the amount of blood taken, and should also strike a balance between minimising distress to the baby (and parents) and obtaining enough information to guide clinical care. To minimise distress resulting from repeated monitoring, the committee emphasised the need to retrieve as much information as possible from 1\xa0sample, so they recommended combining testing wherever possible and agreeing with the laboratory the best ways to coordinate this. The committee agreed that taking minimal blood volumes would be best for the baby, and that this could be achieved by liaising with the laboratory.\n\nThe committee recommended minimum frequencies for monitoring parameters, but they also described situations when increased monitoring may be needed (for example, when there is a change in the composition of parenteral nutrition or when the baby is unstable). They also recommended more frequent monitoring when babies had previous abnormal levels of a particular constituent. However, the committee did not want to be too prescriptive about the level of abnormality or how recently this occurred to allow for a degree of clinical judgement tailored to the needs of each baby.\n\nThe committee agreed that glucose should be monitored when starting parenteral nutrition and at every change of the bag, for safety reasons, because the time when a bag is changed would be a critical time where hypoglycaemia or hyperglycaemia could occur. After that, monitoring should depend on the stability of the baby – that is, an unstable glucose level should be monitored more frequently because of the risks associated with hyperglycaemia or hypoglycaemia.\n\nThe committee agreed that blood pH, potassium, chloride and calcium would usually need to be monitored when starting and when increasing parenteral nutrition. Blood pH is important for a number of reasons, for example, chloride levels cannot be interpreted without knowing the pH, and it is also informative when titrating acetate. Serum sodium is considered in the section on other constituents of neonatal parenteral nutrition – general principles.\n\nThe committee discussed the variability in monitoring triglycerides in clinical practice, where some neonatal units monitor more or less frequently, and some neonatal units do not monitor triglycerides at all. The committee agreed that recommendations would be useful to improve consistency across clinical practice. They agreed that triglycerides should be monitored when increasing dosages of lipid, because they were aware of evidence that suggests that around 10% of babies do not tolerate recommended intakes of lipids. Monitoring should continue when the maintenance dosage is reached. The committee agreed that when a baby is at risk of hypertriglyceridaemia, for example if the baby is critically ill, triglycerides should be monitored to ensure the safety of the baby.\n\nThe committee agreed that phosphate would initially require daily monitoring because amino acid intake affects phosphate levels and amino acid intake is changed every day for the first 4\xa0days of parenteral nutrition.\n\nThe committee decided that after the maintenance dosage is reached, weekly monitoring would be safe. More frequent monitoring would be needed if there are concerns about recent abnormal levels or phosphate levels and bone development, and for preterm babies born at less than 32+0\xa0weeks (because preterm babies are at risk of metabolic bone disease of prematurity where their bones become very brittle as a result of insufficient mineralisation).\n\nThe committee agreed that a number of different factors could affect iron status in babies on parenteral nutrition for longer than 28\xa0days, including the number of transfusions administered as well as the amount of enteral nutrition achieved. It is therefore important to measure ferritin, and iron and transferrin saturations for babies who remain on parenteral nutrition after this time. The committee acknowledged that these measurements should be interpreted with caution in unstable babies because they are acute phase reactants and can be elevated as a result of infective or inflammatory conditions.\n\nAbnormal liver function tests could indicate the onset of parenteral nutrition-associated liver disease, so the committee agreed it was important to carry out regular liver function tests for babies on parenteral nutrition.\n\n## How the recommendations might affect practice\n\nBecause there is no current consensus on the monitoring of lipids, these recommendations may change clinical practice. All other recommendations reflect current practice, so the committee agreed there would be no change in practice.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: monitoring neonatal parenteral nutrition.\n\nReturn to recommendations\n\n# Stopping neonatal parenteral nutrition\n\nRecommendations 1.8.1 to 1.8.3\n\n## Why the committee made the recommendations\n\nThere was some evidence indicating better growth with stopping parenteral nutrition at a higher volume of enteral feeds (140\xa0ml/kg/day). However, there were some inconsistencies between different studies, so the committee also used their knowledge and experience to make the recommendations. The committee based the ranges on the baby's age because the balance between prioritising nutritional intake and minimising the risk of line sepsis may differ depending on the size of the baby. The committee agreed that there were other factors apart from the volume of enteral feeds that should be considered for all babies before stopping parenteral nutrition (for example, tolerance and amount of enteral feeds delivered as well as the clinical situation).\n\nThe lower limit for stopping parenteral nutrition in extremely preterm babies was taken from the evidence, but the upper limit was based on the committee's knowledge and experience. In clinical practice, enteral feeds are not normally fortified at 140\xa0ml/kg/day (as was done in the available evidence), so stopping at this point may risk nutritional deficits, so the committee recommended an upper threshold of 150\xa0ml/kg/day. This may be considered the threshold at which the risks of continuing parenteral nutrition outweigh the benefits. The thresholds for stopping parental nutrition in babies born at or after 28+0\xa0weeks were based on the committee's expertise. The energy stores of older preterm babies and term babies are more replete than those of extremely preterm babies, allowing parenteral nutrition to be stopped at a lower volume.\n\nHowever, the committee highlighted that stopping parenteral nutrition, even when these ranges are reached, should only be made once the other considerations (in recommendation\xa01.8.1) have been taken into account.\n\n## How the recommendations might affect practice\n\nThe committee agreed that the recommendations would reduce variation in clinical practice. For some services, these recommendations may result in a longer duration of parenteral nutrition, which would have associated costs. However, for other services, these recommendations would result in providing parenteral nutrition for a shorter duration and may produce cost savings.\n\nThe committee discussed whether the recommendations could result in smaller volumes of parenteral nutrition being prescribed during the transition from parenteral to enteral nutrition, and that these small volumes would not be an efficient use of costs or resources. However, the committee agreed this could be mitigated by giving consideration to residual prescribed volumes of parenteral nutrition when making the decision to stop parenteral nutrition.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: stopping parenteral nutrition.\n\nReturn to recommendations\n\n# Service design\n\nRecommendations 1.9.1 to 1.9.3\n\n## Why the committee made the recommendations\n\nThere was some evidence that multidisciplinary team services improve outcomes in newborn babies. However, there were many limitations relating to the evidence, and none of the studies were conducted in the UK. The committee made recommendations that they considered would provide optimum care for babies on parenteral nutrition, using the limited evidence (relating to the clinical role of multidisciplinary teams), and their knowledge of current clinical practice reports in the public domain (particularly related to the team's role in service governance).\n\nThe committee acknowledged that inadequacies in the provision of neonatal parenteral nutrition had been highlighted in a 2011 report from the Paediatric Chief Pharmacists Group, Improving practice and reducing risk in the provision of parenteral nutrition for neonates and children, which highlighted the need for improvements in practice\n\nTo address these shortcomings and ensure the safety of babies receiving parenteral nutrition, the committee agreed that neonatal parenteral nutrition services should be overseen and supported by a multidisciplinary team with expertise in neonatal parenteral nutrition. The committee specified the membership of the team to ensure that there is expertise in the clinical, prescribing and nutritional core components of neonatal parenteral nutrition (a consultant neonatologist or paediatrician with a special interest in neonatology, as well as a neonatal pharmacist and dietitian). The committee also recognised that access to other roles may be required, such as neonatal nursing, paediatric gastroenterology or expertise in clinical biochemistry to cover specific clinical or specialist areas of parenteral nutrition. The committee listed these different professionals, but agreed that all those listed would not need to see every baby routinely within the unit. The committee decided that an oversight or support team could be available at a local level or within a clinical network to ensure that every unit has access to these professionals when needed.\n\nThe committee agreed that enhanced multidisciplinary team input (for assessment and management) may be needed for preterm and term babies with complex needs, for example, babies with short gut who need parenteral nutrition for long time periods and who therefore have an increased risk of complications. This may involve more frequent meetings between multidisciplinary team members, and may also mean that other specialists are included in the multidisciplinary team, for example, a gastroenterologist. The committee did not want to be prescriptive about which professionals should be in the 'enhanced' multidisciplinary team because this would depend on the needs of each baby.\n\n## How the recommendations might affect services\n\nThe committee noted that there is currently variation in practice regarding the availability of specialists who are included within multidisciplinary teams, but agreed that these professionals would be available somewhere within a network of care. Arranging and formalising this access may require extra resources. However, babies with complex needs would invariably be seen by professionals from multiple disciplines, so this would not be a change in practice. The recommendations therefore would reduce variation and reinforce current best practice.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: service design.\n\nReturn to recommendations\n\n# Information and support for parents and carers of babies who need neonatal parenteral nutrition\n\nRecommendations 1.10.1 to 1.10.4\n\n## Why the committee made the recommendations\n\nThere was no evidence so the committee used their knowledge and experience to make the recommendations.\n\nGood nutrition underpins good neonatal care, so the committee agreed that giving parents and carers information about parenteral nutrition is important.\n\nThe committee recognised that having a baby in a neonatal unit is a challenging and stressful situation, and agreed that the best approach to working with parents and carers is a collaborative one. This should involve giving parents and carers information tailored to their needs, and helping them to feel involved in their baby's care.\n\nThe committee noted that principles of good information sharing and communication, as well as encouraging shared decision making, are covered in the NICE clinical guideline on patient experience in adult NHS services.\n\nGiven that there was no evidence, the committee made a recommendation for further research. This is important because having a baby in a neonatal unit can be a stressful and difficult time for parents and carers. Information and support can help parents manage these circumstances and help them feel involved and part of their baby's care, which can improve outcomes. Given that the number of babies needing parenteral nutrition is likely to increase as prematurity survival rates improve, understanding what information and support parents need will help to support good outcomes.\n\n## How the recommendations might affect practice\n\nThe committee agreed there is variation in practice. These recommendations should improve consistency in how healthcare professionals support parents and carers, and ensure that they are given timely, consistent and appropriate information about parenteral nutrition.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0I: information and support.\n\nReturn to recommendations\n\nReturn to research recommendation", 'Context': "Parenteral nutrition refers to intravenous feeding, a technique for providing nutrition to those who are unable to tolerate adequate enteral nutrition (orally or through an enteral tube). It is frequently needed by preterm babies while they establish enteral feeds, critically ill babies, and babies with gastrointestinal disorders who need surgery.\n\nInadequate nutrition, particularly in preterm babies, can have short-term and long-term health effects, including longer stays in the neonatal unit, an increased risk of infection, and worsened developmental outcomes. There is also evidence that inappropriate nutritional management soon after birth is linked to the development of metabolic syndrome in adults.\n\nApproximately 95,000\xa0babies born in the UK each year need neonatal care (National Neonatal Audit Programme 2016). Parenteral nutrition is widely used in neonatal care. It has become common practice to start it in preterm babies within the first few hours of life, and also to support term babies who are critically ill.\n\nParenteral nutrition contains nutrients such as glucose, electrolytes, amino acids, lipids, minerals, trace elements and vitamins. It may complement enteral feeding or, in some situations, replace it.\n\nThe National Confidential Enquiry into Patient Outcome and Death enquiry into the care of hospital patients receiving parenteral nutrition (2010) reviewed 264\xa0cases of neonatal parenteral nutrition. It found that 73% of cases represented less than 'good practice', 40% had metabolic complications, 40% did not meet nutritional needs, and in 28% the start of parenteral nutrition was delayed. In 37%, the first parenteral nutrition provided was considered inadequate for the patient's needs.\n\nParenteral nutrition is normally formulated in an aseptic pharmacy unit. It can be in standardised or individualised forms. Prescribing is complex and open to error. Simplified, standardised regimens may reduce this risk, and may reduce costs.\n\nIn current practice, virtually all babies born before 31+0\xa0weeks who weigh less than 1.5\xa0kg need parenteral nutrition for a period that depends on gestation, birthweight and other morbidities. Postnatal growth failure is common in babies born before 31+0\xa0weeks. It is associated with an increased need for respiratory support and increased risk of infection. It is also a risk factor for neurocognitive impairment. Optimal use of parenteral nutrition could potentially avoid postnatal growth failure.\n\nParenteral nutrition is expensive: for a large tertiary neonatal unit, it costs approximately £175,000 a year.\n\nGiven the wide variation in practice, safety concerns and costs, this guideline is needed to ensure that the provision of parenteral nutrition for babies is consistent across units and provides optimal care."}
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https://www.nice.org.uk/guidance/ng154
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This guideline covers parenteral nutrition (intravenous feeding) for babies born preterm, up to 28 days after their due birth date and babies born at term, up to 28 days after their birth. Parenteral nutrition is often needed by preterm babies, critically ill babies, and babies who need surgery.
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ef092dfa2170c5056635aecda1f542dab13b20b1
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nice
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SepsiTest assay for rapidly identifying bloodstream bacteria and fungi
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SepsiTest assay for rapidly identifying bloodstream bacteria and fungi
Evidence-based recommendations on the SepsiTest assay for rapidly identifying bloodstream bacteria and fungi.
# Recommendation
There is currently insufficient evidence to recommend the routine adoption in the NHS of the SepsiTest assay for rapidly identifying bloodstream bacteria and fungi. The test shows promise and further research to provide robust evidence is encouraged, particularly to demonstrate the value of using the test results in clinical decision‑making (see sections 5.18 to 5.22). # Clinical need and practice
# The problem addressed
In current practice, people who are clinically unwell and who have a suspected bloodstream infection have empirically prescribed broad‑spectrum antibiotics, that is, antibiotics that are prescribed based on clinical presentation, until the identity of the pathogen causing the infection is known. Broad‑spectrum antibiotics and, if appropriate, antifungals, are used because they are effective against a wide range of bacterial and fungal pathogens and are likely to achieve a therapeutic response. But, although clinically effective, broad‑spectrum antibiotic use is associated with people developing superinfection and with antimicrobial resistance. Rapidly identifying the bacterial and fungal pathogen may allow earlier targeted treatment and shorten the length of use of broad‑spectrum antibiotics and antifungals, which may help antimicrobial stewardship by conserving the effectiveness of existing antimicrobials.
Three molecular tests, the LightCycler SeptiFast Test MGRADE, SepsiTest and IRIDICA BAC BSI assay, were identified during scoping as relevant to the assessment (see section 3 for additional details). These tests are designed to rapidly detect and identify bacterial and fungal DNA that may be in the bloodstream in people who are suspected of having sepsis. These tests are intended to be used with clinical assessment and established microbiology techniques that provide information on which antimicrobials are likely to be effective against the identified pathogen. The tests are designed to be run on whole blood samples and without the prior incubation or the pre‑culture steps that are needed for tests used in current standard practice. The absence of these steps means that pathogens may be identified earlier. It is possible that blood culture would still be needed to give definitive antimicrobial‑susceptibility data, if this is not provided by the rapid diagnostic test. The rapid detection and identification of bacterial and fungal DNA may be particularly beneficial in people who are suspected of having a severe infection and who need quick medical intervention.
The purpose of this assessment is to evaluate the clinical and cost effectiveness of using the LightCycler SeptiFast Test MGRADE, SepsiTest and IRIDICA BAC BSI assay for rapidly identifying bloodstream bacteria and fungi in the NHS.
# The condition
## Sepsis and bloodstream infection
Sepsis is a life‑threatening condition characterised by the body's inflammatory response to an infection. According to the Surviving Sepsis Campaign's International guidelines for the management of severe sepsis and septic shock, sepsis is diagnosed if there is evidence of systemic inflammation, in addition to a documented or presumed infection in the body. Systemic illness often happens if bacteria invade normally sterile parts of the body. One example of this is when bacteria or fungi invade the bloodstream (bloodstream infection); a process that often causes an inflammatory immune response.
Bacterial infections are the most common cause of sepsis and bloodstream infection, but they can also be caused by fungal infections, and less commonly by viral infections. The most common sites of infection associated with sepsis are the lungs, urinary tract, abdomen and pelvis. Other sources of infection leading to sepsis include skin infections (such as cellulitis), post‑surgical infections and infections of the nervous system (such as meningitis or encephalitis).
People who have recently been admitted to hospital are at risk of getting hospital‑acquired infections that can lead to sepsis and bloodstream infection. The increased use of invasive procedures, such as catheterisation and life support measures, as well as immunosuppressive therapy and antibiotic therapy may have resulted in more healthcare‑associated bloodstream infections. Community‑acquired bloodstream infections may also occur in people who have not had recent contact with healthcare services. The pathogens infecting these people may differ from those associated with hospital‑acquired bloodstream infection.
The bacteria most commonly associated with bloodstream infection in adults include gram‑negative species such as Escherichia coli, Klebsiella and Pseudomonas, and gram‑positive species such as Staphylococcus aureus, non-pyogenic streptococci, Enterococcus and Streptococcus pneumoniae. The types of pathogens causing bloodstream infection can differ in children compared with those causing infection in adults, and can include Neisseria meningitidis. Polymicrobial infection and anaerobic bacteraemia are also thought to occur less often in children.
# The diagnostic and care pathways
## Diagnosing sepsis and bloodstream infection
Diagnostic criteria for sepsis are listed in the Surviving Sepsis Campaign's International guidelines for the management of severe sepsis and septic shock. In summary, regular observations of all vital signs should be taken and recorded, kidney and liver function tests should be done, and inflammatory biomarkers and serum lactate should be measured. These guidelines state that a diagnosis of sepsis should be based on infection, documented or suspected, with hyperthermia or hypothermia, tachycardia and at least 1 indication of altered organ function.
The guidelines also make the following specific recommendations relating to detecting localised and bloodstream infection:
At least 2 samples for blood culture should be collected (aerobic and anaerobic) before antimicrobial therapy is started if such cultures do not cause significant delay (greater than 45 minutes) in the start of antimicrobial administration. At least 1 sample should be drawn percutaneously and 1 drawn through each vascular access device, unless the device was recently (less than 48 hours) inserted. The blood cultures can be drawn at the same time if they are taken from different sites. Cultures from other sites that may be the source of infection, such as urine, cerebrospinal fluid, wounds, respiratory secretions or other bodily fluids, should be collected before starting antimicrobial therapy, if doing so does not cause significant delay in the start of antimicrobial treatment.
Imaging studies such as CT or X‑ray should be done to confirm a potential source of infection.
Assays to diagnose systemic fungal infection should be used if available and invasive candidiasis is suspected.
## Blood cultures
Public Health England's standards for the investigation of blood cultures are available. A blood culture set for diagnosing bloodstream infection is defined as 1 aerobic and 1 anaerobic bottle. For adults it is recommended that 20–30 ml of blood is cultured per set, and that 2 consecutive blood culture sets from 2 separate venepuncture sites should be collected during any 24‑hour period for each septic episode. The first set should be taken before starting antimicrobial treatment because the presence of antibiotics or antifungals may inhibit the growth of pathogens in blood culture. Blood culture sample collection differs for infants and neonates, for whom a single aerobic bottle or low‑volume blood culture bottle may be requested. The criterion for calculating total blood‑culture volume in neonates and children is based on weight rather than age and relates to total patient blood volume. It has been suggested that the volume of blood drawn should be no more than 1% of the patient's total blood volume. In infants and children, the level of bacteraemia is usually higher than in adults and so the sensitivity of detection is not thought to be substantially reduced by a lower blood‑to‑medium ratio.
Blood culture bottles should be incubated within 4 hours of the blood sample being taken. Many laboratories now use automated culture systems that alert laboratory staff once growth has been detected.
When a blood culture has been detected as positive it is recommended that:
Gram staining and rapid antigen testing should be done within 2 hours.
Direct or automated isolate identification should be done within 24 hours (extending to 48 hours if traditional microbiology techniques such as morphological identification are used). Rapid species identification may be done after blood culture using techniques such as MALDI‑TOF mass spectrometry.
Identification should be followed by sensitivity testing to determine the antimicrobials that the identified pathogen is susceptible to. If direct or automated sensitivity testing is used, a report should be made within 24 hours, extended to 48 hours if traditional techniques, such as the disc diffusion method, are used.
A preliminary positive report is made within 2 hours of identification and sensitivity testing, and a final positive report should be made within 5 days of the sample arriving in the laboratory.
If a blood culture is negative, it is recommended that a preliminary negative report is provided within 48 hours of the sample arriving in the laboratory and a final negative report should be issued within 5 days unless extended culture is being done, such as if fungi or unusual, fastidious or slow growing organisms are suspected.
## Treating sepsis and bloodstream infection
Sepsis treatment varies based on the initial infection, the organs affected and the extent of tissue damage. The management of severe sepsis and septic shock is described in the Surviving Sepsis Campaign's International guidelines for the management of severe sepsis and septic shock.
The guidelines recommend that effective intravenous antimicrobials should be given within the first hour of recognising severe sepsis and septic shock. Initial empirical antimicrobial therapy should include 1 or more drugs that have activity against all likely pathogens (bacterial, fungal or viral) and that penetrate in adequate concentrations into the tissues thought to be the source of sepsis. Frequently used broad‑spectrum antibiotics for more serious infections include cephalosporins and aminoglycosides.
The guidelines recommend that the choice of empirical antimicrobial therapy be based on:
the patient's history, including drug intolerances
recent antibiotic treatments (previous 3 months)
underlying disease
the clinical syndrome
susceptibility patterns of pathogens in the community and hospital
previous microbiology reports identifying pathogens that have previously colonised or infected the patient.
Clinicians prescribing antimicrobial therapy should take into account the Department of Health's guidance on antimicrobial stewardship, which is based on the 'start smart then focus' strategy. The guidance recommends that when empirical antimicrobials are prescribed, the clinical diagnosis should be reviewed after 48 to 72 hours to allow an antimicrobial prescribing decision to be made. This decision should take into account available microbiology results to determine if therapy can be stopped or changed; that is, the de‑escalation, substitution or addition of antimicrobial agents to the treatment plan.
Narrowing the spectrum of antimicrobial coverage and shortening the duration of therapy may reduce the risk of a person developing a superinfection, and reduce treatment‑related adverse events. Adverse events associated with using broad‑spectrum antimicrobials may include diarrhoea, nausea, vomiting, hearing loss, damage to the kidneys and an increased risk of superinfection with Clostridium difficile. Narrowing the spectrum of antimicrobial coverage may also be associated with an increase in treatment efficacy in some scenarios.
Reducing the spectrum of antimicrobial coverage and duration of antibiotic therapy may also contribute to antimicrobial stewardship and protect the effectiveness of existing antibiotics. Surveillance data for England for the period 2010 to 2013 suggest that rates of methicillin‑resistant Staphylococcus aureus (MRSA) have fallen while the incidence of bloodstream infections caused by resistant gram-negative Enterobacteriaceae bacteria, such as Klebsiella and Escherichia coli, has increased (English surveillance programme for antimicrobial utilisation and resistance, 2014). Of particular concern in some regions of England is the increasing resistance to carbapenem antibiotics, which are often used as a last resort for treating severe infections when other antibiotics have not brought the infection under control.# The diagnostic tests
# The interventions
## The LightCycler SeptiFast Test MGRADE
The LightCycler SeptiFast Test MGRADE (Roche Diagnostics) is a CE‑marked, in vitro, diagnostic, real‑time polymerase chain reaction (PCR) test that simultaneously detects and identifies DNA from 25 bacterial and fungal pathogens. The test needs 1.5 ml of ethylenediaminetetraacetic acid (EDTA)‑treated whole blood.
The LightCycler SeptiFast Test MGRADE involves 3 distinct processes: specimen preparation by mechanical lysis and purification of DNA, real‑time PCR amplification of target DNA in 3 parallel reactions (gram‑positive bacteria, gram‑negative bacteria and fungi), and detection using fluorescence‑labelled probes specific to the target DNA. The test takes a minimum of 6 hours, depending on laboratory workflow.
The SeptiFast Identification Software set v2.0 analyses the samples and generates a report, which contains all the relevant laboratory data and details of the identified species. The software also includes a crossing point cut‑off rule, which is intended to reduce the positive rate for coagulase‑negative Staphylococci and Streptococcus species based on the assumption that they are contaminants and not causal agents when the crossing point value is less than 20.
If Staphylococcus aureus is identified in a sample, an aliquot of the SeptiFast Test MGRADE eluate can be further tested for the MecA gene using the LightCycler SeptiFast MecA Test MGRADE. The test can determine the likely methicillin resistance of Staphylococcus aureus through PCR, using the LightCycler 2.0 instrument.
The test has an analytical sensitivity of 100 colony‑forming units/ml for coagulase‑negative Staphylococci, Streptococcus agalactiae, Streptococcus pyogenes, Streptococcus pneumonia and Streptococcus mitis. The minimum analytical sensitivity for all other pathogens detected by the LightCycler SeptiFast test MGRADE is 30 colony‑forming units/ml.
## SepsiTest
SepsiTest (Molzym Molecular Diagnostics) is a CE‑marked PCR in vitro test for detecting bacterial and fungal DNA in 1 ml of k‑EDTA- or citrate‑treated whole blood. The test is able to identify species from more than 200 genera of bacteria and 65 genera of fungi.
The SepsiTest involves 3 distinct processes: extracting and purifying microbial DNA using centrifugation, universal PCR and sequencing. The PCR result, which is available after 4 hours, indicates whether bacteria or fungi are present in the sample. Amplicons from positive samples are then sequenced to confirm the PCR result and to determine which bacteria or fungi species are present. If readable sequences are available from sequence analysis, bacteria and fungi can be identified using the SepsiTest‑BLAST online tool. Sequencing results may be available in 3 to 4 hours depending on the analyser used.
The analytical sensitivity of SepsiTest ranges from 10 to 80 colony‑forming units/ml, depending on the target species.
## IRIDICA BAC BSI assay
The IRIDICA BAC BSI assay (Abbott Laboratories) is a CE‑marked, in vitro, diagnostic test for detecting and identifying DNA from bacteria and candida in 5 ml of whole blood treated with EDTA. The test can also detect the MecA (Staphylococcus‑specific methicillin resistance), vanA and vanB (Enterococcus‑specific vancomycin resistance), and KPC (gram‑negative associated carbapenem resistance) genes, which are associated with antibiotic resistance.
The test is designed for use with the IRIDICA system, which combines broad‑range PCR with electrospray ionisation time‑of‑flight mass spectrometry to amplify and detect pathogens. The estimated time to result is at least 5 hours and 55 minutes.
The IRIDICA analysis computer consists of a proprietary database and software, which identifies the organism present in the sample by comparing the sequence of the sample with a library of known sequences.
The BAC BSI assay is able to identify more than 780 bacteria and candida. The mean limit of detection for the assay is 39 colony‑forming units/ml, with a range of 0.25 to 128 colony‑forming units/ml depending on the target species.
# The comparators
Two comparators are included, blood culture alone and blood culture with MALDI‑TOF mass spectrometry:
Blood culture alone refers to the incubation of whole blood followed by the identification of pathogens by traditional microbiology techniques.
Blood culture with MALDI‑TOF mass spectrometry refers to the incubation of whole blood followed by the identification of pathogens using MALDI‑TOF mass spectrometry.# Outcomes
The Diagnostics Advisory Committee (section 6) considered evidence from a number of sources (section 7). Full details of all the evidence are in the committee papers.
# How outcomes were assessed
The assessment consisted of a systematic review of the evidence on test performance and clinical‑effectiveness data for the LightCycler SeptiFast Test MGRADE, SepsiTest and IRIDICA BAC BSI and comparator tests.
Studies were included if they evaluated 1 of the interventions, compared with either blood culture or blood culture with MALDI‑TOF mass spectrometry (MS), to analyse whole blood samples collected from people being treated for suspected sepsis. Studies that compared 1 of the interventions with another intervention were also included. In total, 66 studies met the inclusion criteria. Diagnostic‑accuracy data were reported in 62 of the 66 studies and were included in meta‑analyses, which were based on a bivariate normal model with Markov Chain Monte Carlo simulation. Inter‑study heterogeneity was explored using meta‑regression. Intermediate or clinical outcome measures were reported in 41 of the 66 studies and were included in a narrative analysis.
Sixty four of the 66 studies were single‑index test, single‑gate studies, that is, studies in which only patients with the target condition (suspected sepsis) were recruited. Three of these 64 studies were randomised controlled trials (RCTs). The remaining 2 studies were single‑gate studies that reported results for both the LightCycler SeptiFast Test MGRADE and SepsiTest.
Only 3 of the 66 studies included patients from the UK. Most of the studies were done in other European countries. Of the studies that included patients from the UK, 1 study (Dark et al. 2009) used the SeptiFast assay to test 50 patients and 1 other study (Vincent et al. 2015) used the IRIDICA assay to test 529 patients from 6 European countries. The third UK study (Warhurst et al. 2015) reported the use of SeptiFast in 795 patients with sepsis and was judged to be the highest quality and most applicable included study.
All studies were assessed using the QUADAS‑2 tool. The results of 65 of the 66 studies were considered to be at risk of bias and may not be applicable to the decision problem. The issues of greatest uncertainty included patient selection and blinding to the index test or reference standard. The External Assessment Group also reported concerns about 21 of the 66 studies, which did not report whether the blood samples for the index test and reference standard were drawn at the same time, and 6 of the 66 studies, which used a mixture of reference standards. In addition, only 28 of the 66 studies reported using blood sampling and test methods that were in accordance with the company's instructions for use. Studies also reported different units of analysis for diagnostic‑accuracy data, such as per patient, per sample, per episode of sepsis, and species or pathogen level.
# Diagnostic accuracy
Of the 62 studies that reported diagnostic‑accuracy data, 55 reported data for the LightCycler SeptiFast Test MGRADE; 5 reported data for SepsiTest; and 4 reported data for the IRIDICA BAC BSI assay. Two of the 62 studies that reported data for both the Light Cycler SeptiFast Test MGRADE and SepsiTest were counted as individual studies for each test.
## LightCycler SeptiFast Test MGRADE
There were 54 studies that compared the LightCycler SeptiFast Test MGRADE with blood culture and were combined in a meta‑analysis. The pooled estimate for sensitivity was 0.65 (95% credible interval 0.60 to 0.71; 95% prediction interval 0.29 to 0.90) and for specificity was 0.86 (95% CrI 0.84 to 0.89; 95% prediction interval 0.62 to 0.96). The proportion of discordant results varied across studies from 6% to 46% (median 17%).
One study (Tafelski et al. 2015) compared the LightCycler SeptiFast Test MGRADE with blood culture plus MALDI‑TOF MS. It reported a sensitivity of 0.58 (95% confidence interval 0.30 to 0.86) and a specificity of 0.74 (95% CI 0.64 to 0.85).
Reasons for heterogeneity in sensitivity and specificity estimates between studies were explored using meta‑regression for clinically relevant variables. The following variables were explored:
age (neonates and children)
exposure to antibiotics before blood sample collection
suspected community- or healthcare‑acquired infection
febrile neutropenia
studies with inclusion or exclusion of contaminants.There was no evidence that sensitivity and specificity estimates were affected by these variables.
## SepsiTest
Four studies compared SepsiTest with blood culture and were combined in a meta‑analysis. The pooled estimate for sensitivity was 0.48 (95% CrI 0.21 to 0.74; 95% prediction interval 0.07 to 0.90) and for specificity was 0.86 (95% CrI 0.78 to 0.92; 95% prediction interval 0.66 to 0.95). The proportion of discordant results varied between studies and ranged from 14% to 26% (median 22%).
One study (Loonen et al. 2014) compared SepsiTest with blood culture plus MALDI‑TOF MS. The study reported a sensitivity of 0.11 (95% CI 0.00 to 0.23) and specificity of 0.96 (95% CI 0.92 to 1.00). No subgroup analyses were possible for the SepsiTest.
## IRIDICA BAC BSI
Four studies compared the IRIDICA BAC BSI assay with blood culture and were combined in a meta‑analysis. Two of these studies reported data using an earlier version of the IRIDICA PCR/ESI‑MS analyser known as the PLEX‑ID system, which has different desalter and mass spectrometry modules. The pooled estimate for sensitivity was 0.81 (95% CrI 0.69 to 0.90; 95% prediction interval 0.55 to 0.94) and for specificity was 0.84 (95% CrI 0.71 to 0.92; 95% prediction interval 0.50 to 0.96). The proportion of discordant results varied between studies and ranged from 7% to 30% (median 18%).
No studies compared the IRIDICA BAC BSI assay with blood culture plus MALDI‑TOF MS and no subgroup analyses were possible for this intervention.
# Intermediate and clinical outcomes
There were 41 studies included that reported data relating to the time to pathogen identification for the index test, time to treatment, test‑failure rate, mortality, duration of intensive care unit or hospital stay, duration of antibiotic therapy or reported changes in antimicrobial treatment plan. None of the included studies reported data on re‑admission rates, adverse events associated with broad‑spectrum antimicrobial use, morbidity, changes in disease severity over time, rates of superinfection, rates of resistant infection, or health‑related quality of life.
## Light Cycler SeptiFast Test MGRADE
There were 37 studies that reported data on intermediate and clinical outcomes for the LightCycler SeptiFast Test MGRADE. In addition, 1 study (Schreiber et al. 2013) reported data for both the LightCycler SeptiFast Test MGRADE and SepsiTest. No studies compared the LightCycler SeptiFast Test MGRADE with the IRIDICA BAC BSI assay.
There were 21 studies using the LightCycler SeptiFast Test MGRADE that reported turnaround times of a minimum of 4 hours to a median of 26.25 hours for pathogen identification. Some of these studies also reported the time for pathogen identification using blood cultures, which ranged from a turnaround time of a minimum of 24 hours to a median of 80 hours.
Time-to-treatment change for the LightCycler SeptiFast Test MGRADE was reported in 3 RCTs:
Tafelski et al. (2015) reported a mean time of 18.8 hours (standard deviation 5.6) from taking the blood sample to changing treatment using the LightCycler SeptiFast Test MGRADE and a mean time of 38.3 hours (SD 14.5) using blood culture and MALDI‑TOF MS.
Rodrigues et al. (2013) reported a mean time of 9.7 hours from taking the blood sample to a change in treatment using the LightCycler SeptiFast Test MGRADE compared with a mean time of 50.1 hours using blood culture (p=0.004).
Idelevich et al. (2015) reported a mean time to changing treatment of 21.4 hours (range 16.2 to 46.3 hours) in the LightCycler SeptiFast Test MGRADE group compared with 47.5 hours (range 7.3 to 59.2 hours) in the blood culture group (p=0.018).
There were 7 studies that reported test‑failure rates for the LightCycler SeptiFast Test MGRADE, which ranged from 1.5% to 24.2%. It is not clear why there is a large variation in failure rates between studies.
Duration of stay in an intensive care unit, or hospital, or both were reported in 13 studies that compared the LightCycler SeptiFast Test MGRADE with blood culture. In most of these studies, it was unclear if the duration of stay was recorded from before, during or after blood sampling. Also, most of the studies did not present comparative data. Of the 4 studies that did report between group differences, 1 study (Alvarez et al. 2012) reported a statistically significant difference (p<0.05) in intensive care unit and hospital duration of stay in favour of the LightCycler SeptiFast Test MGRADE. Three other studies (Idelevich et al. 2014; Mancini et al. 2014; Rodrigues et al. 2013) reported no significant difference in duration of stay.
One RCT (Tafelski et al. 2015) reported a duration of empirical antimicrobial therapy (antibiotics which are prescribed based on clinical presentation) of 18.8 hours (SD ±5.6) for patients in the LightCycler SeptiFast Test MGRADE group compared with 38.3 hours (SD ±14.5) for patients in the blood culture with MALDI‑TOF MS group.
There were 14 studies that reported details of change in antimicrobial treatment, 10 of which did not report comparative data. Three studies compared the LightCycler SeptiFast Test MGRADE with blood culture. One RCT (Rodrigues et al. 2013) reported that therapy was adjusted for 35% of patients in the LightCycler SeptiFast Test MGRADE group compared with 24% of patients in the blood culture group. In contrast, a further RCT (Idelevich et al. 2015) reported that 9.5% of patients in the LightCycler SeptiFast Test MGRADE had an adjustment to therapy compared with 10.5% in the blood culture group. One study based on propensity score matching (Mancini et al. 2014) reported no differences in management.
One RCT (Tafelski et al. 2015) compared the LightCycler SeptiFast Test MGRADE with blood culture plus MALDI‑TOF MS. Testing with the LightCycler SeptiFast Test MGRADE resulted in a change of treatment for 9.8% of patients compared with 13.5% of patients in the blood culture plus MALDI‑TOF MS group.
Mortality data were reported in 17 studies, 12 of which reported data on a cohort level only. The mortality rates reported ranged from 4% to 61%; but the length of follow‑up was highly variable across the studies. One study (Alvarez et al. 2012) reported no statistically significant differences between the LightCycler SeptiFast Test MGRADE and blood culture for both 28‑day and 6‑month mortality. One other study (Rodrigues et al. 2013) also reported no statistically significant difference in 28‑day mortality.
One propensity score matching study (Mancini et al. 2014) reported no statistically significant difference in mortality (p=0.39) between a prospective cohort (LightCycler SeptiFast Test MGRADE) and retrospective cohort (blood culture). Although, when more strict matching criteria were applied, the LightCycler SeptiFast Test MGRADE was associated with a statistically significant reduction in mortality (3.13% compared with 14.71%; p=0.04). A reduction in mortality associated with using the LightCycler SeptiFast Test MGRADE was reported in 2 further studies (Idelevich et al. 2015; Tafelski et al. 2015), but the reductions were not statistically significant.
## SepsiTest
One study (Loonen et al. 2014) reported a mortality rate of 3.2% for the study cohort but the duration of follow‑up was not reported. In addition, Schreiber et al. (2013) reported an intensive care unit mortality rate of 16% and a 28‑day mortality rate of 24% for the study cohort.
No other intermediate or clinical‑outcome data were reported for the SepsiTest.
## IRIDICA BAC BSI
One study, which was unpublished at the time of guidance development, reported data relevant to test‑failure rates for the IRIDICA BAC BSI assay. These data are considered to be academic in confidence and cannot be reported at this time.
One study (Vincent et al. 2015) reported that an adjudication panel of 3 clinical experts retrospectively recommended a change in management based on the IRIDICA BAC BSI assay for 41% of all patients. This increased to 57% of patients when the IRIDICA BAC BSI assay was positive and blood culture was negative.
One study (Vincent et al. 2015) reported a mortality rate of 29% for the study cohort, but did not report the duration of follow‑up.
# Costs and cost effectiveness
The External Assessment Group conducted a search to identify studies investigating the cost effectiveness of the LightCycler SeptiFast Test MGRADE, SepsiTest or the IRIDICA BAC BSI assay. The External Assessment Group also constructed a conceptual economic model to determine the cost effectiveness of the technologies.
## Systematic review of cost-effectiveness evidence
Four studies were included and were assessed according to their relevance to the decision problem: 3 studies included the LightCycler SeptiFast Test MGRADE, 2 of which were within‑study cost‑minimisation analyses (that is, a cost‑minimisation analysis conducted within a clinical study), and 1 was a cost‑effectiveness analysis. The remaining study included a cost‑minimisation analysis of the IRIDICA PLEX‑ID hybrid assay. The target population, condition and setting varied across the 4 studies.
The 2 studies that were within‑study cost‑minimisation analyses of using the LightCycler SeptiFast Test MGRADE when compared with blood culture reported cost savings of €178.75 per sample (Mancini et al. 2014) and €183.00 per patient (Alvarez et al. 2012). The third study, Lehmann et al. (2010), reported incremental cost‑effectiveness ratios (ICERs) of €11,477 per incremental survivor and €3,107 per quality‑adjusted life year (QALY) gained when using the LightCycler SeptiFast Test MGRADE compared with blood culture. When the use of an IRIDICA‑PLEX‑ID hybrid system was compared with blood culture, Bilkovski et al. (2014) reported cost savings of $1,123,372 per 422 tests. None of the studies considered the effect of a potential reduction in antibiotic resistance. The External Assessment Group concluded that the existing economic evaluations had limited relevance to either the UK or the decision problem because of differences in patient populations, costs of the interventions and standard care. In particular, Mancini et al. (2014) included haematology patients for whom relatively expensive empirical antifungals were prescribed that are unlikely to be representative of the UK treatment pathway.
## Economic analysis
The External Assessment Group developed a conceptual economic model designed to explore the cost effectiveness of the LightCycler SeptiFast Test MGRADE, SepsiTest and the IRIDICA BAC BSI assay. The population included in the model was hospitalised patients with suspected bloodstream infection.
The model comprised a decision tree with a lifetime time horizon and took the perspective of the NHS and personal social services. The key clinical outcomes included in the model were 30‑day mortality, duration of stay in intensive care unit, duration of hospital stay and antimicrobial treatment.
Data on the diagnostic accuracy of the interventions, intermediate outcomes and clinical outcomes were taken from the clinical‑effectiveness systematic review when possible. Expert opinion was also sought to populate key clinical outcomes and supplement the data available from the systematic review. Routine sources of costs and prevalence data were also used when appropriate. A discount rate of 3.5% per annum was applied to both costs and effects. The potential effect of the tests on antimicrobial stewardship was not included in the model, because there was insufficient evidence to show how the tests would affect antimicrobial use and the subsequent development of resistant organisms.
The incremental cost per test was calculated using the cost of the test, the net effect on duration of intensive care unit and hospital stay, and changes in the costs of antimicrobial treatment. The estimated cost per day for an intensive care unit bed was £1057 and for a general ward bed was £275. A course of empirical antimicrobial treatment was estimated to cost £350.
It was assumed that the cost per test was dependent upon both test throughput and whether laboratory equipment needed to be bought to use the tests. The range of technology costs included in the model were as follows:
LightCycler SeptiFast Test MGRADE £153.67 to £205.54
SepsiTest £108.30 to £149.53
IRIDICA BAC BSI £197.35 to £314.61
MALDI‑TOF MS £6.94 to £232.39.
Incremental QALYs were calculated by assuming 11.32 discounted QALYs per 30‑day mortality avoided, based on the estimated number of discounted life years for an adult patient with sepsis and the estimated quality of life after an episode of sepsis. The model assumed a mean age of 58 years and that 60% of the cohort were male. Patients were assumed to have a utility value of 0.68 at 5 years after an episode of severe sepsis (Cuthbertson et al. 2013) unless the utility value predicted for the age and sex profile of a patient in the general population was lower. In these instances, the lower utility value was applied.
## Economic-analysis results
Five deterministic analyses were done:
Base case 1: interventions compared with blood culture, with clinical‑outcome data taken from the systematic review.
Base case 2: interventions compared with blood culture, with clinical‑outcome estimates taken from expert opinion.
Threshold analyses.
Interventions compared with MALDI‑TOF MS.
Data taken from studies comparing more than 1 intervention.
The following assumptions were common to all analyses:
The only parameter to affect QALY gain or loss was 30‑day mortality rate.
Negative rapid tests did not affect any of the 4 key outcomes.
Failed rapid tests did not affect any of the 4 key outcomes.
If 2.4 tests per day were run, laboratories ran tests Monday to Friday only, with 3 times the number of tests run on Monday to account for samples building up over a weekend.
If 17 or 68 tests per day are run, laboratories did 3 runs per day and worked 24 hours a day, 7 days a week.
The purchase cost of machines needed for the interventions and comparators was equally divided over 7 years of use.
It was assumed that no additional staff costs or laboratory estate costs were incurred when using the interventions.
The time scale of testing was 1 year although discounted QALYs accrued in subsequent years were included.
Incremental QALYs were accrued through the number of avoided 30‑day mortalities.
If accuracy data from Warhurst et al. (2015) were used, the LightCycler SeptiFast Test MGRADE had a failure rate of 6.9%. A failure rate of 1.4% was assumed when pooled accuracy data was used.
IRIDICA BAC BSI had a failure rate of 1.9%.
SepsiTest had a failure rate of 0%.
Patients were treated with either 18 g per day of piperacillin/tazobactam or 3 g per day of meropenem for 7 days.
‑day mortality rates were assumed to be either 13% or 29%.
MALDI‑TOF MS was only used on positive samples (8.7% of all blood cultures).
MALDI‑TOF MS had a sensitivity of 79.8% at species level compared with blood culture.
LightCycler SeptiFast test MGRADE diagnostic-accuracy data were derived from Warhurst et al. (2015) unless otherwise specified.
SepsiTest and IRIDICA BAC BSI diagnostic-accuracy data were derived from the External Assessment Group's meta‑analyses unless otherwise specified.
In this analysis, clinical‑outcome data from the clinical‑effectiveness review were included. This resulted in the assumption that there were no clinical benefits associated with the interventions for 30‑day mortality, duration of stay in the intensive care unit or duration of stay in hospital. The costs of antimicrobials were also unchanged in this analysis. All interventions were compared with blood culture only.
The results of the analysis showed that all the interventions were dominated by blood culture (that is, blood culture was less expensive and more effective than all of the interventions). Regardless of the test throughput assumed in different scenarios, the interventions remained dominated (more expensive with no additional clinical benefit) because of the lack of QALYs gained.
In addition, a threshold analysis was done for base case 1 to assess the reduction in antimicrobial costs that would be needed for each intervention to be cost neutral. The results suggested that the reductions needed would be 44% to 59% for the LightCycler SeptiFast Test MGRADE, 31% to 43% for the SepsiTest and 56% to 90% for the IRIDICA BAC BSI, although the rate of positive tests associated with each intervention suggested that their costs could not be offset solely by a reduction in antimicrobial therapy use.
In this analysis, the key clinical‑outcome parameters were populated using an average of estimated values provided by clinical experts. The External Assessment Group used these values in a range of scenarios that assumed a 30‑day mortality rate of either 13% or 29%, a throughput of 2.4, 17 or 68 tests per day and a maximum acceptable ICER of £20,000 or £30,000 per QALY gained. The comparator used in this analysis was blood culture.
For each scenario, the net monetary benefit of each intervention was estimated. A positive net monetary benefit suggests that the benefits associated with the intervention outweigh the costs, and the intervention with the largest net monetary benefit is estimated to be the most cost effective. MALDI‑TOF MS was also included in the analysis to estimate the relative cost effectiveness between the 2 comparators included in the assessment.
In all scenarios modelled, MALDI‑TOF MS produced a positive net benefit compared with blood culture. In 1 scenario (30‑day mortality rate 13%, 2.4 tests per day, maximum acceptable ICER of £20,000 per QALY gained), SepsiTest had the highest net monetary benefit when it was assumed that equipment to run the test had to be bought. In the same scenario, the IRIDICA BAC BSI assay had the highest net monetary benefit when only the test reagents and consumables were purchased. In all other modelled scenarios, the IRIDICA BAC BSI assay had the highest net monetary benefit.
ICERs were also calculated using the data from expert opinion. When it was assumed that no additional equipment had to be bought or the 30‑day mortality rate was 29%, the ICERs became more favourable because of either a decrease in incremental costs or an increase in incremental QALY gain.
The External Assessment Group also explored the effect of applying the pooled estimates of sensitivity and specificity from the meta‑analyses to the LightCycler SeptiFast Test MGRADE. This assumption produced more favourable ICERs for the LightCycler SeptiFast Test MGRADE through increasing the estimated sensitivity of the test (65% pooled estimate compared with 51% from Warhurst et al. 2015), while maintaining specificity at 86%.
The External Assessment Group used a range of threshold analyses to explore the effect of key clinical outcomes. In all analyses, it was assumed that the comparator equipment had already been bought but that the equipment for the interventions needed to be bought. The threshold levels resulting from the analyses, which assumed 2.4 tests run per day and a maximum acceptable ICER of £20,000 per QALY gained, suggested reductions in 30‑day mortalities ranging from 0.09 to 0.14 per 100 tests would be needed for the interventions to be considered cost effective compared with blood culture. Antimicrobial costs would need to reduce by £149.53 to £314.61 per 100 tests. The results were similar when the interventions were compared with MALDI‑TOF MS. The threshold analyses that assumed either 17 or 68 tests run per day produced lower threshold values. The values of the reductions needed were also lower when a maximum acceptable ICER of £30,000 per QALY gained was assumed.
The External Assessment Group also explored the cost effectiveness of both the LightCycler SeptiFast Test MGRADE and SepsiTest compared with MALDI‑TOF MS, based on data from 2 studies (Tafelski et al. 2015; Loonen et al. 2014) that used MALDI‑TOF MS in addition to blood culture. The effect estimates based on expert opinion were also included in the analysis. It was assumed that both interventions had a failure rate of 0% and that equipment to run the tests needed to be bought. The results of these analyses suggested that when compared with MALDI‑TOF MS (and blood culture), the LightCycler SeptiFast Test MGRADE dominated (less costly and more effective) MALDI‑TOF MS (and blood culture), and SepsiTest had ICERs ranging from £23,375 to £34,848 per QALY gained with a 30‑day mortality rate of 13% and from £10,479 to £15,621 per QALY gained with a 30‑day mortality rate of 29%.
An analysis was run using data from 2 studies (Schreiber et al. 2013; Leitner et al. 2013), which evaluated both the LightCycler SeptiFast Test MGRADE and SepsiTest with blood culture. The analysis was done to compare the relative cost‑effectiveness estimates with those derived in base case 2 that were based on indirect comparisons of the relative effectiveness of the interventions from expert opinion. The analysis assumed a 0% test‑failure rate for both interventions and that equipment to run the tests needed to be bought. A range of scenarios were presented with 30‑day mortality rates of 13% or 29% and a throughput of 2.4, 17 or 68 tests per day. In all scenarios, the ICER for the LightCycler SeptiFast Test MGRADE was greater than £30,000 per QALY gained when compared with SepsiTest.# Considerations
The Diagnostics Advisory Committee reviewed the evidence available on the clinical and cost effectiveness of using the LightCycler SeptiFast Test MGRADE, SepsiTest and IRIDICA BAC BSI assay to rapidly identify bloodstream bacteria and fungi in people with a suspected bloodstream infection.
# Clinical effectiveness
The Committee considered the evidence for the diagnostic accuracy of each of the rapid molecular tests compared with blood culture. It noted that 54 studies reported data for the LightCycler SeptiFast Test MGRADE, 6 of which included children or neonates, 4 reported data for SepsiTest and 4 reported data for the IRIDICA BAC BSI assay. The Committee noted that most of the included studies were considered to have unclear risks of bias, particularly about details of the reference standard and the populations included in the studies. The Committee considered that the unclear risk of bias was attributable to poor reporting in the studies, and concluded that it was not possible to adequately assess the quality of the studies included in the diagnostic accuracy meta‑analyses.
The Committee noted that 2 studies compared either the LightCycler SeptiFast Test MGRADE or SepsiTest with MALDI‑TOF mass spectrometry (MS). It considered that both of these studies had relatively small sample sizes and it is likely that the results are not applicable to the UK because of differences in clinical practice in Europe, where the studies were done. The Committee concluded that there was insufficient evidence to establish either the diagnostic accuracy or the clinical utility of the rapid molecular tests against this comparator. Also, because of insufficient clinical data, the Committee concluded that there was too much uncertainty in the analyses for it to be confident that the rapid molecular tests would be cost effective compared with MALDI‑TOF MS.
The Committee questioned the assumption in the diagnostic accuracy meta‑analyses that blood culture is 100% accurate and noted that clinical specialists consider it to be an imperfect reference standard. It heard from the External Assessment Group that on this basis it was possible that the pooled estimates of sensitivity and specificity had been underestimated in the analysis, and so the rate of false positive and false negative results may also have been overestimated. The Committee discussed the reasons for false positive results with the rapid molecular tests. It noted that false positives may be real false positives in situations in which the rapid molecular test detects DNA from contaminant organisms in the blood sample which may result from the testing process. But it also heard from clinical specialists that it is possible that the rapid molecular tests may give more accurate results in some scenarios, such as the detection of fastidious organisms that may not grow in culture. The Committee also heard from clinical specialists that the rapid molecular tests may detect transient bacteraemia in some people, but that the clinical implications of this are not fully understood. It is possible that people may have extended courses of antibiotics and stay in hospital for longer if transient bacteraemia is detected. The Committee concluded that although the sensitivity and specificity may have been underestimated in the meta‑analyses, the absence of data on the clinical significance of discordant results means that the size of any underestimation cannot be determined.
The Committee discussed the number of positive blood cultures in the included diagnostic accuracy studies and their prevalence in clinical practice. It heard from clinical specialists that blood culture is often negative in practice, with only around 10% of blood cultures being positive. The Committee considered that the low prevalence of positive blood cultures was likely to mean that there would be a relatively low number of false negative rapid molecular test results in routine practice. Also, the absolute rate of false‑positive rapid molecular test results is likely to be high because of the greater prevalence of negative blood cultures. The Committee concluded that although the absolute number of false‑negative rapid molecular test results was likely to be low in practice, the consequences of changing antimicrobial treatment in this group could be severe.
The Committee discussed the studies included in the clinical‑outcomes systematic review. It noted that fewer studies reported clinical‑outcome data compared with diagnostic‑accuracy data, and that studies typically reported data for the LightCycler SeptiFast Test MGRADE only. The Committee noted that most of the studies were done in Europe or the USA and questioned the applicability of the clinical‑outcome studies to the UK. It heard from clinical specialists that although the treatment of sepsis is based on international guidelines, clinical outcomes such as duration of intensive care unit stay and duration of antimicrobial therapy cannot usually be applied to the UK from international studies because of differences in antibiotic prescribing practices. The Committee concluded that although the included studies provide some indication of the likely effect of the rapid molecular tests on clinical outcomes, additional UK‑based studies are needed to show the clinical utility of the tests in practice.
The Committee considered the test turnaround times reported in the studies and heard from clinical specialists that the shorter times seen in research studies are unlikely to be seen in routine clinical practice, unless a molecular service is available 24 hours a day. It noted that 24‑hour services may become available if microbiology laboratories are joined into networks or centralised, but that this was unlikely to happen in the very near future. The Committee also noted that in some studies, the reported test‑failure rates for the LightCycler SeptiFast Test MGRADE were high (up to 24.2%) and considered that this could further affect its potential to rapidly deliver information for clinical decision‑making. The Committee questioned why the reported test‑failure rates were high in some studies but heard from the External Assessment Group that the reasons for the failed tests were not reported. The Committee concluded that faster reporting of results is highly dependent on laboratory infrastructure and that the turnaround times needed to gain benefits from the rapid molecular tests are unlikely to be achieved in routine practice.
The Committee considered the data for mortality and duration of intensive care unit or hospital stay and noted that the studies were unlikely to have had sufficient power to detect statistically significant differences for these clinical endpoints. The Committee also noted that most of the studies did not report statistically significant differences between the rapid molecular tests and standard practice. Also, it heard from clinical specialists that both mortality and duration of stay among people with suspected bloodstream infection are likely to be influenced by multiple factors, and that any differences are unlikely to be solely because of the use of a rapid molecular test. The Committee concluded that mortality and duration of stay may not be appropriate primary clinical outcomes for studies, and suggested that future studies should consider using change in antimicrobial prescribing as a surrogate clinical outcome.
The Committee discussed the plausibility of the rapid molecular tests having an effect on antimicrobial prescribing. It noted that the results of the clinical‑effectiveness analysis suggested that only small numbers of people, if any, would have changes made to their antimicrobial treatment plan. The Committee heard from clinical specialists that there may be some situations in which the rapid molecular tests could affect patient management. Also, it heard that these situations would be restricted to instances in which the rapid test was positive, because the current accuracy of the tests was not sufficient to convince clinicians to withdraw antibiotic therapy on the basis of a negative test result. The Committee concluded that although the rapid molecular tests might give results more quickly, it was unlikely that the information they give would have an effect on patients' treatment plans and antimicrobial prescribing at present.
# Cost effectiveness
The Committee discussed the results of the economic analyses and questioned whether the use of an imperfect reference standard to calculate the estimates of diagnostic accuracy for the rapid molecular tests could have introduced bias. The Committee heard from the External Assessment Group that negative results were assumed not to have an effect on outcomes and that false‑positive results were associated with benefits in the model. The Committee concluded that any underestimate of pooled diagnostic accuracy in the clinical‑effectiveness analysis is unlikely to have a substantial effect on the results of the economic model.
The Committee questioned the assumptions made about the number of tests processed per day. It heard from clinical experts that the estimates based on 68 tests per day were unrealistic and that a large service laboratory would be unlikely to get more than 40 blood cultures per day. The Committee noted that the External Assessment Group had also produced estimates based on 2.4 and 17 tests per day. The Committee heard from the External Assessment Group that an assumption of 68 tests per day was included as an extreme scenario to show the effect on the results of the economic analyses. The Committee concluded that the most representative scenarios in the economic analyses were those that assumed either 2.4 or 17 tests per day.
The Committee discussed the differences in the results produced in the 2 different base cases of the economic analyses. It noted that the main difference between the 2 base cases came from the difference in data source for clinical outcomes: base case 1 used data taken from the systematic review, and base case 2 used data based on expert opinion. The Committee noted that the systematic review suggested that the rapid molecular tests had no effect on clinical outcomes, but some of the clinical experts thought that the tests may be beneficial, although their estimates of the size of the benefit varied widely. The Committee concluded that the tests may offer clinical benefit, but there is too much uncertainty in the size of the benefit to determine the effect of introducing the tests into clinical practice. The Committee also noted that the incremental cost‑effectiveness ratios (ICERs) in base case 2 ranged from the rapid molecular tests being more costly and equally effective (dominated) than blood culture, to being less costly and more effective (dominant) than blood culture alone, when using estimates from individual clinicians. The Committee considered that the wide range of ICERs resulted from the high level of variation between the clinicians' estimates. The Committee concluded that the effect of introducing the rapid molecular tests on NHS resources was highly uncertain and that the results of the economic analyses were subject to substantial uncertainty.
The Committee considered the likely effect of the costs and outcomes that had been excluded from the economic analyses and noted that these included laboratory overhead and additional staff costs, and clinical benefits that may be accrued through improved antimicrobial stewardship. The Committee noted that because the results of the clinical‑effectiveness analysis suggested that the effect of the rapid molecular tests on antimicrobial prescribing was highly uncertain, it would have been inappropriate to extrapolate the clinical outcomes to estimate an effect on antimicrobial stewardship. It also noted that the rapid molecular tests would most likely increase laboratory overhead costs, and possibly staff costs, and concluded that because of the clinical uncertainties their absence from the economic analyses was unlikely to have a substantial effect.
The Committee considered the results of the threshold analyses and noted the reductions in antimicrobial costs that would be needed for the tests to be considered cost effective. The Committee noted that this ranged from £823.34 to £1482.28 per 100 positive tests, depending on whether the rapid molecular tests were compared with blood culture or blood culture plus MALDI‑TOF MS. The Committee concluded that because of the prevalence of positive tests in clinical practice, the costs of the rapid molecular tests were unlikely to be offset by reduced antimicrobial costs alone.
The Committee noted that the economic analyses did not include neonates and children, and that the model was based on an adult population with a mean age of 58 years. The Committee considered that the estimated quality‑adjusted life year (QALY) gain by avoided 30‑day mortalities would be greater for children and neonates because of their greater number of life years remaining, but accepted that there were insufficient clinical‑utility data for this population for an economic analysis.
# Additional considerations
The Committee considered the potential benefits of the interventions in practice. It heard from clinical experts that because the tests can be used directly on whole blood samples, they may be able to give information on a pathogen's identity earlier in the care pathway than tests that need incubated blood samples or samples from culture plates, which could be beneficial for antimicrobial stewardship. Also, it heard that the information from the rapid molecular tests may be used to modify a person's antimicrobial therapy, particularly when empirical antimicrobial therapy (antibiotics which are prescribed based on clinical presentation) has been prescribed. The Committee concluded that one of the key claimed benefits of the rapid molecular tests is their potential to contribute towards antimicrobial stewardship.
The Committee considered that because the rapid molecular tests need to be used in addition to blood culture for antimicrobial susceptibility testing, they may be less suitable for use in neonates and children. The Committee heard from clinical experts that this is a particular issue for tests that need a large volume of whole blood. The Committee also heard from clinical specialists that using a lower volume of blood from these patients for the molecular tests may have an adverse effect on the test's sensitivity and concluded that further exploration of these analytical issues should be encouraged.
# Research considerations
The Committee discussed the value of developing research recommendations for the rapid molecular tests. The Committee considered that for the tests to have clinical utility in both research settings and routine practice, clinicians would need to be certain that the tests are sufficiently accurate, and be confident that basing antimicrobial prescribing decisions on the results of the tests would not lead to adverse outcomes for people. The Committee noted that the reported accuracy data from the systematic review were unlikely to be sufficient for clinical decision‑making at present. The Committee concluded that further research in the UK is needed to determine the clinical scenarios in which the tests may offer most benefit in clinical decision‑making and to quantify their clinical utility. The Committee also considered that future studies should investigate using the rapid molecular tests in conjunction with other biomarkers, such as procalcitonin, and diagnostic tests that may be used to assess people with suspected sepsis.
The Committee considered that, conceptually, the molecular tests show promise for the early identification of fungal pathogens in people who are thought to be at increased risk of developing invasive fungal infections. The Committee concluded that if the accuracy of the tests was sufficient to guide clinical decision‑making in this population, they could offer substantial value and address a clinically unmet need. The Committee encouraged future studies in this population and highlighted that the studies should aim to quantify the clinical utility of the rapid molecular tests, including their effect on antifungal prescribing. The Committee noted that studies planned by the National Institute for Health Research Health Technology Assessment Programme may investigate the use of rapid tests for identifying fungal pathogens.
The Committee considered the utility of further research to quantify the levels of certainty about the results of rapid molecular tests, which clinicians need to have before they decide to change treatment and level of care for patients. The Committee noted that the results of an elicitation exercise could be used to guide the development of future diagnostic tests that are designed to be used to change treatment plans for patients who are acutely unwell, and wished to encourage this research.
The Committee considered that because an increasing number of microbiology laboratories are adopting MALDI‑TOF MS for rapidly identifying bloodstream bacteria and fungi, future studies aiming to establish the clinical utility of rapid molecular tests should include this technology as a comparator when possible.
The Committee noted that there was insufficient evidence to determine whether the tests were clinically effective in children and neonates. It wished to encourage the inclusion of these populations in future research studies, and noted that particular consideration should be given to establishing whether the blood volumes needed for the tests in this assessment are suitable for these populations.
|
{'Recommendation': 'There is currently insufficient evidence to recommend the routine adoption in the NHS of the SepsiTest assay for rapidly identifying bloodstream bacteria and fungi. The test shows promise and further research to provide robust evidence is encouraged, particularly to demonstrate the value of using the test results in clinical decision‑making (see sections\xa05.18 to\xa05.22). ', 'Clinical need and practice': "# The problem addressed\n\nIn current practice, people who are clinically unwell and who have a suspected bloodstream infection have empirically prescribed broad‑spectrum antibiotics, that is, antibiotics that are prescribed based on clinical presentation, until the identity of the pathogen causing the infection is known. Broad‑spectrum antibiotics and, if appropriate, antifungals, are used because they are effective against a wide range of bacterial and fungal pathogens and are likely to achieve a therapeutic response. But, although clinically effective, broad‑spectrum antibiotic use is associated with people developing superinfection and with antimicrobial resistance. Rapidly identifying the bacterial and fungal pathogen may allow earlier targeted treatment and shorten the length of use of broad‑spectrum antibiotics and antifungals, which may help antimicrobial stewardship by conserving the effectiveness of existing antimicrobials.\n\nThree molecular tests, the LightCycler SeptiFast Test MGRADE, SepsiTest and IRIDICA BAC BSI assay, were identified during scoping as relevant to the assessment (see section\xa03 for additional details). These tests are designed to rapidly detect and identify bacterial and fungal DNA that may be in the bloodstream in people who are suspected of having sepsis. These tests are intended to be used with clinical assessment and established microbiology techniques that provide information on which antimicrobials are likely to be effective against the identified pathogen. The tests are designed to be run on whole blood samples and without the prior incubation or the pre‑culture steps that are needed for tests used in current standard practice. The absence of these steps means that pathogens may be identified earlier. It is possible that blood culture would still be needed to give definitive antimicrobial‑susceptibility data, if this is not provided by the rapid diagnostic test. The rapid detection and identification of bacterial and fungal DNA may be particularly beneficial in people who are suspected of having a severe infection and who need quick medical intervention.\n\nThe purpose of this assessment is to evaluate the clinical and cost effectiveness of using the LightCycler SeptiFast Test MGRADE, SepsiTest and IRIDICA BAC BSI assay for rapidly identifying bloodstream bacteria and fungi in the NHS.\n\n# The condition\n\n## Sepsis and bloodstream infection\n\nSepsis is a life‑threatening condition characterised by the body's inflammatory response to an infection. According to the Surviving Sepsis Campaign's International guidelines for the management of severe sepsis and septic shock, sepsis is diagnosed if there is evidence of systemic inflammation, in addition to a documented or presumed infection in the body. Systemic illness often happens if bacteria invade normally sterile parts of the body. One example of this is when bacteria or fungi invade the bloodstream (bloodstream infection); a process that often causes an inflammatory immune response.\n\nBacterial infections are the most common cause of sepsis and bloodstream infection, but they can also be caused by fungal infections, and less commonly by viral infections. The most common sites of infection associated with sepsis are the lungs, urinary tract, abdomen and pelvis. Other sources of infection leading to sepsis include skin infections (such as cellulitis), post‑surgical infections and infections of the nervous system (such as meningitis or encephalitis).\n\nPeople who have recently been admitted to hospital are at risk of getting hospital‑acquired infections that can lead to sepsis and bloodstream infection. The increased use of invasive procedures, such as catheterisation and life support measures, as well as immunosuppressive therapy and antibiotic therapy may have resulted in more healthcare‑associated bloodstream infections. Community‑acquired bloodstream infections may also occur in people who have not had recent contact with healthcare services. The pathogens infecting these people may differ from those associated with hospital‑acquired bloodstream infection.\n\nThe bacteria most commonly associated with bloodstream infection in adults include gram‑negative species such as Escherichia coli, Klebsiella and Pseudomonas, and gram‑positive species such as Staphylococcus aureus, non-pyogenic streptococci, Enterococcus and Streptococcus pneumoniae. The types of pathogens causing bloodstream infection can differ in children compared with those causing infection in adults, and can include Neisseria meningitidis. Polymicrobial infection and anaerobic bacteraemia are also thought to occur less often in children.\n\n# The diagnostic and care pathways\n\n## Diagnosing sepsis and bloodstream infection\n\nDiagnostic criteria for sepsis are listed in the Surviving Sepsis Campaign's International guidelines for the management of severe sepsis and septic shock. In summary, regular observations of all vital signs should be taken and recorded, kidney and liver function tests should be done, and inflammatory biomarkers and serum lactate should be measured. These guidelines state that a diagnosis of sepsis should be based on infection, documented or suspected, with hyperthermia or hypothermia, tachycardia and at least 1\xa0indication of altered organ function.\n\nThe guidelines also make the following specific recommendations relating to detecting localised and bloodstream infection:\n\nAt least 2\xa0samples for blood culture should be collected (aerobic and anaerobic) before antimicrobial therapy is started if such cultures do not cause significant delay (greater than 45\xa0minutes) in the start of antimicrobial administration. At least 1\xa0sample should be drawn percutaneously and 1\xa0drawn through each vascular access device, unless the device was recently (less than 48\xa0hours) inserted. The blood cultures can be drawn at the same time if they are taken from different sites. Cultures from other sites that may be the source of infection, such as urine, cerebrospinal fluid, wounds, respiratory secretions or other bodily fluids, should be collected before starting antimicrobial therapy, if doing so does not cause significant delay in the start of antimicrobial treatment.\n\nImaging studies such as CT or X‑ray should be done to confirm a potential source of infection.\n\nAssays to diagnose systemic fungal infection should be used if available and invasive candidiasis is suspected.\n\n## Blood cultures\n\nPublic Health England's standards for the investigation of blood cultures are available. A blood culture set for diagnosing bloodstream infection is defined as 1\xa0aerobic and 1\xa0anaerobic bottle. For adults it is recommended that 20–30\xa0ml of blood is cultured per set, and that 2\xa0consecutive blood culture sets from 2\xa0separate venepuncture sites should be collected during any 24‑hour period for each septic episode. The first set should be taken before starting antimicrobial treatment because the presence of antibiotics or antifungals may inhibit the growth of pathogens in blood culture. Blood culture sample collection differs for infants and neonates, for whom a single aerobic bottle or low‑volume blood culture bottle may be requested. The criterion for calculating total blood‑culture volume in neonates and children is based on weight rather than age and relates to total patient blood volume. It has been suggested that the volume of blood drawn should be no more than 1% of the patient's total blood volume. In infants and children, the level of bacteraemia is usually higher than in adults and so the sensitivity of detection is not thought to be substantially reduced by a lower blood‑to‑medium ratio.\n\nBlood culture bottles should be incubated within 4\xa0hours of the blood sample being taken. Many laboratories now use automated culture systems that alert laboratory staff once growth has been detected.\n\nWhen a blood culture has been detected as positive it is recommended that:\n\nGram staining and rapid antigen testing should be done within 2\xa0hours.\n\nDirect or automated isolate identification should be done within 24\xa0hours (extending to 48\xa0hours if traditional microbiology techniques such as morphological identification are used). Rapid species identification may be done after blood culture using techniques such as MALDI‑TOF mass spectrometry.\n\nIdentification should be followed by sensitivity testing to determine the antimicrobials that the identified pathogen is susceptible to. If direct or automated sensitivity testing is used, a report should be made within 24\xa0hours, extended to 48\xa0hours if traditional techniques, such as the disc diffusion method, are used.\n\nA preliminary positive report is made within 2\xa0hours of identification and sensitivity testing, and a final positive report should be made within 5\xa0days of the sample arriving in the laboratory.\n\nIf a blood culture is negative, it is recommended that a preliminary negative report is provided within 48\xa0hours of the sample arriving in the laboratory and a final negative report should be issued within 5\xa0days unless extended culture is being done, such as if fungi or unusual, fastidious or slow growing organisms are suspected.\n\n## Treating sepsis and bloodstream infection\n\nSepsis treatment varies based on the initial infection, the organs affected and the extent of tissue damage. The management of severe sepsis and septic shock is described in the Surviving Sepsis Campaign's International guidelines for the management of severe sepsis and septic shock.\n\nThe guidelines recommend that effective intravenous antimicrobials should be given within the first hour of recognising severe sepsis and septic shock. Initial empirical antimicrobial therapy should include 1\xa0or more drugs that have activity against all likely pathogens (bacterial, fungal or viral) and that penetrate in adequate concentrations into the tissues thought to be the source of sepsis. Frequently used broad‑spectrum antibiotics for more serious infections include cephalosporins and aminoglycosides.\n\nThe guidelines recommend that the choice of empirical antimicrobial therapy be based on:\n\nthe patient's history, including drug intolerances\n\nrecent antibiotic treatments (previous 3\xa0months)\n\nunderlying disease\n\nthe clinical syndrome\n\nsusceptibility patterns of pathogens in the community and hospital\n\nprevious microbiology reports identifying pathogens that have previously colonised or infected the patient.\n\nClinicians prescribing antimicrobial therapy should take into account the Department of Health's guidance on antimicrobial stewardship, which is based on the 'start smart then focus' strategy. The guidance recommends that when empirical antimicrobials are prescribed, the clinical diagnosis should be reviewed after 48\xa0to 72\xa0hours to allow an antimicrobial prescribing decision to be made. This decision should take into account available microbiology results to determine if therapy can be stopped or changed; that is, the de‑escalation, substitution or addition of antimicrobial agents to the treatment plan.\n\nNarrowing the spectrum of antimicrobial coverage and shortening the duration of therapy may reduce the risk of a person developing a superinfection, and reduce treatment‑related adverse events. Adverse events associated with using broad‑spectrum antimicrobials may include diarrhoea, nausea, vomiting, hearing loss, damage to the kidneys and an increased risk of superinfection with Clostridium difficile. Narrowing the spectrum of antimicrobial coverage may also be associated with an increase in treatment efficacy in some scenarios.\n\nReducing the spectrum of antimicrobial coverage and duration of antibiotic therapy may also contribute to antimicrobial stewardship and protect the effectiveness of existing antibiotics. Surveillance data for England for the period 2010 to 2013 suggest that rates of methicillin‑resistant Staphylococcus aureus (MRSA) have fallen while the incidence of bloodstream infections caused by resistant gram-negative Enterobacteriaceae bacteria, such as Klebsiella and Escherichia coli, has increased (English surveillance programme for antimicrobial utilisation and resistance, 2014). Of particular concern in some regions of England is the increasing resistance to carbapenem antibiotics, which are often used as a last resort for treating severe infections when other antibiotics have not brought the infection under control.", 'The diagnostic tests': '# The interventions\n\n## The LightCycler SeptiFast Test MGRADE\n\nThe LightCycler SeptiFast Test MGRADE (Roche Diagnostics) is a CE‑marked, in vitro, diagnostic, real‑time polymerase chain reaction (PCR) test that simultaneously detects and identifies DNA from 25\xa0bacterial and fungal pathogens. The test needs 1.5\xa0ml of ethylenediaminetetraacetic acid (EDTA)‑treated whole blood.\n\nThe LightCycler SeptiFast Test MGRADE involves 3\xa0distinct processes: specimen preparation by mechanical lysis and purification of DNA, real‑time PCR amplification of target DNA in 3\xa0parallel reactions (gram‑positive bacteria, gram‑negative bacteria and fungi), and detection using fluorescence‑labelled probes specific to the target DNA. The test takes a minimum of 6\xa0hours, depending on laboratory workflow.\n\nThe SeptiFast Identification Software set v2.0 analyses the samples and generates a report, which contains all the relevant laboratory data and details of the identified species. The software also includes a crossing point cut‑off rule, which is intended to reduce the positive rate for coagulase‑negative Staphylococci and Streptococcus species based on the assumption that they are contaminants and not causal agents when the crossing point value is less than\xa020.\n\nIf Staphylococcus aureus is identified in a sample, an aliquot of the SeptiFast Test MGRADE eluate can be further tested for the MecA gene using the LightCycler SeptiFast MecA Test MGRADE. The test can determine the likely methicillin resistance of Staphylococcus aureus through PCR, using the LightCycler\xa02.0 instrument.\n\nThe test has an analytical sensitivity of 100\xa0colony‑forming units/ml for coagulase‑negative Staphylococci, Streptococcus agalactiae, Streptococcus pyogenes, Streptococcus pneumonia and Streptococcus mitis. The minimum analytical sensitivity for all other pathogens detected by the LightCycler SeptiFast test MGRADE is 30\xa0colony‑forming units/ml.\n\n## SepsiTest\n\nSepsiTest (Molzym Molecular Diagnostics) is a CE‑marked PCR in\xa0vitro test for detecting bacterial and fungal DNA in 1\xa0ml of k‑EDTA- or citrate‑treated whole blood. The test is able to identify species from more than 200\xa0genera of bacteria and 65\xa0genera of fungi.\n\nThe SepsiTest involves 3\xa0distinct processes: extracting and purifying microbial DNA using centrifugation, universal PCR and sequencing. The PCR result, which is available after 4\xa0hours, indicates whether bacteria or fungi are present in the sample. Amplicons from positive samples are then sequenced to confirm the PCR result and to determine which bacteria or fungi species are present. If readable sequences are available from sequence analysis, bacteria and fungi can be identified using the SepsiTest‑BLAST online tool. Sequencing results may be available in 3\xa0to 4\xa0hours depending on the analyser used.\n\nThe analytical sensitivity of SepsiTest ranges from 10\xa0to 80\xa0colony‑forming units/ml, depending on the target species.\n\n## IRIDICA BAC BSI assay\n\nThe IRIDICA BAC BSI assay (Abbott Laboratories) is a CE‑marked, in\xa0vitro, diagnostic test for detecting and identifying DNA from bacteria and candida in 5\xa0ml of whole blood treated with EDTA. The test can also detect the MecA (Staphylococcus‑specific methicillin resistance), vanA and vanB (Enterococcus‑specific vancomycin resistance), and KPC (gram‑negative associated carbapenem resistance) genes, which are associated with antibiotic resistance.\n\nThe test is designed for use with the IRIDICA system, which combines broad‑range PCR with electrospray ionisation time‑of‑flight mass spectrometry to amplify and detect pathogens. The estimated time to result is at least 5\xa0hours and 55\xa0minutes.\n\nThe IRIDICA analysis computer consists of a proprietary database and software, which identifies the organism present in the sample by comparing the sequence of the sample with a library of known sequences.\n\nThe BAC BSI assay is able to identify more than 780\xa0bacteria and candida. The mean limit of detection for the assay is 39\xa0colony‑forming units/ml, with a range of 0.25\xa0to 128\xa0colony‑forming units/ml depending on the target species.\n\n# The comparators\n\nTwo comparators are included, blood culture alone and blood culture with MALDI‑TOF mass spectrometry:\n\nBlood culture alone refers to the incubation of whole blood followed by the identification of pathogens by traditional microbiology techniques.\n\nBlood culture with MALDI‑TOF mass spectrometry refers to the incubation of whole blood followed by the identification of pathogens using MALDI‑TOF mass spectrometry.', 'Outcomes': "The Diagnostics Advisory Committee (section\xa06) considered evidence from a number of sources (section\xa07). Full details of all the evidence are in the committee papers.\n\n# How outcomes were assessed\n\nThe assessment consisted of a systematic review of the evidence on test performance and clinical‑effectiveness data for the LightCycler SeptiFast Test MGRADE, SepsiTest and IRIDICA BAC BSI and comparator tests.\n\nStudies were included if they evaluated 1\xa0of the interventions, compared with either blood culture or blood culture with MALDI‑TOF mass spectrometry (MS), to analyse whole blood samples collected from people being treated for suspected sepsis. Studies that compared 1\xa0of the interventions with another intervention were also included. In total, 66\xa0studies met the inclusion criteria. Diagnostic‑accuracy data were reported in 62\xa0of the 66\xa0studies and were included in meta‑analyses, which were based on a bivariate normal model with Markov Chain Monte Carlo simulation. Inter‑study heterogeneity was explored using meta‑regression. Intermediate or clinical outcome measures were reported in 41\xa0of the 66\xa0studies and were included in a narrative analysis.\n\nSixty four of the 66\xa0studies were single‑index test, single‑gate studies, that is, studies in which only patients with the target condition (suspected sepsis) were recruited. Three of these 64\xa0studies were randomised controlled trials (RCTs). The remaining 2\xa0studies were single‑gate studies that reported results for both the LightCycler SeptiFast Test MGRADE and SepsiTest.\n\nOnly 3\xa0of the 66\xa0studies included patients from the UK. Most of the studies were done in other European countries. Of the studies that included patients from the UK, 1\xa0study (Dark et al. 2009) used the SeptiFast assay to test 50\xa0patients and 1\xa0other study (Vincent et al. 2015) used the IRIDICA assay to test 529\xa0patients from 6\xa0European countries. The third UK study (Warhurst et al. 2015) reported the use of SeptiFast in 795\xa0patients with sepsis and was judged to be the highest quality and most applicable included study.\n\nAll studies were assessed using the QUADAS‑2 tool. The results of 65\xa0of the 66\xa0studies were considered to be at risk of bias and may not be applicable to the decision problem. The issues of greatest uncertainty included patient selection and blinding to the index test or reference standard. The External Assessment Group also reported concerns about 21\xa0of the 66\xa0studies, which did not report whether the blood samples for the index test and reference standard were drawn at the same time, and 6\xa0of the 66\xa0studies, which used a mixture of reference standards. In addition, only 28\xa0of the 66\xa0studies reported using blood sampling and test methods that were in accordance with the company's instructions for use. Studies also reported different units of analysis for diagnostic‑accuracy data, such as per patient, per sample, per episode of sepsis, and species or pathogen level.\n\n# Diagnostic accuracy\n\nOf the 62\xa0studies that reported diagnostic‑accuracy data, 55\xa0reported data for the LightCycler SeptiFast Test MGRADE; 5\xa0reported data for SepsiTest; and 4\xa0reported data for the IRIDICA BAC BSI assay. Two of the 62\xa0studies that reported data for both the Light Cycler SeptiFast Test MGRADE and SepsiTest were counted as individual studies for each test.\n\n## LightCycler SeptiFast Test MGRADE\n\nThere were 54\xa0studies that compared the LightCycler SeptiFast Test MGRADE with blood culture and were combined in a meta‑analysis. The pooled estimate for sensitivity was 0.65 (95% credible interval [CrI]\xa00.60 to\xa00.71; 95% prediction interval\xa00.29 to\xa00.90) and for specificity was 0.86 (95% CrI\xa00.84 to\xa00.89; 95% prediction interval\xa00.62 to\xa00.96). The proportion of discordant results varied across studies from 6% to 46% (median 17%).\n\nOne study (Tafelski et al. 2015) compared the LightCycler SeptiFast Test MGRADE with blood culture plus MALDI‑TOF\xa0MS. It reported a sensitivity of 0.58 (95% confidence interval [CI]\xa00.30 to\xa00.86) and a specificity of 0.74 (95% CI\xa00.64 to\xa00.85).\n\nReasons for heterogeneity in sensitivity and specificity estimates between studies were explored using meta‑regression for clinically relevant variables. The following variables were explored:\n\nage (neonates and children)\n\nexposure to antibiotics before blood sample collection\n\nsuspected community- or healthcare‑acquired infection\n\nfebrile neutropenia\n\nstudies with inclusion or exclusion of contaminants.There was no evidence that sensitivity and specificity estimates were affected by these variables.\n\n## SepsiTest\n\nFour studies compared SepsiTest with blood culture and were combined in a meta‑analysis. The pooled estimate for sensitivity was 0.48 (95% CrI\xa00.21 to\xa00.74; 95% prediction interval\xa00.07 to\xa00.90) and for specificity was 0.86 (95% CrI\xa00.78 to\xa00.92; 95% prediction interval\xa00.66 to\xa00.95). The proportion of discordant results varied between studies and ranged from 14% to 26% (median 22%).\n\nOne study (Loonen et al. 2014) compared SepsiTest with blood culture plus MALDI‑TOF\xa0MS. The study reported a sensitivity of 0.11 (95% CI\xa00.00 to\xa00.23) and specificity of 0.96 (95% CI\xa00.92 to\xa01.00). No subgroup analyses were possible for the SepsiTest.\n\n## IRIDICA BAC BSI\n\nFour studies compared the IRIDICA BAC BSI assay with blood culture and were combined in a meta‑analysis. Two of these studies reported data using an earlier version of the IRIDICA PCR/ESI‑MS analyser known as the PLEX‑ID system, which has different desalter and mass spectrometry modules. The pooled estimate for sensitivity was 0.81 (95% CrI\xa00.69 to\xa00.90; 95% prediction interval\xa00.55 to\xa00.94) and for specificity was 0.84 (95% CrI\xa00.71 to\xa00.92; 95% prediction interval\xa00.50 to\xa00.96). The proportion of discordant results varied between studies and ranged from 7% to 30% (median 18%).\n\nNo studies compared the IRIDICA BAC BSI assay with blood culture plus MALDI‑TOF\xa0MS and no subgroup analyses were possible for this intervention.\n\n# Intermediate and clinical outcomes\n\nThere were 41\xa0studies included that reported data relating to the time to pathogen identification for the index test, time to treatment, test‑failure rate, mortality, duration of intensive care unit or hospital stay, duration of antibiotic therapy or reported changes in antimicrobial treatment plan. None of the included studies reported data on re‑admission rates, adverse events associated with broad‑spectrum antimicrobial use, morbidity, changes in disease severity over time, rates of superinfection, rates of resistant infection, or health‑related quality of life.\n\n## Light Cycler SeptiFast Test MGRADE\n\nThere were 37\xa0studies that reported data on intermediate and clinical outcomes for the LightCycler SeptiFast Test MGRADE. In addition, 1\xa0study (Schreiber et al. 2013) reported data for both the LightCycler SeptiFast Test MGRADE and SepsiTest. No studies compared the LightCycler SeptiFast Test MGRADE with the IRIDICA BAC BSI assay.\n\nThere were 21\xa0studies using the LightCycler SeptiFast Test MGRADE that reported turnaround times of a minimum of 4\xa0hours to a median of 26.25\xa0hours for pathogen identification. Some of these studies also reported the time for pathogen identification using blood cultures, which ranged from a turnaround time of a minimum of 24\xa0hours to a median of 80\xa0hours.\n\nTime-to-treatment change for the LightCycler SeptiFast Test MGRADE was reported in 3\xa0RCTs:\n\nTafelski et al. (2015) reported a mean time of 18.8\xa0hours (standard deviation [SD]\xa05.6) from taking the blood sample to changing treatment using the LightCycler SeptiFast Test MGRADE and a mean time of 38.3\xa0hours (SD\xa014.5) using blood culture and MALDI‑TOF\xa0MS.\n\nRodrigues et al. (2013) reported a mean time of 9.7\xa0hours from taking the blood sample to a change in treatment using the LightCycler SeptiFast Test MGRADE compared with a mean time of 50.1\xa0hours using blood culture (p=0.004).\n\nIdelevich et al. (2015) reported a mean time to changing treatment of 21.4\xa0hours (range 16.2 to 46.3\xa0hours) in the LightCycler SeptiFast Test MGRADE group compared with 47.5\xa0hours (range 7.3 to 59.2\xa0hours) in the blood culture group (p=0.018).\n\nThere were 7\xa0studies that reported test‑failure rates for the LightCycler SeptiFast Test MGRADE, which ranged from 1.5% to 24.2%. It is not clear why there is a large variation in failure rates between studies.\n\nDuration of stay in an intensive care unit, or hospital, or both were reported in 13\xa0studies that compared the LightCycler SeptiFast Test MGRADE with blood culture. In most of these studies, it was unclear if the duration of stay was recorded from before, during or after blood sampling. Also, most of the studies did not present comparative data. Of the 4\xa0studies that did report between group differences, 1\xa0study (Alvarez et al. 2012) reported a statistically significant difference (p<0.05) in intensive care unit and hospital duration of stay in favour of the LightCycler SeptiFast Test MGRADE. Three other studies (Idelevich et al. 2014; Mancini et al. 2014; Rodrigues et al. 2013) reported no significant difference in duration of stay.\n\nOne RCT (Tafelski et al. 2015) reported a duration of empirical antimicrobial therapy (antibiotics which are prescribed based on clinical presentation) of 18.8\xa0hours (SD\xa0±5.6) for patients in the LightCycler SeptiFast Test MGRADE group compared with 38.3\xa0hours (SD\xa0±14.5) for patients in the blood culture with MALDI‑TOF\xa0MS group.\n\nThere were 14\xa0studies that reported details of change in antimicrobial treatment, 10 of which did not report comparative data. Three studies compared the LightCycler SeptiFast Test MGRADE with blood culture. One RCT (Rodrigues et al. 2013) reported that therapy was adjusted for 35% of patients in the LightCycler SeptiFast Test MGRADE group compared with 24% of patients in the blood culture group. In contrast, a further RCT (Idelevich et al. 2015) reported that 9.5% of patients in the LightCycler SeptiFast Test MGRADE had an adjustment to therapy compared with 10.5% in the blood culture group. One study based on propensity score matching (Mancini et al. 2014) reported no differences in management.\n\nOne RCT (Tafelski et al. 2015) compared the LightCycler SeptiFast Test MGRADE with blood culture plus MALDI‑TOF\xa0MS. Testing with the LightCycler SeptiFast Test MGRADE resulted in a change of treatment for 9.8% of patients compared with 13.5% of patients in the blood culture plus MALDI‑TOF\xa0MS group.\n\nMortality data were reported in 17\xa0studies, 12 of which reported data on a cohort level only. The mortality rates reported ranged from 4% to 61%; but the length of follow‑up was highly variable across the studies. One study (Alvarez et al. 2012) reported no statistically significant differences between the LightCycler SeptiFast Test MGRADE and blood culture for both 28‑day and 6‑month mortality. One other study (Rodrigues et al. 2013) also reported no statistically significant difference in 28‑day mortality.\n\nOne propensity score matching study (Mancini et al. 2014) reported no statistically significant difference in mortality (p=0.39) between a prospective cohort (LightCycler SeptiFast Test MGRADE) and retrospective cohort (blood culture). Although, when more strict matching criteria were applied, the LightCycler SeptiFast Test MGRADE was associated with a statistically significant reduction in mortality (3.13% compared with 14.71%; p=0.04). A reduction in mortality associated with using the LightCycler SeptiFast Test MGRADE was reported in 2\xa0further studies (Idelevich et al. 2015; Tafelski et al. 2015), but the reductions were not statistically significant.\n\n## SepsiTest\n\nOne study (Loonen et al. 2014) reported a mortality rate of 3.2% for the study cohort but the duration of follow‑up was not reported. In addition, Schreiber et al. (2013) reported an intensive care unit mortality rate of 16% and a 28‑day mortality rate of 24% for the study cohort.\n\nNo other intermediate or clinical‑outcome data were reported for the SepsiTest.\n\n## IRIDICA BAC BSI\n\nOne study, which was unpublished at the time of guidance development, reported data relevant to test‑failure rates for the IRIDICA BAC BSI assay. These data are considered to be academic in confidence and cannot be reported at this time.\n\nOne study (Vincent et al. 2015) reported that an adjudication panel of 3\xa0clinical experts retrospectively recommended a change in management based on the IRIDICA BAC BSI assay for 41% of all patients. This increased to 57% of patients when the IRIDICA BAC BSI assay was positive and blood culture was negative.\n\nOne study (Vincent et al. 2015) reported a mortality rate of 29% for the study cohort, but did not report the duration of follow‑up.\n\n# Costs and cost effectiveness\n\nThe External Assessment Group conducted a search to identify studies investigating the cost effectiveness of the LightCycler SeptiFast Test MGRADE, SepsiTest or the IRIDICA BAC BSI assay. The External Assessment Group also constructed a conceptual economic model to determine the cost effectiveness of the technologies.\n\n## Systematic review of cost-effectiveness evidence\n\nFour studies were included and were assessed according to their relevance to the decision problem: 3\xa0studies included the LightCycler SeptiFast Test MGRADE, 2\xa0of which were within‑study cost‑minimisation analyses (that is, a cost‑minimisation analysis conducted within a clinical study), and 1\xa0was a cost‑effectiveness analysis. The remaining study included a cost‑minimisation analysis of the IRIDICA PLEX‑ID hybrid assay. The target population, condition and setting varied across the 4\xa0studies.\n\nThe 2\xa0studies that were within‑study cost‑minimisation analyses of using the LightCycler SeptiFast Test MGRADE when compared with blood culture reported cost savings of €178.75 per sample (Mancini et al. 2014) and €183.00 per patient (Alvarez et al. 2012). The third study, Lehmann et al. (2010), reported incremental cost‑effectiveness ratios (ICERs) of €11,477 per incremental survivor and €3,107 per quality‑adjusted life year (QALY) gained when using the LightCycler SeptiFast Test MGRADE compared with blood culture. When the use of an IRIDICA‑PLEX‑ID hybrid system was compared with blood culture, Bilkovski et al. (2014) reported cost savings of $1,123,372 per 422\xa0tests. None of the studies considered the effect of a potential reduction in antibiotic resistance. The External Assessment Group concluded that the existing economic evaluations had limited relevance to either the UK or the decision problem because of differences in patient populations, costs of the interventions and standard care. In particular, Mancini et al. (2014) included haematology patients for whom relatively expensive empirical antifungals were prescribed that are unlikely to be representative of the UK treatment pathway.\n\n## Economic analysis\n\nThe External Assessment Group developed a conceptual economic model designed to explore the cost effectiveness of the LightCycler SeptiFast Test MGRADE, SepsiTest and the IRIDICA BAC BSI assay. The population included in the model was hospitalised patients with suspected bloodstream infection.\n\nThe model comprised a decision tree with a lifetime time horizon and took the perspective of the NHS and personal social services. The key clinical outcomes included in the model were 30‑day mortality, duration of stay in intensive care unit, duration of hospital stay and antimicrobial treatment.\n\nData on the diagnostic accuracy of the interventions, intermediate outcomes and clinical outcomes were taken from the clinical‑effectiveness systematic review when possible. Expert opinion was also sought to populate key clinical outcomes and supplement the data available from the systematic review. Routine sources of costs and prevalence data were also used when appropriate. A discount rate of 3.5% per annum was applied to both costs and effects. The potential effect of the tests on antimicrobial stewardship was not included in the model, because there was insufficient evidence to show how the tests would affect antimicrobial use and the subsequent development of resistant organisms.\n\nThe incremental cost per test was calculated using the cost of the test, the net effect on duration of intensive care unit and hospital stay, and changes in the costs of antimicrobial treatment. The estimated cost per day for an intensive care unit bed was £1057 and for a general ward bed was £275. A course of empirical antimicrobial treatment was estimated to cost £350.\n\nIt was assumed that the cost per test was dependent upon both test throughput and whether laboratory equipment needed to be bought to use the tests. The range of technology costs included in the model were as follows:\n\nLightCycler SeptiFast Test MGRADE £153.67 to £205.54\n\nSepsiTest £108.30 to £149.53\n\nIRIDICA BAC BSI £197.35 to £314.61\n\nMALDI‑TOF\xa0MS £6.94 to £232.39.\n\nIncremental QALYs were calculated by assuming 11.32\xa0discounted QALYs per 30‑day mortality avoided, based on the estimated number of discounted life years for an adult patient with sepsis and the estimated quality of life after an episode of sepsis. The model assumed a mean age of 58\xa0years and that 60% of the cohort were male. Patients were assumed to have a utility value of 0.68 at 5\xa0years after an episode of severe sepsis (Cuthbertson et al. 2013) unless the utility value predicted for the age and sex profile of a patient in the general population was lower. In these instances, the lower utility value was applied.\n\n## Economic-analysis results\n\nFive deterministic analyses were done:\n\nBase case\xa01: interventions compared with blood culture, with clinical‑outcome data taken from the systematic review.\n\nBase case\xa02: interventions compared with blood culture, with clinical‑outcome estimates taken from expert opinion.\n\nThreshold analyses.\n\nInterventions compared with MALDI‑TOF\xa0MS.\n\nData taken from studies comparing more than 1\xa0intervention.\n\nThe following assumptions were common to all analyses:\n\nThe only parameter to affect QALY gain or loss was 30‑day mortality rate.\n\nNegative rapid tests did not affect any of the 4\xa0key outcomes.\n\nFailed rapid tests did not affect any of the 4\xa0key outcomes.\n\nIf 2.4\xa0tests per day were run, laboratories ran tests Monday to Friday only, with 3\xa0times the number of tests run on Monday to account for samples building up over a weekend.\n\nIf 17 or 68\xa0tests per day are run, laboratories did 3\xa0runs per day and worked 24\xa0hours a day, 7\xa0days a week.\n\nThe purchase cost of machines needed for the interventions and comparators was equally divided over 7\xa0years of use.\n\nIt was assumed that no additional staff costs or laboratory estate costs were incurred when using the interventions.\n\nThe time scale of testing was 1\xa0year although discounted QALYs accrued in subsequent years were included.\n\nIncremental QALYs were accrued through the number of avoided 30‑day mortalities.\n\nIf accuracy data from Warhurst et al. (2015) were used, the LightCycler SeptiFast Test MGRADE had a failure rate of 6.9%. A failure rate of 1.4% was assumed when pooled accuracy data was used.\n\nIRIDICA BAC BSI had a failure rate of 1.9%.\n\nSepsiTest had a failure rate of 0%.\n\nPatients were treated with either 18\xa0g per day of piperacillin/tazobactam or 3\xa0g per day of meropenem for 7\xa0days.\n\n‑day mortality rates were assumed to be either 13% or 29%.\n\nMALDI‑TOF\xa0MS was only used on positive samples (8.7% of all blood cultures).\n\nMALDI‑TOF\xa0MS had a sensitivity of 79.8% at species level compared with blood culture.\n\nLightCycler SeptiFast test MGRADE diagnostic-accuracy data were derived from Warhurst et al. (2015) unless otherwise specified.\n\nSepsiTest and IRIDICA BAC BSI diagnostic-accuracy data were derived from the External Assessment Group's meta‑analyses unless otherwise specified.\n\nIn this analysis, clinical‑outcome data from the clinical‑effectiveness review were included. This resulted in the assumption that there were no clinical benefits associated with the interventions for 30‑day mortality, duration of stay in the intensive care unit or duration of stay in hospital. The costs of antimicrobials were also unchanged in this analysis. All interventions were compared with blood culture only.\n\nThe results of the analysis showed that all the interventions were dominated by blood culture (that is, blood culture was less expensive and more effective than all of the interventions). Regardless of the test throughput assumed in different scenarios, the interventions remained dominated (more expensive with no additional clinical benefit) because of the lack of QALYs gained.\n\nIn addition, a threshold analysis was done for base case\xa01 to assess the reduction in antimicrobial costs that would be needed for each intervention to be cost neutral. The results suggested that the reductions needed would be 44% to 59% for the LightCycler SeptiFast Test MGRADE, 31% to 43% for the SepsiTest and 56% to 90% for the IRIDICA BAC BSI, although the rate of positive tests associated with each intervention suggested that their costs could not be offset solely by a reduction in antimicrobial therapy use.\n\nIn this analysis, the key clinical‑outcome parameters were populated using an average of estimated values provided by clinical experts. The External Assessment Group used these values in a range of scenarios that assumed a 30‑day mortality rate of either 13% or 29%, a throughput of 2.4, 17 or 68\xa0tests per day and a maximum acceptable ICER of £20,000 or £30,000 per QALY gained. The comparator used in this analysis was blood culture.\n\nFor each scenario, the net monetary benefit of each intervention was estimated. A positive net monetary benefit suggests that the benefits associated with the intervention outweigh the costs, and the intervention with the largest net monetary benefit is estimated to be the most cost effective. MALDI‑TOF\xa0MS was also included in the analysis to estimate the relative cost effectiveness between the 2\xa0comparators included in the assessment.\n\nIn all scenarios modelled, MALDI‑TOF\xa0MS produced a positive net benefit compared with blood culture. In 1\xa0scenario (30‑day mortality rate 13%, 2.4\xa0tests per day, maximum acceptable ICER of £20,000 per QALY gained), SepsiTest had the highest net monetary benefit when it was assumed that equipment to run the test had to be bought. In the same scenario, the IRIDICA BAC BSI assay had the highest net monetary benefit when only the test reagents and consumables were purchased. In all other modelled scenarios, the IRIDICA BAC BSI assay had the highest net monetary benefit.\n\nICERs were also calculated using the data from expert opinion. When it was assumed that no additional equipment had to be bought or the 30‑day mortality rate was 29%, the ICERs became more favourable because of either a decrease in incremental costs or an increase in incremental QALY gain.\n\nThe External Assessment Group also explored the effect of applying the pooled estimates of sensitivity and specificity from the meta‑analyses to the LightCycler SeptiFast Test MGRADE. This assumption produced more favourable ICERs for the LightCycler SeptiFast Test MGRADE through increasing the estimated sensitivity of the test (65% pooled estimate compared with 51% from Warhurst et al. 2015), while maintaining specificity at 86%.\n\nThe External Assessment Group used a range of threshold analyses to explore the effect of key clinical outcomes. In all analyses, it was assumed that the comparator equipment had already been bought but that the equipment for the interventions needed to be bought. The threshold levels resulting from the analyses, which assumed 2.4\xa0tests run per day and a maximum acceptable ICER of £20,000 per QALY gained, suggested reductions in 30‑day mortalities ranging from 0.09 to 0.14 per 100\xa0tests would be needed for the interventions to be considered cost effective compared with blood culture. Antimicrobial costs would need to reduce by £149.53 to £314.61 per 100\xa0tests. The results were similar when the interventions were compared with MALDI‑TOF\xa0MS. The threshold analyses that assumed either 17\xa0or 68\xa0tests run per day produced lower threshold values. The values of the reductions needed were also lower when a maximum acceptable ICER of £30,000 per QALY gained was assumed.\n\nThe External Assessment Group also explored the cost effectiveness of both the LightCycler SeptiFast Test MGRADE and SepsiTest compared with MALDI‑TOF\xa0MS, based on data from 2\xa0studies (Tafelski et al. 2015; Loonen et al. 2014) that used MALDI‑TOF\xa0MS in addition to blood culture. The effect estimates based on expert opinion were also included in the analysis. It was assumed that both interventions had a failure rate of 0% and that equipment to run the tests needed to be bought. The results of these analyses suggested that when compared with MALDI‑TOF\xa0MS (and blood culture), the LightCycler SeptiFast Test MGRADE dominated (less costly and more effective) MALDI‑TOF\xa0MS (and blood culture), and SepsiTest had ICERs ranging from £23,375 to £34,848 per QALY gained with a 30‑day mortality rate of 13% and from £10,479 to £15,621 per QALY gained with a 30‑day mortality rate of 29%.\n\nAn analysis was run using data from 2\xa0studies (Schreiber et al. 2013; Leitner et al. 2013), which evaluated both the LightCycler SeptiFast Test MGRADE and SepsiTest with blood culture. The analysis was done to compare the relative cost‑effectiveness estimates with those derived in base case\xa02 that were based on indirect comparisons of the relative effectiveness of the interventions from expert opinion. The analysis assumed a 0% test‑failure rate for both interventions and that equipment to run the tests needed to be bought. A range of scenarios were presented with 30‑day mortality rates of 13% or 29% and a throughput of 2.4, 17 or 68\xa0tests per day. In all scenarios, the ICER for the LightCycler SeptiFast Test MGRADE was greater than £30,000 per QALY gained when compared with SepsiTest.", 'Considerations': "The Diagnostics Advisory Committee reviewed the evidence available on the clinical and cost effectiveness of using the LightCycler SeptiFast Test MGRADE, SepsiTest and IRIDICA BAC BSI assay to rapidly identify bloodstream bacteria and fungi in people with a suspected bloodstream infection.\n\n# Clinical effectiveness\n\nThe Committee considered the evidence for the diagnostic accuracy of each of the rapid molecular tests compared with blood culture. It noted that 54\xa0studies reported data for the LightCycler SeptiFast Test MGRADE, 6\xa0of which included children or neonates, 4\xa0reported data for SepsiTest and 4\xa0reported data for the IRIDICA BAC BSI assay. The Committee noted that most of the included studies were considered to have unclear risks of bias, particularly about details of the reference standard and the populations included in the studies. The Committee considered that the unclear risk of bias was attributable to poor reporting in the studies, and concluded that it was not possible to adequately assess the quality of the studies included in the diagnostic accuracy meta‑analyses.\n\nThe Committee noted that 2\xa0studies compared either the LightCycler SeptiFast Test MGRADE or SepsiTest with MALDI‑TOF mass spectrometry (MS). It considered that both of these studies had relatively small sample sizes and it is likely that the results are not applicable to the UK because of differences in clinical practice in Europe, where the studies were done. The Committee concluded that there was insufficient evidence to establish either the diagnostic accuracy or the clinical utility of the rapid molecular tests against this comparator. Also, because of insufficient clinical data, the Committee concluded that there was too much uncertainty in the analyses for it to be confident that the rapid molecular tests would be cost effective compared with MALDI‑TOF\xa0MS.\n\nThe Committee questioned the assumption in the diagnostic accuracy meta‑analyses that blood culture is 100% accurate and noted that clinical specialists consider it to be an imperfect reference standard. It heard from the External Assessment Group that on this basis it was possible that the pooled estimates of sensitivity and specificity had been underestimated in the analysis, and so the rate of false positive and false negative results may also have been overestimated. The Committee discussed the reasons for false positive results with the rapid molecular tests. It noted that false positives may be real false positives in situations in which the rapid molecular test detects DNA from contaminant organisms in the blood sample which may result from the testing process. But it also heard from clinical specialists that it is possible that the rapid molecular tests may give more accurate results in some scenarios, such as the detection of fastidious organisms that may not grow in culture. The Committee also heard from clinical specialists that the rapid molecular tests may detect transient bacteraemia in some people, but that the clinical implications of this are not fully understood. It is possible that people may have extended courses of antibiotics and stay in hospital for longer if transient bacteraemia is detected. The Committee concluded that although the sensitivity and specificity may have been underestimated in the meta‑analyses, the absence of data on the clinical significance of discordant results means that the size of any underestimation cannot be determined.\n\nThe Committee discussed the number of positive blood cultures in the included diagnostic accuracy studies and their prevalence in clinical practice. It heard from clinical specialists that blood culture is often negative in practice, with only around 10% of blood cultures being positive. The Committee considered that the low prevalence of positive blood cultures was likely to mean that there would be a relatively low number of false negative rapid molecular test results in routine practice. Also, the absolute rate of false‑positive rapid molecular test results is likely to be high because of the greater prevalence of negative blood cultures. The Committee concluded that although the absolute number of false‑negative rapid molecular test results was likely to be low in practice, the consequences of changing antimicrobial treatment in this group could be severe.\n\nThe Committee discussed the studies included in the clinical‑outcomes systematic review. It noted that fewer studies reported clinical‑outcome data compared with diagnostic‑accuracy data, and that studies typically reported data for the LightCycler SeptiFast Test MGRADE only. The Committee noted that most of the studies were done in Europe or the USA and questioned the applicability of the clinical‑outcome studies to the UK. It heard from clinical specialists that although the treatment of sepsis is based on international guidelines, clinical outcomes such as duration of intensive care unit stay and duration of antimicrobial therapy cannot usually be applied to the UK from international studies because of differences in antibiotic prescribing practices. The Committee concluded that although the included studies provide some indication of the likely effect of the rapid molecular tests on clinical outcomes, additional UK‑based studies are needed to show the clinical utility of the tests in practice.\n\nThe Committee considered the test turnaround times reported in the studies and heard from clinical specialists that the shorter times seen in research studies are unlikely to be seen in routine clinical practice, unless a molecular service is available 24\xa0hours a day. It noted that 24‑hour services may become available if microbiology laboratories are joined into networks or centralised, but that this was unlikely to happen in the very near future. The Committee also noted that in some studies, the reported test‑failure rates for the LightCycler SeptiFast Test MGRADE were high (up to 24.2%) and considered that this could further affect its potential to rapidly deliver information for clinical decision‑making. The Committee questioned why the reported test‑failure rates were high in some studies but heard from the External Assessment Group that the reasons for the failed tests were not reported. The Committee concluded that faster reporting of results is highly dependent on laboratory infrastructure and that the turnaround times needed to gain benefits from the rapid molecular tests are unlikely to be achieved in routine practice.\n\nThe Committee considered the data for mortality and duration of intensive care unit or hospital stay and noted that the studies were unlikely to have had sufficient power to detect statistically significant differences for these clinical endpoints. The Committee also noted that most of the studies did not report statistically significant differences between the rapid molecular tests and standard practice. Also, it heard from clinical specialists that both mortality and duration of stay among people with suspected bloodstream infection are likely to be influenced by multiple factors, and that any differences are unlikely to be solely because of the use of a rapid molecular test. The Committee concluded that mortality and duration of stay may not be appropriate primary clinical outcomes for studies, and suggested that future studies should consider using change in antimicrobial prescribing as a surrogate clinical outcome.\n\nThe Committee discussed the plausibility of the rapid molecular tests having an effect on antimicrobial prescribing. It noted that the results of the clinical‑effectiveness analysis suggested that only small numbers of people, if any, would have changes made to their antimicrobial treatment plan. The Committee heard from clinical specialists that there may be some situations in which the rapid molecular tests could affect patient management. Also, it heard that these situations would be restricted to instances in which the rapid test was positive, because the current accuracy of the tests was not sufficient to convince clinicians to withdraw antibiotic therapy on the basis of a negative test result. The Committee concluded that although the rapid molecular tests might give results more quickly, it was unlikely that the information they give would have an effect on patients' treatment plans and antimicrobial prescribing at present.\n\n# Cost effectiveness\n\nThe Committee discussed the results of the economic analyses and questioned whether the use of an imperfect reference standard to calculate the estimates of diagnostic accuracy for the rapid molecular tests could have introduced bias. The Committee heard from the External Assessment Group that negative results were assumed not to have an effect on outcomes and that false‑positive results were associated with benefits in the model. The Committee concluded that any underestimate of pooled diagnostic accuracy in the clinical‑effectiveness analysis is unlikely to have a substantial effect on the results of the economic model.\n\nThe Committee questioned the assumptions made about the number of tests processed per day. It heard from clinical experts that the estimates based on 68\xa0tests per day were unrealistic and that a large service laboratory would be unlikely to get more than 40\xa0blood cultures per day. The Committee noted that the External Assessment Group had also produced estimates based on 2.4\xa0and 17\xa0tests per day. The Committee heard from the External Assessment Group that an assumption of 68\xa0tests per day was included as an extreme scenario to show the effect on the results of the economic analyses. The Committee concluded that the most representative scenarios in the economic analyses were those that assumed either 2.4 or 17\xa0tests per day.\n\nThe Committee discussed the differences in the results produced in the 2\xa0different base cases of the economic analyses. It noted that the main difference between the 2\xa0base cases came from the difference in data source for clinical outcomes: base case\xa01 used data taken from the systematic review, and base case\xa02 used data based on expert opinion. The Committee noted that the systematic review suggested that the rapid molecular tests had no effect on clinical outcomes, but some of the clinical experts thought that the tests may be beneficial, although their estimates of the size of the benefit varied widely. The Committee concluded that the tests may offer clinical benefit, but there is too much uncertainty in the size of the benefit to determine the effect of introducing the tests into clinical practice. The Committee also noted that the incremental cost‑effectiveness ratios (ICERs) in base case\xa02 ranged from the rapid molecular tests being more costly and equally effective (dominated) than blood culture, to being less costly and more effective (dominant) than blood culture alone, when using estimates from individual clinicians. The Committee considered that the wide range of ICERs resulted from the high level of variation between the clinicians' estimates. The Committee concluded that the effect of introducing the rapid molecular tests on NHS resources was highly uncertain and that the results of the economic analyses were subject to substantial uncertainty.\n\nThe Committee considered the likely effect of the costs and outcomes that had been excluded from the economic analyses and noted that these included laboratory overhead and additional staff costs, and clinical benefits that may be accrued through improved antimicrobial stewardship. The Committee noted that because the results of the clinical‑effectiveness analysis suggested that the effect of the rapid molecular tests on antimicrobial prescribing was highly uncertain, it would have been inappropriate to extrapolate the clinical outcomes to estimate an effect on antimicrobial stewardship. It also noted that the rapid molecular tests would most likely increase laboratory overhead costs, and possibly staff costs, and concluded that because of the clinical uncertainties their absence from the economic analyses was unlikely to have a substantial effect.\n\nThe Committee considered the results of the threshold analyses and noted the reductions in antimicrobial costs that would be needed for the tests to be considered cost effective. The Committee noted that this ranged from £823.34 to £1482.28 per 100\xa0positive tests, depending on whether the rapid molecular tests were compared with blood culture or blood culture plus MALDI‑TOF\xa0MS. The Committee concluded that because of the prevalence of positive tests in clinical practice, the costs of the rapid molecular tests were unlikely to be offset by reduced antimicrobial costs alone.\n\nThe Committee noted that the economic analyses did not include neonates and children, and that the model was based on an adult population with a mean age of 58\xa0years. The Committee considered that the estimated quality‑adjusted life year (QALY) gain by avoided 30‑day mortalities would be greater for children and neonates because of their greater number of life years remaining, but accepted that there were insufficient clinical‑utility data for this population for an economic analysis.\n\n# Additional considerations\n\nThe Committee considered the potential benefits of the interventions in practice. It heard from clinical experts that because the tests can be used directly on whole blood samples, they may be able to give information on a pathogen's identity earlier in the care pathway than tests that need incubated blood samples or samples from culture plates, which could be beneficial for antimicrobial stewardship. Also, it heard that the information from the rapid molecular tests may be used to modify a person's antimicrobial therapy, particularly when empirical antimicrobial therapy (antibiotics which are prescribed based on clinical presentation) has been prescribed. The Committee concluded that one of the key claimed benefits of the rapid molecular tests is their potential to contribute towards antimicrobial stewardship.\n\nThe Committee considered that because the rapid molecular tests need to be used in addition to blood culture for antimicrobial susceptibility testing, they may be less suitable for use in neonates and children. The Committee heard from clinical experts that this is a particular issue for tests that need a large volume of whole blood. The Committee also heard from clinical specialists that using a lower volume of blood from these patients for the molecular tests may have an adverse effect on the test's sensitivity and concluded that further exploration of these analytical issues should be encouraged.\n\n# Research considerations\n\nThe Committee discussed the value of developing research recommendations for the rapid molecular tests. The Committee considered that for the tests to have clinical utility in both research settings and routine practice, clinicians would need to be certain that the tests are sufficiently accurate, and be confident that basing antimicrobial prescribing decisions on the results of the tests would not lead to adverse outcomes for people. The Committee noted that the reported accuracy data from the systematic review were unlikely to be sufficient for clinical decision‑making at present. The Committee concluded that further research in the UK is needed to determine the clinical scenarios in which the tests may offer most benefit in clinical decision‑making and to quantify their clinical utility. The Committee also considered that future studies should investigate using the rapid molecular tests in conjunction with other biomarkers, such as procalcitonin, and diagnostic tests that may be used to assess people with suspected sepsis.\n\nThe Committee considered that, conceptually, the molecular tests show promise for the early identification of fungal pathogens in people who are thought to be at increased risk of developing invasive fungal infections. The Committee concluded that if the accuracy of the tests was sufficient to guide clinical decision‑making in this population, they could offer substantial value and address a clinically unmet need. The Committee encouraged future studies in this population and highlighted that the studies should aim to quantify the clinical utility of the rapid molecular tests, including their effect on antifungal prescribing. The Committee noted that studies planned by the National Institute for Health Research Health Technology Assessment Programme may investigate the use of rapid tests for identifying fungal pathogens.\n\nThe Committee considered the utility of further research to quantify the levels of certainty about the results of rapid molecular tests, which clinicians need to have before they decide to change treatment and level of care for patients. The Committee noted that the results of an elicitation exercise could be used to guide the development of future diagnostic tests that are designed to be used to change treatment plans for patients who are acutely unwell, and wished to encourage this research.\n\nThe Committee considered that because an increasing number of microbiology laboratories are adopting MALDI‑TOF\xa0MS for rapidly identifying bloodstream bacteria and fungi, future studies aiming to establish the clinical utility of rapid molecular tests should include this technology as a comparator when possible.\n\nThe Committee noted that there was insufficient evidence to determine whether the tests were clinically effective in children and neonates. It wished to encourage the inclusion of these populations in future research studies, and noted that particular consideration should be given to establishing whether the blood volumes needed for the tests in this assessment are suitable for these populations."}
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https://www.nice.org.uk/guidance/dg20
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Evidence-based recommendations on the SepsiTest assay for rapidly identifying bloodstream bacteria and fungi.
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075e4c1b24e38ad76abd9341015bb57723bd5c86
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nice
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Peginterferon beta-1a for treating relapsing–remitting multiple sclerosis
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Peginterferon beta-1a for treating relapsing–remitting multiple sclerosis
Evidence-based recommendations on peginterferon beta‑1a (Plegridy) for treating relapsing–remitting multiple sclerosis in adults.
# Recommendations
Peginterferon beta‑1a is recommended, within its marketing authorisation, as an option for treating relapsing–remitting multiple sclerosis in adults.
Why the committee made these recommendations
Peginterferon beta‑1a is an established drug for relapsing–remitting multiple sclerosis. There is clinical trial evidence showing that the drug slows disease progression and reduces the frequency of relapses when compared with placebo. There is also an indirect comparison suggesting that there are no differences in effectiveness when comparing peginterferon beta‑1a with its main comparators, that is, other beta interferons and glatiramer acetate. However, it involves less frequent injections than other beta interferons, so improves choice for people with relapsing–remitting multiple sclerosis.
The cost-effectiveness estimates for peginterferon beta‑1a compared with other treatments for relapsing–remitting multiple sclerosis, such as other beta interferons and glatiramer acetate, are in line with what NICE usually considers a cost-effective use of NHS resources. Therefore, peginterferon beta‑1a can be recommended.# Information about peginterferon beta-1a
# Marketing authorisation indication
Peginterferon beta‑1a (Plegridy, Biogen Idec Ltd) has been licensed since 2014 'in adult patients for the treatment of relapsing remitting multiple sclerosis'.
# Dosage in the marketing authorisation
Peginterferon beta‑1a is given by subcutaneous injection every 2 weeks at a dose of 125 micrograms.
# Price
The list price for peginterferon beta‑1a is £654.00 per 2 pre-filled pens, each containing 125 micrograms (excluding VAT, BNF online, November 2019). Costs may vary in different settings because of negotiated procurement discounts.# Committee discussion
The appraisal committee considered evidence submitted by Biogen, a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.
The committee was aware that several issues were resolved during the technical engagement stage. It agreed that the company had adequately justified some discrepancies in the company submission (both between the clinical- and cost-effectiveness sections, and when compared with previous appraisals).
The committee recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, table 2, page 36), and took these into account in its decision making. It discussed the following issues, which were outstanding after the technical engagement stage:
issue 1: the population and appropriateness of comparators
issue 2: the minimum clinically significant reduction in outcome measures
issue 3: the generalisability of the ADVANCE trial population
issue 5: treatment waning
issue 6: stopping treatment for any reason
issue 7: the utility values.
# Treatment pathway
## Any relapse can affect people with relapsing–remitting multiple sclerosis and is clinically significant
Relapsing–remitting multiple sclerosis is a chronic, disabling, lifelong neurological condition. People with the condition can have episodes of relapse, in which the symptoms worsen, followed by remission. However, over time, relapses result in worsening disability. The condition is associated with signs and symptoms such as pain, disturbance to muscle tone, chronic fatigue, unsteady gait, speech problems, incontinence, visual disturbance and cognitive impairment. The committee noted that reducing the frequency of relapses was a key outcome for people with the condition. It considered whether there was a clinically meaningful reduction in the number of relapses. The patient and clinical experts explained that even 1 mild relapse can be devastating and can affect a person's family life and career. The committee concluded that any reduction in relapse was clinically significant.
## Peginterferon beta-1a would most likely be offered first line or as an alternative first-line treatment when other options are not tolerated
Peginterferon beta‑1a has been commissioned by NHS England since 2015 for people with relapsing–remitting multiple sclerosis as a first-line treatment or as an alternative when other first-line treatments are not tolerated. The committee noted that the licence is broader than this because it does not restrict peginterferon beta‑1a to a particular line of therapy. It considered whether peginterferon beta‑1a would also be of value in the more severe subgroups of 'highly active' and 'rapidly evolving severe' multiple sclerosis. The patient and clinical experts explained that peginterferon beta‑1a would continue to be used primarily as a first-line treatment or as an alternative when other first-line treatments are not tolerated. They said that it would not be their first choice of treatment for people with more severe forms of relapsing–remitting multiple sclerosis. However, they stated that, in clinical practice, multiple sclerosis does not lend itself to such clear categorisation. They also noted that patient choice is an important aspect of the treatment pathway, so they would not want to exclude use of peginterferon beta‑1a later in the treatment pathway. For example, some people with more severe disease might prefer peginterferon beta‑1a than other options if they were better able to tolerate it. The committee concluded that, in clinical practice, peginterferon beta‑1a would likely continue to be used primarily as a first-line treatment or as an alternative when other first-line treatments are not tolerated. However, given the importance of patient choice, it agreed that any recommendation should not explicitly comment on its use later in the treatment pathway.
## Other beta interferons and glatiramer acetate are the most relevant comparators
At the time of the committee discussion (November 2019), peginterferon beta‑1a was already commissioned by NHS England as a first-line treatment option along with other beta interferons, dimethyl fumarate, glatiramer acetate, teriflunomide, alemtuzumab and ocrelizumab. The clinical experts explained that, of these, other beta interferons and glatiramer acetate were the most relevant comparators. Alemtuzumab and ocrelizumab are more active immunosuppressant treatments with a higher chance of more serious adverse effects, so would typically be used later in the treatment pathway. Also, as of November 2019, the Committee for Medicinal Products for Human Use recommended that the use of alemtuzumab should be restricted to 'relapsing–remitting multiple sclerosis that is highly active despite adequate treatment with at least one disease-modifying therapy or if the disease is worsening rapidly with at least two disabling relapses in a year and brain-imaging showing new damage'. The committee concluded that alemtuzumab and ocrelizumab were not relevant comparators at the place in the pathway where people were most likely to use peginterferon beta‑1a.
## Peginterferon beta-1a offers a less frequent dosing schedule, helping with patient choice
The committee considered how people would choose between the several beta interferons available. The patient and clinical experts explained that, if a treatment with 1 beta interferon had failed, another would not typically be offered. They stated that peginterferon beta‑1a is not considered to be more effective than other beta interferons but has a less frequent dosing schedule. It is administered twice monthly, whereas other beta interferons may need to be administered as often as 3 times a week. The clinical experts stated that people were less likely to develop neutralising antibodies with peginterferon beta‑1a than with other interferons. However, the committee was not shown data to support this and questioned its relevance. One clinical expert explained that, when offering a choice of treatments, clinicians generally remain neutral to allow people to choose the best treatment for their lifestyle. For example, some people prefer the reduced dosing schedule of peginterferon beta‑1a, whereas others, such as those with cognitive issues affecting memory, might prefer a more frequent, regular schedule. The committee concluded that the availability of peginterferon beta‑1a increased patient choice.
# Clinical effectiveness
## The ADVANCE trial has issues with generalisability, but is appropriate for decision making
The company presented the evidence for peginterferon beta‑1a from:
ADVANCE, a phase 3 double-blind randomised placebo-controlled trial and
ATTAIN, a 2‑year blinded follow-up study (of peginterferon beta‑1a only; all people in the placebo arm of ADVANCE switched to peginterferon beta‑1a after 1 year).The ADVANCE trial recruited patients mainly from the eastern European region, and included only 8% from western Europe (of which 14 patients were from the UK). The ERG explained that there were some numerical differences in effectiveness across regions, with region 1 (which included the UK) performing the worst. However, the company stated that it did not find statistical interaction by region. The patient and clinical experts explained that any patients from the UK in the trial were likely not typical of those seen in NHS clinical practice. This was because, given the many active treatments available on the NHS, there would be little incentive for people with multiple sclerosis to join a placebo-controlled trial. Also, there may be differences in clinical practice, treatments and standard of care across regions. The committee agreed that all these factors raised questions around how representative the trial would be of a UK population. However, it noted that most patients in the trial were treatment naive (the expected place in the treatment pathway for peginterferon beta‑1a). It also noted that, if there were any differences in the population, this was unlikely to have had an impact on the treatment effect of peginterferon beta‑1a compared with placebo. The committee concluded that it had minor concerns about the generalisability of the ADVANCE and ATTAIN trials. However, overall, it considered that they were appropriate for decision making.
## It is disappointing that there is no evidence to help address gaps in evidence on areas such as generalisability, treatment waning and stopping treatment
Given its concerns about generalisability, the committee considered whether there was any pharmacoepidemiologic evidence available from current use of peginterferon beta‑1a in the NHS. The company explained that, of around 12,000 people in the UK currently using injectable treatments for relapsing–remitting multiple sclerosis, about 1,400 use peginterferon beta‑1a. The committee stated that, if the company had provided data on these patients, it would have helped inform evidence gaps in areas such as generalisability (see section 3.5), stopping treatment (see section 3.13) and treatment waning (see section 3.14). It was disappointed that it had not been presented with this evidence, which could have helped to address these evidence gaps.
## Peginterferon beta-1a is clinically effective when compared with placebo
In ADVANCE, there were statistically significant (p<0.05) improvements with peginterferon beta‑1a compared with placebo for the primary outcome (annualised relapse rate) and several important secondary outcomes, including disability progression sustained for 3 or 6 months:
annualised relapse rate: rate ratio 0.64 (0.50 to 0.83; p=0.0007)
confirmed disability progression at 3 months: hazard ratio 0.62 (0.40 to 0.97; p=0.04)
confirmed disability progression at 6 months: hazard ratio 0.46 (0.26 to 0.81; p=0.007).The committee agreed that there had been improvements in important outcomes such as relapse frequency when compared with placebo. It also noted its previous conclusion that any reduction in the frequency of relapses was clinically significant (see section 3.1). The committee concluded that peginterferon beta‑1a was both a clinically and statistically significantly effective treatment when compared with placebo.
## Peginterferon beta-1a does not appear to be more effective than its main comparators in an indirect comparison with active treatments
Because there was no direct trial evidence comparing peginterferon beta‑1a with active comparators, the company also conducted indirect analyses comparing it with the other beta interferons, dimethyl fumarate, glatiramer acetate, teriflunomide, alemtuzumab and ocrelizumab. Several of the results are academic in confidence and cannot be presented here. However, overall, the committee concluded that there were no statistically significant differences for peginterferon beta‑1a compared with its main comparators (that is, other beta interferons and glatiramer acetate).
# Adverse events
## Peginterferon beta-1a is an established treatment with a well-known side effect profile
The patient and clinical experts explained that the most common adverse events were injection-site reactions and flu-like symptoms. Although these could sometimes be severe, they were generally mild to moderate and easily treatable with common analgesics such as paracetamol and ibuprofen. The experts were not aware of any differences in adverse effects between the beta interferons. The committee concluded that peginterferon beta‑1a is an established treatment with a well-known side effect profile.
# The company's economic model
## The company's economic model structure is appropriate for decision making
The company estimated disease progression in the model using 21 health states. It defined these using Expanded Disability Status Scale (EDSS) scores ranging from 0 to 9.5 (with a higher score indicating worse disease) and either relapsing–remitting or secondary progressive multiple sclerosis, plus a death state. In each cycle of the model, a patient with relapsing–remitting multiple sclerosis could move to a higher or lower EDSS state (that is, their disability could worsen or improve) or remain in the same state. The disease could also advance from relapsing–remitting multiple sclerosis to secondary progressive multiple sclerosis but could not then move back to relapsing–remitting disease. The clinical experts explained that it was not realistic to assume that patients could not improve from secondary progressive to relapsing–remitting multiple sclerosis. Also, the company assumed that, once treatment with peginterferon beta‑1a stopped, a patient's condition followed the untreated natural history of the disease. However, in clinical practice, people would have several other treatments to choose from. The company stated it had chosen not to include any treatment sequencing because it could have biased the model, making it unclear whether any observed treatment effect was coming from the main intervention or the next line of treatment. The committee agreed with this approach. It noted that the overall structure of the company's model was similar to models used in previous NICE technology appraisals for the first-line treatment of relapsing–remitting multiple sclerosis. The committee concluded that the structure of the company's economic model was appropriate for decision making.
## The baseline population should be based on the multiple sclerosis risk sharing scheme
The company used the characteristics of patients in the ADVANCE trial to reflect the baseline population in the model. The committee discussed whether ADVANCE was the most appropriate source, given its earlier minor concerns that there were issues with generalisability in the trial (see section 3.5). It was aware that models in some previous appraisals for this disease area had used the multiple sclerosis risk sharing scheme (RSS) as the source for its baseline population. The RSS collected data for more than 5,000 patients in the NHS for over 10 years. The committee agreed that this population in the RSS was more generalisable to the NHS than the population in ADVANCE. It concluded that it would have preferred that the model baseline characteristics had been based on the RSS.
# Utility values in the economic model
## Utility values are a source of uncertainty in the model
The company used utility values from Orme et al. (2007) for consistency with previous technology appraisals. It also provided utility values from a more recent study, Thompson et al. (2017). The ERG provided a scenario analysis using Thompson et al. (2017). The committee noted that the utility values in both Thompson et al. and Orme et al. were very similar. However, it noted that there were substantial differences in the quality-adjusted life years generated by the deterministic and probabilistic models. This was unusual and could suggest that there may have been an issue with the underlying utility values used in the model. The committee discussed whether it could identify any underlying problems with the utility values. The company did not adjust utility values to worsen with age, which the committee agreed was unrealistic. It also noted that older people were more likely to be in a higher EDSS score group in the model (in which higher EDSS scores were associated with a worse utility value), and that the Orme et al. and Thompson et al. studies differed with respect to age, which could have led to different model predictions. The committee agreed that, because the utility values seemed to be a key driver of cost effectiveness in the model, the company should have explored this more thoroughly, for example, by using values derived from a meta-analysis. The committee concluded that the utility values were a source of uncertainty in the cost-effectiveness results.
# Assumptions in the economic model
## There is a lack of robust data about the individual stopping rules
The company applied a probability of stopping treatment for any reason in its base-case analysis. It used the annualised stopping rates from 18 trials. It weighted these based on sample size to derive the risk of stopping treatment for any reason for each disease-modifying therapy. The ERG considered that deriving the stopping risk weighted by person time would be more appropriate than using the trial sample size. This was because an annualised stopping rate would not capture changes over time. The company accepted this correction. However, the ERG stated that it would have preferred the use of a 5% stopping rule across all treatments, which was derived from the multiple sclerosis RSS. The committee agreed that it was more likely that different treatments would have different stopping rates. It also noted that data on treatment-specific stopping rates in the UK should be available because they are recorded electronically on NHS payment systems. It was disappointed that these had not been presented. The committee concluded that, in the absence of the actual data, it was more plausible to assume a treatment-specific rate than a flat rate.
## The treatment effect waning cannot be estimated precisely because of a lack of evidence
The company assumed in the model that the treatment effect of all treatments waned over time, and all at the same rate:
years 1 and 2: no waning
years 3 to 5: 75% of full treatment effect
year 6 onwards: 50% of full treatment effect.The clinical experts stated that most treatments for multiple sclerosis become less effective over time. This is either because the person's immune system develops neutralising antibodies, or because the condition worsens and becomes resistant to treatment. It was unclear whether the treatment effect waning with peginterferon beta‑1a would differ from other treatments. The committee noted that peginterferon beta‑1a is an established treatment and that data on treatment effect waning could have been collated. However, the company had not attempted to analyse whether the treatment effect of peginterferon beta‑1a changed over time, which left an important gap in the evidence. The committee concluded that it was appropriate to include some treatment effect waning in the model, and that it would have been more plausible to assume treatment-specific rates rather than a constant rate. However, the committee noted that varying this assumption (that is, using a constant rate for all treatments, or varying the rate by treatment) did not substantially affect cost-effectiveness results. Because of this, the committee accepted the company's base-case assumption.
# ERG's changes to the assumptions in the economic model
## Both the company and ERG's cost-effectiveness results are considered in the decision making
The ERG made several changes to the company's base case. It stated that the most important of these were:
changing the treatment-specific stopping rates to a flat rate of 5% from the multiple sclerosis RSS (because it considered these data more informative than trial data for the outcome of stopping treatment) and
the source of decrements in the utility of caregivers (because its preferred source assumed utility decrements rose with worsening health state).The committee agreed with some, but not all, of the ERG's changes. For example, it agreed that caregiver utility decrements should rise with worsening EDSS health state, and that the company should have used the baseline population from the RSS rather than the trial. However, it disagreed that it was more plausible to assume a constant stopping rate for all treatments than a treatment-specific rate. The committee concluded it would take into account the various company and ERG base cases and scenarios in its decision making.
# Cost-effectiveness estimate
## Peginterferon beta-1a is an established NHS treatment and a cost-effective use of NHS resources
The committee agreed that enough evidence had been presented to consider the cost effectiveness of peginterferon beta‑1a. However, given the number of years that peginterferon beta‑1a has been an established treatment in the NHS, it was disappointed that the company had not provided data reflecting the experience with peginterferon beta‑1a in NHS practice. These data would have helped to address uncertainty in the model, including for stopping rates and treatment waning. The ERG and company presented a number of exploratory analyses that, in part, helped to reduce some of these uncertainties. Results of all these analyses suggested that the incremental cost-effectiveness results of peginterferon beta‑1a were in the range that NICE normally considers a cost-effective use of NHS resources. The results are commercial in confidence because of confidential comparator patient access schemes, so cannot be reported here.
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{'Recommendations': 'Peginterferon beta‑1a is recommended, within its marketing authorisation, as an option for treating relapsing–remitting multiple sclerosis in adults.\n\nWhy the committee made these recommendations\n\nPeginterferon beta‑1a is an established drug for relapsing–remitting multiple sclerosis. There is clinical trial evidence showing that the drug slows disease progression and reduces the frequency of relapses when compared with placebo. There is also an indirect comparison suggesting that there are no differences in effectiveness when comparing peginterferon beta‑1a with its main comparators, that is, other beta interferons and glatiramer acetate. However, it involves less frequent injections than other beta interferons, so improves choice for people with relapsing–remitting multiple sclerosis.\n\nThe cost-effectiveness estimates for peginterferon beta‑1a compared with other treatments for relapsing–remitting multiple sclerosis, such as other beta interferons and glatiramer acetate, are in line with what NICE usually considers a cost-effective use of NHS resources. Therefore, peginterferon beta‑1a can be recommended.', 'Information about peginterferon beta-1a': "# Marketing authorisation indication\n\nPeginterferon beta‑1a (Plegridy, Biogen Idec Ltd) has been licensed since 2014 'in adult patients for the treatment of relapsing remitting multiple sclerosis'.\n\n# Dosage in the marketing authorisation\n\nPeginterferon beta‑1a is given by subcutaneous injection every 2\xa0weeks at a dose of 125\xa0micrograms.\n\n# Price\n\nThe list price for peginterferon beta‑1a is £654.00 per 2\xa0pre-filled pens, each containing 125\xa0micrograms (excluding VAT, BNF online, November 2019). Costs may vary in different settings because of negotiated procurement discounts.", 'Committee discussion': "The appraisal committee considered evidence submitted by Biogen, a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.\n\nThe committee was aware that several issues were resolved during the technical engagement stage. It agreed that the company had adequately justified some discrepancies in the company submission (both between the clinical- and cost-effectiveness sections, and when compared with previous appraisals).\n\nThe committee recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, table\xa02, page 36), and took these into account in its decision making. It discussed the following issues, which were outstanding after the technical engagement stage:\n\nissue\xa01: the population and appropriateness of comparators\n\nissue\xa02: the minimum clinically significant reduction in outcome measures\n\nissue\xa03: the generalisability of the ADVANCE trial population\n\nissue\xa05: treatment waning\n\nissue\xa06: stopping treatment for any reason\n\nissue\xa07: the utility values.\n\n# Treatment pathway\n\n## Any relapse can affect people with relapsing–remitting multiple sclerosis and is clinically significant\n\nRelapsing–remitting multiple sclerosis is a chronic, disabling, lifelong neurological condition. People with the condition can have episodes of relapse, in which the symptoms worsen, followed by remission. However, over time, relapses result in worsening disability. The condition is associated with signs and symptoms such as pain, disturbance to muscle tone, chronic fatigue, unsteady gait, speech problems, incontinence, visual disturbance and cognitive impairment. The committee noted that reducing the frequency of relapses was a key outcome for people with the condition. It considered whether there was a clinically meaningful reduction in the number of relapses. The patient and clinical experts explained that even 1\xa0mild relapse can be devastating and can affect a person's family life and career. The committee concluded that any reduction in relapse was clinically significant.\n\n## Peginterferon beta-1a would most likely be offered first line or as an alternative first-line treatment when other options are not tolerated\n\nPeginterferon beta‑1a has been commissioned by NHS England since 2015 for people with relapsing–remitting multiple sclerosis as a first-line treatment or as an alternative when other first-line treatments are not tolerated. The committee noted that the licence is broader than this because it does not restrict peginterferon beta‑1a to a particular line of therapy. It considered whether peginterferon beta‑1a would also be of value in the more severe subgroups of 'highly active' and 'rapidly evolving severe' multiple sclerosis. The patient and clinical experts explained that peginterferon beta‑1a would continue to be used primarily as a first-line treatment or as an alternative when other first-line treatments are not tolerated. They said that it would not be their first choice of treatment for people with more severe forms of relapsing–remitting multiple sclerosis. However, they stated that, in clinical practice, multiple sclerosis does not lend itself to such clear categorisation. They also noted that patient choice is an important aspect of the treatment pathway, so they would not want to exclude use of peginterferon beta‑1a later in the treatment pathway. For example, some people with more severe disease might prefer peginterferon beta‑1a than other options if they were better able to tolerate it. The committee concluded that, in clinical practice, peginterferon beta‑1a would likely continue to be used primarily as a first-line treatment or as an alternative when other first-line treatments are not tolerated. However, given the importance of patient choice, it agreed that any recommendation should not explicitly comment on its use later in the treatment pathway.\n\n## Other beta interferons and glatiramer acetate are the most relevant comparators\n\nAt the time of the committee discussion (November 2019), peginterferon beta‑1a was already commissioned by NHS England as a first-line treatment option along with other beta interferons, dimethyl fumarate, glatiramer acetate, teriflunomide, alemtuzumab and ocrelizumab. The clinical experts explained that, of these, other beta interferons and glatiramer acetate were the most relevant comparators. Alemtuzumab and ocrelizumab are more active immunosuppressant treatments with a higher chance of more serious adverse effects, so would typically be used later in the treatment pathway. Also, as of November 2019, the Committee for Medicinal Products for Human Use recommended that the use of alemtuzumab should be restricted to 'relapsing–remitting multiple sclerosis that is highly active despite adequate treatment with at least one disease-modifying therapy or if the disease is worsening rapidly with at least two disabling relapses in a year and brain-imaging showing new damage'. The committee concluded that alemtuzumab and ocrelizumab were not relevant comparators at the place in the pathway where people were most likely to use peginterferon beta‑1a.\n\n## Peginterferon beta-1a offers a less frequent dosing schedule, helping with patient choice\n\nThe committee considered how people would choose between the several beta interferons available. The patient and clinical experts explained that, if a treatment with 1\xa0beta interferon had failed, another would not typically be offered. They stated that peginterferon beta‑1a is not considered to be more effective than other beta interferons but has a less frequent dosing schedule. It is administered twice monthly, whereas other beta interferons may need to be administered as often as 3\xa0times a week. The clinical experts stated that people were less likely to develop neutralising antibodies with peginterferon beta‑1a than with other interferons. However, the committee was not shown data to support this and questioned its relevance. One clinical expert explained that, when offering a choice of treatments, clinicians generally remain neutral to allow people to choose the best treatment for their lifestyle. For example, some people prefer the reduced dosing schedule of peginterferon beta‑1a, whereas others, such as those with cognitive issues affecting memory, might prefer a more frequent, regular schedule. The committee concluded that the availability of peginterferon beta‑1a increased patient choice.\n\n# Clinical effectiveness\n\n## The ADVANCE trial has issues with generalisability, but is appropriate for decision making\n\nThe company presented the evidence for peginterferon beta‑1a from:\n\nADVANCE, a phase\xa03 double-blind randomised placebo-controlled trial and\n\nATTAIN, a 2‑year blinded follow-up study (of peginterferon beta‑1a only; all people in the placebo arm of ADVANCE switched to peginterferon beta‑1a after 1\xa0year).The ADVANCE trial recruited patients mainly from the eastern European region, and included only 8% from western Europe (of which 14\xa0patients were from the UK). The ERG explained that there were some numerical differences in effectiveness across regions, with region\xa01 (which included the UK) performing the worst. However, the company stated that it did not find statistical interaction by region. The patient and clinical experts explained that any patients from the UK in the trial were likely not typical of those seen in NHS clinical practice. This was because, given the many active treatments available on the NHS, there would be little incentive for people with multiple sclerosis to join a placebo-controlled trial. Also, there may be differences in clinical practice, treatments and standard of care across regions. The committee agreed that all these factors raised questions around how representative the trial would be of a UK population. However, it noted that most patients in the trial were treatment naive (the expected place in the treatment pathway for peginterferon beta‑1a). It also noted that, if there were any differences in the population, this was unlikely to have had an impact on the treatment effect of peginterferon beta‑1a compared with placebo. The committee concluded that it had minor concerns about the generalisability of the ADVANCE and ATTAIN trials. However, overall, it considered that they were appropriate for decision making.\n\n## It is disappointing that there is no evidence to help address gaps in evidence on areas such as generalisability, treatment waning and stopping treatment\n\nGiven its concerns about generalisability, the committee considered whether there was any pharmacoepidemiologic evidence available from current use of peginterferon beta‑1a in the NHS. The company explained that, of around 12,000 people in the UK currently using injectable treatments for relapsing–remitting multiple sclerosis, about 1,400 use peginterferon beta‑1a. The committee stated that, if the company had provided data on these patients, it would have helped inform evidence gaps in areas such as generalisability (see section\xa03.5), stopping treatment (see section\xa03.13) and treatment waning (see section\xa03.14). It was disappointed that it had not been presented with this evidence, which could have helped to address these evidence gaps.\n\n## Peginterferon beta-1a is clinically effective when compared with placebo\n\nIn ADVANCE, there were statistically significant (p<0.05) improvements with peginterferon beta‑1a compared with placebo for the primary outcome (annualised relapse rate) and several important secondary outcomes, including disability progression sustained for 3\xa0or 6\xa0months:\n\nannualised relapse rate: rate ratio 0.64 (0.50 to 0.83; p=0.0007)\n\nconfirmed disability progression at 3\xa0months: hazard ratio 0.62 (0.40 to 0.97; p=0.04)\n\nconfirmed disability progression at 6\xa0months: hazard ratio 0.46 (0.26 to 0.81; p=0.007).The committee agreed that there had been improvements in important outcomes such as relapse frequency when compared with placebo. It also noted its previous conclusion that any reduction in the frequency of relapses was clinically significant (see section\xa03.1). The committee concluded that peginterferon beta‑1a was both a clinically and statistically significantly effective treatment when compared with placebo.\n\n## Peginterferon beta-1a does not appear to be more effective than its main comparators in an indirect comparison with active treatments\n\nBecause there was no direct trial evidence comparing peginterferon beta‑1a with active comparators, the company also conducted indirect analyses comparing it with the other beta interferons, dimethyl fumarate, glatiramer acetate, teriflunomide, alemtuzumab and ocrelizumab. Several of the results are academic in confidence and cannot be presented here. However, overall, the committee concluded that there were no statistically significant differences for peginterferon beta‑1a compared with its main comparators (that is, other beta interferons and glatiramer acetate).\n\n# Adverse events\n\n## Peginterferon beta-1a is an established treatment with a well-known side effect profile\n\nThe patient and clinical experts explained that the most common adverse events were injection-site reactions and flu-like symptoms. Although these could sometimes be severe, they were generally mild to moderate and easily treatable with common analgesics such as paracetamol and ibuprofen. The experts were not aware of any differences in adverse effects between the beta interferons. The committee concluded that peginterferon beta‑1a is an established treatment with a well-known side effect profile.\n\n# The company's economic model\n\n## The company's economic model structure is appropriate for decision making\n\nThe company estimated disease progression in the model using 21\xa0health states. It defined these using Expanded Disability Status Scale (EDSS) scores ranging from 0\xa0to\xa09.5 (with a higher score indicating worse disease) and either relapsing–remitting or secondary progressive multiple sclerosis, plus a death state. In each cycle of the model, a patient with relapsing–remitting multiple sclerosis could move to a higher or lower EDSS state (that is, their disability could worsen or improve) or remain in the same state. The disease could also advance from relapsing–remitting multiple sclerosis to secondary progressive multiple sclerosis but could not then move back to relapsing–remitting disease. The clinical experts explained that it was not realistic to assume that patients could not improve from secondary progressive to relapsing–remitting multiple sclerosis. Also, the company assumed that, once treatment with peginterferon beta‑1a stopped, a patient's condition followed the untreated natural history of the disease. However, in clinical practice, people would have several other treatments to choose from. The company stated it had chosen not to include any treatment sequencing because it could have biased the model, making it unclear whether any observed treatment effect was coming from the main intervention or the next line of treatment. The committee agreed with this approach. It noted that the overall structure of the company's model was similar to models used in previous NICE technology appraisals for the first-line treatment of relapsing–remitting multiple sclerosis. The committee concluded that the structure of the company's economic model was appropriate for decision making.\n\n## The baseline population should be based on the multiple sclerosis risk sharing scheme\n\nThe company used the characteristics of patients in the ADVANCE trial to reflect the baseline population in the model. The committee discussed whether ADVANCE was the most appropriate source, given its earlier minor concerns that there were issues with generalisability in the trial (see section\xa03.5). It was aware that models in some previous appraisals for this disease area had used the multiple sclerosis risk sharing scheme (RSS) as the source for its baseline population. The RSS collected data for more than 5,000 patients in the NHS for over 10\xa0years. The committee agreed that this population in the RSS was more generalisable to the NHS than the population in ADVANCE. It concluded that it would have preferred that the model baseline characteristics had been based on the RSS.\n\n# Utility values in the economic model\n\n## Utility values are a source of uncertainty in the model\n\nThe company used utility values from Orme et al. (2007) for consistency with previous technology appraisals. It also provided utility values from a more recent study, Thompson et al. (2017). The ERG provided a scenario analysis using Thompson et al. (2017). The committee noted that the utility values in both Thompson et al. and Orme et al. were very similar. However, it noted that there were substantial differences in the quality-adjusted life years generated by the deterministic and probabilistic models. This was unusual and could suggest that there may have been an issue with the underlying utility values used in the model. The committee discussed whether it could identify any underlying problems with the utility values. The company did not adjust utility values to worsen with age, which the committee agreed was unrealistic. It also noted that older people were more likely to be in a higher EDSS score group in the model (in which higher EDSS scores were associated with a worse utility value), and that the Orme et al. and Thompson et al. studies differed with respect to age, which could have led to different model predictions. The committee agreed that, because the utility values seemed to be a key driver of cost effectiveness in the model, the company should have explored this more thoroughly, for example, by using values derived from a meta-analysis. The committee concluded that the utility values were a source of uncertainty in the cost-effectiveness results.\n\n# Assumptions in the economic model\n\n## There is a lack of robust data about the individual stopping rules\n\nThe company applied a probability of stopping treatment for any reason in its base-case analysis. It used the annualised stopping rates from 18\xa0trials. It weighted these based on sample size to derive the risk of stopping treatment for any reason for each disease-modifying therapy. The ERG considered that deriving the stopping risk weighted by person time would be more appropriate than using the trial sample size. This was because an annualised stopping rate would not capture changes over time. The company accepted this correction. However, the ERG stated that it would have preferred the use of a 5% stopping rule across all treatments, which was derived from the multiple sclerosis RSS. The committee agreed that it was more likely that different treatments would have different stopping rates. It also noted that data on treatment-specific stopping rates in the UK should be available because they are recorded electronically on NHS payment systems. It was disappointed that these had not been presented. The committee concluded that, in the absence of the actual data, it was more plausible to assume a treatment-specific rate than a flat rate.\n\n## The treatment effect waning cannot be estimated precisely because of a lack of evidence\n\nThe company assumed in the model that the treatment effect of all treatments waned over time, and all at the same rate:\n\nyears 1\xa0and\xa02: no waning\n\nyears 3\xa0to\xa05: 75% of full treatment effect\n\nyear\xa06 onwards: 50% of full treatment effect.The clinical experts stated that most treatments for multiple sclerosis become less effective over time. This is either because the person's immune system develops neutralising antibodies, or because the condition worsens and becomes resistant to treatment. It was unclear whether the treatment effect waning with peginterferon beta‑1a would differ from other treatments. The committee noted that peginterferon beta‑1a is an established treatment and that data on treatment effect waning could have been collated. However, the company had not attempted to analyse whether the treatment effect of peginterferon beta‑1a changed over time, which left an important gap in the evidence. The committee concluded that it was appropriate to include some treatment effect waning in the model, and that it would have been more plausible to assume treatment-specific rates rather than a constant rate. However, the committee noted that varying this assumption (that is, using a constant rate for all treatments, or varying the rate by treatment) did not substantially affect cost-effectiveness results. Because of this, the committee accepted the company's base-case assumption.\n\n# ERG's changes to the assumptions in the economic model\n\n## Both the company and ERG's cost-effectiveness results are considered in the decision making\n\nThe ERG made several changes to the company's base case. It stated that the most important of these were:\n\nchanging the treatment-specific stopping rates to a flat rate of 5% from the multiple sclerosis RSS (because it considered these data more informative than trial data for the outcome of stopping treatment) and\n\nthe source of decrements in the utility of caregivers (because its preferred source assumed utility decrements rose with worsening health state).The committee agreed with some, but not all, of the ERG's changes. For example, it agreed that caregiver utility decrements should rise with worsening EDSS health state, and that the company should have used the baseline population from the RSS rather than the trial. However, it disagreed that it was more plausible to assume a constant stopping rate for all treatments than a treatment-specific rate. The committee concluded it would take into account the various company and ERG base cases and scenarios in its decision making.\n\n# Cost-effectiveness estimate\n\n## Peginterferon beta-1a is an established NHS treatment and a cost-effective use of NHS resources\n\nThe committee agreed that enough evidence had been presented to consider the cost effectiveness of peginterferon beta‑1a. However, given the number of years that peginterferon beta‑1a has been an established treatment in the NHS, it was disappointed that the company had not provided data reflecting the experience with peginterferon beta‑1a in NHS practice. These data would have helped to address uncertainty in the model, including for stopping rates and treatment waning. The ERG and company presented a number of exploratory analyses that, in part, helped to reduce some of these uncertainties. Results of all these analyses suggested that the incremental cost-effectiveness results of peginterferon beta‑1a were in the range that NICE normally considers a cost-effective use of NHS resources. The results are commercial in confidence because of confidential comparator patient access schemes, so cannot be reported here."}
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https://www.nice.org.uk/guidance/ta624
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Evidence-based recommendations on peginterferon beta‑1a (Plegridy) for treating relapsing–remitting multiple sclerosis in adults.
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13ffb679368348b776033500b1d170fa03ba2e3c
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nice
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Patiromer for treating hyperkalaemia
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Patiromer for treating hyperkalaemia
Evidence based recommendations on patiromer (Veltassa) for treating hyperkalaemia in adults.
# Recommendations
Patiromer is recommended as an option for treating hyperkalaemia in adults only if used:
in emergency care for acute life-threatening hyperkalaemia alongside standard care or
for people with persistent hyperkalaemia and stages 3b to 5 chronic kidney disease or heart failure, if they:
have a confirmed serum potassium level of at least 6.0 mmol/litre and
are not taking, or are taking a reduced dosage of, a renin-angiotensin-aldosterone system (RAAS) inhibitor because of hyperkalaemia and
are not on dialysis.
Stop patiromer if RAAS inhibitors are no longer suitable.
This recommendation is not intended to affect treatment with patiromer that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Patiromer is a treatment for people with high blood potassium levels (hyperkalaemia). It can be used for adults with chronic kidney disease or heart failure, either:
in emergency care alongside standard care for acute life-threatening hyperkalaemia or
for persistent hyperkalaemia if they are able to have RAAS inhibitors.
Treating acute life-threatening hyperkalaemia in emergency care is established clinical practice. Other potassium-lowering treatments are rarely used in this setting because they are poorly tolerated. Patiromer could be a useful addition to emergency care.
Clinical trials show that patiromer lowers serum potassium. But there is no clinical evidence that it extends life or improves quality of life. Patiromer may allow people to stay on RAAS inhibitors (drugs used to treat heart failure and kidney disease) for longer or at a higher dose. This may extend life and improve quality of life.
Considering the benefit from more people being able to stay on RAAS inhibitors, the cost-effectiveness estimates for patiromer suggest that it is a reasonable use of NHS resources. Therefore, it is recommended for treating confirmed persistent hyperkalaemia when started in hospital and alongside standard care for treating acute life-threatening hyperkalaemia in emergency care.# Information about patiromer
# Marketing authorisation indication
Patiromer (Veltassa, Vifor Pharma) has a marketing authorisation in the UK 'for the treatment of hyperkalaemia in adults'.
# Dosage in the marketing authorisation
Patiromer is administered orally. The recommended starting dose is 8.4 g once a day and the maximum dose is 25.2 g. The dose can be increased or decreased after a minimum interval of 1 week based on serum potassium levels. The dose should be reduced or stopped if serum potassium is below the desired range. Patiromer should be taken with or without food and separated by 3 hours from other oral medication. The onset of action for patiromer is 4 to 7 hours and patiromer should not replace emergency treatment for life-threatening hyperkalaemia.
# Price
The list price of patiromer is £172.50 per 30‑sachet pack, available as 8.4 g sachets or 16.8 g sachets (excluding VAT, Department of Health and Social Care communication, November 2019). Costs may vary in different settings because of negotiated procurement discounts.# Committee discussion
The appraisal committee considered evidence submitted by Vifor Pharma and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Treating hyperkalaemia
## Patients in the NHS with serum potassium levels above the normal range do not always need treatment to lower potassium
Hyperkalaemia is a high level of potassium in the blood. The European Resuscitation Council classifies hyperkalaemia as mild (serum potassium level of 5.5 mmol/litre to 5.9 mmol/litre), moderate (6.0 mmol/litre to 6.4 mmol/litre) or severe (6.5 mmol/litre and above). The committee understood that serum potassium tests may incorrectly identify hyperkalaemia, and hyperkalaemia often needs to be confirmed. It concluded that any use of patiromer would be limited to confirmed hyperkalaemia. Hyperkalaemia occurs most commonly in people with chronic kidney disease (stages 3b, 4 and 5) and in heart failure. It can also occur after starting treatments for high blood pressure, chronic kidney disease, proteinuria (protein in the urine), and heart failure. These include potassium-sparing diuretics or renin-angiotensin-aldosterone system (RAAS) inhibitors. RAAS inhibitors include angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs) and aldosterone receptor antagonists. Clinicians routinely monitor serum potassium in people with chronic kidney disease and in people on RAAS inhibitors. In response to consultation, the company provided results from a published study which suggested that healthcare practitioners of patients with cardiac or kidney disease would 'take action' at potassium levels of 5.7 or 5.8 mmol/litre. Interviews with cardiologists and nephrologists cited a consensus to down-titrate or stop RAAS inhibitors at serum potassium levels of more than 6.0 mmol/litre. The committee acknowledged that this was in line with NICE's clinical guideline on chronic kidney disease in adults: assessment and management. The clinical experts at the second committee meeting explained they would consider drug treatment for hyperkalaemia, if there is a well-tolerated treatment available, mainly to optimise the use of RAAS inhibitors. They would consider drug treatment for:
people with chronic kidney disease 3b, 4 and 5 and serum potassium levels above 6.0 mmol/litre and
some people with heart failure and serum potassium levels above 5.5 mmol/litre.The committee understood that many people have both heart failure and chronic kidney disease, so it may be appropriate to start drug treatment at the same serum potassium level for both conditions. It was not presented with evidence for a different effect with patiromer between people with chronic kidney disease and people with heart failure. The company's clinical trials recruited people with serum potassium levels of 5.1 mmol/litre or more. The committee concluded that it was appropriate to focus on level of serum potassium rather than underlying condition, and that most of the people in the company's clinical trials would not have treatment for hyperkalaemia in the NHS (see section 3.8).
## Patiromer has a potential role in treating life-threatening acute hyperkalaemia and chronic hyperkalaemia
The need for, and type of, treatment for hyperkalaemia depends on its severity. Life-threatening acute hyperkalaemia needs emergency treatment in hospital. NICE-accredited clinical practice guidelines for treating acute hyperkalaemia from the UK Renal Association state that the risk of cardiac arrhythmias increases with serum potassium levels above 6.5 mmol/litre. Small rises in serum potassium above this can cause electrocardiogram (ECG) changes. To lower the risk of cardiac arrest, clinicians use active potassium-lowering treatments, then identify and remove the cause of hyperkalaemia. The guidelines include the following treatments:
calcium chloride or calcium gluconate intravenously to protect the heart if there is ECG evidence of hyperkalaemia
insulin and glucose intravenously to move potassium from the blood into cells
nebulised salbutamol as an adjunctive therapy to insulin and glucose for serum potassium levels of 6.5 mmol/litre and above to move potassium from the blood into cells
after severe hyperkalaemia has resolved, potassium-binding agents for 3 or more days (namely, calcium resonium given orally) to remove potassium from the body
stopping or reducing RAAS inhibitors, which can increase serum potassium levels.The aim of treatment for chronic hyperkalaemia is to lower potassium levels to prevent acute life-threatening hyperkalaemia. Treatment includes:
advising people with chronic kidney disease to avoid foods high in potassium
stopping or reducing RAAS inhibitors and potassium-sparing diuretics
avoiding non-steroidal anti-inflammatory drugs and trimethoprim.The clinical expert at the first committee meeting explained that people who have normal serum potassium levels after hyperkalaemia has been corrected do not have long-term (maintenance) treatment with a potassium-lowering drug in current clinical practice. This may be because potassium-binding treatments such as calcium resonium are poorly tolerated by patients. The committee was aware that the onset of action for patiromer is 4 to 7 hours after administration and that the summary of product characteristics states that it should not replace emergency treatment for life-threatening hyperkalaemia. The committee considered that patiromer could have a role in treating life-threatening hyperkalaemia alongside usual care. The clinical experts explained that it would not replace intravenous insulin and glucose, but it might replace calcium resonium. The committee concluded that managing acute life-threatening hyperkalaemia and chronic hyperkalaemia differed and that patiromer had a potential role in both.
## People with chronic hyperkalaemia would welcome an alternative to stopping RAAS inhibitors
The company proposed that people with chronic hyperkalaemia who have patiromer would be less likely to stop RAAS inhibitors than people who do not have patiromer. Therefore, they would live longer and have a lower risk of worsening kidney disease or heart failure and death. However, it did not provide any clinical evidence for this (see section 3.10). NICE's clinical guideline on chronic kidney disease in adults: assessment and management states that RAAS inhibitors should not be routinely started in people with serum potassium levels of 5.0 mmol/litre and above, and should be stopped in people with levels of 6.0 mmol/litre and above. NICE's clinical guideline on chronic heart failure in adults: diagnosis and management states that serum potassium levels should be monitored before and after starting a RAAS inhibitor or changing RAAS inhibitor dose, but does not specify the serum potassium levels at which RAAS inhibitors should be avoided or stopped. The committee and the clinical experts at the committee meetings agreed that RAAS inhibitors would be used in the NHS for many people with serum potassium levels 5.0 mmol/litre and above, and would be stopped when serum potassium levels are 6.0 mmol/litre and above. At levels of serum potassium below 6.0 mmol/litre, clinicians would likely recommend reducing, rather than stopping, the RAAS inhibitor. This is because the perceived benefits of being on treatment outweigh the risks of having a serum potassium level between 5.0 mmol/litre and 6.0 mmol/litre. The committee noted that some people stop RAAS inhibitors for reasons other than hyperkalaemia. It concluded that patients and clinicians are keen for treatment options that would allow them to continue RAAS inhibitors.
## The long-term benefit of continuing RAAS inhibitors on quality of life and survival in people with hyperkalaemia may vary
The clinical experts explained that the benefit, or potential harm, of being on RAAS inhibitor treatment depended on:
the underlying condition
the class of RAAS inhibitor (ACE inhibitors, ARBs, aldosterone receptor antagonists) and
-utcome (for example, cardiovascular disease, worsening of kidney disease, death).Specifically, the clinical experts noted that the benefit of RAAS inhibitors in protecting the kidney had not been documented in people with stages 4 and 5 chronic kidney disease. The committee acknowledged that, for some people, the RAAS inhibitor dose may be reduced rather than stopped completely (see section 3.3). Also, some people may be on multiple RAAS inhibitors, for example an ACE or ARB plus an aldosterone receptor, only 1 of which is stopped because of hyperkalaemia. The committee concluded that factors affecting the harms and benefits of stopping RAAS inhibitors because of hyperkalaemia compared with using another antihypertensive (for people with high blood pressure) or standard care (for people who would not normally be offered another blood pressure lowering drug) could be affected by the:
underlying condition
type of RAAS inhibitor
dose of RAAS inhibitor
number of RAAS inhibitors
reason for stopping a RAAS inhibitor.The committee also concluded that the long-term benefit of continuing RAAS inhibitors on quality of life and survival in people with hyperkalaemia may vary and that it would consider the balance of benefits and harms in its decision making.
## Patiromer is unlikely to replace a low-potassium diet but should be used in addition to a low-potassium diet
The patient experts noted that maintaining a low-potassium diet is challenging because so many foods contain potassium. The clinical experts explained that they consider the diet worth trying; NICE recommends it for people with chronic kidney disease, and it lowers serum potassium compared with an unrestricted diet. They added that a new treatment option would not replace dietary advice but would complement it, and may mean that the diet need not be so strict. The patient expert stressed at the second meeting that people should be encouraged to continue to follow a low-potassium diet. The committee concluded that patiromer is unlikely to replace a strict low-potassium diet, but should be used in addition to a low-potassium diet.
# Company positioning of patiromer
## The company proposes patiromer for a population narrower than that covered by the marketing authorisation
The marketing authorisation indication for patiromer specifies 'treatment of hyperkalaemia in adults'. It was based on the company's trials in which people with serum potassium levels of 5.1 mmol/litre or more were recruited and had treatment (see section 3.8). The company updated its base case in response to consultation to include people with chronic kidney disease (stages 3 to 5, excluding those on dialysis) or heart failure (who may also have chronic kidney disease) and with serum potassium of 6.0 mmol/litre or more in line with clinical expert comments (see section 3.1). The committee heard that, of people with stage 3 chronic kidney disease, those with stage 3b were more likely to develop hyperkalaemia, and more people would likely benefit from RAAS inhibitor compared with people with stage 3a disease. The committee noted that the population in the company's submission was narrower than that covered by the marketing authorisation. The committee recalled that:
starting treatment at the same serum potassium level for chronic kidney disease and heart failure may be appropriate (see section 3.1)
it had not seen evidence justifying different starting levels for chronic kidney disease and for heart failure (see section 3.1)
mmol/litre was the same serum potassium level as that for stopping RAAS inhibitors (see section 3.3).Therefore, the committee concluded that it would appraise patiromer for the population and the starting serum potassium level the company proposed, which was narrower than that covered by the marketing authorisation.
## The company proposes that patiromer will be used alongside standard care for acute hyperkalaemia and started in hospital for chronic hyperkalaemia
The marketing authorisation for patiromer covers using it to lower serum potassium levels. It also specifies that stopping patiromer may result in serum potassium levels rising and treatment should not be stopped without consulting a clinician. The company proposed that patiromer would be used:
for acute hyperkalaemia, instead of calcium resonium and permanently stopping RAAS inhibitors
instead of stopping RAAS inhibitors to manage chronic hyperkalaemia and to prevent life-threatening hyperkalaemia, in people with hyperkalaemia identified through routine monitoring. It also explained that patiromer would be started in hospitals.The committee noted that the marketing authorisation states that patiromer should not replace emergency treatment for life-threatening hyperkalaemia. It considered that patiromer would not replace standard emergency care for acute life-threatening hyperkalaemia, but it could also be used instead of calcium resonium alongside standard care. The committee concluded that it would appraise patiromer alongside standard care for life-threatening hyperkalaemia, and for confirmed chronic hyperkalaemia.
# Clinical effectiveness
## Trials do not show that patiromer is more clinically effective than NHS standard care or increases length or quality of life in chronic hyperkalaemia
The key evidence for the clinical effectiveness of patiromer came from OPAL‑HK. This was a phase 3, 12‑week, single-blind study that included people with stages 3 and 4 chronic kidney disease, with or without heart failure, who were having a RAAS inhibitor, with serum potassium between 5.1 mmol/litre and 6.5 mmol/litre. The study had 2 parts and its primary outcome was change in serum potassium:
Part A, 4 weeks (n=243): single-arm dose-ranging study. Everyone had patiromer, and the dosage was adjusted up to a maximum of 50.4 g daily to achieve a target serum potassium between 3.8 mmol/litre and 5.1 mmol/litre.
Part B, 8 weeks (n=107): randomised, placebo-controlled trial of stopping compared with continuing patiromer, including only people having patiromer whose hyperkalaemia in part A responded (people who had a serum potassium level of 5.5 mmol/litre or more at the beginning of part A and a serum potassium level between 3.8 mmol/litre and 5.1 mmol/litre at the end of part A) and who were still having treatment with a RAAS inhibitor.During part A of the study, serum potassium decreased for the total population by 1.01 mmol/litre. In part B of the study, for people whose hyperkalaemia responded to patiromer (as defined above), serum potassium levels were 0.72 mmol/litre higher in the placebo arm than the patiromer arm. However, the serum potassium levels in both arms were not within the range that would be treated in the NHS. Also, part B of the trial addressed stopping patiromer in people already on it whose hyperkalaemia had responded rather than starting patiromer in people who might benefit from it. The company submitted additional clinical evidence in response to consultation, from the PEARL‑HF and AMBER trials. However, the ERG noted that the studies were not relevant to the scope of the appraisal because the patients did not have hyperkalaemia at baseline. The committee concluded that the trial evidence did not show patiromer was more clinically effective than current NHS standard care or that patiromer increases length or quality of life for people having treatment for chronic hyperkalaemia.
## Patiromer could be beneficial in treating acute life-threatening hyperkalaemia
The committee noted that acute hyperkalaemia can be fatal and treating acute life-threatening hyperkalaemia in hospital is established clinical practice. The committee agreed that lowering potassium levels for patients needing emergency care was a life-saving intervention. It therefore concluded that randomised evidence was not needed to show that treating life-threatening hyperkalaemia in emergency care prolonged life. As such, the uncontrolled evidence showing that patiromer reduces serum potassium (see section 3.8) was sufficient for the committee to conclude that it could be useful for people with hyperkalaemia needing treatment in emergency care, alongside standard care.
## Stopping RAAS inhibitors likely increases the risk of death, hospitalisation and disease progression
Data were not collected in OPAL‑HK on the effect of patiromer on long-term outcomes such as progression of chronic kidney disease or mortality. However, the company proposed in its model that people with hyperkalaemia who take patiromer live longer and have a better quality of life than people who do not because treatment with patiromer would allow them to maintain or restart treatment with RAAS inhibitors. The committee noted that the company provided only exploratory data from a single-arm trial (OPAL‑HK) of patiromer. The company also submitted evidence from AMBER. This was a randomised trial comparing patiromer plus spironolactone with placebo plus spironolactone to see whether patiromer use results in more persistent use of spironolactone (a RAAS inhibitor). It showed that 20% more patients taking patiromer stayed on spironolactone than those taking placebo. However, the patients in the trial did not have hyperkalaemia at baseline; potassium levels were between 4.3 mmol/litre and 5.1 mmol/litre. Independent of this, based on targeted reviews for chronic kidney disease and heart failure, the company presented data from a network meta-analysis of randomised controlled trials and several observational studies. It assumed that, because these studies showed that starting a RAAS inhibitor is associated with living longer, stopping a RAAS inhibitor would be associated with dying earlier. The company presented evidence that RAAS inhibitors are associated with delayed disease progression, and therefore improved quality of life. The committee recognised that the company's evidence addressed the decision problem indirectly. It noted that the trials in the company's literature search compared starting RAAS inhibitors with not starting them, rather than the question relevant to this appraisal, that is, reducing or stopping RAAS inhibitors compared with continuing them. The committee recognised that worsening underlying disease may lead to worse hyperkalaemia, and that it was unclear whether the clinical benefit seen in the trials would translate to continued use of RAAS inhibitors. It concluded that, in the population being considered, stopping RAAS inhibitors would generally be associated with an increased risk of adverse outcomes and disease progression. The committee was not satisfied that the company had presented robust data on how patiromer alters dosing of RAAS inhibitors compared with standard care, or the extent to which such alterations improved length and quality of life. However, the committee was also aware of NICE's guidance which recommends stopping RAAS inhibitors at serum potassium levels of 6.0 mmol/litre and above (see section 3.3). It concluded that starting RAAS inhibitors prolongs life for many people, so stopping them for people who benefit from them would likely shorten life.
## There is insufficient evidence to prove that lowering serum potassium levels improves long-term outcomes
The company proposed in its model that lowering serum potassium with patiromer causes people to live longer. It based this on a review of evidence on the association between serum potassium and adverse outcomes for people with chronic kidney disease or heart failure. This evidence, from observational cohort studies, showed that a higher risk of death, hospitalisation and major adverse cardiovascular events was associated with high, but also with lower than normal, serum potassium levels. Using these data, the company assumed that, because people with higher than normal serum potassium have a higher risk of death, patiromer prolongs life because it lowers serum potassium. The committee noted that the observational data did not guarantee an independent causal effect between high serum potassium levels and death. Importantly, even if it did, the committee noted that the company did not provide evidence that lowering serum potassium extends life. The committee was aware of DIAMOND, an ongoing randomised controlled trial of patiromer compared with placebo for adults with hyperkalaemia and heart failure. Its primary outcome was time to first occurrence of hospitalisation or death. The DIAMOND trial results may, in future, provide evidence for a link between patiromer and length of life. The committee concluded that there was insufficient evidence to prove that lowering serum potassium levels for people in outpatient care improves outcomes.
# Cost-effectiveness modelling
## The company's updated model addresses some of the committee's concerns
In response to consultation the company made significant revisions to its model. It modelled the cost effectiveness of patiromer using a Markov model with 26 health states, which included stages 3 and 4 chronic kidney disease and end-stage kidney disease (stage 5 chronic kidney disease). Within each chronic kidney disease state patients were grouped into one of 3 serum potassium level categories (less than 5.5 mmol/litre, 5.5 to 6.0 mmol/litre and more than 6.0 mmol/litre). The company also made other changes including:
-nly including patients with serum potassium levels of 6.0 mmol/litre or more
not assuming a direct link between lowering serum potassium and mortality, only an indirect link through continued RAAS inhibitor use
modelling separate chronic kidney disease health states for stages 3 and 4 (previously modelled as the same health state)
revising the proportion of hyperkalaemia episodes resulting in hospitalisation from 100% to:
% for people with serum potassium more than 5.0 mmol/litre
% for people with serum potassium between 5.5 mmol/litre and 6.0 mmol/litre and
% for people with serum potassium of more than 6.0 mmol/litre.The committee noted that although the company had attempted to address many of its concerns, some issues remained. These included the rate of recurrence of hyperkalaemia (see section 3.14) and the source of data for stopping patiromer (see section 3.15).
## The very limited clinical evidence increases uncertainty
The company updated the population in its economic model to people with serum potassium of 6.0 mmol/litre or more to match the committee's conclusion about when treatment for hyperkalaemia starts in the NHS (see section 3.1). However, the committee noted that few patients in the OPAL-HK trial had serum potassium levels above 6.0 mmol/litre. This meant that the data for patiromer in the economic model was based on only 26 patients. The committee agreed this was appropriate for people with heart failure and stages 3b, 4 and 5 chronic kidney disease. It was aware that the company had included people with stage 3a chronic kidney disease, but considered that the absolute benefit would be greater in people with stage 3b chronic kidney disease. The committee was also aware that all patients in the OPAL‑HK trial had chronic kidney disease and some also had heart failure. It considered that given its conclusion that it was appropriate to focus on the level of serum potassium rather than the underlying condition (see section 3.1), it was likely that the results would also hold for people with heart failure alone. This is because the main benefit of potassium-lowering treatments in chronic hyperkalaemia is to allow people to take RAAS inhibitors, which are beneficial in heart failure. However, the committee concluded that the very limited clinical evidence informing the model increased the uncertainty associated with the cost-effectiveness estimates.
## The rate of recurrence of hyperkalaemia used by the company is unrealistically low
To inform the rate of recurrence of hyperkalaemia in the model, the company used data from the clinical practice research datalink. The ERG highlighted that the rate of recurrence was very low, between 0.04% to 1.03% per month depending on serum potassium levels and chronic kidney disease stage. This was much lower than the rate in the placebo arm of OPAL‑HK. The rate was so low, in part because it was estimated from a large sample of patients in the clinical practice research datalink data with serum potassium lower than 5.5 mmol/litre at baseline. So, it did not reflect the population in the model. To model recurrence in the patiromer arm, the company applied the hazard ratio from the OPAL‑HK trial to the annual rate derived from these data. The committee was concerned that, given the very low baseline rate of hyperkalaemia recurrence, the probability of hyperkalaemia recurring increased only slightly when people stopped taking patiromer. It concluded that this was unlikely because patiromer is not disease-modifying, so serum potassium would be expected to increase once treatment stops. It also concluded that the rate of recurrence was unrealistically low for this population. However, the committee was unclear what effect using a higher rate of recurrence would have on the cost-effectiveness results because both patients taking and not taking patiromer would experience more episodes of hyperkalaemia.
## The company's source of data for stopping patiromer is not appropriate
In its updated base case, the company used US claims registry data to model the rate at which people stop treatment with patiromer. Previously it used data from AMETHYST‑DN, a 1‑year trial of patiromer at different doses in people with type 2 diabetes, chronic kidney disease and serum potassium between 4.3 mmol/litre and 6.0 mmol/litre. The company explained that it had used US claims data because this would better reflect stopping in clinical practice than would randomised controlled trial data from AMETHYST‑DN. The ERG explained that the US claims data were unlikely to represent use of patiromer in UK clinical practice because the settings are very different. The ERG continued to use the data from AMETHYST‑DN in its base case, in which over half of the patients remained on treatment at 3 years. The ERG also did a scenario analysis using OPAL‑HK data to model stopping patiromer. This curve was closer to the US claims data curve, with just under a third of patients on treatment at 1 year. However, the committee noted that the short trial period for OPAL‑HK (12 weeks) meant that extrapolating these data is uncertain. The committee considered that the average time on treatment in the NHS would be longer than seen in the US claims data. This was because the condition of the population in this appraisal, with chronic kidney disease and heart failure and serum potassium greater than 6.0 mmol/litre, was likely to worsen over time. They would therefore need to continue treatment with patiromer while taking RAAS inhibitors. It concluded that the rate at which people stop patiromer was more likely to lie somewhere between the rates based on OPAL‑HK and AMETHYST‑DN.
## The company's approach to modelling the association between RAAS inhibitor use and outcomes is appropriate, but the data are inadequate
The company modelled an association between the use of RAAS inhibitors and the risks of mortality, hospitalisation and major adverse cardiovascular events. This was based on odds ratios from a network meta-analysis of clinical trials of starting RAAS inhibitors (Xie et al. 2016). The committee recalled and accepted evidence from the clinical and patient experts that maintaining RAAS inhibitor therapy is likely to benefit certain patients (see section 3.10). The committee did not see robust evidence of patiromer's effect on RAAS inhibitor use. However, it was aware that clinicians are encouraged to stop RAAS inhibitor treatment for people with serum potassium levels of 6.0 mmol/litre and above. The committee considered that any guidance for patiromer would be limited to people who could take RAAS inhibitors. It concluded that the company's approach to modelling the association between RAAS inhibitor use and outcomes was appropriate.
# Cost-effectiveness estimates
## Patiromer is recommended as a treatment option
The company's base-case incremental cost-effectiveness ratio (ICER) was £6,774 per quality-adjusted life year gained for patiromer compared with standard care. The committee recalled that this analysis was based on US claims data for stopping patiromer and may not reflect UK clinical practice (see section 3.15). Therefore, the committee also considered the ERG's analyses that varied the source of data for stopping patiromer:
ERG's base case: stopping patiromer based on data from AMETHYST‑DN, everyone stops treatment at 5 years
ERG's scenario: stopping patiromer based on data from OPAL‑HK.The committee recalled its conclusion that the rate at which people stop patiromer was likely to lie between the 2 ERG scenarios (see section 3.15). In both ERG scenarios, the ICER was higher than in the company's base case. The committee considered that the model was sensitive to treatment duration because the low baseline rate of recurrence of hyperkalaemia means that longer treatment with patiromer incurs costs which outweigh the benefits (see section 3.14). It therefore considered that with a higher baseline rate of hyperkalaemia recurrence, longer treatment duration may not increase the ICERs as much as in the ERG's analysis. The committee therefore concluded that patiromer was likely to represent a cost-effective use of NHS resources for treating chronic hyperkalaemia and, based on the conclusion in section 3.9, alongside standard care for treating acute hyperkalaemia. It emphasised that uncertainties remained around patiromer's clinical benefit and that these could be addressed by clinical trials (see section 5.1).
# Innovation
## The company has not shown that patiromer is innovative
The company proposed several benefits of patiromer but did not show evidence of these. They included not needing to modify RAAS inhibitor treatment and avoiding a restrictive low-potassium diet. The committee was aware that other gastrointestinal potassium binders exist and that patiromer does not represent a step-change in treatment. It concluded that patiromer could not be considered innovative.# Recommendations for research
The committee noted that there was no clinical evidence showing that having patiromer improved length or quality of life or allowed patients to stay on optimal doses of renin-angiotensin-aldosterone system (RAAS) inhibitors. It therefore considered that it would be valuable to have studies comparing patiromer plus standard care with standard care alone in people with confirmed hyperkalaemia of 6.0 mmol/litre and above, and that these should investigate:
mortality
disease progression
patterns of RAAS inhibitor use
healthcare utilisation and
health-related quality of life.The committee recalled that the DIAMOND trial is ongoing and may help to provide evidence on mortality (see section 3.11). However, the trial is not going to complete until 2022. The committee concluded that the guidance should be reviewed when evidence from DIAMOND is available.
|
{'Recommendations': 'Patiromer is recommended as an option for treating hyperkalaemia in adults only if used:\n\nin emergency care for acute life-threatening hyperkalaemia alongside standard care or\n\nfor people with persistent hyperkalaemia and stages\xa03b\xa0to\xa05 chronic kidney disease or heart failure, if they:\n\n\n\nhave a confirmed serum potassium level of at least 6.0\xa0mmol/litre and\n\nare not taking, or are taking a reduced dosage of, a renin-angiotensin-aldosterone system (RAAS) inhibitor because of hyperkalaemia and\n\nare not on dialysis.\n\n\n\nStop patiromer if RAAS inhibitors are no longer suitable.\n\nThis recommendation is not intended to affect treatment with patiromer that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nPatiromer is a treatment for people with high blood potassium levels (hyperkalaemia). It can be used for adults with chronic kidney disease or heart failure, either:\n\nin emergency care alongside standard care for acute life-threatening hyperkalaemia or\n\nfor persistent hyperkalaemia if they are able to have RAAS inhibitors.\n\nTreating acute life-threatening hyperkalaemia in emergency care is established clinical practice. Other potassium-lowering treatments are rarely used in this setting because they are poorly tolerated. Patiromer could be a useful addition to emergency care.\n\nClinical trials show that patiromer lowers serum potassium. But there is no clinical evidence that it extends life or improves quality of life. Patiromer may allow people to stay on RAAS inhibitors (drugs used to treat heart failure and kidney disease) for longer or at a higher dose. This may extend life and improve quality of life.\n\nConsidering the benefit from more people being able to stay on RAAS inhibitors, the cost-effectiveness estimates for patiromer suggest that it is a reasonable use of NHS resources. Therefore, it is recommended for treating confirmed persistent hyperkalaemia when started in hospital and alongside standard care for treating acute life-threatening hyperkalaemia in emergency care.', 'Information about patiromer': "# Marketing authorisation indication\n\nPatiromer (Veltassa, Vifor Pharma) has a marketing authorisation in the UK 'for the treatment of hyperkalaemia in adults'.\n\n# Dosage in the marketing authorisation\n\nPatiromer is administered orally. The recommended starting dose is 8.4\xa0g once a day and the maximum dose is 25.2\xa0g. The dose can be increased or decreased after a minimum interval of 1\xa0week based on serum potassium levels. The dose should be reduced or stopped if serum potassium is below the desired range. Patiromer should be taken with or without food and separated by 3\xa0hours from other oral medication. The onset of action for patiromer is 4\xa0to 7\xa0hours and patiromer should not replace emergency treatment for life-threatening hyperkalaemia.\n\n# Price\n\nThe list price of patiromer is £172.50 per 30‑sachet pack, available as 8.4\xa0g sachets or 16.8\xa0g sachets (excluding VAT, Department of Health and Social Care communication, November 2019). Costs may vary in different settings because of negotiated procurement discounts.", 'Committee discussion': "The appraisal committee considered evidence submitted by Vifor Pharma and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Treating hyperkalaemia\n\n## Patients in the NHS with serum potassium levels above the normal range do not always need treatment to lower potassium\n\nHyperkalaemia is a high level of potassium in the blood. The European Resuscitation Council classifies hyperkalaemia as mild (serum potassium level of 5.5\xa0mmol/litre to 5.9\xa0mmol/litre), moderate (6.0\xa0mmol/litre to 6.4\xa0mmol/litre) or severe (6.5\xa0mmol/litre and above). The committee understood that serum potassium tests may incorrectly identify hyperkalaemia, and hyperkalaemia often needs to be confirmed. It concluded that any use of patiromer would be limited to confirmed hyperkalaemia. Hyperkalaemia occurs most commonly in people with chronic kidney disease (stages\xa03b, 4\xa0and\xa05) and in heart failure. It can also occur after starting treatments for high blood pressure, chronic kidney disease, proteinuria (protein in the urine), and heart failure. These include potassium-sparing diuretics or renin-angiotensin-aldosterone system (RAAS) inhibitors. RAAS inhibitors include angiotensin-converting enzyme (ACE) inhibitors, angiotensin\xa0II receptor blockers (ARBs) and aldosterone receptor antagonists. Clinicians routinely monitor serum potassium in people with chronic kidney disease and in people on RAAS inhibitors. In response to consultation, the company provided results from a published study which suggested that healthcare practitioners of patients with cardiac or kidney disease would 'take action' at potassium levels of 5.7\xa0or 5.8\xa0mmol/litre. Interviews with cardiologists and nephrologists cited a consensus to down-titrate or stop RAAS inhibitors at serum potassium levels of more than 6.0\xa0mmol/litre. The committee acknowledged that this was in line with NICE's clinical guideline on chronic kidney disease in adults: assessment and management. The clinical experts at the second committee meeting explained they would consider drug treatment for hyperkalaemia, if there is a well-tolerated treatment available, mainly to optimise the use of RAAS inhibitors. They would consider drug treatment for:\n\npeople with chronic kidney disease 3b,\xa04 and\xa05 and serum potassium levels above 6.0\xa0mmol/litre and\n\nsome people with heart failure and serum potassium levels above 5.5\xa0mmol/litre.The committee understood that many people have both heart failure and chronic kidney disease, so it may be appropriate to start drug treatment at the same serum potassium level for both conditions. It was not presented with evidence for a different effect with patiromer between people with chronic kidney disease and people with heart failure. The company's clinical trials recruited people with serum potassium levels of 5.1\xa0mmol/litre or more. The committee concluded that it was appropriate to focus on level of serum potassium rather than underlying condition, and that most of the people in the company's clinical trials would not have treatment for hyperkalaemia in the NHS (see section\xa03.8).\n\n## Patiromer has a potential role in treating life-threatening acute hyperkalaemia and chronic hyperkalaemia\n\nThe need for, and type of, treatment for hyperkalaemia depends on its severity. Life-threatening acute hyperkalaemia needs emergency treatment in hospital. NICE-accredited clinical practice guidelines for treating acute hyperkalaemia from the UK Renal Association state that the risk of cardiac arrhythmias increases with serum potassium levels above 6.5\xa0mmol/litre. Small rises in serum potassium above this can cause electrocardiogram (ECG) changes. To lower the risk of cardiac arrest, clinicians use active potassium-lowering treatments, then identify and remove the cause of hyperkalaemia. The guidelines include the following treatments:\n\ncalcium chloride or calcium gluconate intravenously to protect the heart if there is ECG evidence of hyperkalaemia\n\ninsulin and glucose intravenously to move potassium from the blood into cells\n\nnebulised salbutamol as an adjunctive therapy to insulin and glucose for serum potassium levels of 6.5\xa0mmol/litre and above to move potassium from the blood into cells\n\nafter severe hyperkalaemia has resolved, potassium-binding agents for 3\xa0or more days (namely, calcium resonium given orally) to remove potassium from the body\n\nstopping or reducing RAAS inhibitors, which can increase serum potassium levels.The aim of treatment for chronic hyperkalaemia is to lower potassium levels to prevent acute life-threatening hyperkalaemia. Treatment includes:\n\nadvising people with chronic kidney disease to avoid foods high in potassium\n\nstopping or reducing RAAS inhibitors and potassium-sparing diuretics\n\navoiding non-steroidal anti-inflammatory drugs and trimethoprim.The clinical expert at the first committee meeting explained that people who have normal serum potassium levels after hyperkalaemia has been corrected do not have long-term (maintenance) treatment with a potassium-lowering drug in current clinical practice. This may be because potassium-binding treatments such as calcium resonium are poorly tolerated by patients. The committee was aware that the onset of action for patiromer is 4\xa0to 7\xa0hours after administration and that the summary of product characteristics states that it should not replace emergency treatment for life-threatening hyperkalaemia. The committee considered that patiromer could have a role in treating life-threatening hyperkalaemia alongside usual care. The clinical experts explained that it would not replace intravenous insulin and glucose, but it might replace calcium resonium. The committee concluded that managing acute life-threatening hyperkalaemia and chronic hyperkalaemia differed and that patiromer had a potential role in both.\n\n## People with chronic hyperkalaemia would welcome an alternative to stopping RAAS inhibitors\n\nThe company proposed that people with chronic hyperkalaemia who have patiromer would be less likely to stop RAAS inhibitors than people who do not have patiromer. Therefore, they would live longer and have a lower risk of worsening kidney disease or heart failure and death. However, it did not provide any clinical evidence for this (see section\xa03.10). NICE's clinical guideline on chronic kidney disease in adults: assessment and management states that RAAS inhibitors should not be routinely started in people with serum potassium levels of 5.0\xa0mmol/litre and above, and should be stopped in people with levels of 6.0\xa0mmol/litre and above. NICE's clinical guideline on chronic heart failure in adults: diagnosis and management states that serum potassium levels should be monitored before and after starting a RAAS inhibitor or changing RAAS inhibitor dose, but does not specify the serum potassium levels at which RAAS inhibitors should be avoided or stopped. The committee and the clinical experts at the committee meetings agreed that RAAS inhibitors would be used in the NHS for many people with serum potassium levels 5.0\xa0mmol/litre and above, and would be stopped when serum potassium levels are 6.0\xa0mmol/litre and above. At levels of serum potassium below 6.0\xa0mmol/litre, clinicians would likely recommend reducing, rather than stopping, the RAAS inhibitor. This is because the perceived benefits of being on treatment outweigh the risks of having a serum potassium level between 5.0\xa0mmol/litre and 6.0\xa0mmol/litre. The committee noted that some people stop RAAS inhibitors for reasons other than hyperkalaemia. It concluded that patients and clinicians are keen for treatment options that would allow them to continue RAAS inhibitors.\n\n## The long-term benefit of continuing RAAS inhibitors on quality of life and survival in people with hyperkalaemia may vary\n\nThe clinical experts explained that the benefit, or potential harm, of being on RAAS inhibitor treatment depended on:\n\nthe underlying condition\n\nthe class of RAAS inhibitor (ACE inhibitors, ARBs, aldosterone receptor antagonists) and\n\noutcome (for example, cardiovascular disease, worsening of kidney disease, death).Specifically, the clinical experts noted that the benefit of RAAS inhibitors in protecting the kidney had not been documented in people with stages\xa04 and\xa05 chronic kidney disease. The committee acknowledged that, for some people, the RAAS inhibitor dose may be reduced rather than stopped completely (see section\xa03.3). Also, some people may be on multiple RAAS inhibitors, for example an ACE or ARB plus an aldosterone receptor, only 1\xa0of which is stopped because of hyperkalaemia. The committee concluded that factors affecting the harms and benefits of stopping RAAS inhibitors because of hyperkalaemia compared with using another antihypertensive (for people with high blood pressure) or standard care (for people who would not normally be offered another blood pressure lowering drug) could be affected by the:\n\nunderlying condition\n\ntype of RAAS inhibitor\n\ndose of RAAS inhibitor\n\nnumber of RAAS inhibitors\n\nreason for stopping a RAAS inhibitor.The committee also concluded that the long-term benefit of continuing RAAS inhibitors on quality of life and survival in people with hyperkalaemia may vary and that it would consider the balance of benefits and harms in its decision making.\n\n## Patiromer is unlikely to replace a low-potassium diet but should be used in addition to a low-potassium diet\n\nThe patient experts noted that maintaining a low-potassium diet is challenging because so many foods contain potassium. The clinical experts explained that they consider the diet worth trying; NICE recommends it for people with chronic kidney disease, and it lowers serum potassium compared with an unrestricted diet. They added that a new treatment option would not replace dietary advice but would complement it, and may mean that the diet need not be so strict. The patient expert stressed at the second meeting that people should be encouraged to continue to follow a low-potassium diet. The committee concluded that patiromer is unlikely to replace a strict low-potassium diet, but should be used in addition to a low-potassium diet.\n\n# Company positioning of patiromer\n\n## The company proposes patiromer for a population narrower than that covered by the marketing authorisation\n\nThe marketing authorisation indication for patiromer specifies 'treatment of hyperkalaemia in adults'. It was based on the company's trials in which people with serum potassium levels of 5.1\xa0mmol/litre or more were recruited and had treatment (see section\xa03.8). The company updated its base case in response to consultation to include people with chronic kidney disease (stages\xa03 to\xa05, excluding those on dialysis) or heart failure (who may also have chronic kidney disease) and with serum potassium of 6.0\xa0mmol/litre or more in line with clinical expert comments (see section\xa03.1). The committee heard that, of people with stage\xa03 chronic kidney disease, those with stage\xa03b were more likely to develop hyperkalaemia, and more people would likely benefit from RAAS inhibitor compared with people with stage\xa03a disease. The committee noted that the population in the company's submission was narrower than that covered by the marketing authorisation. The committee recalled that:\n\nstarting treatment at the same serum potassium level for chronic kidney disease and heart failure may be appropriate (see section\xa03.1)\n\nit had not seen evidence justifying different starting levels for chronic kidney disease and for heart failure (see section\xa03.1)\n\nmmol/litre was the same serum potassium level as that for stopping RAAS inhibitors (see section\xa03.3).Therefore, the committee concluded that it would appraise patiromer for the population and the starting serum potassium level the company proposed, which was narrower than that covered by the marketing authorisation.\n\n## The company proposes that patiromer will be used alongside standard care for acute hyperkalaemia and started in hospital for chronic hyperkalaemia\n\nThe marketing authorisation for patiromer covers using it to lower serum potassium levels. It also specifies that stopping patiromer may result in serum potassium levels rising and treatment should not be stopped without consulting a clinician. The company proposed that patiromer would be used:\n\nfor acute hyperkalaemia, instead of calcium resonium and permanently stopping RAAS inhibitors\n\ninstead of stopping RAAS inhibitors to manage chronic hyperkalaemia and to prevent life-threatening hyperkalaemia, in people with hyperkalaemia identified through routine monitoring. It also explained that patiromer would be started in hospitals.The committee noted that the marketing authorisation states that patiromer should not replace emergency treatment for life-threatening hyperkalaemia. It considered that patiromer would not replace standard emergency care for acute life-threatening hyperkalaemia, but it could also be used instead of calcium resonium alongside standard care. The committee concluded that it would appraise patiromer alongside standard care for life-threatening hyperkalaemia, and for confirmed chronic hyperkalaemia.\n\n# Clinical effectiveness\n\n## Trials do not show that patiromer is more clinically effective than NHS standard care or increases length or quality of life in chronic hyperkalaemia\n\nThe key evidence for the clinical effectiveness of patiromer came from OPAL‑HK. This was a phase\xa03, 12‑week, single-blind study that included people with stages 3\xa0and\xa04 chronic kidney disease, with or without heart failure, who were having a RAAS inhibitor, with serum potassium between 5.1\xa0mmol/litre and 6.5\xa0mmol/litre. The study had 2\xa0parts and its primary outcome was change in serum potassium:\n\nPart\xa0A, 4\xa0weeks (n=243): single-arm dose-ranging study. Everyone had patiromer, and the dosage was adjusted up to a maximum of 50.4\xa0g daily to achieve a target serum potassium between 3.8\xa0mmol/litre and 5.1\xa0mmol/litre.\n\nPart\xa0B, 8\xa0weeks (n=107): randomised, placebo-controlled trial of stopping compared with continuing patiromer, including only people having patiromer whose hyperkalaemia in part\xa0A responded (people who had a serum potassium level of 5.5\xa0mmol/litre or more at the beginning of part A and a serum potassium level between 3.8\xa0mmol/litre and 5.1\xa0mmol/litre at the end of part\xa0A) and who were still having treatment with a RAAS inhibitor.During part\xa0A of the study, serum potassium decreased for the total population by 1.01\xa0mmol/litre. In part\xa0B of the study, for people whose hyperkalaemia responded to patiromer (as defined above), serum potassium levels were 0.72\xa0mmol/litre higher in the placebo arm than the patiromer arm. However, the serum potassium levels in both arms were not within the range that would be treated in the NHS. Also, part\xa0B of the trial addressed stopping patiromer in people already on it whose hyperkalaemia had responded rather than starting patiromer in people who might benefit from it. The company submitted additional clinical evidence in response to consultation, from the PEARL‑HF and AMBER trials. However, the ERG noted that the studies were not relevant to the scope of the appraisal because the patients did not have hyperkalaemia at baseline. The committee concluded that the trial evidence did not show patiromer was more clinically effective than current NHS standard care or that patiromer increases length or quality of life for people having treatment for chronic hyperkalaemia.\n\n## Patiromer could be beneficial in treating acute life-threatening hyperkalaemia\n\nThe committee noted that acute hyperkalaemia can be fatal and treating acute life-threatening hyperkalaemia in hospital is established clinical practice. The committee agreed that lowering potassium levels for patients needing emergency care was a life-saving intervention. It therefore concluded that randomised evidence was not needed to show that treating life-threatening hyperkalaemia in emergency care prolonged life. As such, the uncontrolled evidence showing that patiromer reduces serum potassium (see section\xa03.8) was sufficient for the committee to conclude that it could be useful for people with hyperkalaemia needing treatment in emergency care, alongside standard care.\n\n## Stopping RAAS inhibitors likely increases the risk of death, hospitalisation and disease progression\n\nData were not collected in OPAL‑HK on the effect of patiromer on long-term outcomes such as progression of chronic kidney disease or mortality. However, the company proposed in its model that people with hyperkalaemia who take patiromer live longer and have a better quality of life than people who do not because treatment with patiromer would allow them to maintain or restart treatment with RAAS inhibitors. The committee noted that the company provided only exploratory data from a single-arm trial (OPAL‑HK) of patiromer. The company also submitted evidence from AMBER. This was a randomised trial comparing patiromer plus spironolactone with placebo plus spironolactone to see whether patiromer use results in more persistent use of spironolactone (a RAAS inhibitor). It showed that 20% more patients taking patiromer stayed on spironolactone than those taking placebo. However, the patients in the trial did not have hyperkalaemia at baseline; potassium levels were between 4.3\xa0mmol/litre and 5.1\xa0mmol/litre. Independent of this, based on targeted reviews for chronic kidney disease and heart failure, the company presented data from a network meta-analysis of randomised controlled trials and several observational studies. It assumed that, because these studies showed that starting a RAAS inhibitor is associated with living longer, stopping a RAAS inhibitor would be associated with dying earlier. The company presented evidence that RAAS inhibitors are associated with delayed disease progression, and therefore improved quality of life. The committee recognised that the company's evidence addressed the decision problem indirectly. It noted that the trials in the company's literature search compared starting RAAS inhibitors with not starting them, rather than the question relevant to this appraisal, that is, reducing or stopping RAAS inhibitors compared with continuing them. The committee recognised that worsening underlying disease may lead to worse hyperkalaemia, and that it was unclear whether the clinical benefit seen in the trials would translate to continued use of RAAS inhibitors. It concluded that, in the population being considered, stopping RAAS inhibitors would generally be associated with an increased risk of adverse outcomes and disease progression. The committee was not satisfied that the company had presented robust data on how patiromer alters dosing of RAAS inhibitors compared with standard care, or the extent to which such alterations improved length and quality of life. However, the committee was also aware of NICE's guidance which recommends stopping RAAS inhibitors at serum potassium levels of 6.0\xa0mmol/litre and above (see section\xa03.3). It concluded that starting RAAS inhibitors prolongs life for many people, so stopping them for people who benefit from them would likely shorten life.\n\n## There is insufficient evidence to prove that lowering serum potassium levels improves long-term outcomes\n\nThe company proposed in its model that lowering serum potassium with patiromer causes people to live longer. It based this on a review of evidence on the association between serum potassium and adverse outcomes for people with chronic kidney disease or heart failure. This evidence, from observational cohort studies, showed that a higher risk of death, hospitalisation and major adverse cardiovascular events was associated with high, but also with lower than normal, serum potassium levels. Using these data, the company assumed that, because people with higher than normal serum potassium have a higher risk of death, patiromer prolongs life because it lowers serum potassium. The committee noted that the observational data did not guarantee an independent causal effect between high serum potassium levels and death. Importantly, even if it did, the committee noted that the company did not provide evidence that lowering serum potassium extends life. The committee was aware of DIAMOND, an ongoing randomised controlled trial of patiromer compared with placebo for adults with hyperkalaemia and heart failure. Its primary outcome was time to first occurrence of hospitalisation or death. The DIAMOND trial results may, in future, provide evidence for a link between patiromer and length of life. The committee concluded that there was insufficient evidence to prove that lowering serum potassium levels for people in outpatient care improves outcomes.\n\n# Cost-effectiveness modelling\n\n## The company's updated model addresses some of the committee's concerns\n\nIn response to consultation the company made significant revisions to its model. It modelled the cost effectiveness of patiromer using a Markov model with 26\xa0health states, which included stages\xa03 and\xa04 chronic kidney disease and end-stage kidney disease (stage\xa05 chronic kidney disease). Within each chronic kidney disease state patients were grouped into one of 3\xa0serum potassium level categories (less than 5.5\xa0mmol/litre, 5.5\xa0to 6.0\xa0mmol/litre and more than 6.0\xa0mmol/litre). The company also made other changes including:\n\nonly including patients with serum potassium levels of 6.0\xa0mmol/litre or more\n\nnot assuming a direct link between lowering serum potassium and mortality, only an indirect link through continued RAAS inhibitor use\n\nmodelling separate chronic kidney disease health states for stages\xa03 and\xa04 (previously modelled as the same health state)\n\nrevising the proportion of hyperkalaemia episodes resulting in hospitalisation from 100% to:\n\n\n\n% for people with serum potassium more than 5.0\xa0mmol/litre\n\n% for people with serum potassium between 5.5\xa0mmol/litre and 6.0\xa0mmol/litre and\n\n% for people with serum potassium of more than 6.0\xa0mmol/litre.The committee noted that although the company had attempted to address many of its concerns, some issues remained. These included the rate of recurrence of hyperkalaemia (see section\xa03.14) and the source of data for stopping patiromer (see section\xa03.15).\n\n\n\n## The very limited clinical evidence increases uncertainty\n\nThe company updated the population in its economic model to people with serum potassium of 6.0\xa0mmol/litre or more to match the committee's conclusion about when treatment for hyperkalaemia starts in the NHS (see section\xa03.1). However, the committee noted that few patients in the OPAL-HK trial had serum potassium levels above 6.0\xa0mmol/litre. This meant that the data for patiromer in the economic model was based on only 26\xa0patients. The committee agreed this was appropriate for people with heart failure and stages\xa03b, 4\xa0and\xa05 chronic kidney disease. It was aware that the company had included people with stage\xa03a chronic kidney disease, but considered that the absolute benefit would be greater in people with stage\xa03b chronic kidney disease. The committee was also aware that all patients in the OPAL‑HK trial had chronic kidney disease and some also had heart failure. It considered that given its conclusion that it was appropriate to focus on the level of serum potassium rather than the underlying condition (see section\xa03.1), it was likely that the results would also hold for people with heart failure alone. This is because the main benefit of potassium-lowering treatments in chronic hyperkalaemia is to allow people to take RAAS inhibitors, which are beneficial in heart failure. However, the committee concluded that the very limited clinical evidence informing the model increased the uncertainty associated with the cost-effectiveness estimates.\n\n## The rate of recurrence of hyperkalaemia used by the company is unrealistically low\n\nTo inform the rate of recurrence of hyperkalaemia in the model, the company used data from the clinical practice research datalink. The ERG highlighted that the rate of recurrence was very low, between 0.04% to 1.03% per month depending on serum potassium levels and chronic kidney disease stage. This was much lower than the rate in the placebo arm of OPAL‑HK. The rate was so low, in part because it was estimated from a large sample of patients in the clinical practice research datalink data with serum potassium lower than 5.5\xa0mmol/litre at baseline. So, it did not reflect the population in the model. To model recurrence in the patiromer arm, the company applied the hazard ratio from the OPAL‑HK trial to the annual rate derived from these data. The committee was concerned that, given the very low baseline rate of hyperkalaemia recurrence, the probability of hyperkalaemia recurring increased only slightly when people stopped taking patiromer. It concluded that this was unlikely because patiromer is not disease-modifying, so serum potassium would be expected to increase once treatment stops. It also concluded that the rate of recurrence was unrealistically low for this population. However, the committee was unclear what effect using a higher rate of recurrence would have on the cost-effectiveness results because both patients taking and not taking patiromer would experience more episodes of hyperkalaemia.\n\n## The company's source of data for stopping patiromer is not appropriate\n\nIn its updated base case, the company used US claims registry data to model the rate at which people stop treatment with patiromer. Previously it used data from AMETHYST‑DN, a 1‑year trial of patiromer at different doses in people with type\xa02 diabetes, chronic kidney disease and serum potassium between 4.3\xa0mmol/litre and 6.0\xa0mmol/litre. The company explained that it had used US claims data because this would better reflect stopping in clinical practice than would randomised controlled trial data from AMETHYST‑DN. The ERG explained that the US claims data were unlikely to represent use of patiromer in UK clinical practice because the settings are very different. The ERG continued to use the data from AMETHYST‑DN in its base case, in which over half of the patients remained on treatment at 3\xa0years. The ERG also did a scenario analysis using OPAL‑HK data to model stopping patiromer. This curve was closer to the US claims data curve, with just under a third of patients on treatment at 1\xa0year. However, the committee noted that the short trial period for OPAL‑HK (12\xa0weeks) meant that extrapolating these data is uncertain. The committee considered that the average time on treatment in the NHS would be longer than seen in the US claims data. This was because the condition of the population in this appraisal, with chronic kidney disease and heart failure and serum potassium greater than 6.0\xa0mmol/litre, was likely to worsen over time. They would therefore need to continue treatment with patiromer while taking RAAS inhibitors. It concluded that the rate at which people stop patiromer was more likely to lie somewhere between the rates based on OPAL‑HK and AMETHYST‑DN.\n\n## The company's approach to modelling the association between RAAS inhibitor use and outcomes is appropriate, but the data are inadequate\n\nThe company modelled an association between the use of RAAS inhibitors and the risks of mortality, hospitalisation and major adverse cardiovascular events. This was based on odds ratios from a network meta-analysis of clinical trials of starting RAAS inhibitors (Xie et al. 2016). The committee recalled and accepted evidence from the clinical and patient experts that maintaining RAAS inhibitor therapy is likely to benefit certain patients (see section\xa03.10). The committee did not see robust evidence of patiromer's effect on RAAS inhibitor use. However, it was aware that clinicians are encouraged to stop RAAS inhibitor treatment for people with serum potassium levels of 6.0\xa0mmol/litre and above. The committee considered that any guidance for patiromer would be limited to people who could take RAAS inhibitors. It concluded that the company's approach to modelling the association between RAAS inhibitor use and outcomes was appropriate.\n\n# Cost-effectiveness estimates\n\n## Patiromer is recommended as a treatment option\n\nThe company's base-case incremental cost-effectiveness ratio (ICER) was £6,774 per quality-adjusted life year gained for patiromer compared with standard care. The committee recalled that this analysis was based on US claims data for stopping patiromer and may not reflect UK clinical practice (see section\xa03.15). Therefore, the committee also considered the ERG's analyses that varied the source of data for stopping patiromer:\n\nERG's base case: stopping patiromer based on data from AMETHYST‑DN, everyone stops treatment at 5\xa0years\n\nERG's scenario: stopping patiromer based on data from OPAL‑HK.The committee recalled its conclusion that the rate at which people stop patiromer was likely to lie between the 2\xa0ERG scenarios (see section\xa03.15). In both ERG scenarios, the ICER was higher than in the company's base case. The committee considered that the model was sensitive to treatment duration because the low baseline rate of recurrence of hyperkalaemia means that longer treatment with patiromer incurs costs which outweigh the benefits (see section\xa03.14). It therefore considered that with a higher baseline rate of hyperkalaemia recurrence, longer treatment duration may not increase the ICERs as much as in the ERG's analysis. The committee therefore concluded that patiromer was likely to represent a cost-effective use of NHS resources for treating chronic hyperkalaemia and, based on the conclusion in section\xa03.9, alongside standard care for treating acute hyperkalaemia. It emphasised that uncertainties remained around patiromer's clinical benefit and that these could be addressed by clinical trials (see section\xa05.1).\n\n# Innovation\n\n## The company has not shown that patiromer is innovative\n\nThe company proposed several benefits of patiromer but did not show evidence of these. They included not needing to modify RAAS inhibitor treatment and avoiding a restrictive low-potassium diet. The committee was aware that other gastrointestinal potassium binders exist and that patiromer does not represent a step-change in treatment. It concluded that patiromer could not be considered innovative.", 'Recommendations for research': 'The committee noted that there was no clinical evidence showing that having patiromer improved length or quality of life or allowed patients to stay on optimal doses of renin-angiotensin-aldosterone system (RAAS) inhibitors. It therefore considered that it would be valuable to have studies comparing patiromer plus standard care with standard care alone in people with confirmed hyperkalaemia of 6.0\xa0mmol/litre and above, and that these should investigate:\n\nmortality\n\ndisease progression\n\npatterns of RAAS inhibitor use\n\nhealthcare utilisation and\n\nhealth-related quality of life.The committee recalled that the DIAMOND trial is ongoing and may help to provide evidence on mortality (see section\xa03.11). However, the trial is not going to complete until 2022. The committee concluded that the guidance should be reviewed when evidence from DIAMOND is available.'}
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https://www.nice.org.uk/guidance/ta623
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Evidence based recommendations on patiromer (Veltassa) for treating hyperkalaemia in adults.
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a4f447a52e8b8149c3a4847c35201ab768d9c0ff
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nice
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Sotagliflozin with insulin for treating type 1 diabetes
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Sotagliflozin with insulin for treating type 1 diabetes
Evidence-based recommendations on sotagliflozin with insulin for treating type 1 diabetes in adults with a body mass index (BMI) of at least 27 kg/m2, when insulin alone does not provide adequate glycaemic control despite optimal insulin therapy.
# Recommendations
Sotagliflozin with insulin is recommended as an option for treating type 1 diabetes in adults with a body mass index (BMI) of at least 27 kg/m2, when insulin alone does not provide adequate glycaemic control despite optimal insulin therapy, only if:
sotagliflozin is given as one 200 mg tablet daily
they are on insulin doses of 0.5 units/kg of body weight/day or more and
they have completed a structured education programme that is evidence based, quality assured, delivered by trained educators and includes information about diabetic ketoacidosis, such as:
how to recognise its risk factors, signs and symptoms
how and when to monitor blood ketone levels
what actions to take for elevated blood ketones and
treatment is started and supervised by a consultant physician specialising in endocrinology and diabetes treatment, and haemoglobin A1c (HbA1c) levels are assessed after 6 months and regularly after this.
Stop sotagliflozin if there has not been a sustained improvement in glycaemic control (that is, a fall in HbA1c level of about 0.3% or 3 mmol/mol).
These recommendations are not intended to affect treatment with sotagliflozin that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Sotagliflozin (one 200 mg tablet daily) is an option for some people who cannot manage their type 1 diabetes with insulin alone.
Evidence from clinical trials run for 1 year in this population shows improvements in blood glucose (HbA1c) and weight loss, and improvements in quality of life, with sotagliflozin plus insulin compared with people on placebo plus insulin. The company assumes that the improvement in HbA1c results in a lower risk of long-term complications over a person's lifetime. It's reasonable to assume some relationship between lowering HbA1c and reducing diabetic complications, and between lowering BMI and improving quality of life.
If sotagliflozin improves HbA1c for only 2 years, and no other physiological factors, the cost-effectiveness estimate for sotagliflozin plus insulin compared with insulin alone is within the range that NICE normally considers an acceptable use of NHS resources. Sotagliflozin with insulin is therefore recommended as an option for type 1 diabetes in adults. Because of the increased risk of diabetic ketoacidosis, sotagliflozin should be stopped if blood glucose control does not improve.# Information about sotagliflozin
Marketing authorisation indication
Sotagliflozin is indicated 'as an adjunct to insulin therapy to improve glycaemic control in adults with type 1 diabetes mellitus with a body mass index (BMI) 27 kg/m2 or more, who have failed to achieve adequate glycaemic control despite optimal insulin therapy'.
Sotagliflozin should not be started in people with type 1 diabetes with a low insulin need. It should not be started in people with a glomerular filtration rate of less than 60 ml/min and should be stopped at a glomerular filtration rate persistently below 45 ml/min. Sotagliflozin should be initiated and supervised by a physician experienced in the management of type 1 diabetes mellitus. During treatment with sotagliflozin, insulin therapy should be continuously optimised to prevent ketosis and diabetic ketoacidosis, and the insulin dose should only be reduced to avoid hypoglycaemia.
Dosage in the marketing authorisation
Administered orally as a 200 mg tablet once daily before the first meal of the day. After at least 3 months, if additional glycaemic control is needed, in patients tolerating sotagliflozin 200 mg, the dose may be increased to 400 mg once daily.
Price
The list price of sotagliflozin is £39.20 for 30×200 mg tablets (company submission document B). The treatment cost at list price is £477.30 per year. Costs may vary in different settings because of negotiated procurement discounts.# Committee discussion
The appraisal committee considered evidence submitted by Sanofi and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Clinical management
## People normally have structured education and optimised insulin therapy
Type 1 diabetes is an autoimmune metabolic disease that destroys insulin-producing cells of the pancreas. This raises the levels of blood glucose, which increases the risk of long-term diabetes-related complications. These include, but are not limited to, retinopathy, neuropathy, cardiovascular disease and death. People with type 1 diabetes manage their condition by making choices about diet and physical activity and by injecting insulin. The NICE guideline on type 1 diabetes in adults recommends that people have individualised care, including structured education (for example, the Dose Adjustment For Normal Eating programme), and advice on diet and physical activity (that is, lifestyle), and on managing blood glucose. The guideline advises on targets for haemoglobin A1c (HbA1c) levels, self-monitoring of blood glucose, and preventing and managing hypoglycaemia and diabetic ketoacidosis. It also encourages people to identify and control risk factors for cardiovascular disease, manage diabetes-related complications and optimise their insulin therapy. Optimised management of insulin may include injection technique and rotating sites, dosing of insulin, skills for self-monitoring, and using continuous subcutaneous insulin infusion ('insulin pump') instead of multiple injections of insulin. The clinical experts explained that people who optimally manage insulin would normally have done a structured education course, as described in NICE's quality standard on diabetes in adults. For people who, despite best efforts, cannot reach optimal glycaemic control, or who cannot improve control without it causing disabling hypoglycaemia, there were no other pharmacological options in established clinical practice at the time of the first committee meeting for this appraisal. The NICE technology appraisal guidance on dapagliflozin with insulin for type 1 diabetes recommends dapagliflozin as an option for people with type 1 diabetes with a body mass index (BMI) of 27 kg/m2 or more on insulin doses of 0.5 units/kg of body weight/day or more. This was published during the development of this appraisal, and so was not considered routine practice.
# Experience of people with type 1 diabetes
## There is a need for interventions that help people control their diabetes without adverse effects from treatment
Managing blood glucose involves, for most people, multiple blood glucose finger prick tests and multiple insulin injections every day. People adjust the dose of insulin according to their diet, activity level and other circumstances such as stress and illness. A clinical expert explained that although insulin pumps and structured education such as DAFNE are useful tools, managing the condition is demanding and requires a disciplined balance of insulin, diet and lifestyle. The risk of hypoglycaemia from injected insulin, and having to adjust doses, can considerably affect wellbeing and quality of life. Treatment with insulin can be associated with weight gain. The clinical experts further highlighted that only about 30% of people reach their glycaemic target, and there is an unmet clinical need for an additional treatment for people who cannot safely reach optimal glycaemic control. The clinical experts suggested that sodium-glucose cotransporter (SGLT) inhibitors such as sotagliflozin could increase the proportion of time someone spends in an appropriate blood glucose range. The committee concluded that there is an unmet need for treatments that help people control their diabetes without treatment-related adverse effects.
# People who might take sotagliflozin
## Sotagliflozin is clinically appropriate for a restricted population
Sotagliflozin is a dual inhibitor of sodium glucose cotransporter type 1 (SGLT1) and SGLT2. It has a marketing authorisation only for type 1 diabetes. The European Medicines Agency restricted the marketing authorisation for sotagliflozin with insulin to people with a BMI of 27 kg/m2 or more who do not have adequate glycaemic control despite optimal insulin therapy because of the association between treatment with sotagliflozin and diabetic ketoacidosis. The summary of product characteristics for sotagliflozin states 'sotagliflozin should be initiated and supervised by a physician experienced in the management of type 1 diabetes mellitus', and that it 'should not be initiated when patients are at a higher risk of diabetic ketoacidosis', such as people with a 'low insulin need'. One of the clinical experts explained that it was important to identify people in whom the benefit of treatment outweighs the risk of diabetic ketoacidosis and this would require specialist knowledge. Low insulin need is defined as less than 0.5 units of insulin/kg of body weight/day in NICE's technology appraisal guidance on dapagliflozin with insulin for type 1 diabetes. In the same guidance, the clinical population consisted of people:
with a BMI of 27 kg/m2 or more
who have completed a structured education programme
with insulin needs of 0.5 units/kg of body weight/day or more
with inadequate glycaemic control despite structured education as defined by NICE's quality standard on diabetes in adults
with optimised insulin therapy
who are aware of the increased risk of diabetic ketoacidosis and are able to do blood glucose and ketone testing to enable them to prevent, recognise and treat diabetic ketoacidosis and hypoglycaemia.The committee was aware that dapagliflozin, an SGLT2 inhibitor, has properties in common with sotagliflozin. So it considered that the same criteria used to define the population for dapagliflozin would also apply to sotagliflozin. The committee concluded that sotagliflozin was clinically appropriate for a restricted population, and in line with the summary of product characteristics, sotagliflozin would need to be started and supervised by a consultant physician specialising in endocrinology and diabetes.
# Clinical evidence
## The key trials for sotagliflozin, inTandem1 and inTandem2, do not include dose escalation
The main evidence for sotagliflozin came from 2 trials, inTandem1 and inTandem2. These trials compared sotagliflozin plus insulin therapy at 2 doses (200 mg or 400 mg) with placebo plus insulin therapy over 52 weeks. They were randomised and included 1,575 people with inadequately controlled type 1 diabetes, of whom 916 had a BMI of 27 kg/m2 or more. The primary endpoint in both trials was the difference between groups in the change in HbA1c from baseline at 24 weeks. The committee was aware that the summary of product characteristics for sotagliflozin stated that if someone needs additional glycaemic control after 3 months on sotagliflozin, the dose may be increased to 400 mg once daily. However, the company provided no clinical evidence for escalating the dose, as this was not included in the clinical trials. Therefore, the committee had not seen enough evidence to make recommendations on increasing the dose of sotagliflozin from one 200 mg to two 200 mg tablets daily.
## The pooled inTandem trial data are appropriate for decision making
The committee heard from the clinical experts that inTandem1 was likely to be less generalisable to the NHS than inTandem2, because inTandem1 had no UK sites, and it was based in the USA where there is higher use of continuous subcutaneous insulin infusion (insulin pumps) than the UK, and the average BMI is higher. inTandem2 had many sites in Europe and the UK. The committee considered that higher use of insulin pumps in inTandem1 and inTandem2 than in clinical practice may mean that the risk of diabetic ketoacidosis is higher in the trials than in the NHS. The company clarified that the average BMI in the pooled analyses of the inTandem1 and inTandem2 data for people with a BMI of 27 kg/m2 or more was 32 kg/m2, and that this was in line with the average BMI for the NHS for people with a BMI of 27 kg/m2 or more based on the UK National Diabetes Audit data. The committee agreed that although inTandem1 was likely to be more generalisable to NHS practice than inTandem2, it was important to pool these trials to consider all of the relevant data. It concluded that the pooled inTandem results were generalisable to the NHS and appropriate for decision making.
## The company limited the trial data to people who are likely to receive sotagliflozin in clinical practice
The committee considered whether the trial population reflected the restricted population that was clinically appropriate for sotagliflozin (see section 3.3). People were recruited to the inTandem1 and inTandem2 trials if their HbA1c levels were between 7% (about 53 mmol/mol) and 11% (about 97 mmol/mol). The trials included a 6‑week lead-in period, during which insulin dose was optimised. After optimisation, HbA1c was less than 7% (about 53 mmol/mol) for 17% to 20% of people across the inTandem1 and inTandem2 trials. The clinical experts acknowledged that the target for glycaemic control in the NICE guideline on type 1 diabetes in adults was 6.5% (about 48 mmol/mol) but explained that an HbA1c target of 7% (about 53 mmol/mol) or less was reasonable, and they would be unlikely to intensify treatment in people with an HbA1c of less than 7% (about 53 mmol/mol). Furthermore, the committee recalled that sotagliflozin is clinically appropriate for a restricted population (see section 3.3). The company submitted evidence on the clinical effectiveness of sotagliflozin in the clinically appropriate restricted population (that is, people with a BMI of at least 27 kg/m2, an HbA1c of greater than 7% (about 53 mmol/mol) after the optimisation period, and with insulin requirements of 0.5 units/kg of body weight/day or more). The committee agreed that this population was similar to people who would have treatment with sotagliflozin in clinical practice (except that it would be used in people with insulin requirements of 0.5 units/kg of body weight/day or more) and that it would focus on these data.
## In the short term, sotagliflozin improves HbA1c and BMI but the impact on other parameters is mixed
The company presented data for the subgroup eligible for treatment with sotagliflozin, as requested by the committee (see section 3.3). The pooled inTandem1 and inTandem2 trial results for this subgroup showed a larger reduction in HbA1c from baseline at 24 weeks in people randomised to sotagliflozin plus insulin therapy than people randomised to placebo plus insulin therapy. This difference was larger from 0 to 24 weeks (0.39%, about 14 mmol/mol) than from 24 and 52 weeks (0.28%, about 3 mmol/mol). The ERG explained that, based on the trial data, HbA1c was likely to return to baseline by the end of the second year. In addition, people randomised to sotagliflozin plus insulin therapy had a greater reduction in BMI than people randomised to placebo plus insulin therapy at 24 weeks (0.8 kg/m2), which increased at 52 weeks (0.93 kg/m2). The committee also saw that at 52 weeks randomisation to 200 mg of sotagliflozin lowered both systolic and diastolic blood pressure, had a mixed effect on cholesterol, and worsened the estimated glomerular filtration rate, reflecting reduced renal function. The committee was aware that, because the 52‑week data had been calculated by the NICE team without confidence intervals, the statistical significance of the results was unknown and only limited conclusions could be drawn. It concluded that sotagliflozin with insulin modestly improved HbA1c and BMI compared with insulin alone, and the impact on other parameters was mixed.
# Blood glucose and risk of diabetes-related complications
## Lowering blood glucose (HbA1c) levels decreases the risk of diabetes-related complications
HbA1c is a recognised surrogate endpoint for long-term complications of diabetes. Treatment to lower HbA1c levels in type 1 diabetes to near-normal levels decreases the risk of complications such as myocardial infarction, stroke and retinopathy. The Diabetes Control and Complications Trial (DCCT) showed an average relative decrease in HbA1c levels of 2% (about 22 mmol/mol) over 10 years in people who had intensive therapy, that is, multiple daily insulin injections (or an insulin pump) compared with those who had conventional glycaemic control, that is, no more than 2 injections. This reduced the risk of microvascular complications by over half. The DCCT's 30‑year, observational, follow‑on study (Epidemiology of Diabetes Interventions and Complications ) showed that people who had previously been randomised to intensive therapy had a lower risk of macrovascular complications and death than people who had been randomised to conventional glycaemic control. The company used data from EDIC in its economic model to infer the risk of complications based on changes in physiological parameters such as HbA1c and BMI. The committee discussed whether the results of EDIC were generalisable to therapies such as sotagliflozin that lower blood glucose by a much smaller magnitude and with only short-term evidence. It agreed that this was an area of uncertainty, and that the company had not shown evidence of a beneficial impact of sotagliflozin on diabetes complications. The committee concluded that while there is no evidence of sotagliflozin reducing the risk of complications, sotagliflozin plus insulin lowered blood glucose more than insulin alone (see section 3.7), and data from EDIC could be used to show that lowering blood glucose levels decreases the risk of diabetes-related complications.
# Adverse events
## Diabetic ketoacidosis risk is higher with sotagliflozin plus insulin than with insulin alone
The committee noted that sotagliflozin was associated with an increased risk of adverse events including genital tract infection, urinary tract infection and, in particular, diabetic ketoacidosis. The committee was aware that the European Medicines Agency limited the marketing authorisation to people with a BMI of 27 kg/m2 or more, and excluded people with a 'low insulin need' (see section 3.3) to reduce the risk of this potentially life-threatening adverse effect. However, the company confirmed that sotagliflozin was still associated with an increased risk of diabetic ketoacidosis in this restricted population. The incidence in the inTandem1 and inTamden2 pooled population with a BMI of 27 kg/m2 or more was 8 times higher (3.2 events for every 100 patient years) in the sotagliflozin plus insulin arm than in the insulin alone arm (0.4 events for every 100 patient years); these results included people with a low insulin need. The clinical experts explained that they would not offer sotagliflozin to someone who had not received structured education as defined in NICE's quality standard on diabetes in adults, and who could not recognise the signs and symptoms of diabetic ketoacidosis. The committee concluded that sotagliflozin should not be offered to someone who had not completed structured education to the specification defined in the NICE quality standard, and who was not able to detect diabetic ketoacidosis.
# The company's economic model
## The model uses risk equations to link changes in HbA1c and other parameters from the trials to diabetes complications over a lifetime
The company used a patient-level model (CORE Diabetes Model version 9) to simulate disease progression and complications over a lifetime time horizon. The company defined treatment effects after 1 year of treatment as changes in HbA1c, BMI, systolic blood pressure, serum lipids and, as confirmed in the committee's second meeting, diastolic blood pressure and renal function measured by estimated glomerular filtration rate. The company derived these from a pooled analysis of inTandem1 and inTandem2, limited to the committee's preferred population. To estimate complications linked to changes in HbA1c, systolic blood pressure, lipid parameters and renal function in the economic model, the company used risk equations based on the UKPDS 68 study. There was an additional adjustment to these equations in the CORE model using data from the EDIC study for HbA1c and systolic blood pressure only and not the lipid parameters or renal function. The ERG explained that changes in the ratio of total cholesterol to high density lipoprotein cholesterol were linked to changes in ischaemic heart disease, myocardial infarction and stroke. Plasma triglycerides did not affect diabetes-related complications in the model. The ERG explained that other baseline characteristics in the model also affected the probability of having a complication and therefore could affect life length, quality of life or both. These baseline characteristics included BMI, total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol and estimated glomerular filtration rate. The company's model assumed that sotagliflozin affected all physiological parameters in the economic model and predicted that sotagliflozin increased length of life and improved quality of life. The ERG noted that the key parameters driving the cost effectiveness of sotagliflozin were HbA1c followed by BMI. The committee was concerned that the company was not able to explain how changes in BMI affect complications in its model during the committee meeting. The committee recalled the evidence that sotagliflozin might affect all physiological parameters, but because it was not clear how the company's model worked, it agreed that it would be reasonable to consider analyses for sotagliflozin affecting all or some physiological variables, and analyses that affected only HbA1c.
## Small changes seen in the inTandem trials may translate to a reduced risk of long-term complications in the economic model
The committee noted that the improvement in HbA1c level in DCCT and EDIC (for multiple daily injections of insulin compared with conventional glycaemic control) was substantially bigger (about a 2% reduction), and sustained for substantially longer (over 10 years) than the improvement in HbA1c level in the pooled inTandem trials (0.39% reduction over 1 year with sotagliflozin plus insulin compared with placebo plus insulin) in the preferred population. The committee was concerned that the company had assumed that the benefit associated with the smaller and shorter reduction in HbA1c seen from inTandem was proportional to the benefit of a sustained larger difference in HbA1c seen in DCCT and EDIC in terms of fewer complications (see section 3.8). The committee was concerned by the company's approach that reducing HbA1c immediately lowered the incidence of microvascular and macrovascular complications. It heard from the clinical experts that, although there are data to show lowering HbA1c is associated with a decrease in diabetic complications, there are no data to show that weight loss alone would reduce diabetes-related complications. The committee was aware that in studies of type 2 diabetes, weight loss is associated with an improved quality of life. But the committee had not seen any evidence to support this in type 1 diabetes. The committee concluded that it was reasonable to assume some relationship between lowering HbA1c and reducing diabetic complications, and an association between lowering BMI and improving quality of life.
# Cost-effectiveness estimate
## The company's updated base case includes many of the committee's preferences
The company's revised base case included many of the committee's preferred assumptions:
people with a BMI of 27 kg/m2 or more, insulin needs of 0.5 units/kg of body weight/day or more and HbA1c of 7% (about 53 mmol/mol) or more after people optimised their insulin (see section 3.3)
baseline characteristics from the pooled trial data (see section 3.5)
treatment efficacy with sotagliflozin based on 52‑week data improving HbA1c and BMI with treatment efficacy waning after the first year (see section 3.7)
treatment with sotagliflozin for 2 years based on pooled trial data, which suggests that the effect of sotagliflozin on HbA1c returns to baseline at the end of the second year (see section 3.7) and treatment should stop if glycaemic control does not improve (see section 3.15)
updated adverse events including case fatality for diabetic ketoacidosis to reflect the UK (0.7%), severe hypoglycaemia (4.45% in line with assumptions in NICE technology appraisal guidance on dapagliflozin with insulin for type 1 diabetes) and Fournier's gangrene.The probabilistic cost-effectiveness estimates for sotagliflozin compared with standard care for the company's revised base case were £16,093 per quality-adjusted life year (QALY) gained. Although the company had addressed most of the committee's preferences, the committee was concerned that the company had only used data at 24 weeks from the pooled inTandem trials and had not used the 52‑week data. Furthermore, because of uncertainties associated with how the model worked, the committee concluded that it wanted to see scenarios limiting the benefit of treatment with sotagliflozin to improvement in HbA1c.
## The ERG's scenario analyses explore the extrapolation of trial results over a patient's lifetime
The ERG updated the company's base case so that it was better aligned with all of the committee preferences. It:
identified an error in the company model and changed the mortality probability for severe hypoglycaemia from 4% to 4.45% (see section 3.12)
used 24- and 52‑week data from inTandem1 and inTandem2 to estimate the treatment effect of sotagliflozin (see section 3.12).The impact of these adjustments increased the company's probabilistic base-case incremental cost-effectiveness ratio (ICER) for sotagliflozin compared with insulin from £16,093 to £19,046 per QALY gained.The committee had concerns that sotagliflozin was assumed to affect all physiological parameters in the economic model (see section 3.10). The ERG provided 2 scenario analyses to address these concerns:
treatment effect for all physiological parameters
treatment effect for HbA1c only.These scenarios resulted in probabilistic ICERs of £15,163 and £25,115 per QALY gained respectively. The committee noted that both of these scenarios included a relationship between physiological parameters (see section 3.10) and the long-term risk of macrovascular and microvascular complications. The committee recalled its conclusions that sotagliflozin with insulin modestly improved HbA1c and BMI, compared with insulin alone (see section 3.7). It concluded that the most plausible ICER is between £15,163 per QALY gained and £25,115 per QALY gained.
## Sotagliflozin with insulin appears to be cost effective when insulin alone does not provide adequate glycaemic control despite optimal insulin therapy
The committee concluded that sotagliflozin with insulin appears to be a cost-effective use of NHS resources for treating type 1 diabetes in adults with a BMI of 27 kg/m2 or more when insulin alone does not provide adequate glycaemic control despite optimal insulin therapy. It also considered the recommendations for starting treatment used in NICE's technology appraisal guidance on dapagliflozin with insulin for type 1 diabetes would be relevant to this appraisal. The committee further concluded that all the following criteria should also be included in the recommendation:
people are on insulin doses of 0.5 units/kg of body weight/day or more (see section 3.3)
people have completed a structured education programme such as DAFNE, which includes training on diabetes ketoacidosis, before starting treatment (see section 3.3)
treatment is started and supervised by a consultant physician specialising in endocrinology and diabetes (see section 3.3)
HbA1c level is assessed after 6 months (and regularly after this), and sotagliflozin is stopped if there has not been a sustained improvement in glycaemic control, that is, a fall in HbA1c level of at least 0.3% (see section 3.15).
## People should stop sotagliflozin if glycaemic control does not improve
The committee noted that the cost-effectiveness estimates (see section 3.13) did not include treatment discontinuation or a stopping rule if glycaemic control was not improved. The committee was aware that in NICE's technology appraisal guidance on dapagliflozin with insulin for type 1 diabetes, a clinically meaningful reduction in HbA1c levels was defined as at least 0.3 percentage points. The clinical experts explained that it would be reasonable to stop treatment if there was not a clinically meaningful decrease in glycaemic control, defined as a change in HbA1c level of at least 0.3 percentage points. The committee recognised that, in general, ongoing treatment in the absence of a clinically meaningful improvement in HbA1c level would subject the person to risks of diabetic ketoacidosis and the NHS to costs. It concluded that HbA1c should be assessed after 6 months of starting treatment and then regularly after this, and that sotagliflozin should be stopped if glycaemic control does not improve (that is, a fall in HbA1c level of at least 0.3%).
## Equality issues
No equality issues were raised by stakeholders.
## There are no additional benefits not adequately captured in the QALY
The committee recognised that there is an unmet need for people with inadequately controlled type 1 diabetes despite optimised insulin therapy. It agreed that sotagliflozin is innovative, but all health benefits are likely to be captured in the model. Furthermore, the committee did not consider sotagliflozin a step change in managing type 1 diabetes because of the modest benefits seen in the clinical trials (see section 3.7).
|
{'Recommendations': "Sotagliflozin with insulin is recommended as an option for treating type\xa01 diabetes in adults with a body mass index (BMI) of at least 27\xa0kg/m2, when insulin alone does not provide adequate glycaemic control despite optimal insulin therapy, only if:\n\nsotagliflozin is given as one 200\xa0mg tablet daily\n\nthey are on insulin doses of 0.5\xa0units/kg of body weight/day or more and\n\nthey have completed a structured education programme that is evidence based, quality assured, delivered by trained educators and includes information about diabetic ketoacidosis, such as:\n\n\n\nhow to recognise its risk factors, signs and symptoms\n\nhow and when to monitor blood ketone levels\n\nwhat actions to take for elevated blood ketones and\n\n\n\ntreatment is started and supervised by a consultant physician specialising in endocrinology and diabetes treatment, and haemoglobin A1c (HbA1c) levels are assessed after 6\xa0months and regularly after this.\n\nStop sotagliflozin if there has not been a sustained improvement in glycaemic control (that is, a fall in HbA1c level of about 0.3% or 3\xa0mmol/mol).\n\nThese recommendations are not intended to affect treatment with sotagliflozin that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nSotagliflozin (one 200\xa0mg tablet daily) is an option for some people who cannot manage their type\xa01 diabetes with insulin alone.\n\nEvidence from clinical trials run for 1\xa0year in this population shows improvements in blood glucose (HbA1c) and weight loss, and improvements in quality of life, with sotagliflozin plus insulin compared with people on placebo plus insulin. The company assumes that the improvement in HbA1c results in a lower risk of long-term complications over a person's lifetime. It's reasonable to assume some relationship between lowering HbA1c and reducing diabetic complications, and between lowering BMI and improving quality of life.\n\nIf sotagliflozin improves HbA1c for only 2\xa0years, and no other physiological factors, the cost-effectiveness estimate for sotagliflozin plus insulin compared with insulin alone is within the range that NICE normally considers an acceptable use of NHS resources. Sotagliflozin with insulin is therefore recommended as an option for type\xa01 diabetes in adults. Because of the increased risk of diabetic ketoacidosis, sotagliflozin should be stopped if blood glucose control does not improve.", 'Information about sotagliflozin': "Marketing authorisation indication\n\nSotagliflozin is indicated 'as an adjunct to insulin therapy to improve glycaemic control in adults with type\xa01 diabetes mellitus with a body mass index (BMI) 27\xa0kg/m2 or more, who have failed to achieve adequate glycaemic control despite optimal insulin therapy'.\n\nSotagliflozin should not be started in people with type\xa01 diabetes with a low insulin need. It should not be started in people with a glomerular filtration rate of less than 60\xa0ml/min and should be stopped at a glomerular filtration rate persistently below 45\xa0ml/min. Sotagliflozin should be initiated and supervised by a physician experienced in the management of type\xa01 diabetes mellitus. During treatment with sotagliflozin, insulin therapy should be continuously optimised to prevent ketosis and diabetic ketoacidosis, and the insulin dose should only be reduced to avoid hypoglycaemia.\n\nDosage in the marketing authorisation\n\nAdministered orally as a 200\xa0mg tablet once daily before the first meal of the day. After at least 3\xa0months, if additional glycaemic control is needed, in patients tolerating sotagliflozin 200\xa0mg, the dose may be increased to 400\xa0mg once daily.\n\nPrice\n\nThe list price of sotagliflozin is £39.20 for 30×200\xa0mg tablets (company submission document\xa0B). The treatment cost at list price is £477.30 per year. Costs may vary in different settings because of negotiated procurement discounts.", 'Committee discussion': "The appraisal committee considered evidence submitted by Sanofi and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Clinical management\n\n## People normally have structured education and optimised insulin therapy\n\nType\xa01 diabetes is an autoimmune metabolic disease that destroys insulin-producing cells of the pancreas. This raises the levels of blood glucose, which increases the risk of long-term diabetes-related complications. These include, but are not limited to, retinopathy, neuropathy, cardiovascular disease and death. People with type\xa01 diabetes manage their condition by making choices about diet and physical activity and by injecting insulin. The NICE guideline on type\xa01 diabetes in adults recommends that people have individualised care, including structured education (for example, the Dose Adjustment For Normal Eating [DAFNE] programme), and advice on diet and physical activity (that is, lifestyle), and on managing blood glucose. The guideline advises on targets for haemoglobin\xa0A1c (HbA1c) levels, self-monitoring of blood glucose, and preventing and managing hypoglycaemia and diabetic ketoacidosis. It also encourages people to identify and control risk factors for cardiovascular disease, manage diabetes-related complications and optimise their insulin therapy. Optimised management of insulin may include injection technique and rotating sites, dosing of insulin, skills for self-monitoring, and using continuous subcutaneous insulin infusion ('insulin pump') instead of multiple injections of insulin. The clinical experts explained that people who optimally manage insulin would normally have done a structured education course, as described in NICE's quality standard on diabetes in adults. For people who, despite best efforts, cannot reach optimal glycaemic control, or who cannot improve control without it causing disabling hypoglycaemia, there were no other pharmacological options in established clinical practice at the time of the first committee meeting for this appraisal. The NICE technology appraisal guidance on dapagliflozin with insulin for type\xa01 diabetes recommends dapagliflozin as an option for people with type\xa01 diabetes with a body mass index (BMI) of 27\xa0kg/m2 or more on insulin doses of 0.5\xa0units/kg of body weight/day or more. This was published during the development of this appraisal, and so was not considered routine practice.\n\n# Experience of people with type\xa01 diabetes\n\n## There is a need for interventions that help people control their diabetes without adverse effects from treatment\n\nManaging blood glucose involves, for most people, multiple blood glucose finger prick tests and multiple insulin injections every day. People adjust the dose of insulin according to their diet, activity level and other circumstances such as stress and illness. A clinical expert explained that although insulin pumps and structured education such as DAFNE are useful tools, managing the condition is demanding and requires a disciplined balance of insulin, diet and lifestyle. The risk of hypoglycaemia from injected insulin, and having to adjust doses, can considerably affect wellbeing and quality of life. Treatment with insulin can be associated with weight gain. The clinical experts further highlighted that only about 30% of people reach their glycaemic target, and there is an unmet clinical need for an additional treatment for people who cannot safely reach optimal glycaemic control. The clinical experts suggested that sodium-glucose cotransporter (SGLT) inhibitors such as sotagliflozin could increase the proportion of time someone spends in an appropriate blood glucose range. The committee concluded that there is an unmet need for treatments that help people control their diabetes without treatment-related adverse effects.\n\n# People who might take sotagliflozin\n\n## Sotagliflozin is clinically appropriate for a restricted population\n\nSotagliflozin is a dual inhibitor of sodium glucose cotransporter type\xa01 (SGLT1) and SGLT2. It has a marketing authorisation only for type\xa01 diabetes. The European Medicines Agency restricted the marketing authorisation for sotagliflozin with insulin to people with a BMI of 27\xa0kg/m2 or more who do not have adequate glycaemic control despite optimal insulin therapy because of the association between treatment with sotagliflozin and diabetic ketoacidosis. The summary of product characteristics for sotagliflozin states 'sotagliflozin should be initiated and supervised by a physician experienced in the management of type\xa01 diabetes mellitus', and that it 'should not be initiated when patients are at a higher risk of diabetic ketoacidosis', such as people with a 'low insulin need'. One of the clinical experts explained that it was important to identify people in whom the benefit of treatment outweighs the risk of diabetic ketoacidosis and this would require specialist knowledge. Low insulin need is defined as less than 0.5\xa0units of insulin/kg of body weight/day in NICE's technology appraisal guidance on dapagliflozin with insulin for type\xa01 diabetes. In the same guidance, the clinical population consisted of people:\n\nwith a BMI of 27\xa0kg/m2 or more\n\nwho have completed a structured education programme\n\nwith insulin needs of 0.5\xa0units/kg of body weight/day or more\n\nwith inadequate glycaemic control despite structured education as defined by NICE's quality standard on diabetes in adults\n\nwith optimised insulin therapy\n\nwho are aware of the increased risk of diabetic ketoacidosis and are able to do blood glucose and ketone testing to enable them to prevent, recognise and treat diabetic ketoacidosis and hypoglycaemia.The committee was aware that dapagliflozin, an SGLT2 inhibitor, has properties in common with sotagliflozin. So it considered that the same criteria used to define the population for dapagliflozin would also apply to sotagliflozin. The committee concluded that sotagliflozin was clinically appropriate for a restricted population, and in line with the summary of product characteristics, sotagliflozin would need to be started and supervised by a consultant physician specialising in endocrinology and diabetes.\n\n# Clinical evidence\n\n## The key trials for sotagliflozin, inTandem1 and inTandem2, do not include dose escalation\n\nThe main evidence for sotagliflozin came from 2\xa0trials, inTandem1 and inTandem2. These trials compared sotagliflozin plus insulin therapy at 2\xa0doses (200\xa0mg or 400\xa0mg) with placebo plus insulin therapy over 52\xa0weeks. They were randomised and included 1,575\xa0people with inadequately controlled type\xa01 diabetes, of whom 916 had a BMI of 27\xa0kg/m2 or more. The primary endpoint in both trials was the difference between groups in the change in HbA1c from baseline at 24\xa0weeks. The committee was aware that the summary of product characteristics for sotagliflozin stated that if someone needs additional glycaemic control after 3\xa0months on sotagliflozin, the dose may be increased to 400\xa0mg once daily. However, the company provided no clinical evidence for escalating the dose, as this was not included in the clinical trials. Therefore, the committee had not seen enough evidence to make recommendations on increasing the dose of sotagliflozin from one 200\xa0mg to two 200\xa0mg tablets daily.\n\n## The pooled inTandem trial data are appropriate for decision making\n\nThe committee heard from the clinical experts that inTandem1 was likely to be less generalisable to the NHS than inTandem2, because inTandem1 had no UK sites, and it was based in the USA where there is higher use of continuous subcutaneous insulin infusion (insulin pumps) than the UK, and the average BMI is higher. inTandem2 had many sites in Europe and the UK. The committee considered that higher use of insulin pumps in inTandem1 and inTandem2 than in clinical practice may mean that the risk of diabetic ketoacidosis is higher in the trials than in the NHS. The company clarified that the average BMI in the pooled analyses of the inTandem1 and inTandem2 data for people with a BMI of 27\xa0kg/m2 or more was 32\xa0kg/m2, and that this was in line with the average BMI for the NHS for people with a BMI of 27\xa0kg/m2 or more based on the UK National Diabetes Audit data. The committee agreed that although inTandem1 was likely to be more generalisable to NHS practice than inTandem2, it was important to pool these trials to consider all of the relevant data. It concluded that the pooled inTandem results were generalisable to the NHS and appropriate for decision making.\n\n## The company limited the trial data to people who are likely to receive sotagliflozin in clinical practice\n\nThe committee considered whether the trial population reflected the restricted population that was clinically appropriate for sotagliflozin (see section\xa03.3). People were recruited to the inTandem1 and inTandem2 trials if their HbA1c levels were between 7% (about 53\xa0mmol/mol) and 11% (about 97\xa0mmol/mol). The trials included a 6‑week lead-in period, during which insulin dose was optimised. After optimisation, HbA1c was less than 7% (about 53\xa0mmol/mol) for 17% to 20% of people across the inTandem1 and inTandem2 trials. The clinical experts acknowledged that the target for glycaemic control in the NICE guideline on type 1 diabetes in adults was 6.5% (about 48\xa0mmol/mol) but explained that an HbA1c target of 7% (about 53\xa0mmol/mol) or less was reasonable, and they would be unlikely to intensify treatment in people with an HbA1c of less than 7% (about 53\xa0mmol/mol). Furthermore, the committee recalled that sotagliflozin is clinically appropriate for a restricted population (see section\xa03.3). The company submitted evidence on the clinical effectiveness of sotagliflozin in the clinically appropriate restricted population (that is, people with a BMI of at least 27\xa0kg/m2, an HbA1c of greater than 7% (about 53\xa0mmol/mol) after the optimisation period, and with insulin requirements of 0.5\xa0units/kg of body weight/day or more). The committee agreed that this population was similar to people who would have treatment with sotagliflozin in clinical practice (except that it would be used in people with insulin requirements of 0.5\xa0units/kg of body weight/day or more) and that it would focus on these data.\n\n## In the short term, sotagliflozin improves HbA1c and BMI but the impact on other parameters is mixed\n\nThe company presented data for the subgroup eligible for treatment with sotagliflozin, as requested by the committee (see section 3.3). The pooled inTandem1 and inTandem2 trial results for this subgroup showed a larger reduction in HbA1c from baseline at 24\xa0weeks in people randomised to sotagliflozin plus insulin therapy than people randomised to placebo plus insulin therapy. This difference was larger from 0\xa0to 24\xa0weeks (0.39%, about 14\xa0mmol/mol) than from 24\xa0and 52\xa0weeks (0.28%, about 3\xa0mmol/mol). The ERG explained that, based on the trial data, HbA1c was likely to return to baseline by the end of the second year. In addition, people randomised to sotagliflozin plus insulin therapy had a greater reduction in BMI than people randomised to placebo plus insulin therapy at 24\xa0weeks (0.8\xa0kg/m2), which increased at 52\xa0weeks (0.93\xa0kg/m2). The committee also saw that at 52\xa0weeks randomisation to 200\xa0mg of sotagliflozin lowered both systolic and diastolic blood pressure, had a mixed effect on cholesterol, and worsened the estimated glomerular filtration rate, reflecting reduced renal function. The committee was aware that, because the 52‑week data had been calculated by the NICE team without confidence intervals, the statistical significance of the results was unknown and only limited conclusions could be drawn. It concluded that sotagliflozin with insulin modestly improved HbA1c and BMI compared with insulin alone, and the impact on other parameters was mixed.\n\n# Blood glucose and risk of diabetes-related complications\n\n## Lowering blood glucose (HbA1c) levels decreases the risk of diabetes-related complications\n\nHbA1c is a recognised surrogate endpoint for long-term complications of diabetes. Treatment to lower HbA1c levels in type\xa01 diabetes to near-normal levels decreases the risk of complications such as myocardial infarction, stroke and retinopathy. The Diabetes Control and Complications Trial (DCCT) showed an average relative decrease in HbA1c levels of 2% (about 22\xa0mmol/mol) over 10\xa0years in people who had intensive therapy, that is, multiple daily insulin injections (or an insulin pump) compared with those who had conventional glycaemic control, that is, no more than 2\xa0injections. This reduced the risk of microvascular complications by over half. The DCCT's 30‑year, observational, follow‑on study (Epidemiology of Diabetes Interventions and Complications [EDIC]) showed that people who had previously been randomised to intensive therapy had a lower risk of macrovascular complications and death than people who had been randomised to conventional glycaemic control. The company used data from EDIC in its economic model to infer the risk of complications based on changes in physiological parameters such as HbA1c and BMI. The committee discussed whether the results of EDIC were generalisable to therapies such as sotagliflozin that lower blood glucose by a much smaller magnitude and with only short-term evidence. It agreed that this was an area of uncertainty, and that the company had not shown evidence of a beneficial impact of sotagliflozin on diabetes complications. The committee concluded that while there is no evidence of sotagliflozin reducing the risk of complications, sotagliflozin plus insulin lowered blood glucose more than insulin alone (see section\xa03.7), and data from EDIC could be used to show that lowering blood glucose levels decreases the risk of diabetes-related complications.\n\n# Adverse events\n\n## Diabetic ketoacidosis risk is higher with sotagliflozin plus insulin than with insulin alone\n\nThe committee noted that sotagliflozin was associated with an increased risk of adverse events including genital tract infection, urinary tract infection and, in particular, diabetic ketoacidosis. The committee was aware that the European Medicines Agency limited the marketing authorisation to people with a BMI of 27\xa0kg/m2 or more, and excluded people with a 'low insulin need' (see section 3.3) to reduce the risk of this potentially life-threatening adverse effect. However, the company confirmed that sotagliflozin was still associated with an increased risk of diabetic ketoacidosis in this restricted population. The incidence in the inTandem1 and inTamden2 pooled population with a BMI of 27\xa0kg/m2 or more was 8\xa0times higher (3.2\xa0events for every 100\xa0patient years) in the sotagliflozin plus insulin arm than in the insulin alone arm (0.4\xa0events for every 100\xa0patient years); these results included people with a low insulin need. The clinical experts explained that they would not offer sotagliflozin to someone who had not received structured education as defined in NICE's quality standard on diabetes in adults, and who could not recognise the signs and symptoms of diabetic ketoacidosis. The committee concluded that sotagliflozin should not be offered to someone who had not completed structured education to the specification defined in the NICE quality standard, and who was not able to detect diabetic ketoacidosis.\n\n# The company's economic model\n\n## The model uses risk equations to link changes in HbA1c and other parameters from the trials to diabetes complications over a lifetime\n\nThe company used a patient-level model (CORE Diabetes Model version\xa09) to simulate disease progression and complications over a lifetime time horizon. The company defined treatment effects after 1\xa0year of treatment as changes in HbA1c, BMI, systolic blood pressure, serum lipids and, as confirmed in the committee's second meeting, diastolic blood pressure and renal function measured by estimated glomerular filtration rate. The company derived these from a pooled analysis of inTandem1 and inTandem2, limited to the committee's preferred population. To estimate complications linked to changes in HbA1c, systolic blood pressure, lipid parameters and renal function in the economic model, the company used risk equations based on the UKPDS\xa068 study. There was an additional adjustment to these equations in the CORE model using data from the EDIC study for HbA1c and systolic blood pressure only and not the lipid parameters or renal function. The ERG explained that changes in the ratio of total cholesterol to high density lipoprotein cholesterol were linked to changes in ischaemic heart disease, myocardial infarction and stroke. Plasma triglycerides did not affect diabetes-related complications in the model. The ERG explained that other baseline characteristics in the model also affected the probability of having a complication and therefore could affect life length, quality of life or both. These baseline characteristics included BMI, total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol and estimated glomerular filtration rate. The company's model assumed that sotagliflozin affected all physiological parameters in the economic model and predicted that sotagliflozin increased length of life and improved quality of life. The ERG noted that the key parameters driving the cost effectiveness of sotagliflozin were HbA1c followed by BMI. The committee was concerned that the company was not able to explain how changes in BMI affect complications in its model during the committee meeting. The committee recalled the evidence that sotagliflozin might affect all physiological parameters, but because it was not clear how the company's model worked, it agreed that it would be reasonable to consider analyses for sotagliflozin affecting all or some physiological variables, and analyses that affected only HbA1c.\n\n## Small changes seen in the inTandem trials may translate to a reduced risk of long-term complications in the economic model\n\nThe committee noted that the improvement in HbA1c level in DCCT and EDIC (for multiple daily injections of insulin compared with conventional glycaemic control) was substantially bigger (about a 2% [about 22\xa0mmol/mol] reduction), and sustained for substantially longer (over 10\xa0years) than the improvement in HbA1c level in the pooled inTandem trials (0.39% reduction [about 14\xa0mmol/mol] over 1\xa0year with sotagliflozin plus insulin compared with placebo plus insulin) in the preferred population. The committee was concerned that the company had assumed that the benefit associated with the smaller and shorter reduction in HbA1c seen from inTandem was proportional to the benefit of a sustained larger difference in HbA1c seen in DCCT and EDIC in terms of fewer complications (see section\xa03.8). The committee was concerned by the company's approach that reducing HbA1c immediately lowered the incidence of microvascular and macrovascular complications. It heard from the clinical experts that, although there are data to show lowering HbA1c is associated with a decrease in diabetic complications, there are no data to show that weight loss alone would reduce diabetes-related complications. The committee was aware that in studies of type\xa02 diabetes, weight loss is associated with an improved quality of life. But the committee had not seen any evidence to support this in type\xa01 diabetes. The committee concluded that it was reasonable to assume some relationship between lowering HbA1c and reducing diabetic complications, and an association between lowering BMI and improving quality of life.\n\n# Cost-effectiveness estimate\n\n## The company's updated base case includes many of the committee's preferences\n\nThe company's revised base case included many of the committee's preferred assumptions:\n\npeople with a BMI of 27\xa0kg/m2 or more, insulin needs of 0.5\xa0units/kg of body weight/day or more and HbA1c of 7% (about 53\xa0mmol/mol) or more after people optimised their insulin (see section\xa03.3)\n\nbaseline characteristics from the pooled trial data (see section\xa03.5)\n\ntreatment efficacy with sotagliflozin based on 52‑week data improving HbA1c and BMI with treatment efficacy waning after the first year (see section\xa03.7)\n\ntreatment with sotagliflozin for 2\xa0years based on pooled trial data, which suggests that the effect of sotagliflozin on HbA1c returns to baseline at the end of the second year (see section\xa03.7) and treatment should stop if glycaemic control does not improve (see section\xa03.15)\n\nupdated adverse events including case fatality for diabetic ketoacidosis to reflect the UK (0.7%), severe hypoglycaemia (4.45% in line with assumptions in NICE technology appraisal guidance on dapagliflozin with insulin for type\xa01 diabetes) and Fournier's gangrene.The probabilistic cost-effectiveness estimates for sotagliflozin compared with standard care for the company's revised base case were £16,093 per quality-adjusted life year (QALY) gained. Although the company had addressed most of the committee's preferences, the committee was concerned that the company had only used data at 24\xa0weeks from the pooled inTandem trials and had not used the 52‑week data. Furthermore, because of uncertainties associated with how the model worked, the committee concluded that it wanted to see scenarios limiting the benefit of treatment with sotagliflozin to improvement in HbA1c.\n\n## The ERG's scenario analyses explore the extrapolation of trial results over a patient's lifetime\n\nThe ERG updated the company's base case so that it was better aligned with all of the committee preferences. It:\n\nidentified an error in the company model and changed the mortality probability for severe hypoglycaemia from 4% to 4.45% (see section\xa03.12)\n\nused 24- and 52‑week data from inTandem1 and inTandem2 to estimate the treatment effect of sotagliflozin (see section\xa03.12).The impact of these adjustments increased the company's probabilistic base-case incremental cost-effectiveness ratio (ICER) for sotagliflozin compared with insulin from £16,093 to £19,046 per QALY gained.The committee had concerns that sotagliflozin was assumed to affect all physiological parameters in the economic model (see section\xa03.10). The ERG provided 2\xa0scenario analyses to address these concerns:\n\ntreatment effect for all physiological parameters\n\ntreatment effect for HbA1c only.These scenarios resulted in probabilistic ICERs of £15,163 and £25,115 per QALY gained respectively. The committee noted that both of these scenarios included a relationship between physiological parameters (see section\xa03.10) and the long-term risk of macrovascular and microvascular complications. The committee recalled its conclusions that sotagliflozin with insulin modestly improved HbA1c and BMI, compared with insulin alone (see section\xa03.7). It concluded that the most plausible ICER is between £15,163 per QALY gained and £25,115 per QALY gained.\n\n## Sotagliflozin with insulin appears to be cost effective when insulin alone does not provide adequate glycaemic control despite optimal insulin therapy\n\nThe committee concluded that sotagliflozin with insulin appears to be a cost-effective use of NHS resources for treating type\xa01 diabetes in adults with a BMI of 27\xa0kg/m2 or more when insulin alone does not provide adequate glycaemic control despite optimal insulin therapy. It also considered the recommendations for starting treatment used in NICE's technology appraisal guidance on dapagliflozin with insulin for type\xa01 diabetes would be relevant to this appraisal. The committee further concluded that all the following criteria should also be included in the recommendation:\n\npeople are on insulin doses of 0.5\xa0units/kg of body weight/day or more (see section\xa03.3)\n\npeople have completed a structured education programme such as DAFNE, which includes training on diabetes ketoacidosis, before starting treatment (see section\xa03.3)\n\ntreatment is started and supervised by a consultant physician specialising in endocrinology and diabetes (see section\xa03.3)\n\nHbA1c level is assessed after 6\xa0months (and regularly after this), and sotagliflozin is stopped if there has not been a sustained improvement in glycaemic control, that is, a fall in HbA1c level of at least 0.3% (see section\xa03.15).\n\n## People should stop sotagliflozin if glycaemic control does not improve\n\nThe committee noted that the cost-effectiveness estimates (see section\xa03.13) did not include treatment discontinuation or a stopping rule if glycaemic control was not improved. The committee was aware that in NICE's technology appraisal guidance on dapagliflozin with insulin for type\xa01 diabetes, a clinically meaningful reduction in HbA1c levels was defined as at least 0.3\xa0percentage points. The clinical experts explained that it would be reasonable to stop treatment if there was not a clinically meaningful decrease in glycaemic control, defined as a change in HbA1c level of at least 0.3\xa0percentage points. The committee recognised that, in general, ongoing treatment in the absence of a clinically meaningful improvement in HbA1c level would subject the person to risks of diabetic ketoacidosis and the NHS to costs. It concluded that HbA1c should be assessed after 6\xa0months of starting treatment and then regularly after this, and that sotagliflozin should be stopped if glycaemic control does not improve (that is, a fall in HbA1c level of at least\xa00.3%).\n\n## Equality issues\n\nNo equality issues were raised by stakeholders.\n\n## There are no additional benefits not adequately captured in the QALY\n\nThe committee recognised that there is an unmet need for people with inadequately controlled type\xa01 diabetes despite optimised insulin therapy. It agreed that sotagliflozin is innovative, but all health benefits are likely to be captured in the model. Furthermore, the committee did not consider sotagliflozin a step change in managing type\xa01 diabetes because of the modest benefits seen in the clinical trials (see section\xa03.7)."}
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https://www.nice.org.uk/guidance/ta622
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Evidence-based recommendations on sotagliflozin with insulin for treating type 1 diabetes in adults with a body mass index (BMI) of at least 27 kg/m2, when insulin alone does not provide adequate glycaemic control despite optimal insulin therapy.
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afb2f067c3f0e9cd3d165b95abb928fb3e082061
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nice
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Bipolar disorder: assessment and management
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Bipolar disorder: assessment and management
This guideline covers recognising, assessing and treating bipolar disorder (formerly known as manic depression) in children, young people and adults. The recommendations apply to bipolar I, bipolar II, mixed affective and rapid cycling disorders. It aims to improve access to treatment and quality of life in people with bipolar disorder.
# Introduction
Bipolar disorder is a potentially lifelong and disabling condition characterised by episodes of mania (abnormally elevated mood or irritability and related symptoms with severe functional impairment or psychotic symptoms for 7 days or more) or hypomania (abnormally elevated mood or irritability and related symptoms with decreased or increased function for 4 days or more) and episodes of depressed mood. It is often comorbid with other disorders such as anxiety disorders, substance misuse, personality disorders and attention deficit hyperactivity disorder (ADHD).
The peak age of onset is 15 to 19 years, and there is often a substantial delay between onset and first contact with mental health services. The lifetime prevalence of bipolar I disorder (mania and depression) is estimated at 1% of the adult population, and bipolar II disorder (hypomania and depression) affects approximately 0.4% of adults. Bipolar disorder in children under 12 years is very rare.
Since the publication of the previous NICE guideline (CG38) in 2006, there have been some important advances in our knowledge of the care pathway and treatment approaches that are most likely to benefit people with bipolar disorder. All areas of CG38 have been updated.
This guideline covers the recognition, assessment and management of bipolar disorder in children, young people and adults. It includes specific recommendations for diagnosis in children and young people because presentation in these age groups can be complicated by other conditions such as ADHD. The recommendations apply to people with bipolar I, bipolar II, mixed affective and rapid cycling disorders. Non‑bipolar affective disorders are not covered because these are addressed by other guidelines, and this guideline does not make specific recommendations about other mental disorders that commonly coexist with bipolar disorder.
# Safeguarding children
Remember that child maltreatment:
is common
can present anywhere, such as emergency departments, primary and secondary care and community settings (such as the child's home).
Be aware of or suspect abuse as a contributory factor to or cause of bipolar disorder in children. Abuse may also coexist with bipolar disorder. See NICE's guideline on child maltreatment for clinical features that may be associated with maltreatment.
This section has been agreed with the Royal College of Paediatrics and Child Health.# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
The recommendations cover children, young people and adults with suspected or diagnosed bipolar disorder and apply to bipolar I, bipolar II, mixed affective and rapid cycling disorders.
# Care for adults, children and young people across all phases of bipolar disorder
## Improving the experience of care
Use this guideline in conjunction with NICE's guideline on service user experience in adult mental health to improve the experience of care for adults with bipolar disorder using mental health services, and for adults, children and young people:
promote a positive recovery message from the point of diagnosis and throughout care
build supportive and empathic relationships as an essential part of care.
Follow the recommendations in general principles of care in NICE's guideline on psychosis and schizophrenia in children and young people to improve the experience of care for children and young people with bipolar disorder.
## Treatment and support for specific populations
Follow the recommendations in race, culture and ethnicity in NICE's clinical guideline on psychosis and schizophrenia in adults when working with people with bipolar disorder from black, Asian and minority ethnic groups.
See NICE's guideline on antenatal and postnatal mental health for guidance on the management of bipolar disorder during pregnancy and the postnatal period and in women and girls of childbearing potential.
Ensure that people with bipolar disorder and a coexisting learning disability are offered the same range of treatments and services as other people with bipolar disorder.
Ensure that older people with bipolar disorder are offered the same range of treatments and services as younger people with bipolar disorder.
Offer people with bipolar disorder and coexisting disorders, such as personality disorder, attention deficit hyperactivity disorder, anxiety disorders or substance misuse, treatment in line with the relevant NICE guideline, in addition to their treatment for bipolar disorder. See NICE's guidelines on antisocial personality disorder, borderline personality disorder, attention deficit hyperactivity disorder, generalised anxiety disorder and psychosis with coexisting substance misuse, be alert to the potential for drug interactions and use clinical judgement.
Offer people with rapid cycling bipolar disorder the same interventions as people with other types of bipolar disorder because there is currently no strong evidence to suggest that people with rapid cycling bipolar disorder should be treated differently.
## Information and support
Consider identifying and offering assistance with education, financial and employment problems that may result from the behaviour associated with bipolar disorder, such as mania and hypomania. If the person with bipolar disorder agrees, this could include talking directly with education staff, creditors and employers about bipolar disorder and its possible effects, and how the person can be supported.
Encourage people with bipolar disorder to develop advance statements while their condition is stable, in collaboration with their carers if possible.
Explain and discuss making a lasting power of attorney with adults with bipolar disorder and their carers if there are financial problems resulting from mania or hypomania.
## Support for carers of people with bipolar disorder
Offer carers of people with bipolar disorder an assessment (provided by mental health services) of their own needs and discuss with them their strengths and views. Develop a care plan to address any identified needs, give a copy to the carer and their GP and ensure it is reviewed annually.
Advise carers about their statutory right to a formal carer's assessment provided by social care services and explain how to access this. See NICE's guideline on supporting adult carers.
Give carers written and verbal information in an accessible format about:
diagnosis and management of bipolar disorder
positive outcomes and recovery
types of support for carers
role of teams and services
getting help in a crisis. When providing information, offer the carer support if necessary.
As early as possible negotiate with the person with bipolar disorder and their carers about how information about the person will be shared. When discussing rights to confidentiality, emphasise the importance of sharing information about risks and the need for carers to understand the person's perspective. Foster a collaborative approach that supports both people with bipolar disorder and their carers, and respects their individual needs and interdependence.
Review regularly how information is shared, especially if there are communication and collaboration difficulties between the person and their carer.
Include carers in decision‑making if the person agrees.
Offer a carer‑focused education and support programme, which may be part of a family intervention for bipolar disorder, as early as possible to all carers. The intervention should:
be available as needed
have a positive message about recovery.
Identify children, young people and adults at risk of abuse or neglect who are dependent on, living with or caring for a person with bipolar disorder and:
review the need for an assessment according to local safeguarding procedures for children or adults as appropriate
-ffer psychological and social support as needed.
# Recognising and managing bipolar disorder in adults in primary care
## Recognising bipolar disorder in primary care and referral
When adults present in primary care with depression, ask about previous periods of overactivity or disinhibited behaviour. If the overactivity or disinhibited behaviour lasted for 4 days or more, consider referral for a specialist mental health assessment.
Refer people urgently for a specialist mental health assessment if mania or severe depression is suspected or they are a danger to themselves or others.
Do not use questionnaires in primary care to identify bipolar disorder in adults.
## Managing bipolar disorder in primary care
December 2022: The MHRA has issued new safety advice on risks associated with valproate for anyone under 55.
When working with people with bipolar disorder in primary care:
engage with and develop an ongoing relationship with them and their carers
support them to carry out care plans developed in secondary care and achieve their recovery goals
follow crisis plans developed in secondary care and liaise with secondary care specialists if necessary
review their treatment and care, including medication, at least annually and more often if the person, carer or healthcare professional has any concerns.
Offer people with bipolar depression:
a psychological intervention that has been developed specifically for bipolar disorder and has a published evidence-based manual describing how it should be delivered or
a choice of psychological intervention (cognitive behavioural therapy, interpersonal therapy or behavioural couples therapy) in line with the advice on treatment options for more severe depression in the NICE guideline on depression.Discuss with the person the possible benefits and risks of psychological interventions and their preference. Monitor mood and if there are signs of hypomania or deterioration of the depressive symptoms, liaise with or refer the person to secondary care. If the person develops mania or severe depression, refer them urgently to secondary care.
Psychological therapists working with people with bipolar depression in primary care should have training in and experience of working with people with bipolar disorder.
Do not start lithium to treat bipolar disorder in primary care for people who have not taken lithium before, except under shared‑care arrangements.
Do not start valproate in primary care to treat bipolar disorder.
If bipolar disorder is managed solely in primary care, re‑refer to secondary care if any one of the following applies:
there is a poor or partial response to treatment
the person's functioning declines significantly
treatment adherence is poor
the person develops intolerable or medically important side effects from medication
comorbid alcohol or drug misuse is suspected
the person is considering stopping any medication after a period of relatively stable mood
a woman with bipolar disorder is pregnant or planning a pregnancy.
## Physical health
Develop and use practice case registers to monitor the physical and mental health of people with bipolar disorder in primary care.
Monitor the physical health of people with bipolar disorder when responsibility for monitoring is transferred from secondary care, and then at least annually. The health check should be comprehensive, including all the checks recommended in recommendation 1.2.12 and focusing on physical health problems such as cardiovascular disease, diabetes, obesity and respiratory disease. A copy of the results should be sent to the care coordinator and psychiatrist, and put in the secondary care records.
Ensure that the physical health check for people with bipolar disorder, performed at least annually, includes:
weight or BMI, diet, nutritional status and level of physical activity
cardiovascular status, including pulse and blood pressure
metabolic status, including fasting blood glucose or glycosylated haemoglobin (HbA1c), and blood lipid profile
liver function
renal and thyroid function, and calcium levels, for people taking long‑term lithium.
Identify people with bipolar disorder who have hypertension, have abnormal lipid levels, are obese or at risk of obesity, have diabetes or are at risk of diabetes (as indicated by abnormal blood glucose levels), or are physically inactive, at the earliest opportunity. Follow NICE's guidelines on hypertension, lipid modification, prevention of cardiovascular disease, obesity, physical activity and preventing type 2 diabetes.
Offer treatment to people with bipolar disorder who have diabetes and/or cardiovascular disease in primary care in line with NICE's guidelines on type 1 diabetes in adults: diagnosis and management, type 2 diabetes in adults: management and lipid modification.
# Assessing suspected bipolar disorder in adults in secondary care
Assessment of suspected bipolar disorder, and subsequent management, should be conducted in a service that can:
-ffer the full range of pharmacological, psychological, social, occupational and educational interventions for people with bipolar disorder consistent with this guideline
be competent to provide all interventions offered
place emphasis on engagement as well as risk management
provide treatment and care in the least restrictive and stigmatising environment possible, and in an atmosphere of hope and optimism in line with NICE's guideline on service user experience in adult mental health. This might be an early intervention in psychosis service, a specialist bipolar disorder team, or a specialist integrated community‑based team.
When assessing suspected bipolar disorder:
undertake a full psychiatric assessment, documenting a detailed history of mood, episodes of overactivity and disinhibition or other episodic and sustained changes in behaviour, symptoms between episodes, triggers to previous episodes and patterns of relapse, and family history
assess the development and changing nature of the mood disorder and associated clinical problems throughout the person's life (for example, early childhood trauma, developmental disorder or cognitive dysfunction in later life)
assess social and personal functioning and current psychosocial stressors
assess for potential mental and physical comorbidities
assess the person's physical health and review medication and side effects, including weight gain
discuss treatment history and identify interventions that have been effective or ineffective in the past
encourage people to invite a family member or carer to give a corroborative history
discuss possible factors associated with changes in mood, including relationships, psychosocial factors and lifestyle changes
identify personal recovery goals.
Take into account the possibility of differential diagnoses including schizophrenia spectrum disorders, personality disorders, drug misuse, alcohol‑use disorders, attention deficit hyperactivity disorder and underlying physical disorders such as hypo‑ or hyperthyroidism.
If bipolar disorder is diagnosed, develop a care plan in collaboration with the person with bipolar disorder based on the assessment carried out in recommendation 1.3.2 as soon as possible after assessment and, depending on their needs, using the care programme approach. Give the person and their GP a copy of the plan, and encourage the person to share it with their carers.
Carry out a risk assessment in conjunction with the person with bipolar disorder, and their carer if possible, focusing on areas that are likely to present possible danger or harm, such as self‑neglect, self‑harm, suicidal thoughts and intent, risks to others, including family members, driving, spending money excessively, financial or sexual exploitation, disruption in family and love relationships, disinhibited and sexualised behaviour, and risks of sexually transmitted diseases. For the management of risk, follow the recommendations in section 1.4.
# Managing crisis, risk and behaviour that challenges in adults with bipolar disorder in secondary care
Develop a risk management plan jointly with the person, and their carer if possible, covering:
identifiable personal, social, occupational, or environmental triggers and early warning signs and symptoms of relapse
a protocol for applying the person's own coping strategies and increasing doses of medication or taking additional medication (which may be given to the person in advance) for people at risk of onset of mania or for whom early warning signs and symptoms can be identified
agreements between primary and secondary care about how to respond to an increase in risk or concern about possible risk
information about who to contact if the person with bipolar disorder and, if appropriate, their carer, is concerned or in a crisis, including the names of healthcare professionals in primary and secondary care who can be contacted.Give the person and their GP a copy of the plan, and encourage the person to share it with their carers.
Offer crisis services to support people with bipolar disorder who are in crisis, in line with the section on service-level interventions in NICEs guideline on psychosis and schizophrenia in adults.
If people with bipolar disorder pose an immediate risk to themselves or others during an acute episode, see:
NICE's guideline on violence and aggression: short-term management in mental health, health and community settings and service user experience in adult mental health for advice on managing agitation, challenging behaviour and imminent violence, and on rapid tranquillisation or
NICE's guideline on self-harm for advice on managing acts of self‑harm and suicide risk.
# Managing mania or hypomania in adults in secondary care
## Support and advice
Ensure that people with mania or hypomania have access to calming environments and reduced stimulation. Advise them not to make important decisions until they have recovered from mania or hypomania and encourage them to maintain their relationships with their carers if possible.
## Pharmacological interventions
December 2022: The MHRA has issued new safety advice on risks associated with valproate for anyone under 55.
If a person develops mania or hypomania and is taking an antidepressant (as defined by the British National Formulary ) as monotherapy:
consider stopping the antidepressant and
-ffer an antipsychotic as set out in recommendation 1.5.3, regardless of whether the antidepressant is stopped.
If a person develops mania or hypomania and is not taking an antipsychotic or mood stabiliser, offer haloperidol, olanzapine, quetiapine or risperidone, taking into account any advance statements, the person's preference and clinical context (including physical comorbidity, previous response to treatment and side effects). Follow the recommendations on using antipsychotics in section 1.10.
If the first antipsychotic is poorly tolerated at any dose (including rapid weight gain) or ineffective at the maximum licensed dose, offer an alternative antipsychotic from the drugs listed in recommendation 1.5.3, taking into account any advance statements, the person's preference and clinical context (including physical comorbidity, previous response to treatment and side effects).
If an alternative antipsychotic is not sufficiently effective at the maximum licensed dose, consider adding lithium. If adding lithium is ineffective, or if lithium is not suitable (for example, because the person does not agree to routine blood monitoring), consider adding valproate instead. Do not offer valproate to women or girls of childbearing potential (including young girls who are likely to need treatment into their childbearing years) for long-term treatment or to treat an acute episode, unless other options are ineffective or not tolerated and the pregnancy prevention programme is in place. Follow the MHRA safety advice on valproate use by women and girls. Although its use is common in UK clinical practice, in September 2014 this was an off-label use of lithium. See NICE's information on prescribing medicines. In September 2014 semi-sodium valproate had a UK marketing authorisation for the treatment of mania if lithium is not tolerated or is contraindicated; this was an off-label use of sodium valproate, although its use was common in UK clinical practice. See NICE's information on prescribing medicines. See update information for important safety advice from the MHRA on the use of valproate.
If a person develops mania or hypomania and is taking an antidepressant (as defined by the BNF) in combination with a mood stabiliser, consider stopping the antidepressant.
If the person is already taking lithium, check plasma lithium levels to optimise treatment (see section 1.10). Consider adding haloperidol, olanzapine, quetiapine or risperidone, depending on the person's preference and previous response to treatment.
If the person is already taking valproate or another mood stabiliser as prophylactic treatment, consider increasing the dose, up to the maximum level in the BNF if necessary, depending on clinical response. If there is no improvement, consider adding haloperidol, olanzapine, quetiapine or risperidone, depending on the person's preference and previous response to treatment. Follow the recommendations on using antipsychotics and valproate in section 1.10.If a woman or girl of childbearing potential is already taking valproate, advise her to gradually stop the drug because of the risk of fetal malformations and adverse neurodevelopmental outcomes after any exposure in pregnancy. See the MHRA safety advice on valproate use by women and girls.
If the clinical presentation is of a mixed affective state, characterised by both manic and depressive symptoms, follow recommendations 1.5.1 to 1.5.8 for the treatment of mania, and monitor closely for the emergence of depression.
Do not offer lamotrigine to treat mania.
## Electroconvulsive therapy
For the treatment of severe mania that has not responded to other interventions, see NICE's technology appraisal guidance on the use of electroconvulsive therapy.
## Reviewing treatment for mania
Within 4 weeks of resolution of symptoms, discuss with the person, and their carers if appropriate, whether to continue treatment for mania or start long‑term treatment (see section 1.7). Explain the potential benefits of long‑term treatment and the risks, including side effects of medication used for long‑term treatment.
If the person decides to continue treatment for mania, offer it for a further 3 to 6 months, and then review.
# Managing bipolar depression in adults in secondary care
## Psychological interventions
Offer adults with bipolar depression:
a psychological intervention that has been developed specifically for bipolar disorder and has a published evidence-based manual describing how it should be delivered or
a choice of psychological intervention (cognitive behavioural therapy, interpersonal therapy or behavioural couples therapy) in line with the advice on treatment options for more severe depression in the NICE guideline on depression. Discuss with the person the possible benefits and risks of psychological interventions and their preference. Monitor mood for signs of mania or hypomania or deterioration of the depressive symptoms.
Psychological therapists working with people with bipolar depression should have training in, and experience of, working with people with bipolar disorder.
## Pharmacological interventions
December 2022: The MHRA has issued new safety advice on risks associated with valproate for anyone under 55.
If a person develops moderate or severe bipolar depression and is not taking a drug to treat their bipolar disorder, offer fluoxetine combined with olanzapine, or quetiapine on its own, depending on the person's preference and previous response to treatment.
If the person prefers, consider either olanzapine (without fluoxetine) or lamotrigine on its own.
If there is no response to fluoxetine combined with olanzapine, or quetiapine, consider lamotrigine on its own.Follow the recommendations on using antipsychotics and lamotrigine in section 1.10.In September 2014, this was an off-label use of olanzapine. Although their use was common in UK clinical practice, in September 2014 this was an off-label use of fluoxetine and of lamotrigine. See NICE's information on prescribing medicines.
If a person develops moderate or severe bipolar depression and is already taking lithium, check their plasma lithium level. If it is inadequate, increase the dose of lithium; if it is at maximum level, add either fluoxetine combined with olanzapine or add quetiapine, depending on the person's preference and previous response to treatment.
If the person prefers, consider adding olanzapine (without fluoxetine) or lamotrigine to lithium.
If there is no response to adding fluoxetine combined with olanzapine, or adding quetiapine, stop the additional treatment and consider adding lamotrigine to lithium. Follow the recommendations in section 1.10 on using lithium, antipsychotics and lamotrigine. In September 2014 aripiprazole had a UK marketing authorisation for up to 12 weeks of treatment for moderate to severe manic episodes in bipolar I disorder in young people aged 13 and older.In September 2014, these were off-label uses of olanzapine, risperidone, haloperidol, quetiapine, lamotrigine, lithium and valproate for children and young people. See NICE's information on prescribing medicines.
If a person develops moderate or severe bipolar depression and is already taking valproate, consider increasing the dose within the therapeutic range. If the maximum tolerated dose, or the top of the therapeutic range, has been reached and there is a limited response to valproate, add fluoxetine combined with olanzapine or add quetiapine, depending on the person's preference and previous response to treatment.
If the person prefers, consider adding olanzapine (without fluoxetine) or lamotrigine to valproate.
If there is no response to adding fluoxetine combined with olanzapine, or adding quetiapine, stop the additional treatment and consider adding lamotrigine to valproate.Follow the recommendations in section 1.10 on using valproate, antipsychotics and lamotrigine.If a woman or girl of childbearing potential is already taking valproate, advise her to gradually stop the drug because of the risk of fetal malformations and adverse neurodevelopmental outcomes after any exposure in pregnancy. See the MHRA safety advice on valproate use by women and girls.In September 2014 aripiprazole had a UK marketing authorisation for up to 12 weeks of treatment for moderate to severe manic episodes in bipolar I disorder in young people aged 13 and older.In September 2014, these were off-label uses of olanzapine, risperidone, haloperidol, quetiapine, lamotrigine, lithium and valproate for children and young people. See NICE's information on prescribing medicines.
Follow the recommendations on using antipsychotics in section 1.10 and be aware of the potential interactions between valproate and fluoxetine, lamotrigine and olanzapine. See the MHRA safety advice on valproate use by women and girls.
Take into account toxicity in overdose when prescribing psychotropic medication during periods of high suicide risk. Assess the need to limit the quantity of medication supplied to reduce the risk to life if the person overdoses.
## Reviewing treatment for bipolar depression
Within 4 weeks of resolution of symptoms, discuss with the person, and their carers if appropriate, whether to continue psychological or pharmacological treatment for bipolar depression or start long‑term treatment (see section 1.7). Explain the potential benefits of long‑term treatment and the risks, including side effects of medication used for long‑term treatment.
If the person decides to continue psychological or pharmacological treatment for bipolar depression, offer it for a further 3 to 6 months, and then review.
# Managing bipolar disorder in adults in the longer term in secondary care
## Discussing long‑term treatment
After each episode of mania or bipolar depression, discuss with the person, and their carers if appropriate, managing their bipolar disorder in the longer term. Discussion should aim to help people understand that bipolar disorder is commonly a long‑term relapsing and remitting condition that needs self‑management and engagement with primary and secondary care professionals and involvement of carers. The discussion should cover:
the nature and variable course of bipolar disorder
the role of psychological and pharmacological interventions to prevent relapse and reduce symptoms
the risk of relapse after reducing or stopping medication for an acute episode
the potential benefits and risks of long‑term medication and psychological interventions, and the need to monitor mood and medication
the potential benefits and risks of stopping medication, including for women who may wish to become pregnant
the person's history of bipolar disorder, including:
the severity and frequency of episodes of mania or bipolar depression, with a focus on associated risks and adverse consequences
previous response to treatment
symptoms between episodes
potential triggers for relapse, early warning signs, and self‑management strategies
possible duration of treatment, and when and how often this should be reviewed.Provide clear written information about bipolar disorder, including NICE's information for the public, and ensure there is enough time to discuss options and concerns.
## Psychological interventions
Offer a family intervention to people with bipolar disorder who are living, or in close contact, with their family in line with recommendation 1.3.7.2. in NICE's guideline on psychosis and schizophrenia in adults.
Offer a structured psychological intervention (individual, group or family), which has been designed for bipolar disorder and has a published evidence-based manual describing how it should be delivered, to prevent relapse or for people who have some persisting symptoms between episodes of mania or bipolar depression.
Individual and group psychological interventions for bipolar disorder to prevent relapse should:
provide information about bipolar disorder
consider the impact of thoughts and behaviour on moods and relapse
include self‑monitoring of mood, thoughts and behaviour
address relapse risk, distress and how to improve functioning
develop plans for relapse management and staying well
consider problem‑solving to address communication patterns and managing functional difficulties. In addition:
individual programmes should be tailored to the person's needs based on an individualised assessment and psychological formulation
group programmes should include discussion of the information provided with a focus on its relevance for the participants.
## Pharmacological interventions
December 2022: The MHRA has issued new safety advice on risks associated with valproate for anyone under 55. We are reviewing the recommendations in this section.
When planning long‑term pharmacological treatment to prevent relapse, take into account drugs that have been effective during episodes of mania or bipolar depression. Discuss with the person whether they prefer to continue this treatment or switch to lithium, and explain that lithium is the most effective long‑term treatment for bipolar disorder.
Offer lithium as a first‑line, long‑term pharmacological treatment for bipolar disorder and:
if lithium is ineffective, consider adding valproate
if lithium is poorly tolerated, or is not suitable (for example, because the person does not agree to routine blood monitoring), consider valproate or olanzapine instead or, if it has been effective during an episode of mania or bipolar depression, quetiapine. Discuss with the person the possible benefits and risks of each drug for them, following the recommendations in section 1.10. If a woman or girl of childbearing potential is already taking valproate, advise her to gradually stop the drug because of the risk of fetal malformations and adverse neurodevelopmental outcomes after any exposure in pregnancy. See the MHRA safety advice on valproate use by women and girls. In September 2014 semi-sodium valproate had a UK marketing authorisation for this indication in people who have had mania that has responded to treatment with semi-sodium valproate; it was an off-label use of sodium valproate, although its use was common in UK clinical practice. See NICE's information on prescribing medicines. See update information for important safety advice from the MHRA on the use of valproate.
If stopping long‑term pharmacological treatment:
discuss with the person how to recognise early signs of relapse and what to do if symptoms recur
stop treatment gradually (see section 1.10) and monitor the person for signs of relapse.
Continue monitoring symptoms, mood and mental state for 2 years after medication has stopped entirely. This may be undertaken in primary care (see recommendation 1.9.3).
# Monitoring physical health in secondary care
Healthcare professionals in secondary care should ensure, as part of the care programme approach, that people with bipolar disorder receive physical healthcare from primary care as described in recommendations 1.2.10 to 1.2.14 after responsibility for monitoring has been transferred from secondary care.
People with bipolar disorder, especially those taking antipsychotics and long‑term medication, should be offered a combined healthy eating and physical activity programme by their mental healthcare provider.
If a person has rapid or excessive weight gain, abnormal lipid levels or problems with blood glucose management, take into account the effects of medication, mental state, other physical health and lifestyle factors in the development of these problems and offer interventions in line with NICE's guidelines on obesity, lipid modification or preventing type 2 diabetes.
Routinely monitor weight and cardiovascular and metabolic indicators of morbidity in people with bipolar disorder. These should be audited in the annual team report.
Trusts should ensure that they take account of relevant guidelines on the monitoring and treatment of cardiovascular and metabolic disease in people with bipolar disorder through board‑level performance indicators.
# Promoting recovery and return to primary care
## Continuing treatment in secondary care
Continue treatment and care in an early intervention in psychosis service, a specialist bipolar disorder service or a specialist integrated community‑based team. Share physical health monitoring with primary care as outlined in section 1.2 and section 1.8.
Consider intensive case management for people with bipolar disorder who are likely to disengage from treatment or services.
## Return to primary care
Offer people with bipolar disorder whose symptoms have responded effectively to treatment and remain stable the option to return to primary care for further management. If they wish to do this, record it in their notes and coordinate transfer of responsibilities through the care programme approach.
When making transfer arrangements for a return to primary care, agree a care plan with the person, which includes:
clear, individualised social and emotional recovery goals
a crisis plan indicating early warning symptoms and triggers of both mania and depression relapse and preferred response during relapse, including liaison and referral pathways
an assessment of the person's mental state
a medication plan with a date for review by primary care, frequency and nature of monitoring for effectiveness and adverse effects, and what should happen in the event of a relapse.Give the person and their GP a copy of the plan, and encourage the person to share it with their carers.
Encourage and support the person to visit their GP and discuss the care plan before discharge and transfer.
## Employment, education and occupational activities
Offer supported employment programmes to people with bipolar disorder in primary or secondary care who wish to find or return to work. Consider other occupational or educational activities, including pre‑vocational training, for people who are unable to work or unsuccessful in finding employment.
# How to use medication
When using any psychotropic medication for bipolar disorder ensure that:
the person is given information that is suitable for their developmental level about the purpose and likely side effects of treatment including any monitoring that is required, and give them an opportunity to ask questions
the choice of medication is made in collaboration with the person with bipolar disorder, taking into account the carer's views if the person agrees
the overall medication regimen is regularly reviewed so that drugs that are not needed after the acute episode are stopped.
Discuss the use of alcohol, tobacco, prescription and non‑prescription medication and illicit drugs with the person, and their carer if appropriate. Explain the possible interference of these substances with the therapeutic effects of prescribed medication and psychological interventions.
When offering psychotropic medication to older people, take into account its impact on cognitive functioning in older people and:
use medication at lower doses
take into account the increased risk of drug interactions
take into account the negative impact that anticholinergic medication, or drugs with anticholinergic activity, can have on cognitive function and mobility
ensure that medical comorbidities have been recognised and treated.
Do not offer gabapentin or topiramate to treat bipolar disorder.
## Using antipsychotic medication
Before starting antipsychotic medication, measure and record the person's:
weight or BMI
pulse
blood pressure
fasting blood glucose or HbA1c
blood lipid profile.
Before starting antipsychotic medication, offer the person an electrocardiogram (ECG) if:
it is specified in the drug's summary of product characteristics (SPC) or
a physical examination has identified a specific cardiovascular risk (such as hypertension) or
there is a family history of cardiovascular disease, a history of sudden collapse, or other cardiovascular risk factors such as cardiac arrhythmia or
the person is being admitted as an inpatient.
Treatment with antipsychotic medication should be considered an explicit individual therapeutic trial. Carry out the following:
Discuss and record the side effects that the person is most willing to tolerate.
Record the indications and expected benefits and risks of antipsychotic medication, and the expected time for a change in symptoms and appearance of side effects.
At the start of treatment prescribe a dose that is appropriate for the phase and severity of the illness.
Do not routinely prescribe a dose above the maximum recommended in the BNF or SPC.
Justify and record reasons for doses outside the range given in the BNF or SPC, and inform the person that such treatment is unlicensed.
Record the rationale for continuing, changing or stopping medication, and the effects of such changes.
Monitor and record the following during dose titration and then regularly and systematically throughout treatment:
pulse and blood pressure after each dose change
weight or BMI weekly for the first 6 weeks, then at 12 weeks
fasting blood glucose or HbA1c, and blood lipid profile at 12 weeks
response to treatment, including changes in symptoms and behaviour
side effects and their impact on physical health and functioning
the emergence of movement disorders
adherence.
The secondary care team should maintain responsibility for monitoring the efficacy and tolerability of antipsychotic medication for at least the first 12 months or until the person's condition has stabilised, whichever is longer. Thereafter, the responsibility for this monitoring may be transferred to primary care under shared‑care arrangements.
If out‑of‑range test results are reported at any stage of treatment, the healthcare professional who ordered the tests should ensure that the person is offered further investigations and treatment as needed.
'As required' (p.r.n.) prescriptions of antipsychotic medication should be made as described in recommendation 1.10.7. Review clinical indications, frequency of administration, therapeutic benefits and side effects each week or more often if needed. Ensure that p.r.n. prescriptions have not unintentionally led to a total antipsychotic dosage above the maximum specified in the BNF or SPC.
Do not start regular combined antipsychotic medication, except for short periods (for example, when changing medication).
If stopping an antipsychotic drug, reduce the dose gradually over at least 4 weeks to minimise the risk of relapse.
## Using lithium
When starting lithium:
advise the person that poor adherence or rapid discontinuation may increase the risk of relapse
measure the person's weight or BMI and arrange tests for urea and electrolytes including calcium, estimated glomerular filtration rate (eGFR), thyroid function and a full blood count
arrange an ECG for people with cardiovascular disease or risk factors for it
ensure the person is given appropriate national information (or a locally available equivalent) on taking lithium safely
establish a shared‑care arrangement with the person's GP for prescribing lithium and monitoring adverse effects.
Measure plasma lithium levels 1 week after starting lithium and 1 week after every dose change, and weekly until the levels are stable. Aim to maintain plasma lithium level between 0.6 and 0.8 mmol per litre in people being prescribed lithium for the first time.
Consider maintaining plasma lithium levels at 0.8 to 1.0 mmol per litre for a trial period of at least 6 months for people who:
have had a relapse while taking lithium in the past or
are taking lithium and have subthreshold symptoms with functional impairment.
Advise people taking lithium to:
seek medical attention if they develop diarrhoea or vomiting or become acutely ill for any reason
ensure they maintain their fluid intake, particularly after sweating (for example, after exercise, in hot climates or if they have a fever), if they are immobile for long periods or if they develop a chest infection or pneumonia
talk to their doctor as soon as possible if they become pregnant or are planning a pregnancy.
Warn people taking lithium not to take over‑the‑counter non‑steroidal anti‑inflammatory drugs and avoid prescribing these drugs for people with bipolar disorder if possible; if they are prescribed, this should be on a regular (not p.r.n.) basis and the person should be monitored monthly until a stable lithium level is reached and then every 3 months.
Measure the person's plasma lithium level every 3 months for the first year.
After the first year, measure plasma lithium levels every 6 months, or every 3 months for people in any of the following groups:
-lder people
people taking drugs that interact with lithium
people who are at risk of impaired renal or thyroid function, raised calcium levels or other complications
people who have poor symptom control
people with poor adherence
people whose last plasma lithium level was 0.8 mmol per litre or higher.
Measure the person's weight or BMI and arrange tests for urea and electrolytes including calcium, estimated glomerular filtration rate (eGFR) and thyroid function every 6 months, and more often if there is evidence of impaired renal or thyroid function, raised calcium levels or an increase in mood symptoms that might be related to impaired thyroid function.
Monitor lithium dose and plasma lithium levels more frequently if urea levels and creatinine levels become elevated, or eGFR falls over 2 or more tests, and assess the rate of deterioration of renal function. For further information see NICE's guidelines on chronic kidney disease and acute kidney injury.
When discussing whether to continue lithium, take into account clinical efficacy, other risk factors for renal impairment and cardiovascular disease, and degree of renal impairment; if needed seek advice from a renal specialist and a clinician with expertise in managing bipolar disorder.
Monitor the person at every appointment for symptoms of neurotoxicity, including paraesthesia, ataxia, tremor and cognitive impairment, which can occur at therapeutic levels of lithium.
If stopping lithium, reduce the dose gradually over at least 4 weeks, and preferably up to 3 months, even if the person has started taking another antimanic drug.
During dose reduction and for 3 months after lithium treatment is stopped, monitor the person closely for early signs of mania and depression.
## Using valproate
December 2022: The MHRA has issued new safety advice on risks associated with valproate for anyone under 55.
Do not offer valproate to women or girls of childbearing potential (including young girls who are likely to need treatment into their childbearing years) for long‑term treatment or to treat an acute episode, unless other options are ineffective or not tolerated and the pregnancy prevention programme is in place. See MHRA safety advice on valproate use by women and girls.
If a woman or girl of childbearing potential is already taking valproate, advise her to gradually stop the drug because of the risk of fetal malformations and adverse neurodevelopmental outcomes after any exposure in pregnancy. See the MHRA safety advice on valproate use by women and girls.
When starting valproate, measure the person's weight or BMI and carry out a full blood count and liver function tests. Do not offer valproate to women and girls of childbearing age (including young girls who are likely to need treatment into their childbearing years) unless other options are ineffective or not tolerated and the pregnancy prevention programme is in place. See the MHRA safety advice on valproate use by women and girls.
Advise people taking valproate, and their carers, how to recognise the signs and symptoms of blood and liver disorders and to seek immediate medical help if any of these develop. Stop valproate immediately if abnormal liver function or blood dyscrasia is detected.Although the absolute values of hepatic enzymes are a poor indicator of the extent of hepatic damage, it is generally accepted that if these are persistently elevated to over 3 times the upper normal limit, continuing to rise or accompanied by clinical symptoms, the suspected drug should be withdrawn. Raised hepatic enzymes of any magnitude accompanied by reduced albumin or impaired clotting suggest severe liver disease.
When prescribing valproate, be aware of its interactions with other anticonvulsants (particularly carbamazepine and lamotrigine) and with olanzapine and smoking.
Do not routinely measure plasma valproate levels unless there is evidence of ineffectiveness, poor adherence or toxicity.
Measure the person's weight or BMI and carry out liver function tests and a full blood count again after 6 months of treatment with valproate and repeat annually.
Monitor sedation, tremor and gait disturbance carefully in older people.
If stopping valproate, reduce the dose gradually over at least 4 weeks to minimise the risk of relapse.
## Using lamotrigine
When starting lamotrigine:
carry out a full blood count, urea and electrolytes and liver function tests
be aware of its interaction with valproate
follow the instructions for initial dosage and dosage titration outlined in the SPC and BNF, taking into account the need for slow titration in people who have not taken lamotrigine before.
Advise people taking lamotrigine to:
contact their doctor immediately if they develop a rash while the dose of lamotrigine is being increased
tell you if they are pregnant or planning a pregnancy.
Do not routinely measure plasma lamotrigine levels unless there is evidence of ineffectiveness, poor adherence or toxicity.
If stopping lamotrigine, reduce the dose gradually over at least 4 weeks to minimise the risk of relapse.
# Recognising, diagnosing and managing bipolar disorder in children and young people
## Recognition and referral
Do not use questionnaires in primary care to identify bipolar disorder in children or young people.
If bipolar disorder is suspected in primary care in children or young people aged under 14 years, refer them to child and adolescent mental health services (CAMHS).
If bipolar disorder is suspected in primary care in young people aged 14 years or over, refer them to a specialist early intervention in psychosis service or a CAMHS team with expertise in the assessment and management of bipolar disorder in line with the recommendations in this guideline. The service should be multidisciplinary and have:
engagement or assertive outreach approaches
family involvement and family intervention
access to structured psychological interventions and psychologically informed care
vocational and educational interventions
access to pharmacological interventions
professionals who are trained and competent in working with young people with bipolar disorder.
Diagnosis of bipolar disorder in children or young people should be made only after a period of intensive, prospective longitudinal monitoring by a healthcare professional or multidisciplinary team trained and experienced in the assessment, diagnosis and management of bipolar disorder in children and young people, and in collaboration with the child or young person's parents or carers.
When diagnosing bipolar disorder in children or young people take account of the following:
mania must be present
euphoria must be present on most days and for most of the time, for at least 7 days
irritability is not a core diagnostic criterion.
Do not make a diagnosis of bipolar disorder in children or young people on the basis of depression with a family history of bipolar disorder but follow them up.
When assessing suspected bipolar disorder in children or young people, follow recommendations 1.3.2 to 1.3.4 for adults, but involve parents or carers routinely and take into account the child or young person's educational and social functioning.
## Management in young people
When offering treatment to young people with bipolar disorder, take into account their cognitive ability, emotional maturity, developmental level, their capacity to consent to treatment, the severity of their bipolar disorder and risk of suicide or self‑harm or any other risk outlined in recommendation 1.3.5.
December 2022: The MHRA has issued new safety advice on risks associated with valproate for anyone under 55.
To treat mania or hypomania in young people see NICE's technology appraisal guidance on aripiprazole for treating moderate to severe manic episodes in adolescents with bipolar I disorder and also consider the recommendations for adults in section 1.5. Refer to the BNF for children to modify drug treatments, be aware of the increased potential for a range of side effects, and do not routinely continue antipsychotic treatment for longer than 12 weeks. In September 2014 aripiprazole had a UK marketing authorisation for up to 12 weeks of treatment for moderate to severe manic episodes in bipolar I disorder in young people aged 13 and older.In September 2014, this was an off-label use of olanzapine, risperidone, haloperidol, quetiapine, lamotrigine, lithium and valproate for children and young people. See NICE's information on prescribing medicines.
Do not offer valproate to girls or young women of childbearing potential. See the MHRA safety advice on valproate use by women and girls.
Offer a structured psychological intervention (individual cognitive behavioural therapy or interpersonal therapy) to young people with bipolar depression. The intervention should be of at least 3 months' duration and have a published evidence-based manual describing how it should be delivered.
If after 4 to 6 weeks there is no or a limited response to cognitive behavioural therapy or interpersonal therapy, carry out a multidisciplinary review and consider an alternative individual or family psychological intervention.
If there is a risk of suicide or self‑harm or any other risk outlined in recommendation 1.3.5, carry out an urgent review and develop a risk management plan as outlined in recommendation 1.4.1.
After the multidisciplinary review, if there are coexisting factors such as comorbid conditions, persisting psychosocial risk factors such as family discord, or parental mental ill‑health, consider:
an alternative psychological intervention for bipolar depression for the young person, their parents or other family member or
an additional psychological intervention for any coexisting mental health problems in line with relevant NICE guidance for the young person, their parents or other family member.
If the young person's bipolar depression is moderate to severe, consider a pharmacological intervention in addition to a psychological intervention. Follow the recommendations for pharmacological interventions for adults in section 1.6 but refer to the BNF for children to modify drug treatments, and do not routinely continue antipsychotic treatment for longer than 12 weeks. At 12 weeks, carry out a full multidisciplinary review of mental and physical health, and consider further management of depression or long‑term management. In September 2014, this was an off-label use of olanzapine, quetiapine and lamotrigine for children and young people. See NICE's information on prescribing medicines.
After the multidisciplinary review, consider a structured individual or family psychological intervention for managing bipolar disorder in young people in the longer term.
# Terms used in this guideline
## Carer
A person who provides unpaid support to a partner, family member, friend or neighbour who is ill, struggling or disabled.
## Children
People aged 12 years and under.
## Depression
The severity of bipolar depression is defined in line with NICE's clinical guideline on depression as follows:
Mild depression Few, if any, symptoms in excess of the 5 required to make the diagnosis, with symptoms resulting in minor functional impairment.
Moderate depression Symptoms or functional impairment that are between mild and severe.
Severe depression Most symptoms, with symptoms markedly interfering with functioning. Can occur with or without psychotic symptoms.
## Evidence‑based manual
A manual based on at least 1 randomised controlled trial published in a peer‑reviewed journal showing effectiveness of the intervention in reducing depression symptoms in bipolar depression or, when used as long‑term treatment, reducing relapse in people with bipolar disorder.
## Older people
People aged 65 years and over.
## Young people
People aged 13 to 17 years.
## Valproate
Refers to 3 formulations of valproate available in the UK: sodium valproate, valproic acid and semi‑sodium valproate. At the time of publication (September 2014), sodium valproate and valproic acid had UK marketing authorisation for the treatment of epilepsy. Semi‑sodium valproate had a UK marketing authorisation for the treatment of acute mania and for continuation treatment in people who have had mania that has responded to treatment with semi‑sodium valproate. Both semi‑sodium and sodium valproate are metabolised to valproic acid (also known as valproate), which is the pharmacologically active component. Valproate must not be used in pregnancy, and only used in girls and women when there is no alternative and the pregnancy prevention programme is in place. This is because of the risk of malformations and developmental abnormalities in the baby. See update information for important safety advice from the MHRA on the use of valproate.# Research recommendations
The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. The Guideline Development Group's full set of research recommendations is detailed in the full guideline.
# Maintenance treatment
In the maintenance treatment of bipolar disorder, what is the relative effect on quality of life of lithium, an antipsychotic (haloperidol, olanzapine, quetiapine or risperidone), or a combination of lithium and an antipsychotic?
## Why this is important
Lithium and antipsychotic medication are known to reduce the risk of relapse when used long‑term in people with bipolar disorder. Relapses do still occur and the response is usually to add another mood‑stabilising drug. However, lithium and antipsychotics are associated with a number of side effects, some of which can adversely affect physical health. The relative effects of lithium, an antipsychotic or a combination of these drugs, regarding efficacy, tolerability, cost effectiveness and quality of life, are unknown. Such information is important to people with bipolar disorder to help them make an informed choice about the treatment options available to them, and to the NHS to inform the best use of resources.
The suggested programme of research should involve a pragmatic 3‑arm RCT comparing lithium monotherapy with antipsychotic monotherapy (haloperidol, olanzapine, quetiapine or risperidone) and a combination of lithium and an antipsychotic. The study should last at least 1 year with the primary outcome being quality of life. Symptom control, relapse, function and economic outcomes should also be measured.
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{'Introduction': "Bipolar disorder is a potentially lifelong and disabling condition characterised by episodes of mania (abnormally elevated mood or irritability and related symptoms with severe functional impairment or psychotic symptoms for 7\xa0days or more) or hypomania (abnormally elevated mood or irritability and related symptoms with decreased or increased function for 4\xa0days or more) and episodes of depressed mood. It is often comorbid with other disorders such as anxiety disorders, substance misuse, personality disorders and attention deficit hyperactivity disorder (ADHD).\n\nThe peak age of onset is 15\xa0to 19\xa0years, and there is often a substantial delay between onset and first contact with mental health services. The lifetime prevalence of bipolar\xa0I disorder (mania and depression) is estimated at 1% of the adult population, and bipolar\xa0II disorder (hypomania and depression) affects approximately 0.4% of adults. Bipolar disorder in children under 12\xa0years is very rare.\n\nSince the publication of the previous NICE guideline (CG38) in 2006, there have been some important advances in our knowledge of the care pathway and treatment approaches that are most likely to benefit people with bipolar disorder. All areas of CG38 have been updated.\n\nThis guideline covers the recognition, assessment and management of bipolar disorder in children, young people and adults. It includes specific recommendations for diagnosis in children and young people because presentation in these age groups can be complicated by other conditions such as ADHD. The recommendations apply to people with bipolar\xa0I, bipolar\xa0II, mixed affective and rapid cycling disorders. Non‑bipolar affective disorders are not covered because these are addressed by other guidelines, and this guideline does not make specific recommendations about other mental disorders that commonly coexist with bipolar disorder.\n\n# Safeguarding children\n\nRemember that child maltreatment:\n\nis common\n\ncan present anywhere, such as emergency departments, primary and secondary care and community settings (such as the child's home).\n\nBe aware of or suspect abuse as a contributory factor to or cause of bipolar disorder in children. Abuse may also coexist with bipolar disorder. See NICE's guideline on child maltreatment for clinical features that may be associated with maltreatment.\n\nThis section has been agreed with the Royal College of Paediatrics and Child Health.", 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThe recommendations cover children, young people and adults with suspected or diagnosed bipolar disorder and apply to bipolar\xa0I, bipolar\xa0II, mixed affective and rapid cycling disorders.\n\n# Care for adults, children and young people across all phases of bipolar disorder\n\n## Improving the experience of care\n\nUse this guideline in conjunction with NICE's guideline on service user experience in adult mental health to improve the experience of care for adults with bipolar disorder using mental health services, and for adults, children and young people:\n\npromote a positive recovery message from the point of diagnosis and throughout care\n\nbuild supportive and empathic relationships as an essential part of care.\n\nFollow the recommendations in general principles of care in NICE's guideline on psychosis and schizophrenia in children and young people to improve the experience of care for children and young people with bipolar disorder.\n\n## Treatment and support for specific populations\n\nFollow the recommendations in race, culture and ethnicity in NICE's clinical guideline on psychosis and schizophrenia in adults when working with people with bipolar disorder from black, Asian and minority ethnic groups.\n\nSee NICE's guideline on antenatal and postnatal mental health for guidance on the management of bipolar disorder during pregnancy and the postnatal period and in women and girls of childbearing potential.\n\nEnsure that people with bipolar disorder and a coexisting learning disability are offered the same range of treatments and services as other people with bipolar disorder.\n\nEnsure that older people with bipolar disorder are offered the same range of treatments and services as younger people with bipolar disorder.\n\nOffer people with bipolar disorder and coexisting disorders, such as personality disorder, attention deficit hyperactivity disorder, anxiety disorders or substance misuse, treatment in line with the relevant NICE guideline, in addition to their treatment for bipolar disorder. See NICE's guidelines on antisocial personality disorder, borderline personality disorder, attention deficit hyperactivity disorder, generalised anxiety disorder and psychosis with coexisting substance misuse, be alert to the potential for drug interactions and use clinical judgement.\n\nOffer people with rapid cycling bipolar disorder the same interventions as people with other types of bipolar disorder because there is currently no strong evidence to suggest that people with rapid cycling bipolar disorder should be treated differently.\n\n## Information and support\n\nConsider identifying and offering assistance with education, financial and employment problems that may result from the behaviour associated with bipolar disorder, such as mania and hypomania. If the person with bipolar disorder agrees, this could include talking directly with education staff, creditors and employers about bipolar disorder and its possible effects, and how the person can be supported.\n\nEncourage people with bipolar disorder to develop advance statements while their condition is stable, in collaboration with their carers if possible.\n\nExplain and discuss making a lasting power of attorney with adults with bipolar disorder and their carers if there are financial problems resulting from mania or hypomania.\n\n## Support for carers of people with bipolar disorder\n\nOffer carers of people with bipolar disorder an assessment (provided by mental health services) of their own needs and discuss with them their strengths and views. Develop a care plan to address any identified needs, give a copy to the carer and their GP and ensure it is reviewed annually.\n\nAdvise carers about their statutory right to a formal carer's assessment provided by social care services and explain how to access this. See NICE's guideline on supporting adult carers.\n\nGive carers written and verbal information in an accessible format about:\n\ndiagnosis and management of bipolar disorder\n\npositive outcomes and recovery\n\ntypes of support for carers\n\nrole of teams and services\n\ngetting help in a crisis. When providing information, offer the carer support if necessary.\n\nAs early as possible negotiate with the person with bipolar disorder and their carers about how information about the person will be shared. When discussing rights to confidentiality, emphasise the importance of sharing information about risks and the need for carers to understand the person's perspective. Foster a collaborative approach that supports both people with bipolar disorder and their carers, and respects their individual needs and interdependence.\n\nReview regularly how information is shared, especially if there are communication and collaboration difficulties between the person and their carer.\n\nInclude carers in decision‑making if the person agrees.\n\nOffer a carer‑focused education and support programme, which may be part of a family intervention for bipolar disorder, as early as possible to all carers. The intervention should:\n\nbe available as needed\n\nhave a positive message about recovery.\n\nIdentify children, young people and adults at risk of abuse or neglect who are dependent on, living with or caring for a person with bipolar disorder and:\n\nreview the need for an assessment according to local safeguarding procedures for children or adults as appropriate\n\noffer psychological and social support as needed.\n\n# Recognising and managing bipolar disorder in adults in primary care\n\n## Recognising bipolar disorder in primary care and referral\n\nWhen adults present in primary care with depression, ask about previous periods of overactivity or disinhibited behaviour. If the overactivity or disinhibited behaviour lasted for 4\xa0days or more, consider referral for a specialist mental health assessment.\n\nRefer people urgently for a specialist mental health assessment if mania or severe depression is suspected or they are a danger to themselves or others.\n\nDo not use questionnaires in primary care to identify bipolar disorder in adults.\n\n## Managing bipolar disorder in primary care\n\nDecember 2022: The MHRA has issued new safety advice on risks associated with valproate for anyone under 55.\n\nWhen working with people with bipolar disorder in primary care:\n\nengage with and develop an ongoing relationship with them and their carers\n\nsupport them to carry out care plans developed in secondary care and achieve their recovery goals\n\nfollow crisis plans developed in secondary care and liaise with secondary care specialists if necessary\n\nreview their treatment and care, including medication, at least annually and more often if the person, carer or healthcare professional has any concerns.\n\nOffer people with bipolar depression:\n\na psychological intervention that has been developed specifically for bipolar disorder and has a published evidence-based manual describing how it should be delivered or\n\na choice of psychological intervention (cognitive behavioural therapy, interpersonal therapy or behavioural couples therapy) in line with the advice on treatment options for more severe depression in the NICE guideline on depression.Discuss with the person the possible benefits and risks of psychological interventions and their preference. Monitor mood and if there are signs of hypomania or deterioration of the depressive symptoms, liaise with or refer the person to secondary care. If the person develops mania or severe depression, refer them urgently to secondary care.\n\nPsychological therapists working with people with bipolar depression in primary care should have training in and experience of working with people with bipolar disorder.\n\nDo not start lithium to treat bipolar disorder in primary care for people who have not taken lithium before, except under shared‑care arrangements.\n\nDo not start valproate in primary care to treat bipolar disorder.\n\nIf bipolar disorder is managed solely in primary care, re‑refer to secondary care if any one of the following applies:\n\nthere is a poor or partial response to treatment\n\nthe person's functioning declines significantly\n\ntreatment adherence is poor\n\nthe person develops intolerable or medically important side effects from medication\n\ncomorbid alcohol or drug misuse is suspected\n\nthe person is considering stopping any medication after a period of relatively stable mood\n\na woman with bipolar disorder is pregnant or planning a pregnancy.\n\n## Physical health\n\nDevelop and use practice case registers to monitor the physical and mental health of people with bipolar disorder in primary care.\n\nMonitor the physical health of people with bipolar disorder when responsibility for monitoring is transferred from secondary care, and then at least annually. The health check should be comprehensive, including all the checks recommended in recommendation\xa01.2.12 and focusing on physical health problems such as cardiovascular disease, diabetes, obesity and respiratory disease. A copy of the results should be sent to the care coordinator and psychiatrist, and put in the secondary care records.\n\nEnsure that the physical health check for people with bipolar disorder, performed at least annually, includes:\n\nweight or BMI, diet, nutritional status and level of physical activity\n\ncardiovascular status, including pulse and blood pressure\n\nmetabolic status, including fasting blood glucose or glycosylated haemoglobin (HbA1c), and blood lipid profile\n\nliver function\n\nrenal and thyroid function, and calcium levels, for people taking long‑term lithium.\n\nIdentify people with bipolar disorder who have hypertension, have abnormal lipid levels, are obese or at risk of obesity, have diabetes or are at risk of diabetes (as indicated by abnormal blood glucose levels), or are physically inactive, at the earliest opportunity. Follow NICE's guidelines on hypertension, lipid modification, prevention of cardiovascular disease, obesity, physical activity and preventing type\xa02 diabetes.\n\nOffer treatment to people with bipolar disorder who have diabetes and/or cardiovascular disease in primary care in line with NICE's guidelines on type 1 diabetes in adults: diagnosis and management, type 2 diabetes in adults: management and lipid modification.\n\n# Assessing suspected bipolar disorder in adults in secondary care\n\nAssessment of suspected bipolar disorder, and subsequent management, should be conducted in a service that can:\n\noffer the full range of pharmacological, psychological, social, occupational and educational interventions for people with bipolar disorder consistent with this guideline\n\nbe competent to provide all interventions offered\n\nplace emphasis on engagement as well as risk management\n\nprovide treatment and care in the least restrictive and stigmatising environment possible, and in an atmosphere of hope and optimism in line with NICE's guideline on service user experience in adult mental health. This might be an early intervention in psychosis service, a specialist bipolar disorder team, or a specialist integrated community‑based team.\n\nWhen assessing suspected bipolar disorder:\n\nundertake a full psychiatric assessment, documenting a detailed history of mood, episodes of overactivity and disinhibition or other episodic and sustained changes in behaviour, symptoms between episodes, triggers to previous episodes and patterns of relapse, and family history\n\nassess the development and changing nature of the mood disorder and associated clinical problems throughout the person's life (for example, early childhood trauma, developmental disorder or cognitive dysfunction in later life)\n\nassess social and personal functioning and current psychosocial stressors\n\nassess for potential mental and physical comorbidities\n\nassess the person's physical health and review medication and side effects, including weight gain\n\ndiscuss treatment history and identify interventions that have been effective or ineffective in the past\n\nencourage people to invite a family member or carer to give a corroborative history\n\ndiscuss possible factors associated with changes in mood, including relationships, psychosocial factors and lifestyle changes\n\nidentify personal recovery goals.\n\nTake into account the possibility of differential diagnoses including schizophrenia spectrum disorders, personality disorders, drug misuse, alcohol‑use disorders, attention deficit hyperactivity disorder and underlying physical disorders such as hypo‑ or hyperthyroidism.\n\nIf bipolar disorder is diagnosed, develop a care plan in collaboration with the person with bipolar disorder based on the assessment carried out in recommendation\xa01.3.2 as soon as possible after assessment and, depending on their needs, using the care programme approach. Give the person and their GP a copy of the plan, and encourage the person to share it with their carers.\n\nCarry out a risk assessment in conjunction with the person with bipolar disorder, and their carer if possible, focusing on areas that are likely to present possible danger or harm, such as self‑neglect, self‑harm, suicidal thoughts and intent, risks to others, including family members, driving, spending money excessively, financial or sexual exploitation, disruption in family and love relationships, disinhibited and sexualised behaviour, and risks of sexually transmitted diseases. For the management of risk, follow the recommendations in section\xa01.4.\n\n# Managing crisis, risk and behaviour that challenges in adults with bipolar disorder in secondary care\n\nDevelop a risk management plan jointly with the person, and their carer if possible, covering:\n\nidentifiable personal, social, occupational, or environmental triggers and early warning signs and symptoms of relapse\n\na protocol for applying the person's own coping strategies and increasing doses of medication or taking additional medication (which may be given to the person in advance) for people at risk of onset of mania or for whom early warning signs and symptoms can be identified\n\nagreements between primary and secondary care about how to respond to an increase in risk or concern about possible risk\n\ninformation about who to contact if the person with bipolar disorder and, if appropriate, their carer, is concerned or in a crisis, including the names of healthcare professionals in primary and secondary care who can be contacted.Give the person and their GP a copy of the plan, and encourage the person to share it with their carers.\n\nOffer crisis services to support people with bipolar disorder who are in crisis, in line with the section on service-level interventions in NICEs guideline on psychosis and schizophrenia in adults.\n\nIf people with bipolar disorder pose an immediate risk to themselves or others during an acute episode, see:\n\nNICE's guideline on violence and aggression: short-term management in mental health, health and community settings and service user experience in adult mental health for advice on managing agitation, challenging behaviour and imminent violence, and on rapid tranquillisation or\n\nNICE's guideline on self-harm for advice on managing acts of self‑harm and suicide risk.\n\n# Managing mania or hypomania in adults in secondary care\n\n## Support and advice\n\nEnsure that people with mania or hypomania have access to calming environments and reduced stimulation. Advise them not to make important decisions until they have recovered from mania or hypomania and encourage them to maintain their relationships with their carers if possible.\n\n## Pharmacological interventions\n\nDecember 2022: The MHRA has issued new safety advice on risks associated with valproate for anyone under 55.\n\nIf a person develops mania or hypomania and is taking an antidepressant (as defined by the British National Formulary [BNF]) as monotherapy:\n\nconsider stopping the antidepressant and\n\noffer an antipsychotic as set out in recommendation\xa01.5.3, regardless of whether the antidepressant is stopped.\n\nIf a person develops mania or hypomania and is not taking an antipsychotic or mood stabiliser, offer haloperidol, olanzapine, quetiapine or risperidone, taking into account any advance statements, the person's preference and clinical context (including physical comorbidity, previous response to treatment and side effects). Follow the recommendations on using antipsychotics in section 1.10.\n\nIf the first antipsychotic is poorly tolerated at any dose (including rapid weight gain) or ineffective at the maximum licensed dose, offer an alternative antipsychotic from the drugs listed in recommendation\xa01.5.3, taking into account any advance statements, the person's preference and clinical context (including physical comorbidity, previous response to treatment and side effects).\n\nIf an alternative antipsychotic is not sufficiently effective at the maximum licensed dose, consider adding lithium. If adding lithium is ineffective, or if lithium is not suitable (for example, because the person does not agree to routine blood monitoring), consider adding valproate instead. Do not offer valproate to women or girls of childbearing potential (including young girls who are likely to need treatment into their childbearing years) for long-term treatment or to treat an acute episode, unless other options are ineffective or not tolerated and the pregnancy prevention programme is in place. Follow the MHRA safety advice on valproate use by women and girls. Although its use is common in UK clinical practice, in September\xa02014 this was an off-label use of lithium. See NICE's information on prescribing medicines. In September\xa02014 semi-sodium valproate had a UK marketing authorisation for the treatment of mania if lithium is not tolerated or is contraindicated; this was an off-label use of sodium valproate, although its use was common in UK clinical practice. See NICE's information on prescribing medicines. See update information for important safety advice from the MHRA on the use of valproate. [amended 2020]\n\nIf a person develops mania or hypomania and is taking an antidepressant (as defined by the BNF) in combination with a mood stabiliser, consider stopping the antidepressant.\n\nIf the person is already taking lithium, check plasma lithium levels to optimise treatment (see section 1.10). Consider adding haloperidol, olanzapine, quetiapine or risperidone, depending on the person's preference and previous response to treatment.\n\nIf the person is already taking valproate or another mood stabiliser as prophylactic treatment, consider increasing the dose, up to the maximum level in the BNF if necessary, depending on clinical response. If there is no improvement, consider adding haloperidol, olanzapine, quetiapine or risperidone, depending on the person's preference and previous response to treatment. Follow the recommendations on using antipsychotics and valproate in section 1.10.If a woman or girl of childbearing potential is already taking valproate, advise her to gradually stop the drug because of the risk of fetal malformations and adverse neurodevelopmental outcomes after any exposure in pregnancy. See the MHRA safety advice on valproate use by women and girls. [amended 2020]\n\nIf the clinical presentation is of a mixed affective state, characterised by both manic and depressive symptoms, follow recommendations 1.5.1 to 1.5.8 for the treatment of mania, and monitor closely for the emergence of depression.\n\nDo not offer lamotrigine to treat mania.\n\n## Electroconvulsive therapy\n\nFor the treatment of severe mania that has not responded to other interventions, see NICE's technology appraisal guidance on the use of electroconvulsive therapy.\n\n## Reviewing treatment for mania\n\nWithin 4\xa0weeks of resolution of symptoms, discuss with the person, and their carers if appropriate, whether to continue treatment for mania or start long‑term treatment (see section 1.7). Explain the potential benefits of long‑term treatment and the risks, including side effects of medication used for long‑term treatment.\n\nIf the person decides to continue treatment for mania, offer it for a further 3\xa0to 6\xa0months, and then review.\n\n# Managing bipolar depression in adults in secondary care\n\n## Psychological interventions\n\nOffer adults with bipolar depression:\n\na psychological intervention that has been developed specifically for bipolar disorder and has a published evidence-based manual describing how it should be delivered or\n\na choice of psychological intervention (cognitive behavioural therapy, interpersonal therapy or behavioural couples therapy) in line with the advice on treatment options for more severe depression in the NICE guideline on depression. Discuss with the person the possible benefits and risks of psychological interventions and their preference. Monitor mood for signs of mania or hypomania or deterioration of the depressive symptoms.\n\nPsychological therapists working with people with bipolar depression should have training in, and experience of, working with people with bipolar disorder.\n\n## Pharmacological interventions\n\nDecember 2022: The MHRA has issued new safety advice on risks associated with valproate for anyone under 55.\n\nIf a person develops moderate or severe bipolar depression and is not taking a drug to treat their bipolar disorder, offer fluoxetine combined with olanzapine, or quetiapine on its own, depending on the person's preference and previous response to treatment.\n\nIf the person prefers, consider either olanzapine (without fluoxetine) or lamotrigine on its own.\n\nIf there is no response to fluoxetine combined with olanzapine, or quetiapine, consider lamotrigine on its own.Follow the recommendations on using antipsychotics and lamotrigine in section 1.10.In September\xa02014, this was an off-label use of olanzapine. Although their use was common in UK clinical practice, in September\xa02014 this was an off-label use of fluoxetine and of lamotrigine. See NICE's information on prescribing medicines.\n\nIf a person develops moderate or severe bipolar depression and is already taking lithium, check their plasma lithium level. If it is inadequate, increase the dose of lithium; if it is at maximum level, add either fluoxetine combined with olanzapine or add quetiapine, depending on the person's preference and previous response to treatment.\n\nIf the person prefers, consider adding olanzapine (without fluoxetine) or lamotrigine to lithium.\n\nIf there is no response to adding fluoxetine combined with olanzapine, or adding quetiapine, stop the additional treatment and consider adding lamotrigine to lithium. Follow the recommendations in section 1.10 on using lithium, antipsychotics and lamotrigine. In September\xa02014 aripiprazole had a UK marketing authorisation for up to 12\xa0weeks of treatment for moderate to severe manic episodes in bipolar I disorder in young people aged\xa013 and older.In September\xa02014, these were off-label uses of olanzapine, risperidone, haloperidol, quetiapine, lamotrigine, lithium and valproate for children and young people. See NICE's information on prescribing medicines.\n\nIf a person develops moderate or severe bipolar depression and is already taking valproate, consider increasing the dose within the therapeutic range. If the maximum tolerated dose, or the top of the therapeutic range, has been reached and there is a limited response to valproate, add fluoxetine combined with olanzapine or add quetiapine, depending on the person's preference and previous response to treatment.\n\nIf the person prefers, consider adding olanzapine (without fluoxetine) or lamotrigine to valproate.\n\nIf there is no response to adding fluoxetine combined with olanzapine, or adding quetiapine, stop the additional treatment and consider adding lamotrigine to valproate.Follow the recommendations in section\xa01.10 on using valproate, antipsychotics and lamotrigine.If a woman or girl of childbearing potential is already taking valproate, advise her to gradually stop the drug because of the risk of fetal malformations and adverse neurodevelopmental outcomes after any exposure in pregnancy. See the MHRA safety advice on valproate use by women and girls.In September\xa02014 aripiprazole had a UK marketing authorisation for up to 12\xa0weeks of treatment for moderate to severe manic episodes in bipolar I disorder in young people aged\xa013 and older.In September\xa02014, these were off-label uses of olanzapine, risperidone, haloperidol, quetiapine, lamotrigine, lithium and valproate for children and young people. See NICE's information on prescribing medicines. [amended 2020]\n\nFollow the recommendations on using antipsychotics in section\xa01.10 and be aware of the potential interactions between valproate and fluoxetine, lamotrigine and olanzapine. See the MHRA safety advice on valproate use by women and girls. [amended 2020]\n\nTake into account toxicity in overdose when prescribing psychotropic medication during periods of high suicide risk. Assess the need to limit the quantity of medication supplied to reduce the risk to life if the person overdoses.\n\n## Reviewing treatment for bipolar depression\n\nWithin 4\xa0weeks of resolution of symptoms, discuss with the person, and their carers if appropriate, whether to continue psychological or pharmacological treatment for bipolar depression or start long‑term treatment (see section\xa01.7). Explain the potential benefits of long‑term treatment and the risks, including side effects of medication used for long‑term treatment.\n\nIf the person decides to continue psychological or pharmacological treatment for bipolar depression, offer it for a further 3\xa0to 6\xa0months, and then review.\n\n# Managing bipolar disorder in adults in the longer term in secondary care\n\n## Discussing long‑term treatment\n\nAfter each episode of mania or bipolar depression, discuss with the person, and their carers if appropriate, managing their bipolar disorder in the longer term. Discussion should aim to help people understand that bipolar disorder is commonly a long‑term relapsing and remitting condition that needs self‑management and engagement with primary and secondary care professionals and involvement of carers. The discussion should cover:\n\nthe nature and variable course of bipolar disorder\n\nthe role of psychological and pharmacological interventions to prevent relapse and reduce symptoms\n\nthe risk of relapse after reducing or stopping medication for an acute episode\n\nthe potential benefits and risks of long‑term medication and psychological interventions, and the need to monitor mood and medication\n\nthe potential benefits and risks of stopping medication, including for women who may wish to become pregnant\n\nthe person's history of bipolar disorder, including:\n\n\n\nthe severity and frequency of episodes of mania or bipolar depression, with a focus on associated risks and adverse consequences\n\nprevious response to treatment\n\nsymptoms between episodes\n\npotential triggers for relapse, early warning signs, and self‑management strategies\n\n\n\npossible duration of treatment, and when and how often this should be reviewed.Provide clear written information about bipolar disorder, including NICE's information for the public, and ensure there is enough time to discuss options and concerns.\n\n## Psychological interventions\n\nOffer a family intervention to people with bipolar disorder who are living, or in close contact, with their family in line with recommendation\xa01.3.7.2. in NICE's guideline on psychosis and schizophrenia in adults.\n\nOffer a structured psychological intervention (individual, group or family), which has been designed for bipolar disorder and has a published evidence-based manual describing how it should be delivered, to prevent relapse or for people who have some persisting symptoms between episodes of mania or bipolar depression.\n\nIndividual and group psychological interventions for bipolar disorder to prevent relapse should:\n\nprovide information about bipolar disorder\n\nconsider the impact of thoughts and behaviour on moods and relapse\n\ninclude self‑monitoring of mood, thoughts and behaviour\n\naddress relapse risk, distress and how to improve functioning\n\ndevelop plans for relapse management and staying well\n\nconsider problem‑solving to address communication patterns and managing functional difficulties. In addition:\n\nindividual programmes should be tailored to the person's needs based on an individualised assessment and psychological formulation\n\ngroup programmes should include discussion of the information provided with a focus on its relevance for the participants.\n\n## Pharmacological interventions\n\nDecember 2022: The MHRA has issued new safety advice on risks associated with valproate for anyone under 55. We are reviewing the recommendations in this section.\n\nWhen planning long‑term pharmacological treatment to prevent relapse, take into account drugs that have been effective during episodes of mania or bipolar depression. Discuss with the person whether they prefer to continue this treatment or switch to lithium, and explain that lithium is the most effective long‑term treatment for bipolar disorder.\n\nOffer lithium as a first‑line, long‑term pharmacological treatment for bipolar disorder and:\n\nif lithium is ineffective, consider adding valproate\n\nif lithium is poorly tolerated, or is not suitable (for example, because the person does not agree to routine blood monitoring), consider valproate or olanzapine instead or, if it has been effective during an episode of mania or bipolar depression, quetiapine. Discuss with the person the possible benefits and risks of each drug for them, following the recommendations in section\xa01.10. If a woman or girl of childbearing potential is already taking valproate, advise her to gradually stop the drug because of the risk of fetal malformations and adverse neurodevelopmental outcomes after any exposure in pregnancy. See the MHRA safety advice on valproate use by women and girls. In September\xa02014 semi-sodium valproate had a UK marketing authorisation for this indication in people who have had mania that has responded to treatment with semi-sodium valproate; it was an off-label use of sodium valproate, although its use was common in UK clinical practice. See NICE's information on prescribing medicines. See update information for important safety advice from the MHRA on the use of valproate. [amended 2020]\n\nIf stopping long‑term pharmacological treatment:\n\ndiscuss with the person how to recognise early signs of relapse and what to do if symptoms recur\n\nstop treatment gradually (see section\xa01.10) and monitor the person for signs of relapse.\n\nContinue monitoring symptoms, mood and mental state for 2\xa0years after medication has stopped entirely. This may be undertaken in primary care (see recommendation 1.9.3).\n\n# Monitoring physical health in secondary care\n\nHealthcare professionals in secondary care should ensure, as part of the care programme approach, that people with bipolar disorder receive physical healthcare from primary care as described in recommendations 1.2.10 to 1.2.14 after responsibility for monitoring has been transferred from secondary care.\n\nPeople with bipolar disorder, especially those taking antipsychotics and long‑term medication, should be offered a combined healthy eating and physical activity programme by their mental healthcare provider.\n\nIf a person has rapid or excessive weight gain, abnormal lipid levels or problems with blood glucose management, take into account the effects of medication, mental state, other physical health and lifestyle factors in the development of these problems and offer interventions in line with NICE's guidelines on obesity, lipid modification or preventing type 2 diabetes.\n\nRoutinely monitor weight and cardiovascular and metabolic indicators of morbidity in people with bipolar disorder. These should be audited in the annual team report.\n\nTrusts should ensure that they take account of relevant guidelines on the monitoring and treatment of cardiovascular and metabolic disease in people with bipolar disorder through board‑level performance indicators.\n\n# Promoting recovery and return to primary care\n\n## Continuing treatment in secondary care\n\nContinue treatment and care in an early intervention in psychosis service, a specialist bipolar disorder service or a specialist integrated community‑based team. Share physical health monitoring with primary care as outlined in section\xa01.2 and section\xa01.8.\n\nConsider intensive case management for people with bipolar disorder who are likely to disengage from treatment or services.\n\n## Return to primary care\n\nOffer people with bipolar disorder whose symptoms have responded effectively to treatment and remain stable the option to return to primary care for further management. If they wish to do this, record it in their notes and coordinate transfer of responsibilities through the care programme approach.\n\nWhen making transfer arrangements for a return to primary care, agree a care plan with the person, which includes:\n\nclear, individualised social and emotional recovery goals\n\na crisis plan indicating early warning symptoms and triggers of both mania and depression relapse and preferred response during relapse, including liaison and referral pathways\n\nan assessment of the person's mental state\n\na medication plan with a date for review by primary care, frequency and nature of monitoring for effectiveness and adverse effects, and what should happen in the event of a relapse.Give the person and their GP a copy of the plan, and encourage the person to share it with their carers.\n\nEncourage and support the person to visit their GP and discuss the care plan before discharge and transfer.\n\n## Employment, education and occupational activities\n\nOffer supported employment programmes to people with bipolar disorder in primary or secondary care who wish to find or return to work. Consider other occupational or educational activities, including pre‑vocational training, for people who are unable to work or unsuccessful in finding employment.\n\n# How to use medication\n\nWhen using any psychotropic medication for bipolar disorder ensure that:\n\nthe person is given information that is suitable for their developmental level about the purpose and likely side effects of treatment including any monitoring that is required, and give them an opportunity to ask questions\n\nthe choice of medication is made in collaboration with the person with bipolar disorder, taking into account the carer's views if the person agrees\n\nthe overall medication regimen is regularly reviewed so that drugs that are not needed after the acute episode are stopped.\n\nDiscuss the use of alcohol, tobacco, prescription and non‑prescription medication and illicit drugs with the person, and their carer if appropriate. Explain the possible interference of these substances with the therapeutic effects of prescribed medication and psychological interventions.\n\nWhen offering psychotropic medication to older people, take into account its impact on cognitive functioning in older people and:\n\nuse medication at lower doses\n\ntake into account the increased risk of drug interactions\n\ntake into account the negative impact that anticholinergic medication, or drugs with anticholinergic activity, can have on cognitive function and mobility\n\nensure that medical comorbidities have been recognised and treated.\n\nDo not offer gabapentin or topiramate to treat bipolar disorder.\n\n## Using antipsychotic medication\n\nBefore starting antipsychotic medication, measure and record the person's:\n\nweight or BMI\n\npulse\n\nblood pressure\n\nfasting blood glucose or HbA1c\n\nblood lipid profile.\n\nBefore starting antipsychotic medication, offer the person an electrocardiogram (ECG) if:\n\nit is specified in the drug's summary of product characteristics (SPC) or\n\na physical examination has identified a specific cardiovascular risk (such as hypertension) or\n\nthere is a family history of cardiovascular disease, a history of sudden collapse, or other cardiovascular risk factors such as cardiac arrhythmia or\n\nthe person is being admitted as an inpatient.\n\nTreatment with antipsychotic medication should be considered an explicit individual therapeutic trial. Carry out the following:\n\nDiscuss and record the side effects that the person is most willing to tolerate.\n\nRecord the indications and expected benefits and risks of antipsychotic medication, and the expected time for a change in symptoms and appearance of side effects.\n\nAt the start of treatment prescribe a dose that is appropriate for the phase and severity of the illness.\n\nDo not routinely prescribe a dose above the maximum recommended in the BNF or SPC.\n\nJustify and record reasons for doses outside the range given in the BNF or SPC, and inform the person that such treatment is unlicensed.\n\nRecord the rationale for continuing, changing or stopping medication, and the effects of such changes.\n\nMonitor and record the following during dose titration and then regularly and systematically throughout treatment:\n\npulse and blood pressure after each dose change\n\nweight or BMI weekly for the first 6\xa0weeks, then at 12\xa0weeks\n\nfasting blood glucose or HbA1c, and blood lipid profile at 12\xa0weeks\n\nresponse to treatment, including changes in symptoms and behaviour\n\nside effects and their impact on physical health and functioning\n\nthe emergence of movement disorders\n\nadherence.\n\nThe secondary care team should maintain responsibility for monitoring the efficacy and tolerability of antipsychotic medication for at least the first 12\xa0months or until the person's condition has stabilised, whichever is longer. Thereafter, the responsibility for this monitoring may be transferred to primary care under shared‑care arrangements.\n\nIf out‑of‑range test results are reported at any stage of treatment, the healthcare professional who ordered the tests should ensure that the person is offered further investigations and treatment as needed.\n\n'As required' (p.r.n.) prescriptions of antipsychotic medication should be made as described in recommendation\xa01.10.7. Review clinical indications, frequency of administration, therapeutic benefits and side effects each week or more often if needed. Ensure that p.r.n. prescriptions have not unintentionally led to a total antipsychotic dosage above the maximum specified in the BNF or SPC.\n\nDo not start regular combined antipsychotic medication, except for short periods (for example, when changing medication).\n\nIf stopping an antipsychotic drug, reduce the dose gradually over at least 4\xa0weeks to minimise the risk of relapse.\n\n## Using lithium\n\nWhen starting lithium:\n\nadvise the person that poor adherence or rapid discontinuation may increase the risk of relapse\n\nmeasure the person's weight or BMI and arrange tests for urea and electrolytes including calcium, estimated glomerular filtration rate (eGFR), thyroid function and a full blood count\n\narrange an ECG for people with cardiovascular disease or risk factors for it\n\nensure the person is given appropriate national information (or a locally available equivalent) on taking lithium safely\n\nestablish a shared‑care arrangement with the person's GP for prescribing lithium and monitoring adverse effects.\n\nMeasure plasma lithium levels 1\xa0week after starting lithium and 1\xa0week after every dose change, and weekly until the levels are stable. Aim to maintain plasma lithium level between 0.6\xa0and 0.8\xa0mmol per litre in people being prescribed lithium for the first time.\n\nConsider maintaining plasma lithium levels at 0.8 to 1.0\xa0mmol per litre for a trial period of at least 6\xa0months for people who:\n\nhave had a relapse while taking lithium in the past or\n\nare taking lithium and have subthreshold symptoms with functional impairment.\n\nAdvise people taking lithium to:\n\nseek medical attention if they develop diarrhoea or vomiting or become acutely ill for any reason\n\nensure they maintain their fluid intake, particularly after sweating (for example, after exercise, in hot climates or if they have a fever), if they are immobile for long periods or if they develop a chest infection or pneumonia\n\ntalk to their doctor as soon as possible if they become pregnant or are planning a pregnancy.\n\nWarn people taking lithium not to take over‑the‑counter non‑steroidal anti‑inflammatory drugs and avoid prescribing these drugs for people with bipolar disorder if possible; if they are prescribed, this should be on a regular (not p.r.n.) basis and the person should be monitored monthly until a stable lithium level is reached and then every 3\xa0months.\n\nMeasure the person's plasma lithium level every 3\xa0months for the first year.\n\nAfter the first year, measure plasma lithium levels every 6\xa0months, or every 3\xa0months for people in any of the following groups:\n\nolder people\n\npeople taking drugs that interact with lithium\n\npeople who are at risk of impaired renal or thyroid function, raised calcium levels or other complications\n\npeople who have poor symptom control\n\npeople with poor adherence\n\npeople whose last plasma lithium level was 0.8\xa0mmol per litre or higher.\n\nMeasure the person's weight or BMI and arrange tests for urea and electrolytes including calcium, estimated glomerular filtration rate (eGFR) and thyroid function every 6\xa0months, and more often if there is evidence of impaired renal or thyroid function, raised calcium levels or an increase in mood symptoms that might be related to impaired thyroid function.\n\nMonitor lithium dose and plasma lithium levels more frequently if urea levels and creatinine levels become elevated, or eGFR falls over 2\xa0or more tests, and assess the rate of deterioration of renal function. For further information see NICE's guidelines on chronic kidney disease and acute kidney injury.\n\nWhen discussing whether to continue lithium, take into account clinical efficacy, other risk factors for renal impairment and cardiovascular disease, and degree of renal impairment; if needed seek advice from a renal specialist and a clinician with expertise in managing bipolar disorder.\n\nMonitor the person at every appointment for symptoms of neurotoxicity, including paraesthesia, ataxia, tremor and cognitive impairment, which can occur at therapeutic levels of lithium.\n\nIf stopping lithium, reduce the dose gradually over at least 4\xa0weeks, and preferably up to 3\xa0months, even if the person has started taking another antimanic drug.\n\nDuring dose reduction and for 3\xa0months after lithium treatment is stopped, monitor the person closely for early signs of mania and depression.\n\n## Using valproate\n\nDecember 2022: The MHRA has issued new safety advice on risks associated with valproate for anyone under 55.\n\nDo not offer valproate to women or girls of childbearing potential (including young girls who are likely to need treatment into their childbearing years) for long‑term treatment or to treat an acute episode, unless other options are ineffective or not tolerated and the pregnancy prevention programme is in place. See MHRA safety advice on valproate use by women and girls. [amended 2020]\n\nIf a woman or girl of childbearing potential is already taking valproate, advise her to gradually stop the drug because of the risk of fetal malformations and adverse neurodevelopmental outcomes after any exposure in pregnancy. See the MHRA safety advice on valproate use by women and girls. [amended 2020]\n\nWhen starting valproate, measure the person's weight or BMI and carry out a full blood count and liver function tests. Do not offer valproate to women and girls of childbearing age (including young girls who are likely to need treatment into their childbearing years) unless other options are ineffective or not tolerated and the pregnancy prevention programme is in place. See the MHRA safety advice on valproate use by women and girls. [amended 2020]\n\nAdvise people taking valproate, and their carers, how to recognise the signs and symptoms of blood and liver disorders and to seek immediate medical help if any of these develop. Stop valproate immediately if abnormal liver function or blood dyscrasia is detected.Although the absolute values of hepatic enzymes are a poor indicator of the extent of hepatic damage, it is generally accepted that if these are persistently elevated to over 3\xa0times the upper normal limit, continuing to rise or accompanied by clinical symptoms, the suspected drug should be withdrawn. Raised hepatic enzymes of any magnitude accompanied by reduced albumin or impaired clotting suggest severe liver disease.\n\nWhen prescribing valproate, be aware of its interactions with other anticonvulsants (particularly carbamazepine and lamotrigine) and with olanzapine and smoking.\n\nDo not routinely measure plasma valproate levels unless there is evidence of ineffectiveness, poor adherence or toxicity.\n\nMeasure the person's weight or BMI and carry out liver function tests and a full blood count again after 6\xa0months of treatment with valproate and repeat annually.\n\nMonitor sedation, tremor and gait disturbance carefully in older people.\n\nIf stopping valproate, reduce the dose gradually over at least 4\xa0weeks to minimise the risk of relapse.\n\n## Using lamotrigine\n\nWhen starting lamotrigine:\n\ncarry out a full blood count, urea and electrolytes and liver function tests\n\nbe aware of its interaction with valproate\n\nfollow the instructions for initial dosage and dosage titration outlined in the SPC and BNF, taking into account the need for slow titration in people who have not taken lamotrigine before.\n\nAdvise people taking lamotrigine to:\n\ncontact their doctor immediately if they develop a rash while the dose of lamotrigine is being increased\n\ntell you if they are pregnant or planning a pregnancy.\n\nDo not routinely measure plasma lamotrigine levels unless there is evidence of ineffectiveness, poor adherence or toxicity.\n\nIf stopping lamotrigine, reduce the dose gradually over at least 4\xa0weeks to minimise the risk of relapse.\n\n# Recognising, diagnosing and managing bipolar disorder in children and young people\n\n## Recognition and referral\n\nDo not use questionnaires in primary care to identify bipolar disorder in children or young people.\n\nIf bipolar disorder is suspected in primary care in children or young people aged under 14\xa0years, refer them to child and adolescent mental health services (CAMHS).\n\nIf bipolar disorder is suspected in primary care in young people aged 14\xa0years or over, refer them to a specialist early intervention in psychosis service or a CAMHS team with expertise in the assessment and management of bipolar disorder in line with the recommendations in this guideline. The service should be multidisciplinary and have:\n\nengagement or assertive outreach approaches\n\nfamily involvement and family intervention\n\naccess to structured psychological interventions and psychologically informed care\n\nvocational and educational interventions\n\naccess to pharmacological interventions\n\nprofessionals who are trained and competent in working with young people with bipolar disorder.\n\nDiagnosis of bipolar disorder in children or young people should be made only after a period of intensive, prospective longitudinal monitoring by a healthcare professional or multidisciplinary team trained and experienced in the assessment, diagnosis and management of bipolar disorder in children and young people, and in collaboration with the child or young person's parents or carers.\n\nWhen diagnosing bipolar disorder in children or young people take account of the following:\n\nmania must be present\n\neuphoria must be present on most days and for most of the time, for at least 7\xa0days\n\nirritability is not a core diagnostic criterion.\n\nDo not make a diagnosis of bipolar disorder in children or young people on the basis of depression with a family history of bipolar disorder but follow them up.\n\nWhen assessing suspected bipolar disorder in children or young people, follow recommendations\xa01.3.2 to 1.3.4 for adults, but involve parents or carers routinely and take into account the child or young person's educational and social functioning.\n\n## Management in young people\n\nWhen offering treatment to young people with bipolar disorder, take into account their cognitive ability, emotional maturity, developmental level, their capacity to consent to treatment, the severity of their bipolar disorder and risk of suicide or self‑harm or any other risk outlined in recommendation\xa01.3.5.\n\nDecember 2022: The MHRA has issued new safety advice on risks associated with valproate for anyone under 55.\n\nTo treat mania or hypomania in young people see NICE's technology appraisal guidance on aripiprazole for treating moderate to severe manic episodes in adolescents with bipolar\xa0I disorder and also consider the recommendations for adults in section\xa01.5. Refer to the BNF for children to modify drug treatments, be aware of the increased potential for a range of side effects, and do not routinely continue antipsychotic treatment for longer than 12\xa0weeks. In September\xa02014 aripiprazole had a UK marketing authorisation for up to 12\xa0weeks of treatment for moderate to severe manic episodes in bipolar I disorder in young people aged 13 and older.In September\xa02014, this was an off-label use of olanzapine, risperidone, haloperidol, quetiapine, lamotrigine, lithium and valproate for children and young people. See NICE's information on prescribing medicines.\n\nDo not offer valproate to girls or young women of childbearing potential. See the MHRA safety advice on valproate use by women and girls. [amended 2020]\n\nOffer a structured psychological intervention (individual cognitive behavioural therapy or interpersonal therapy) to young people with bipolar depression. The intervention should be of at least 3\xa0months' duration and have a published evidence-based manual describing how it should be delivered.\n\nIf after 4\xa0to 6\xa0weeks there is no or a limited response to cognitive behavioural therapy or interpersonal therapy, carry out a multidisciplinary review and consider an alternative individual or family psychological intervention.\n\nIf there is a risk of suicide or self‑harm or any other risk outlined in recommendation\xa01.3.5, carry out an urgent review and develop a risk management plan as outlined in recommendation\xa01.4.1.\n\nAfter the multidisciplinary review, if there are coexisting factors such as comorbid conditions, persisting psychosocial risk factors such as family discord, or parental mental ill‑health, consider:\n\nan alternative psychological intervention for bipolar depression for the young person, their parents or other family member or\n\nan additional psychological intervention for any coexisting mental health problems in line with relevant NICE guidance for the young person, their parents or other family member.\n\nIf the young person's bipolar depression is moderate to severe, consider a pharmacological intervention in addition to a psychological intervention. Follow the recommendations for pharmacological interventions for adults in section\xa01.6 but refer to the BNF for children to modify drug treatments, and do not routinely continue antipsychotic treatment for longer than 12\xa0weeks. At 12\xa0weeks, carry out a full multidisciplinary review of mental and physical health, and consider further management of depression or long‑term management. In September\xa02014, this was an off-label use of olanzapine, quetiapine and lamotrigine for children and young people. See NICE's information on prescribing medicines.\n\nAfter the multidisciplinary review, consider a structured individual or family psychological intervention for managing bipolar disorder in young people in the longer term.\n\n# Terms used in this guideline\n\n## Carer\n\nA person who provides unpaid support to a partner, family member, friend or neighbour who is ill, struggling or disabled.\n\n## Children\n\nPeople aged 12\xa0years and under.\n\n## Depression\n\nThe severity of bipolar depression is defined in line with NICE's clinical guideline on depression as follows:\n\nMild depression Few, if any, symptoms in excess of the 5 required to make the diagnosis, with symptoms resulting in minor functional impairment.\n\nModerate depression Symptoms or functional impairment that are between mild and severe.\n\nSevere depression Most symptoms, with symptoms markedly interfering with functioning. Can occur with or without psychotic symptoms.\n\n## Evidence‑based manual\n\nA manual based on at least 1 randomised controlled trial published in a peer‑reviewed journal showing effectiveness of the intervention in reducing depression symptoms in bipolar depression or, when used as long‑term treatment, reducing relapse in people with bipolar disorder.\n\n## Older people\n\nPeople aged 65\xa0years and over.\n\n## Young people\n\nPeople aged 13\xa0to 17\xa0years.\n\n## Valproate\n\nRefers to 3\xa0formulations of valproate available in the UK: sodium valproate, valproic acid and semi‑sodium valproate. At the time of publication (September\xa02014), sodium valproate and valproic acid had UK marketing authorisation for the treatment of epilepsy. Semi‑sodium valproate had a UK marketing authorisation for the treatment of acute mania and for continuation treatment in people who have had mania that has responded to treatment with semi‑sodium valproate. Both semi‑sodium and sodium valproate are metabolised to valproic acid (also known as valproate), which is the pharmacologically active component. Valproate must not be used in pregnancy, and only used in girls and women when there is no alternative and the pregnancy prevention programme is in place. This is because of the risk of malformations and developmental abnormalities in the baby. See update information for important safety advice from the MHRA on the use of valproate.", 'Research recommendations': "The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. The Guideline Development Group's full set of research recommendations is detailed in the full guideline.\n\n# Maintenance treatment\n\nIn the maintenance treatment of bipolar disorder, what is the relative effect on quality of life of lithium, an antipsychotic (haloperidol, olanzapine, quetiapine or risperidone), or a combination of lithium and an antipsychotic?\n\n## Why this is important\n\nLithium and antipsychotic medication are known to reduce the risk of relapse when used long‑term in people with bipolar disorder. Relapses do still occur and the response is usually to add another mood‑stabilising drug. However, lithium and antipsychotics are associated with a number of side effects, some of which can adversely affect physical health. The relative effects of lithium, an antipsychotic or a combination of these drugs, regarding efficacy, tolerability, cost effectiveness and quality of life, are unknown. Such information is important to people with bipolar disorder to help them make an informed choice about the treatment options available to them, and to the NHS to inform the best use of resources.\n\nThe suggested programme of research should involve a pragmatic 3‑arm RCT comparing lithium monotherapy with antipsychotic monotherapy (haloperidol, olanzapine, quetiapine or risperidone) and a combination of lithium and an antipsychotic. The study should last at least 1\xa0year with the primary outcome being quality of life. Symptom control, relapse, function and economic outcomes should also be measured."}
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https://www.nice.org.uk/guidance/cg185
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This guideline covers recognising, assessing and treating bipolar disorder (formerly known as manic depression) in children, young people and adults. The recommendations apply to bipolar I, bipolar II, mixed affective and rapid cycling disorders. It aims to improve access to treatment and quality of life in people with bipolar disorder.
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476ae201edf015fb7b6500870b935e0d94fc02ad
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nice
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Antenatal and postnatal mental health: clinical management and service guidance
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Antenatal and postnatal mental health: clinical management and service guidance
This guideline covers recognising, assessing and treating mental health problems in women who are planning to have a baby, are pregnant, or have had a baby or been pregnant in the past year. It covers depression, anxiety disorders, eating disorders, drug- and alcohol-use disorders and severe mental illness (such as psychosis, bipolar disorder and schizophrenia). It promotes early detection and good management of mental health problems to improve women’s quality of life during pregnancy and in the year after giving birth.
# Introduction
In pregnancy and the postnatal period, many mental health problems have a similar nature, course and potential for relapse as at other times. However, there can be differences; for example, bipolar disorder shows an increased rate of relapse and first presentation in the postnatal period. Some changes in mental health state and functioning (such as appetite) may represent normal pregnancy changes, but they may be a symptom of a mental health problem.
The management of mental health problems during pregnancy and the postnatal period differs from at other times because of the nature of this life stage and the potential impact of any difficulties and treatments on the woman and the baby. There are risks associated with taking psychotropic medication in pregnancy and during breastfeeding and risks of stopping medication taken for an existing mental health problem. There is also an increased risk of postpartum psychosis.
Depression and anxiety are the most common mental health problems during pregnancy, with around 12% of women experiencing depression and 13% experiencing anxiety at some point; many women will experience both. Depression and anxiety also affect 15‑20% of women in the first year after childbirth. During pregnancy and the postnatal period, anxiety disorders, including panic disorder, generalised anxiety disorder (GAD), obsessive‑compulsive disorder (OCD), post‑traumatic stress disorder (PTSD) and tokophobia (an extreme fear of childbirth), can occur on their own or can coexist with depression. Psychosis can re‑emerge or be exacerbated during pregnancy and the postnatal period. Postpartum psychosis affects between 1 and 2 in 1,000 women who have given birth. Women with bipolar I disorder are at particular risk, but postpartum psychosis can occur in women with no previous psychiatric history.
Changes to body shape, including weight gain, in pregnancy and after childbirth may be a concern for women with an eating disorder. Although the prevalence of anorexia nervosa and bulimia nervosa is lower in pregnant women, the prevalence of binge eating disorder is higher. Smoking and the use of illicit drugs and alcohol in pregnancy are common, and prematurity, intrauterine growth restriction and fetal compromise are more common in women who use these substances, particularly women who smoke.
Between 2006 and 2008 there were 1.27 maternal deaths per 100,000 maternal deliveries in the UK as a result of mental health problems. Although response to treatment for mental health problems is good, these problems frequently go unrecognised and untreated in pregnancy and the postnatal period. If untreated, women can continue to have symptoms, sometimes for many years, and these can also affect their babies and other family members.
This guideline makes recommendations for the recognition, assessment, care and treatment of mental health problems in women during pregnancy and the postnatal period (up to 1 year after childbirth) and in women who are planning a pregnancy. The guideline covers depression, anxiety disorders, eating disorders, drug and alcohol‑use disorders and severe mental illness (such as psychosis, bipolar disorder, schizophrenia and severe depression). It covers subthreshold symptoms as well as mild, moderate and severe mental health problems. However, the guideline focuses on aspects of expression, risks and management that are of special relevance in pregnancy and the postnatal period.
The recommendations are relevant to all healthcare professionals who recognise, assess and refer for or provide interventions for mental health problems in pregnancy and the postnatal period. It will also be relevant to non‑NHS services, such as social services and the voluntary and private sectors, but does not make specific recommendations for these. The guideline also makes recommendations about the primary and secondary care services needed to support the effective identification and treatment of most mental health problems in pregnancy and the postnatal period. This guideline should be read in conjunction with other NICE guidelines on the treatment and management of specific mental health problems. The guideline indicates where modifications to treatment and management are needed in pregnancy and the postnatal period.
The guideline draws on the best available evidence. However, there are significant limitations to the evidence base, including limited data on the risks of psychotropic medication in pregnancy and during breastfeeding.
# Medicines
No psychotropic medication has a UK marketing authorisation specifically for women who are pregnant or breastfeeding. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. The woman (or those with authority to give consent on her behalf) should provide informed consent, which should be documented. See the General Medical Council's Good practice in prescribing and managing medicines and devices for further information. Where recommendations have been made for the use of medicines outside their licensed indications ('off‑label use'), these medicines are marked in the recommendations.# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Using this guideline in conjunction with other NICE guidelines
## Improving the experience of care
Use this guideline in conjunction with the NICE guidelines on service user experience in adult mental health and patient experience in adult NHS services to improve the experience of care for women with a mental health problem in pregnancy or the postnatal period.
## Assessment and treatment in pregnancy and the postnatal period
Use this guideline in conjunction with the NICE guideline for a specific mental health problem (see our topic pages on pregnancy and mental health and wellbeing) to inform assessment and treatment decisions in pregnancy and the postnatal period, and take into account:
any variations in the nature and presentation of the mental health problem in pregnancy or the postnatal period
the setting for assessment and treatment (for example, primary or secondary care services or in the community, the home or remotely by phone or computer)
recommendations on assessment and care planning in pregnancy and the postnatal period
recommendations 1.4.10 to 1.4.37 on starting, using and stopping treatment in pregnancy and the postnatal period
recommendations 1.8.1 to 1.8.23 on treating specific mental health problems in pregnancy and the postnatal period.
# Considerations for women of childbearing potential
Discuss with all women of childbearing potential who have a new, existing or past mental health problem:
the use of contraception and any plans for a pregnancy
how pregnancy and childbirth might affect a mental health problem, including the risk of relapse
how a mental health problem and its treatment might affect the woman, the fetus and baby
how a mental health problem and its treatment might affect parenting.
When prescribing psychotropic medication or antiepileptics for women or girls of childbearing potential (including young girls who are likely to need treatment into their childbearing years), take account of the latest data on the risks to the fetus and baby. Follow the MHRA safety advice on antiepileptic drugs in pregnancy.
Do not offer valproate for acute or long‑term treatment of a mental health problem in women or girls of childbearing potential (including young girls who are likely to need treatment into their childbearing years), unless other options are ineffective or not tolerated and the pregnancy prevention programme is in place. See the MHRA safety advice on valproate use by women and girls.
# Principles of care in pregnancy and the postnatal period
## Supporting women and their partners, families and carers
Acknowledge the woman's role in caring for her baby and support her to do this in a non‑judgmental and compassionate way.
Involve the woman and, if she agrees, her partner, family or carer, in all decisions about her care and the care of her baby.
When working with girls and young women with a mental health problem in pregnancy or the postnatal period:
be familiar with local and national guidelines on confidentiality and the rights of the child
be aware of the recommendations in section 1.4 of the NICE guideline on pregnancy and complex social factors
ensure continuity of care for the mental health problem if care is transferred from adolescent to adult services.
Take into account and, if appropriate, assess and address the needs of partners, families and carers that might affect a woman with a mental health problem in pregnancy and the postnatal period. These include:
the welfare of the baby and other dependent children and adults
the role of the partner, family or carer in providing support
the potential effect of any mental health problem on the woman's relationship with her partner, family or carer.
## Coordinated care
Develop an integrated care plan for a woman with a mental health problem in pregnancy and the postnatal period that sets out:
the care and treatment for the mental health problem
the roles of all healthcare professionals, including who is responsible for:
coordinating the integrated care plan
the schedule of monitoring
providing the interventions and agreeing the outcomes with the woman.
The healthcare professional responsible for coordinating the integrated care plan should ensure that:
everyone involved in a woman's care is aware of their responsibilities
there is effective sharing of information with all services involved and with the woman herself
mental health (including mental wellbeing) is taken into account as part of all care plans
all interventions for mental health problems are delivered in a timely manner, taking into account the stage of the pregnancy or age of the baby.
# Treatment decisions, advice and monitoring for women who are planning a pregnancy, are pregnant or are in the postnatal period
## Information and advice
Provide culturally relevant information on mental health problems in pregnancy and the postnatal period to the woman and, if she agrees, her partner, family or carer. Ensure that the woman understands that mental health problems are not uncommon during these periods and instil hope about treatment.
Consider referring a woman to a secondary mental health service (preferably a specialist perinatal mental health service) for preconception counselling if she has a current or past severe mental health problem and is planning a pregnancy.
Discuss treatment and prevention options and any particular concerns the woman has about the pregnancy or the fetus or baby. Provide information to the woman and, if she agrees, her partner, family or carer, about:
the potential benefits of psychological interventions and psychotropic medication
the possible consequences of no treatment
the possible harms associated with treatment
what might happen if treatment is changed or stopped, particularly if psychotropic medication is stopped abruptly.
Discuss breastfeeding with all women who may need to take psychotropic medication in pregnancy or in the postnatal period. Explain to them the benefits of breastfeeding, the potential risks associated with taking psychotropic medication when breastfeeding and with stopping some medications in order to breastfeed. Discuss treatment options that would enable a woman to breastfeed if she wishes and support women who choose not to breastfeed.
If needed, seek more detailed advice about the possible risks of mental health problems or the benefits and harms of treatment in pregnancy and the postnatal period from a secondary mental health service (preferably a specialist perinatal mental health service). This might include advice on the risks and possible harms of taking psychotropic medication while breastfeeding and how medication might affect a woman's ability to care for her baby (for example, sedation).
Mental health professionals providing detailed advice about the possible risks of mental health problems or the benefits and harms of treatment in pregnancy and the postnatal period should include discussion of the following, depending on individual circumstances:
the uncertainty about the benefits, risks and harms of treatments for mental health problems in pregnancy and the postnatal period
the likely benefits of each treatment, taking into account the severity of the mental health problem
the woman's response to any previous treatment
the background risk of harm to the woman and the fetus or baby associated with the mental health problem and the risk to mental health and parenting associated with no treatment
the possibility of the sudden onset of symptoms of mental health problems in pregnancy and the postnatal period, particularly in the first few weeks after childbirth (for example, in bipolar disorder)
the risks or harms to the woman and the fetus or baby associated with each treatment option
the need for prompt treatment because of the potential effect of an untreated mental health problem on the fetus or baby
the risk or harms to the woman and the fetus or baby associated with stopping or changing a treatment.
When discussing likely benefits and risks of treatment with the woman and, if she agrees, her partner, family or carer:
acknowledge the woman's central role in reaching a decision about her treatment and that the role of the professional is to inform that decision with balanced and up‑to‑date information and advice
use absolute values based on a common denominator (that is, numbers out of 100 or 1,000)
acknowledge and describe, if possible, the uncertainty around any estimate of risk, harm or benefit
use high‑quality decision aids in a variety of numerical and pictorial formats that focus on a personalised view of the risks and benefits, in line with the NICE guideline on patient experience in adult NHS services
consider providing records of the consultation, in a variety of visual, verbal or audio formats.
## Monitoring and increased contact
Healthcare professionals working in universal services and those caring for women in mental health services should:
assess the level of contact and support needed by women with a mental health problem (current or past) and those at risk of developing one
agree the level of contact and support with each woman, including those who are not having treatment for a mental health problem
monitor regularly for symptoms throughout pregnancy and the postnatal period, particularly in the first few weeks after childbirth.
Discuss and plan how symptoms will be monitored (for example, by using validated self‑report questionnaires, such as the Edinburgh Postnatal Depression Scale , Patient Health Questionnaire or the 7‑item Generalized Anxiety Disorder scale ).
## Starting, using and stopping treatment
Before starting any treatment in pregnancy and the postnatal period, discuss with the woman the higher threshold for pharmacological interventions arising from the changing risk‑benefit ratio for psychotropic medication at this time and the likely benefits of a psychological intervention.
If the optimal treatment for a woman with a mental health problem is psychotropic medication combined with a psychological intervention, but she declines or stops taking psychotropic medication in pregnancy or the postnatal period, ensure that:
she is adequately supported and
has the opportunity to discuss the risk associated with stopping psychotropic medication and
is offered, or can continue with, a psychological intervention.
When psychotropic medication is started in pregnancy and the postnatal period, consider seeking advice, preferably from a specialist in perinatal mental health, and:
choose the drug with the lowest risk profile for the woman, fetus and baby, taking into account a woman's previous response to medication
use the lowest effective dose (this is particularly important when the risks of adverse effects to the woman, fetus and baby may be dose related), but note that sub‑therapeutic doses may also expose the fetus to risks and not treat the mental health problem effectively
use a single drug, if possible, in preference to 2 or more drugs
take into account that dosages may need to be adjusted in pregnancy.
When a woman with severe mental illness decides to stop psychotropic medication in pregnancy and the postnatal period, discuss with her:
her reasons for doing so
the possibility of:
restarting the medication
switching to other medication
having a psychological intervention
increasing the level of monitoring and support.Ensure she knows about any risks to herself, the fetus or baby when stopping medication.
When a woman with depression or an anxiety disorder decides to stop taking psychotropic medication in pregnancy and the postnatal period, discuss with her:
her reasons for doing so
the possibility of:
having a psychological intervention
restarting the medication if the depression or anxiety disorder is or has been severe and there has been a previous good response to treatment
switching to other medication
increasing the level of monitoring and support while she is not taking any medication. Ensure she knows about any risks to herself, the fetus or baby when stopping medication.
If a pregnant woman has taken psychotropic medication with known teratogenic risk at any time in the first trimester:
confirm the pregnancy as soon as possible
explain that stopping or switching the medication after pregnancy is confirmed may not remove the risk of fetal malformations
-ffer screening for fetal abnormalities and counselling about continuing the pregnancy
explain the need for additional monitoring and the risks to the fetus if she continues to take the medication.Seek advice from a specialist if there is uncertainty about the risks associated with specific drugs.
For guidance on safe prescribing of antidepressants and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.
When choosing a tricyclic antidepressant (TCA), selective serotonin reuptake inhibitor (SSRI) or (serotonin‑) noradrenaline reuptake inhibitor , take into account:
the woman's previous response to these drugs
the stage of pregnancy (for example, see the MHRA's drug safety update on SSRI/SNRI antidepressant medicines: for information on a small increased risk of postpartum haemorrhage with SSRI and SNRI antidepressant medicines when used in the month before delivery)
what is known about the reproductive safety of these drugs (for example, the risk of fetal cardiac abnormalities and persistent pulmonary hypertension in the newborn baby)
the uncertainty about whether any increased risk to the fetus and other problems for the woman or baby can be attributed directly to these drugs or may be caused by other factors
the risk of discontinuation symptoms in the woman and neonatal adaptation syndrome in the baby with most TCAs, SSRIs and (S)NRIs, in particular paroxetine and venlafaxine.In December 2014, this was an off-label use of TCAs, SSRIs and (S)NRIs. See NICE's information on prescribing medicines.
When assessing the risks and benefits of TCAs, SSRIs or (S)NRIs for a woman who is considering breastfeeding, take into account:
the benefits of breastfeeding for the woman and baby
the uncertainty about the safety of these drugs for the breastfeeding baby
the risks associated with switching from or stopping a previously effective medication. Seek advice from a specialist (preferably from a specialist perinatal mental health service) if there is uncertainty about specific drugs. See also the UK Drugs in Lactation Advisory Service for information on the use of specific drugs.
Do not offer benzodiazepines to women in pregnancy and the postnatal period except for the short‑term treatment of severe anxiety and agitation.
Consider gradually stopping benzodiazepines in women who are planning a pregnancy, pregnant or considering breastfeeding.
When assessing the risks and benefits of antipsychotic medication for a pregnant woman, take into account risk factors for gestational diabetes and excessive weight gain.In December 2014, this was an off-label use of antipsychotic medication. See NICE's information on prescribing medicines.
When choosing an antipsychotic, take into account that there are limited data on the safety of these drugs in pregnancy and the postnatal period.
Measure prolactin levels in women who are taking prolactin‑raising antipsychotic medication and planning a pregnancy, because raised prolactin levels reduce the chances of conception. If prolactin levels are raised, consider a prolactin‑sparing antipsychotic.
If a pregnant woman is stable on an antipsychotic and likely to relapse without medication, advise her to continue the antipsychotic.
Advise pregnant women taking antipsychotic medication about diet and monitor for excessive weight gain, in line with the NICE guideline on weight management before, during and after pregnancy.
Monitor for gestational diabetes in pregnant women taking antipsychotic medication in line with the NICE guideline on diabetes in pregnancy and offer an oral glucose tolerance test.
Do not offer depot antipsychotics to a woman who is planning a pregnancy, pregnant or considering breastfeeding, unless she is responding well to a depot and has a previous history of non‑adherence with oral medication.
Do not offer valproate for acute or long‑term treatment of a mental health problem in women or girls who are planning a pregnancy, pregnant or considering breastfeeding. Valproate must not be used in girls and women unless alternative treatments are not suitable and the pregnancy prevention programme is in place. See the MHRA safety advice on valproate use by women and girls.
If a woman or girl is already taking valproate and is planning a pregnancy, advise her to gradually stop the drug because of the risk of fetal malformations and adverse neurodevelopment outcomes after any exposure in pregnancy. See the MHRA safety advice on valproate use by women and girls.
If a woman or girl is already taking valproate and becomes pregnant, stop the drug because of the risk of fetal malformations and adverse neurodevelopmental outcomes. See the MHRA safety advice on valproate use by women and girls.
Do not offer carbamazepine to treat a mental health problem in women who are planning a pregnancy, pregnant or considering breastfeeding.
If a woman is already taking carbamazepine and is planning a pregnancy or becomes pregnant, discuss with the woman the possibility of stopping the drug (because of the risk of adverse drug interactions and fetal malformations). Follow the MHRA safety advice on antiepileptic drugs in pregnancy.
If a woman is taking lamotrigine, check lamotrigine levels frequently before pregnancy, during pregnancy and into the postnatal period because they vary substantially at these times. Follow the MHRA safety advice on antiepileptic drugs in pregnancy. In December 2014, this was an off-label use of lamotrigine. See NICE's information on prescribing medicines.
Do not offer lithium to women who are planning a pregnancy or pregnant, unless antipsychotic medication has not been effective. In December 2014, this was an off-label use of lithium. See NICE's information on prescribing medicines.
If antipsychotic medication has not been effective and lithium is offered to a woman who is planning a pregnancy or pregnant, ensure:
the woman knows that there is a risk of fetal heart malformations when lithium is taken in the first trimester, but the size of the risk is uncertain
the woman knows that lithium levels may be high in breast milk with a risk of toxicity for the baby
lithium levels are monitored more frequently throughout pregnancy and the postnatal period.
If a woman taking lithium becomes pregnant, consider stopping the drug gradually over 4 weeks if she is well. Explain to her that:
stopping medication may not remove the risk of fetal heart malformations
there is a risk of relapse, particularly in the postnatal period, if she has bipolar disorder.
If a woman taking lithium becomes pregnant and is not well or is at high risk of relapse, consider:
switching gradually to an antipsychotic or
stopping lithium and restarting it in the second trimester (if the woman is not planning to breastfeed and her symptoms have responded better to lithium than to other drugs in the past) or
continuing with lithium if she is at high risk of relapse and an antipsychotic is unlikely to be effective.
If a woman continues taking lithium during pregnancy:
check plasma lithium levels every 4 weeks, then weekly from the 36th week
adjust the dose to keep plasma lithium levels in the woman's therapeutic range
ensure the woman maintains an adequate fluid balance
ensure the woman gives birth in hospital
ensure monitoring by the obstetric team when labour starts, including checking plasma lithium levels and fluid balance because of the risk of dehydration and lithium toxicity
stop lithium during labour and check plasma lithium levels 12 hours after her last dose.
# Recognising mental health problems in pregnancy and the postnatal period and referral
Recognise that women who have a mental health problem (or are worried that they might have) may be:
unwilling to disclose or discuss their problem because of fear of stigma, negative perceptions of them as a mother or fear that their baby might be taken into care
reluctant to engage, or have difficulty in engaging, in treatment because of avoidance associated with their mental health problem or dependence on alcohol or drugs.
All healthcare professionals referring a woman to a maternity service should ensure that communications with that service (including those relating to initial referral) share information on any past and present mental health problem.
## Depression and anxiety disorders
Recognise that the range and prevalence of anxiety disorders (including generalised anxiety disorder, obsessive‑compulsive disorder, panic disorder, phobias, post‑traumatic stress disorder and social anxiety disorder) and depression are under‑recognised throughout pregnancy and the postnatal period.
At a woman's first contact with primary care or her booking visit, and during the early postnatal period, consider asking the following depression identification questions as part of a general discussion about a woman's mental health and wellbeing:
During the past month, have you often been bothered by feeling down, depressed or hopeless?
During the past month, have you often been bothered by having little interest or pleasure in doing things?Also consider asking about anxiety using the 2‑item Generalized Anxiety Disorder scale (GAD‑2):
Over the last 2 weeks, how often have you been bothered by feeling nervous, anxious or on edge?
Over the last 2 weeks, how often have you been bothered by not being able to stop or control worrying? For questions about anxiety: an answer of 'not at all' scores 0; 'several days' scores 1; 'more than half the days' scores 2; 'nearly every day' scores 3.
If a woman responds positively to either of the depression identification questions in recommendation 1.5.4, is at risk of developing a mental health problem, or there is clinical concern, consider:
using the Edinburgh Postnatal Depression Scale (EPDS) or the Patient Health Questionnaire (PHQ‑9) as part of a full assessment or
referring the woman to her GP or, if a severe mental health problem is suspected, to a mental health professional.
If a woman scores 3 or more on the GAD‑2 scale, consider:
using the GAD‑7 scale for further assessment or
referring the woman to her GP or, if a severe mental health problem is suspected, to a mental health professional.
If a woman scores less than 3 on the GAD‑2 scale, but you are still concerned she may have an anxiety disorder, ask the following question:
Do you find yourself avoiding places or activities and does this cause you problems?If she responds positively, consider:
using the GAD‑7 scale for further assessment or
referring the woman to her GP or, if a severe mental health problem is suspected, to a mental health professional.
At all contacts after the first contact with primary care or the booking visit, the health visitor, and other healthcare professionals who have regular contact with a woman in pregnancy and the postnatal period (first year after birth), should consider:
asking the 2 depression identification questions and the GAD‑2 (see recommendation 1.5.4) as part of a general discussion about her mental health and wellbeing and
using the EPDS or the PHQ‑9 as part of monitoring.
## Severe mental illness
At a woman's first contact with services in pregnancy and the postnatal period, ask about:
any past or present severe mental illness
past or present treatment by a specialist mental health service, including inpatient care
any severe perinatal mental illness in a first‑degree relative (mother, sister or daughter).
Refer to a secondary mental health service (preferably a specialist perinatal mental health service) for assessment and treatment, all women who:
have or are suspected to have severe mental illness
have any history of severe mental illness (during pregnancy or the postnatal period or at any other time).Ensure that the woman's GP knows about the referral.
If a woman has any past or present severe mental illness or there is a family history of severe perinatal mental illness in a first‑degree relative, be alert for possible symptoms of postpartum psychosis in the first 2 weeks after childbirth.
If a woman has sudden onset of symptoms suggesting postpartum psychosis, refer her to a secondary mental health service (preferably a specialist perinatal mental health service) for immediate assessment (within 4 hours of referral).
## Alcohol and drug misuse
If alcohol misuse is suspected, use the Alcohol Use Disorders Identification Test (AUDIT) as an identification tool in line with recommendation 1.2.1.4 of the NICE guideline on alcohol-use disorders.
If drug misuse is suspected, follow the recommendations on identification and assessment in section 1.2 of the NICE guideline on drug misuse in over 16s: psychosocial interventions.
# Assessment and care planning in pregnancy and the postnatal period
Assessment and diagnosis of a suspected mental health problem in pregnancy and the postnatal period should include:
history of any mental health problem, including in pregnancy or the postnatal period
physical wellbeing (including weight, smoking, nutrition and activity level) and history of any physical health problem
alcohol and drug misuse
the woman's attitude towards the pregnancy, including denial of pregnancy
the woman's experience of pregnancy and any problems experienced by her, the fetus or the baby
the mother–baby relationship
any past or present treatment for a mental health problem, and response to any treatment
social networks and quality of interpersonal relationships
living conditions and social isolation
family history (first‑degree relative) of mental health problems
domestic violence and abuse, sexual abuse, trauma or childhood maltreatment
housing, employment, economic and immigration status
responsibilities as a carer for other children and young people or other adults.
When assessing or treating a mental health problem in pregnancy or the postnatal period, take account of any learning disabilities or acquired cognitive impairments, and assess the need to consult with a specialist when developing care plans.
Carry out a risk assessment in conjunction with the woman and, if she agrees, her partner, family or carer. Focus on areas that are likely to present possible risk such as self‑neglect, self‑harm, suicidal thoughts and intent, risks to others (including the baby), smoking, drug or alcohol misuse and domestic violence and abuse.
If there is a risk of, or there are concerns about, suspected child maltreatment, follow local safeguarding protocols.
If there is a risk of self‑harm or suicide:
assess whether the woman has adequate social support and is aware of sources of help
arrange help appropriate to the level of risk
inform all relevant healthcare professionals (including the GP and those identified in the care plan )
advise the woman, and her partner, family or carer, to seek further help if the situation deteriorates.
Professionals in secondary mental health services, including specialist perinatal mental health services, should develop a written care plan in collaboration with a woman who has or has had a severe mental illness. If she agrees, her partner, family or carer should also be involved. The plan should cover pregnancy, childbirth and the postnatal period (including the potential impact of the illness on the baby) and should include:
a clear statement of jointly agreed treatment goals and how outcomes will be routinely monitored
increased contact with and referral to specialist perinatal mental health services
the names and contact details of key professionals.The care plan should be recorded in all versions of the woman's notes (her own records and maternity, primary care and mental health notes) and a copy given to the woman and all involved professionals.
# Providing interventions in pregnancy and the postnatal period
All healthcare professionals providing assessment and interventions for mental health problems in pregnancy and the postnatal period should understand the variations in their presentation and course at these times, how these variations affect treatment, and the context in which they are assessed and treated (for example, maternity services, health visiting and mental health services).
All interventions for mental health problems in pregnancy and the postnatal period should be delivered by competent practitioners. Psychological and psychosocial interventions should be based on the relevant treatment manual(s), which should guide the structure and duration of the intervention. Practitioners should consider using competence frameworks developed from the relevant treatment manual(s) and for all interventions practitioners should:
receive regular high‑quality supervision
use routine outcome measures and ensure that the woman is involved in reviewing the efficacy of the treatment
engage in monitoring and evaluation of treatment adherence and practitioner competence – for example, by using video and audio tapes, and external audit and scrutiny where appropriate.
When a woman with a known or suspected mental health problem is referred in pregnancy or the postnatal period, assess for treatment within 2 weeks of referral and provide psychological interventions within 1 month of initial assessment.
When offering psychotropic medication during pregnancy and the postnatal period, follow the principles in recommendations 1.4.10 to 1.4.37.
Provide interventions for mental health problems in pregnancy and the postnatal period within a stepped‑care model of service delivery in line with recommendation 1.5.1.3 of the NICE guideline on common mental health disorders.
# Treating specific mental health problems in pregnancy and the postnatal period
## Interventions for depression
For guidance on safe prescribing of antidepressants and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.
For a woman with persistent subthreshold depressive symptoms, or mild to moderate depression, in pregnancy or the postnatal period, consider facilitated self‑help (delivered as described in NICE's guideline on depression in adults).
For a woman with a history of severe depression who initially presents with mild depression in pregnancy or the postnatal period, consider a TCA, SSRI or (S)NRI.
For a woman with moderate or severe depression in pregnancy or the postnatal period, consider the following options:
a high-intensity psychological intervention (for example, CBT)
a TCA, SSRI or (S)NRI if the woman understands the risks associated with the medication and the mental health problem in pregnancy and the postnatal period and:
she has expressed a preference for medication or
she declines psychological interventions or
her symptoms have not responded to psychological interventions
a high‑intensity psychological intervention in combination with medication if the woman understands the risks associated with the medication and the mental health problem in pregnancy and the postnatal period and there is no response, or a limited response, to a high‑intensity psychological intervention or medication alone.
If a woman who is taking a TCA, SSRI or (S)NRI for mild to moderate depression becomes pregnant, discuss stopping the medication gradually and consider facilitated self‑help (delivered as described in NICE's guideline on depression in adults).
If a pregnant woman is taking a TCA, SSRI or (S)NRI for moderate depression and wants to stop her medication, take into account previous response to treatment, stage of pregnancy, risk of relapse, risk associated with medication and her preference, and discuss with her the following options:
switching to a high‑intensity psychological intervention (for example, CBT)
changing medication if there is a drug that is effective for her with a lower risk of adverse effects.
If a pregnant woman is taking a TCA, SSRI or (S)NRI for severe depression, take into account previous response to treatment, stage of pregnancy, risk of relapse, risk associated with medication and her preference, and discuss with her the following options:
continuing with the current medication
changing medication if there is a drug that is effective for her with a lower risk of adverse effects
combining medication with a high‑intensity psychological intervention (for example, CBT)
switching to a high‑intensity psychological intervention (for example, CBT) if she decides to stop taking medication.
## Interventions for anxiety disorders
For guidance on safe prescribing of antidepressants and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.
For a woman with tokophobia (an extreme fear of childbirth), offer an opportunity to discuss her fears with a healthcare professional with expertise in providing perinatal mental health support in line with the NICE guideline on caesarean birth .
For a woman with persistent subthreshold symptoms of anxiety in pregnancy or the postnatal period, consider facilitated self‑help. This should consist of use of CBT‑based self‑help materials over 2 to 3 months with support (either face to face or by telephone) for a total of 2 to 3 hours over 6 sessions.
For a woman with an anxiety disorder in pregnancy or the postnatal period, offer a low-intensity psychological intervention (for example, facilitated self‑help) or a high‑intensity psychological intervention (for example, CBT) as initial treatment in line with the recommendations set out in the NICE guideline for the specific mental health problem and be aware that:
-nly high‑intensity psychological interventions are recommended for post‑traumatic stress disorder
high‑intensity psychological interventions are recommended for the initial treatment of social anxiety disorder
progress should be closely monitored and a high‑intensity psychological intervention offered within 2 weeks if symptoms have not improved.
If a woman who is taking a TCA, SSRI or (S)NRI for an anxiety disorder becomes pregnant, discuss with her the following options:
stopping the medication gradually and switching to a high‑intensity psychological intervention (for example, CBT)
continuing with medication if she understands the risks associated with the medication and the mental health problem in pregnancy and the postnatal period and:
has expressed a preference for medication or
declines psychological interventions or
her symptoms have not responded to psychological interventions
changing medication if there is a drug that is effective for her with a lower risk of adverse effects
combining medication with a high‑intensity psychological intervention (for example, CBT) if the woman understands the risks associated with the medication and the mental health problem in pregnancy and the postnatal period and there is no response, or a limited response, to a high‑intensity psychological intervention alone.
## Psychological interventions for eating disorders
For a woman with an eating disorder in pregnancy or the postnatal period:
-ffer a psychological intervention in line with the NICE guideline on eating disorders
monitor the woman's condition carefully throughout pregnancy and the postnatal period
assess the need for fetal growth scans
discuss the importance of healthy eating during pregnancy and the postnatal period in line with the NICE guideline on maternal and child nutrition
advise her about feeding the baby in line with the NICE guideline on maternal and child nutrition and support her with this.
## Interventions for alcohol and drug misuse
If hazardous drug or alcohol misuse is identified in pregnancy or the postnatal period, refer or offer brief interventions in line with section 1.3.1 of the NICE guideline on drug misuse in over 16s: psychosocial interventions or the NICE guideline on alcohol-use disorders: prevention.
If harmful or dependent drug or alcohol misuse is identified in pregnancy or the postnatal period, refer the woman to a specialist substance misuse service for advice and treatment.
Offer assisted alcohol withdrawal in collaboration with specialist mental health and alcohol services (preferably in an inpatient setting) to pregnant women who are dependent on alcohol. Work with a woman who does not want assisted alcohol withdrawal to help her reduce her alcohol intake.
Offer detoxification in collaboration with specialist mental health and substance misuse services to pregnant women who are dependent on opioids. Monitor closely after completion of detoxification. Work with a woman who does not want detoxification to help her reduce her opioid intake. Recognise the risk of accidental overdose in women who stop or reduce drug misuse in pregnancy but start misusing again after childbirth.
## Interventions for severe mental illness
Consider psychological interventions for women with bipolar disorder. This includes:
CBT, IPT and behavioural couples therapy for bipolar depression
structured individual, group and family interventions designed for bipolar disorder to reduce the risk of relapse, particularly when medication is changed or stopped.
If a pregnant woman develops mania or psychosis and is not taking psychotropic medication, offer an antipsychotic.
Consider psychological interventions (CBT or family intervention) delivered as described in the section on how to deliver psychological interventions in the NICE guideline on psychosis and schizophrenia in adults, for a woman with psychosis or schizophrenia who becomes pregnant and is at risk of relapse arising from:
stress associated with pregnancy or the postnatal period
a change in medication, including stopping antipsychotic medication.
Offer an antipsychotic in line with recommendations 1.5.3 and 1.5.4 of the NICE guideline on bipolar disorder as prophylactic medication if a woman with bipolar disorder:
becomes pregnant and is stopping lithium, or
plans to breastfeed.
If a pregnant woman with bipolar disorder develops mania while taking prophylactic medication:
check the dose of the prophylactic medication and adherence
increase the dose if the prophylactic medication is an antipsychotic
suggest changing to an antipsychotic if she is taking another type of prophylactic medication
consider lithium if there is no response to an increase in dose or change of drug and the woman has severe mania
consider electroconvulsive therapy (ECT) if there has been no response to lithium.
## Interventions for sleep problems
Advise pregnant women who have a sleep problem about sleep hygiene (including having a healthy bedtime routine, avoiding caffeine and reducing activity before sleep). For women with a severe or chronic sleep problem, consider promethazine. In December 2014, this was an off-label use of promethazine. See NICE's information on prescribing medicines.
## Electroconvulsive therapy
Consider electroconvulsive therapy (ECT) for pregnant women with severe depression, severe mixed affective states or mania, or catatonia, whose physical health or that of the fetus is at serious risk.
## Rapid tranquillisation
A pregnant woman requiring rapid tranquillisation should be treated according to the NICE guidelines on the short-term management of violence and aggression, psychosis and schizophrenia and bipolar disorder (see our topic page on mental health and wellbeing for details), except that:
she should not be secluded after rapid tranquillisation
restraint procedures should be adapted to avoid possible harm to the fetus
when choosing an agent for rapid tranquillisation in a pregnant woman, an antipsychotic or a benzodiazepine with a short half‑life should be considered; if an antipsychotic is used, it should be at the minimum effective dose because of neonatal extrapyramidal symptoms; if a benzodiazepine is used, the risks of floppy baby syndrome should be taken into account
during the perinatal period, the woman's care should be managed in close collaboration with a paediatrician and an anaesthetist.
# Considerations for women and their babies in the postnatal period
## Reviewing treatment for women with severe mental illness
After childbirth, review and assess the need for starting, restarting or adjusting psychotropic medication as soon as a woman with a past or present severe mental illness is medically stable.
## Monitoring babies for effects of psychotropic medication taken in pregnancy
If a woman has taken psychotropic medication during pregnancy, carry out a full neonatal assessment of the newborn baby, bearing in mind:
the variation in the onset of adverse effects of psychotropic medication
the need for further monitoring
the need to inform relevant healthcare professionals and the woman and her partner, family or carer of any further monitoring, particularly if the woman has been discharged early.
## Care of women and their babies if there has been alcohol or drug misuse in pregnancy
If there has been alcohol or drug misuse in pregnancy, offer treatment and support after childbirth to both the woman and the baby, including:
a full neonatal assessment for any congenital abnormalities or neonatal adaptation syndrome
continuing psychological treatment and support for the woman
monitoring of the baby.
## Traumatic birth, stillbirth and miscarriage
Offer advice and support to women who have had a traumatic birth or miscarriage and wish to talk about their experience. Take into account the effect of the birth or miscarriage on the partner and encourage them to accept support from family and friends.
Offer women who have post‑traumatic stress disorder, which has resulted from a traumatic birth, miscarriage, stillbirth or neonatal death, a high-intensity psychological intervention (trauma‑focused CBT or eye movement desensitisation and reprocessing ) in line with the NICE guideline on post-traumatic stress disorder.
Do not offer single‑session high‑intensity psychological interventions with an explicit focus on 're‑living' the trauma to women who have a traumatic birth.
Discuss with a woman whose baby is stillborn or dies soon after birth, and her partner and family, the option of 1 or more of the following:
seeing a photograph of the baby
having mementos of the baby
seeing the baby
holding the baby.This should be facilitated by an experienced practitioner and the woman and her partner and family should be offered a follow‑up appointment in primary or secondary care. If it is known that the baby has died in utero, this discussion should take place before the delivery, and continue after delivery if needed.
## Psychotropic medication and breastfeeding
Encourage women with a mental health problem to breastfeed, unless they are taking carbamazepine, clozapine or lithium (valproate is not recommended to treat a mental health problem in women or girls of childbearing potential – see the MHRA safety advice on valproate use by women and girls). However, support each woman in the choice of feeding method that best suits her and her family.
When assessing the risks and benefits of TCAs, SSRIs or (S)NRIs for women who are breastfeeding, take into account:
the limited data about the safety of these drugs and
the risks associated with switching from a previously effective medication. Seek advice from a specialist (preferably from a specialist perinatal mental health service) if needed for specific drugs. See also the UK Drugs in Lactation Advisory Service for information on the use of specific drugs.
When assessing the risks and benefits of antipsychotic medication for women who are breastfeeding, take into account:
the limited data on the safety of these drugs and
the level of antipsychotic medication in breast milk depends on the drug.
If a woman is taking psychotropic medication while breastfeeding, monitor the baby for adverse effects.
## The mother–baby relationship
Recognise that some women with a mental health problem may experience difficulties with the mother–baby relationship. Assess the nature of this relationship, including verbal interaction, emotional sensitivity and physical care, at all postnatal contacts. Discuss any concerns that the woman has about her relationship with her baby and provide information and treatment for the mental health problem.
Consider further intervention to improve the mother–baby relationship if any problems in the relationship have not resolved.
# The organisation of services
Women who need inpatient care for a mental health problem within 12 months of childbirth should normally be admitted to a specialist mother and baby unit, unless there are specific reasons for not doing so.
Managers and senior healthcare professionals responsible for perinatal mental health services (including those working in maternity and primary care services) should ensure that:
there are clearly specified care pathways so that all primary and secondary healthcare professionals involved in the care of women during pregnancy and the postnatal period know how to access assessment and treatment
staff have supervision and training, covering mental health problems, assessment methods and referral routes, to allow them to follow the care pathways.
Clinical networks should be established for perinatal mental health services, managed by a coordinating board of healthcare professionals, commissioners, managers, and service users and carers. These networks should provide:
a specialist multidisciplinary perinatal service in each locality, which provides direct services, consultation and advice to maternity services, other mental health services and community services; in areas of high morbidity these services may be provided by separate specialist perinatal teams
access to specialist expert advice on the risks and benefits of psychotropic medication during pregnancy and breastfeeding
clear referral and management protocols for services across all levels of the existing stepped‑care frameworks for mental health problems, to ensure effective transfer of information and continuity of care
pathways of care for service users, with defined roles and competencies for all professional groups involved.
Each managed perinatal mental health network should have designated specialist inpatient services and cover a population where there are between 25,000 and 50,000 live births a year, depending on the local psychiatric morbidity rates.
Specialist perinatal inpatient services should:
provide facilities designed specifically for mothers and babies (typically with 6 to 12 beds)
be staffed by specialist perinatal mental health staff
be staffed to provide appropriate care for babies
have effective liaison with general medical and mental health services
have available the full range of therapeutic services
be closely integrated with community‑based mental health services to ensure continuity of care and minimum length of stay.
# Terms used in this guideline
## Anxiety disorders
These include generalised anxiety disorder, panic disorder, obsessive‑compulsive disorder, phobias, post‑traumatic stress disorder and social anxiety disorder.
## Baby
Refers to an infant aged between 0 and 12 months.
## High‑intensity psychological intervention
A formal psychological intervention usually delivered face to face (either in a group or individually) by a qualified therapist who has specific training in the delivery of the intervention.
## Low‑intensity intervention
A psychological or psychosocial intervention delivered by a trained coach or facilitator (rather than a therapist) to enable use of self‑help materials.
## Postnatal period
This is defined in this guideline as up to 1 year after childbirth.
## Postpartum psychosis
Psychosis often with mania and/or depressive symptoms in the immediate postnatal period, which can become very severe extremely quickly.
## Psychotropic medication
This is defined in this guideline as all medication used to treat mental health problems.
## Severe mental illness
This is defined in this guideline as severe and incapacitating depression, psychosis, schizophrenia, bipolar disorder, schizoaffective disorder and postpartum psychosis.
## Traumatic birth
This includes births, whether preterm or full term, which are physically traumatic (for example, instrumental or assisted deliveries or emergency caesarean sections, severe perineal tears, postpartum haemorrhage) and births that are experienced as traumatic, even when the delivery is obstetrically straightforward.
## Valproate
Refers to 3 formulations of valproate available in the UK: sodium valproate and valproic acid (licensed for the treatment of epilepsy) and semi‑sodium valproate (licensed for the treatment of acute mania and continuation treatment in people whose mania responds to treatment). Both semi‑sodium and sodium valproate are metabolised to valproic acid (also known as valproate), which is the pharmacologically active component. Valproate must not be used in pregnancy, and only used in girls and women when there is no alternative and a pregnancy prevention plan is in place. This is because of the risk of malformations and developmental abnormalities in the baby. See update information for important safety advice from the MHRA on the use of valproate.
## Woman/women
Refer(s) to female(s) of childbearing potential, including girls and young women under 18 years.# Recommendations for research
The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. The Guideline Development Group's full set of recommendations for research are detailed in the full guideline.
# Preventing postpartum psychosis
What methods can improve the identification of women at high risk of postpartum psychosis and reduce this risk?
## Why this is important
Postpartum psychosis is a severe mental illness with a rapid onset and a major impact on the woman and her ability to care for her baby. It is associated with an increased risk of mortality in both the woman and her baby. Prophylactic treatment can be effective for women who are known to be at high risk, but for some women postpartum psychosis may be their first episode of severe mental illness. Better identification of women at high risk and a greater understanding of prophylactic and acute treatment would have a significant impact on maternal and child welfare, and on service costs.
The question should be addressed by a programme of research into the prevention, treatment and management of postpartum psychosis comprising:
The development of a tool for routine clinical use to improve the identification of women at high risk of developing postpartum psychosis. This should be tested in a prospective cohort study.
The development of a set of interventions intended to prevent the onset of postpartum psychosis and a method for their effective and efficient delivery.
The testing of the clinical and cost effectiveness of the interventions in a large scale randomised controlled trial.
The development and testing of a programme for the implementation of an effective strategy for preventing and identifying postpartum psychosis.
# The safety of drugs for bipolar disorder in pregnancy and the postnatal period
How safe are drugs used to treat bipolar disorder in pregnancy and the postnatal period?
## Why this is important
Drugs are effective for the acute treatment of bipolar disorder and for preventing relapse. All drugs used to treat mental health problems may carry some risk for the woman, fetus and baby. For some drugs such as sodium valproate these risks are well described, but the data are drawn from epilepsy case registers. For others such as lithium, the data are very limited. In addition, the prevalence of adverse outcomes for the woman, fetus or baby in untreated bipolar disorder is not well described.
The question should be addressed by establishing a long‑term register of women with bipolar disorder to provide data on:
the drugs used for treating bipolar disorder in pregnancy
the following outcomes (by drug type and for women who had no treatment for bipolar disorder in pregnancy):
maternal outcomes (for example, episodes of mood disorder in pregnancy and the postnatal period, miscarriage, preterm delivery)
congenital malformations (for example, spinal cord and cardiac malformation)
baby outcomes (for example, mortality, birthweight)
childhood outcomes (for example, cognitive development).
# Psychological interventions focused on the mother‑baby relationship
Are interventions designed to improve the quality of the mother–baby relationship in the first year after childbirth effective in women with a diagnosed mental health problem?
## Why this is important
Problems in the mother–baby relationship in the first year after childbirth may increase maternal mental health problems and are associated with a range of problems for the baby, including delayed cognitive and emotional development. A number of interventions are effective in improving the interaction between women and their babies, but it is not known if these are effective in women with a diagnosed mental health problem.
The question should be addressed in a randomised controlled trial comparing an intervention (proven to be effective in improving the quality of mother–baby interactions in women without a diagnosed mental health problem) against standard care. The trial should report the following outcomes, with a follow‑up period of at least 2 years:
the mental health of the woman
the emotional and cognitive development of the baby
the quality of the interaction.
The trial should also examine the cost effectiveness of the intervention.
# Structured clinical management for moderate to severe personality disorders in pregnancy and the postnatal period
Is structured clinical management for moderate to severe personality disorders in pregnancy and the postnatal period effective at improving outcomes for women and their babies?
## Why this is important
Personality disorders are associated with poor engagement with maternity services and perinatal mental health services and this leads to poor mental and physical health outcomes for the woman, fetus and baby. The complex psychological interventions that are effective for treating personality disorder may present problems for engagement even in those motivated to seek treatment. Structured clinical management is a psychologically informed model of case management, which is effective for treating personality disorder and may have greater flexibility and capacity to engage women with personality disorder in pregnancy and the postnatal period.
The question should be addressed in a randomised controlled trial comparing structured clinical management of personality disorder in pregnancy and the postnatal period against standard care. The trial should report the following outcomes, with a follow‑up period of at least 2 years:
the mental and physical health of the woman
the physical health of the fetus
the mental and physical health of the baby
the quality of the mother–baby relationship.
The trial should also examine the cost effectiveness of the intervention.
# Psychological interventions for moderate to severe anxiety disorders in pregnancy
Are psychological interventions effective for treating moderate to severe anxiety disorders (including obsessive‑compulsive disorder, panic disorder, post‑traumatic stress disorder and social anxiety disorder) in pregnancy?
## Why this is important
Anxiety disorders are often not identified or treated in pregnancy. In addition, many women who are taking medication for such problems stop taking it when they are pregnant. The development of effective psychological interventions is therefore important. Although there are effective psychological interventions for anxiety disorders, there is limited evidence about their effectiveness in pregnancy and how these interventions might be adapted for use in pregnant women.
The question should be addressed by a programme of research evaluating psychological interventions (including individual and group approaches) for moderate to severe anxiety disorders in pregnancy, comprising:
a development programme to establish the adaptations to effective interventions (for example, mode of delivery, duration, content, and intensity of treatment) that are needed for use in pregnancy
the testing of the adapted interventions in a series of pilot studies
the testing of the clinical and cost effectiveness of the adapted interventions in large‑scale randomised controlled trials
the development and testing of a programme for the implementation of psychological interventions for moderate to severe anxiety disorders.
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{'Introduction': "In pregnancy and the postnatal period, many mental health problems have a similar nature, course and potential for relapse as at other times. However, there can be differences; for example, bipolar disorder shows an increased rate of relapse and first presentation in the postnatal period. Some changes in mental health state and functioning (such as appetite) may represent normal pregnancy changes, but they may be a symptom of a mental health problem.\n\nThe management of mental health problems during pregnancy and the postnatal period differs from at other times because of the nature of this life stage and the potential impact of any difficulties and treatments on the woman and the baby. There are risks associated with taking psychotropic medication in pregnancy and during breastfeeding and risks of stopping medication taken for an existing mental health problem. There is also an increased risk of postpartum psychosis.\n\nDepression and anxiety are the most common mental health problems during pregnancy, with around 12%\xa0of women experiencing depression and 13%\xa0experiencing anxiety at some point; many women will experience both. Depression and anxiety also affect 15‑20%\xa0of women in the first year after childbirth. During pregnancy and the postnatal period, anxiety disorders, including panic disorder, generalised anxiety disorder (GAD), obsessive‑compulsive disorder (OCD), post‑traumatic stress disorder (PTSD) and tokophobia (an extreme fear of childbirth), can occur on their own or can coexist with depression. Psychosis can re‑emerge or be exacerbated during pregnancy and the postnatal period. Postpartum psychosis affects between 1\xa0and 2\xa0in 1,000\xa0women who have given birth. Women with bipolar\xa0I disorder are at particular risk, but postpartum psychosis can occur in women with no previous psychiatric history.\n\nChanges to body shape, including weight gain, in pregnancy and after childbirth may be a concern for women with an eating disorder. Although the prevalence of anorexia nervosa and bulimia nervosa is lower in pregnant women, the prevalence of binge eating disorder is higher. Smoking and the use of illicit drugs and alcohol in pregnancy are common, and prematurity, intrauterine growth restriction and fetal compromise are more common in women who use these substances, particularly women who smoke.\n\nBetween 2006 and 2008 there were 1.27\xa0maternal deaths per 100,000\xa0maternal deliveries in the UK as a result of mental health problems. Although response to treatment for mental health problems is good, these problems frequently go unrecognised and untreated in pregnancy and the postnatal period. If untreated, women can continue to have symptoms, sometimes for many years, and these can also affect their babies and other family members.\n\nThis guideline makes recommendations for the recognition, assessment, care and treatment of mental health problems in women during pregnancy and the postnatal period (up to 1\xa0year after childbirth) and in women who are planning a pregnancy. The guideline covers depression, anxiety disorders, eating disorders, drug and alcohol‑use disorders and severe mental illness (such as psychosis, bipolar disorder, schizophrenia and severe depression). It covers subthreshold symptoms as well as mild, moderate and severe mental health problems. However, the guideline focuses on aspects of expression, risks and management that are of special relevance in pregnancy and the postnatal period.\n\nThe recommendations are relevant to all healthcare professionals who recognise, assess and refer for or provide interventions for mental health problems in pregnancy and the postnatal period. It will also be relevant to non‑NHS services, such as social services and the voluntary and private sectors, but does not make specific recommendations for these. The guideline also makes recommendations about the primary and secondary care services needed to support the effective identification and treatment of most mental health problems in pregnancy and the postnatal period. This guideline should be read in conjunction with other NICE guidelines on the treatment and management of specific mental health problems. The guideline indicates where modifications to treatment and management are needed in pregnancy and the postnatal period.\n\nThe guideline draws on the best available evidence. However, there are significant limitations to the evidence base, including limited data on the risks of psychotropic medication in pregnancy and during breastfeeding.\n\n# Medicines\n\nNo psychotropic medication has a UK marketing authorisation specifically for women who are pregnant or breastfeeding. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. The woman (or those with authority to give consent on her behalf) should provide informed consent, which should be documented. See the General Medical Council's Good practice in prescribing and managing medicines and devices for further information. Where recommendations have been made for the use of medicines outside their licensed indications ('off‑label use'), these medicines are marked in the recommendations.", 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Using this guideline in conjunction with other NICE guidelines\n\n## Improving the experience of care\n\nUse this guideline in conjunction with the NICE guidelines on service user experience in adult mental health and patient experience in adult NHS services to improve the experience of care for women with a mental health problem in pregnancy or the postnatal period. \n\n## Assessment and treatment in pregnancy and the postnatal period\n\nUse this guideline in conjunction with the NICE guideline for a specific mental health problem (see our topic pages on pregnancy and mental health and wellbeing) to inform assessment and treatment decisions in pregnancy and the postnatal period, and take into account:\n\nany variations in the nature and presentation of the mental health problem in pregnancy or the postnatal period\n\nthe setting for assessment and treatment (for example, primary or secondary care services or in the community, the home or remotely by phone or computer)\n\nrecommendations on assessment and care planning in pregnancy and the postnatal period\n\nrecommendations 1.4.10 to 1.4.37 on starting, using and stopping treatment in pregnancy and the postnatal period\n\nrecommendations 1.8.1 to 1.8.23 on treating specific mental health problems in pregnancy and the postnatal period. \n\n# Considerations for women of childbearing potential\n\nDiscuss with all women of childbearing potential who have a new, existing or past mental health problem:\n\nthe use of contraception and any plans for a pregnancy\n\nhow pregnancy and childbirth might affect a mental health problem, including the risk of relapse\n\nhow a mental health problem and its treatment might affect the woman, the fetus and baby\n\nhow a mental health problem and its treatment might affect parenting. \n\nWhen prescribing psychotropic medication or antiepileptics for women or girls of childbearing potential (including young girls who are likely to need treatment into their childbearing years), take account of the latest data on the risks to the fetus and baby. Follow the MHRA safety advice on antiepileptic drugs in pregnancy. [2014, amended 2021]\n\nDo not offer valproate for acute or long‑term treatment of a mental health problem in women or girls of childbearing potential (including young girls who are likely to need treatment into their childbearing years), unless other options are ineffective or not tolerated and the pregnancy prevention programme is in place. See the MHRA safety advice on valproate use by women and girls. [amended 2020]\n\n# Principles of care in pregnancy and the postnatal period\n\n## Supporting women and their partners, families and carers\n\nAcknowledge the woman's role in caring for her baby and support her to do this in a non‑judgmental and compassionate way. \n\nInvolve the woman and, if she agrees, her partner, family or carer, in all decisions about her care and the care of her baby. \n\nWhen working with girls and young women with a mental health problem in pregnancy or the postnatal period:\n\nbe familiar with local and national guidelines on confidentiality and the rights of the child\n\nbe aware of the recommendations in section 1.4 of the NICE guideline on pregnancy and complex social factors\n\nensure continuity of care for the mental health problem if care is transferred from adolescent to adult services. \n\nTake into account and, if appropriate, assess and address the needs of partners, families and carers that might affect a woman with a mental health problem in pregnancy and the postnatal period. These include:\n\nthe welfare of the baby and other dependent children and adults\n\nthe role of the partner, family or carer in providing support\n\nthe potential effect of any mental health problem on the woman's relationship with her partner, family or carer. \n\n## Coordinated care\n\nDevelop an integrated care plan for a woman with a mental health problem in pregnancy and the postnatal period that sets out:\n\nthe care and treatment for the mental health problem\n\nthe roles of all healthcare professionals, including who is responsible for:\n\n\n\ncoordinating the integrated care plan\n\nthe schedule of monitoring\n\nproviding the interventions and agreeing the outcomes with the woman. \n\n\n\nThe healthcare professional responsible for coordinating the integrated care plan should ensure that:\n\neveryone involved in a woman's care is aware of their responsibilities\n\nthere is effective sharing of information with all services involved and with the woman herself\n\nmental health (including mental wellbeing) is taken into account as part of all care plans\n\nall interventions for mental health problems are delivered in a timely manner, taking into account the stage of the pregnancy or age of the baby. \n\n# Treatment decisions, advice and monitoring for women who are planning a pregnancy, are pregnant or are in the postnatal period\n\n## Information and advice\n\nProvide culturally relevant information on mental health problems in pregnancy and the postnatal period to the woman and, if she agrees, her partner, family or carer. Ensure that the woman understands that mental health problems are not uncommon during these periods and instil hope about treatment. \n\nConsider referring a woman to a secondary mental health service (preferably a specialist perinatal mental health service) for preconception counselling if she has a current or past severe mental health problem and is planning a pregnancy. \n\nDiscuss treatment and prevention options and any particular concerns the woman has about the pregnancy or the fetus or baby. Provide information to the woman and, if she agrees, her partner, family or carer, about:\n\nthe potential benefits of psychological interventions and psychotropic medication\n\nthe possible consequences of no treatment\n\nthe possible harms associated with treatment\n\nwhat might happen if treatment is changed or stopped, particularly if psychotropic medication is stopped abruptly. \n\nDiscuss breastfeeding with all women who may need to take psychotropic medication in pregnancy or in the postnatal period. Explain to them the benefits of breastfeeding, the potential risks associated with taking psychotropic medication when breastfeeding and with stopping some medications in order to breastfeed. Discuss treatment options that would enable a woman to breastfeed if she wishes and support women who choose not to breastfeed. \n\nIf needed, seek more detailed advice about the possible risks of mental health problems or the benefits and harms of treatment in pregnancy and the postnatal period from a secondary mental health service (preferably a specialist perinatal mental health service). This might include advice on the risks and possible harms of taking psychotropic medication while breastfeeding and how medication might affect a woman's ability to care for her baby (for example, sedation). \n\nMental health professionals providing detailed advice about the possible risks of mental health problems or the benefits and harms of treatment in pregnancy and the postnatal period should include discussion of the following, depending on individual circumstances:\n\nthe uncertainty about the benefits, risks and harms of treatments for mental health problems in pregnancy and the postnatal period\n\nthe likely benefits of each treatment, taking into account the severity of the mental health problem\n\nthe woman's response to any previous treatment\n\nthe background risk of harm to the woman and the fetus or baby associated with the mental health problem and the risk to mental health and parenting associated with no treatment\n\nthe possibility of the sudden onset of symptoms of mental health problems in pregnancy and the postnatal period, particularly in the first few weeks after childbirth (for example, in bipolar disorder)\n\nthe risks or harms to the woman and the fetus or baby associated with each treatment option\n\nthe need for prompt treatment because of the potential effect of an untreated mental health problem on the fetus or baby\n\nthe risk or harms to the woman and the fetus or baby associated with stopping or changing a treatment. \n\nWhen discussing likely benefits and risks of treatment with the woman and, if she agrees, her partner, family or carer:\n\nacknowledge the woman's central role in reaching a decision about her treatment and that the role of the professional is to inform that decision with balanced and up‑to‑date information and advice\n\nuse absolute values based on a common denominator (that is, numbers out of 100\xa0or\xa01,000)\n\nacknowledge and describe, if possible, the uncertainty around any estimate of risk, harm or benefit\n\nuse high‑quality decision aids in a variety of numerical and pictorial formats that focus on a personalised view of the risks and benefits, in line with the NICE guideline on patient experience in adult NHS services\n\nconsider providing records of the consultation, in a variety of visual, verbal or audio formats. \n\n## Monitoring and increased contact\n\nHealthcare professionals working in universal services and those caring for women in mental health services should:\n\nassess the level of contact and support needed by women with a mental health problem (current or past) and those at risk of developing one\n\nagree the level of contact and support with each woman, including those who are not having treatment for a mental health problem\n\nmonitor regularly for symptoms throughout pregnancy and the postnatal period, particularly in the first few weeks after childbirth. \n\nDiscuss and plan how symptoms will be monitored (for example, by using validated self‑report questionnaires, such as the Edinburgh Postnatal Depression Scale [EPDS], Patient Health Questionnaire [PHQ‑9] or the 7‑item Generalized Anxiety Disorder scale [GAD‑7]). \n\n## Starting, using and stopping treatment\n\nBefore starting any treatment in pregnancy and the postnatal period, discuss with the woman the higher threshold for pharmacological interventions arising from the changing risk‑benefit ratio for psychotropic medication at this time and the likely benefits of a psychological intervention. \n\nIf the optimal treatment for a woman with a mental health problem is psychotropic medication combined with a psychological intervention, but she declines or stops taking psychotropic medication in pregnancy or the postnatal period, ensure that:\n\nshe is adequately supported and\n\nhas the opportunity to discuss the risk associated with stopping psychotropic medication and\n\nis offered, or can continue with, a psychological intervention. \n\nWhen psychotropic medication is started in pregnancy and the postnatal period, consider seeking advice, preferably from a specialist in perinatal mental health, and:\n\nchoose the drug with the lowest risk profile for the woman, fetus and baby, taking into account a woman's previous response to medication\n\nuse the lowest effective dose (this is particularly important when the risks of adverse effects to the woman, fetus and baby may be dose related), but note that sub‑therapeutic doses may also expose the fetus to risks and not treat the mental health problem effectively\n\nuse a single drug, if possible, in preference to 2 or more drugs\n\ntake into account that dosages may need to be adjusted in pregnancy. \n\nWhen a woman with severe mental illness decides to stop psychotropic medication in pregnancy and the postnatal period, discuss with her:\n\nher reasons for doing so\n\nthe possibility of:\n\n\n\nrestarting the medication\n\nswitching to other medication\n\nhaving a psychological intervention\n\n\n\nincreasing the level of monitoring and support.Ensure she knows about any risks to herself, the fetus or baby when stopping medication. \n\nWhen a woman with depression or an anxiety disorder decides to stop taking psychotropic medication in pregnancy and the postnatal period, discuss with her:\n\nher reasons for doing so\n\nthe possibility of:\n\n\n\nhaving a psychological intervention\n\nrestarting the medication if the depression or anxiety disorder is or has been severe and there has been a previous good response to treatment\n\nswitching to other medication\n\n\n\nincreasing the level of monitoring and support while she is not taking any medication. Ensure she knows about any risks to herself, the fetus or baby when stopping medication. \n\nIf a pregnant woman has taken psychotropic medication with known teratogenic risk at any time in the first trimester:\n\nconfirm the pregnancy as soon as possible\n\nexplain that stopping or switching the medication after pregnancy is confirmed may not remove the risk of fetal malformations\n\noffer screening for fetal abnormalities and counselling about continuing the pregnancy\n\nexplain the need for additional monitoring and the risks to the fetus if she continues to take the medication.Seek advice from a specialist if there is uncertainty about the risks associated with specific drugs. \n\nFor guidance on safe prescribing of antidepressants and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.\n\nWhen choosing a tricyclic antidepressant (TCA), selective serotonin reuptake inhibitor (SSRI) or (serotonin‑) noradrenaline reuptake inhibitor [(S)NRI], take into account:\n\nthe woman's previous response to these drugs\n\nthe stage of pregnancy (for example, see the MHRA's drug safety update on SSRI/SNRI antidepressant medicines: for information on a small increased risk of postpartum haemorrhage with SSRI and SNRI antidepressant medicines when used in the month before delivery)\n\nwhat is known about the reproductive safety of these drugs (for example, the risk of fetal cardiac abnormalities and persistent pulmonary hypertension in the newborn baby)\n\nthe uncertainty about whether any increased risk to the fetus and other problems for the woman or baby can be attributed directly to these drugs or may be caused by other factors\n\nthe risk of discontinuation symptoms in the woman and neonatal adaptation syndrome in the baby with most TCAs, SSRIs and (S)NRIs, in particular paroxetine and venlafaxine.In December 2014, this was an off-label use of TCAs, SSRIs and (S)NRIs. See NICE's information on prescribing medicines. \n\nWhen assessing the risks and benefits of TCAs, SSRIs or (S)NRIs for a woman who is considering breastfeeding, take into account:\n\nthe benefits of breastfeeding for the woman and baby\n\nthe uncertainty about the safety of these drugs for the breastfeeding baby\n\nthe risks associated with switching from or stopping a previously effective medication. Seek advice from a specialist (preferably from a specialist perinatal mental health service) if there is uncertainty about specific drugs. See also the UK Drugs in Lactation Advisory Service for information on the use of specific drugs. \n\nDo not offer benzodiazepines to women in pregnancy and the postnatal period except for the short‑term treatment of severe anxiety and agitation. \n\nConsider gradually stopping benzodiazepines in women who are planning a pregnancy, pregnant or considering breastfeeding. \n\nWhen assessing the risks and benefits of antipsychotic medication for a pregnant woman, take into account risk factors for gestational diabetes and excessive weight gain.In December 2014, this was an off-label use of antipsychotic medication. See NICE's information on prescribing medicines. \n\nWhen choosing an antipsychotic, take into account that there are limited data on the safety of these drugs in pregnancy and the postnatal period. \n\nMeasure prolactin levels in women who are taking prolactin‑raising antipsychotic medication and planning a pregnancy, because raised prolactin levels reduce the chances of conception. If prolactin levels are raised, consider a prolactin‑sparing antipsychotic. \n\nIf a pregnant woman is stable on an antipsychotic and likely to relapse without medication, advise her to continue the antipsychotic. \n\nAdvise pregnant women taking antipsychotic medication about diet and monitor for excessive weight gain, in line with the NICE guideline on weight management before, during and after pregnancy. \n\nMonitor for gestational diabetes in pregnant women taking antipsychotic medication in line with the NICE guideline on diabetes in pregnancy and offer an oral glucose tolerance test. \n\nDo not offer depot antipsychotics to a woman who is planning a pregnancy, pregnant or considering breastfeeding, unless she is responding well to a depot and has a previous history of non‑adherence with oral medication. \n\nDo not offer valproate for acute or long‑term treatment of a mental health problem in women or girls who are planning a pregnancy, pregnant or considering breastfeeding. Valproate must not be used in girls and women unless alternative treatments are not suitable and the pregnancy prevention programme is in place. See the MHRA safety advice on valproate use by women and girls. [amended 2020]\n\nIf a woman or girl is already taking valproate and is planning a pregnancy, advise her to gradually stop the drug because of the risk of fetal malformations and adverse neurodevelopment outcomes after any exposure in pregnancy. See the MHRA safety advice on valproate use by women and girls. [amended 2020]\n\nIf a woman or girl is already taking valproate and becomes pregnant, stop the drug because of the risk of fetal malformations and adverse neurodevelopmental outcomes. See the MHRA safety advice on valproate use by women and girls. [amended 2020]\n\nDo not offer carbamazepine to treat a mental health problem in women who are planning a pregnancy, pregnant or considering breastfeeding. \n\nIf a woman is already taking carbamazepine and is planning a pregnancy or becomes pregnant, discuss with the woman the possibility of stopping the drug (because of the risk of adverse drug interactions and fetal malformations). Follow the MHRA safety advice on antiepileptic drugs in pregnancy. [2014, amended 2021]\n\nIf a woman is taking lamotrigine, check lamotrigine levels frequently before pregnancy, during pregnancy and into the postnatal period because they vary substantially at these times. Follow the MHRA safety advice on antiepileptic drugs in pregnancy. [2014, amended 2021]In December 2014, this was an off-label use of lamotrigine. See NICE's information on prescribing medicines.\n\nDo not offer lithium to women who are planning a pregnancy or pregnant, unless antipsychotic medication has not been effective. In December 2014, this was an off-label use of lithium. See NICE's information on prescribing medicines. \n\nIf antipsychotic medication has not been effective and lithium is offered to a woman who is planning a pregnancy or pregnant, ensure:\n\nthe woman knows that there is a risk of fetal heart malformations when lithium is taken in the first trimester, but the size of the risk is uncertain\n\nthe woman knows that lithium levels may be high in breast milk with a risk of toxicity for the baby\n\nlithium levels are monitored more frequently throughout pregnancy and the postnatal period. \n\nIf a woman taking lithium becomes pregnant, consider stopping the drug gradually over 4\xa0weeks if she is well. Explain to her that:\n\nstopping medication may not remove the risk of fetal heart malformations\n\nthere is a risk of relapse, particularly in the postnatal period, if she has bipolar disorder. \n\nIf a woman taking lithium becomes pregnant and is not well or is at high risk of relapse, consider:\n\nswitching gradually to an antipsychotic or\n\nstopping lithium and restarting it in the second trimester (if the woman is not planning to breastfeed and her symptoms have responded better to lithium than to other drugs in the past) or\n\ncontinuing with lithium if she is at high risk of relapse and an antipsychotic is unlikely to be effective. \n\nIf a woman continues taking lithium during pregnancy:\n\ncheck plasma lithium levels every 4\xa0weeks, then weekly from the 36th week\n\nadjust the dose to keep plasma lithium levels in the woman's therapeutic range\n\nensure the woman maintains an adequate fluid balance\n\nensure the woman gives birth in hospital\n\nensure monitoring by the obstetric team when labour starts, including checking plasma lithium levels and fluid balance because of the risk of dehydration and lithium toxicity\n\nstop lithium during labour and check plasma lithium levels 12\xa0hours after her last dose. \n\n# Recognising mental health problems in pregnancy and the postnatal period and referral\n\nRecognise that women who have a mental health problem (or are worried that they might have) may be:\n\nunwilling to disclose or discuss their problem because of fear of stigma, negative perceptions of them as a mother or fear that their baby might be taken into care\n\nreluctant to engage, or have difficulty in engaging, in treatment because of avoidance associated with their mental health problem or dependence on alcohol or drugs. \n\nAll healthcare professionals referring a woman to a maternity service should ensure that communications with that service (including those relating to initial referral) share information on any past and present mental health problem. \n\n## Depression and anxiety disorders\n\nRecognise that the range and prevalence of anxiety disorders (including generalised anxiety disorder, obsessive‑compulsive disorder, panic disorder, phobias, post‑traumatic stress disorder and social anxiety disorder) and depression are under‑recognised throughout pregnancy and the postnatal period. \n\nAt a woman's first contact with primary care or her booking visit, and during the early postnatal period, consider asking the following depression identification questions as part of a general discussion about a woman's mental health and wellbeing:\n\nDuring the past month, have you often been bothered by feeling down, depressed or hopeless?\n\nDuring the past month, have you often been bothered by having little interest or pleasure in doing things?Also consider asking about anxiety using the 2‑item Generalized Anxiety Disorder scale (GAD‑2):\n\nOver the last 2 weeks, how often have you been bothered by feeling nervous, anxious or on edge?\n\nOver the last 2 weeks, how often have you been bothered by not being able to stop or control worrying? For questions about anxiety: an answer of 'not at all' scores 0; 'several days' scores 1; 'more than half the days' scores 2; 'nearly every day' scores 3.\xa0\n\nIf a woman responds positively to either of the depression identification questions in recommendation 1.5.4, is at risk of developing a mental health problem, or there is clinical concern, consider:\n\nusing the Edinburgh Postnatal Depression Scale (EPDS) or the Patient Health Questionnaire (PHQ‑9) as part of a full assessment or\n\nreferring the woman to her GP or, if a severe mental health problem is suspected, to a mental health professional. \n\nIf a woman scores 3 or more on the GAD‑2 scale, consider:\n\nusing the GAD‑7 scale for further assessment or\n\nreferring the woman to her GP or, if a severe mental health problem is suspected, to a mental health professional. \n\nIf a woman scores less than 3 on the GAD‑2 scale, but you are still concerned she may have an anxiety disorder, ask the following question:\n\nDo you find yourself avoiding places or activities and does this cause you problems?If she responds positively, consider:\n\nusing the GAD‑7 scale for further assessment or\n\nreferring the woman to her GP or, if a severe mental health problem is suspected, to a mental health professional. \n\nAt all contacts after the first contact with primary care or the booking visit, the health visitor, and other healthcare professionals who have regular contact with a woman in pregnancy and the postnatal period (first year after birth), should consider:\n\nasking the 2\xa0depression identification questions and the GAD‑2 (see recommendation 1.5.4) as part of a general discussion about her mental health and wellbeing and\n\nusing the EPDS or the PHQ‑9 as part of monitoring. \n\n## Severe mental illness\n\nAt a woman's first contact with services in pregnancy and the postnatal period, ask about:\n\nany past or present severe mental illness\n\npast or present treatment by a specialist mental health service, including inpatient care\n\nany severe perinatal mental illness in a first‑degree relative (mother, sister or daughter). \n\nRefer to a secondary mental health service (preferably a specialist perinatal mental health service) for assessment and treatment, all women who:\n\nhave or are suspected to have severe mental illness\n\nhave any history of severe mental illness (during pregnancy or the postnatal period or at any other time).Ensure that the woman's GP knows about the referral. \n\nIf a woman has any past or present severe mental illness or there is a family history of severe perinatal mental illness in a first‑degree relative, be alert for possible symptoms of postpartum psychosis in the first 2\xa0weeks after childbirth. \n\nIf a woman has sudden onset of symptoms suggesting postpartum psychosis, refer her to a secondary mental health service (preferably a specialist perinatal mental health service) for immediate assessment (within 4\xa0hours of referral). \n\n## Alcohol and drug misuse\n\nIf alcohol misuse is suspected, use the Alcohol Use Disorders Identification Test (AUDIT) as an identification tool in line with recommendation 1.2.1.4 of the NICE guideline on alcohol-use disorders. \n\nIf drug misuse is suspected, follow the recommendations on identification and assessment in section 1.2 of the NICE guideline on drug misuse in over 16s: psychosocial interventions. \n\n# Assessment and care planning in pregnancy and the postnatal period\n\nAssessment and diagnosis of a suspected mental health problem in pregnancy and the postnatal period should include:\n\nhistory of any mental health problem, including in pregnancy or the postnatal period\n\nphysical wellbeing (including weight, smoking, nutrition and activity level) and history of any physical health problem\n\nalcohol and drug misuse\n\nthe woman's attitude towards the pregnancy, including denial of pregnancy\n\nthe woman's experience of pregnancy and any problems experienced by her, the fetus or the baby\n\nthe mother–baby relationship\n\nany past or present treatment for a mental health problem, and response to any treatment\n\nsocial networks and quality of interpersonal relationships\n\nliving conditions and social isolation\n\nfamily history (first‑degree relative) of mental health problems\n\ndomestic violence and abuse, sexual abuse, trauma or childhood maltreatment\n\nhousing, employment, economic and immigration status\n\nresponsibilities as a carer for other children and young people or other adults. \n\nWhen assessing or treating a mental health problem in pregnancy or the postnatal period, take account of any learning disabilities or acquired cognitive impairments, and assess the need to consult with a specialist when developing care plans. \n\nCarry out a risk assessment in conjunction with the woman and, if she agrees, her partner, family or carer. Focus on areas that are likely to present possible risk such as self‑neglect, self‑harm, suicidal thoughts and intent, risks to others (including the baby), smoking, drug or alcohol misuse and domestic violence and abuse. \n\nIf there is a risk of, or there are concerns about, suspected child maltreatment, follow local safeguarding protocols. \n\nIf there is a risk of self‑harm or suicide:\n\nassess whether the woman has adequate social support and is aware of sources of help\n\narrange help appropriate to the level of risk\n\ninform all relevant healthcare professionals (including the GP and those identified in the care plan [see recommendation 1.6.6])\n\nadvise the woman, and her partner, family or carer, to seek further help if the situation deteriorates. \n\nProfessionals in secondary mental health services, including specialist perinatal mental health services, should develop a written care plan in collaboration with a woman who has or has had a severe mental illness. If she agrees, her partner, family or carer should also be involved. The plan should cover pregnancy, childbirth and the postnatal period (including the potential impact of the illness on the baby) and should include:\n\na clear statement of jointly agreed treatment goals and how outcomes will be routinely monitored\n\nincreased contact with and referral to specialist perinatal mental health services\n\nthe names and contact details of key professionals.The care plan should be recorded in all versions of the woman's notes (her own records and maternity, primary care and mental health notes) and a copy given to the woman and all involved professionals. \n\n# Providing interventions in pregnancy and the postnatal period\n\nAll healthcare professionals providing assessment and interventions for mental health problems in pregnancy and the postnatal period should understand the variations in their presentation and course at these times, how these variations affect treatment, and the context in which they are assessed and treated (for example, maternity services, health visiting and mental health services). \n\nAll interventions for mental health problems in pregnancy and the postnatal period should be delivered by competent practitioners. Psychological and psychosocial interventions should be based on the relevant treatment manual(s), which should guide the structure and duration of the intervention. Practitioners should consider using competence frameworks developed from the relevant treatment manual(s) and for all interventions practitioners should:\n\nreceive regular high‑quality supervision\n\nuse routine outcome measures and ensure that the woman is involved in reviewing the efficacy of the treatment\n\nengage in monitoring and evaluation of treatment adherence and practitioner competence – for example, by using video and audio tapes, and external audit and scrutiny where appropriate. \n\nWhen a woman with a known or suspected mental health problem is referred in pregnancy or the postnatal period, assess for treatment within 2\xa0weeks of referral and provide psychological interventions within 1\xa0month of initial assessment. \n\nWhen offering psychotropic medication during pregnancy and the postnatal period, follow the principles in recommendations 1.4.10 to 1.4.37. \n\nProvide interventions for mental health problems in pregnancy and the postnatal period within a stepped‑care model of service delivery in line with recommendation 1.5.1.3 of the NICE guideline on common mental health disorders. \n\n# Treating specific mental health problems in pregnancy and the postnatal period\n\n## Interventions for depression\n\nFor guidance on safe prescribing of antidepressants and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.\n\nFor a woman with persistent subthreshold depressive symptoms, or mild to moderate depression, in pregnancy or the postnatal period, consider facilitated self‑help (delivered as described in NICE's guideline on depression in adults). \n\nFor a woman with a history of severe depression who initially presents with mild depression in pregnancy or the postnatal period, consider a TCA, SSRI or (S)NRI. \n\nFor a woman with moderate or severe depression in pregnancy or the postnatal period, consider the following options:\n\na high-intensity psychological intervention (for example, CBT)\n\na TCA, SSRI or (S)NRI if the woman understands the risks associated with the medication and the mental health problem in pregnancy and the postnatal period and:\n\n\n\nshe has expressed a preference for medication or\n\nshe declines psychological interventions or\n\nher symptoms have not responded to psychological interventions\n\n\n\na high‑intensity psychological intervention in combination with medication if the woman understands the risks associated with the medication and the mental health problem in pregnancy and the postnatal period and there is no response, or a limited response, to a high‑intensity psychological intervention or medication alone. \n\nIf a woman who is taking a TCA, SSRI or (S)NRI for mild to moderate depression becomes pregnant, discuss stopping the medication gradually and consider facilitated self‑help (delivered as described in NICE's guideline on depression in adults). \n\nIf a pregnant woman is taking a TCA, SSRI or (S)NRI for moderate depression and wants to stop her medication, take into account previous response to treatment, stage of pregnancy, risk of relapse, risk associated with medication and her preference, and discuss with her the following options:\n\nswitching to a high‑intensity psychological intervention (for example, CBT)\n\nchanging medication if there is a drug that is effective for her with a lower risk of adverse effects. \n\nIf a pregnant woman is taking a TCA, SSRI or (S)NRI for severe depression, take into account previous response to treatment, stage of pregnancy, risk of relapse, risk associated with medication and her preference, and discuss with her the following options:\n\ncontinuing with the current medication\n\nchanging medication if there is a drug that is effective for her with a lower risk of adverse effects\n\ncombining medication with a high‑intensity psychological intervention (for example, CBT)\n\nswitching to a high‑intensity psychological intervention (for example, CBT) if she decides to stop taking medication. \n\n## Interventions for anxiety disorders\n\nFor guidance on safe prescribing of antidepressants and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.\n\nFor a woman with tokophobia (an extreme fear of childbirth), offer an opportunity to discuss her fears with a healthcare professional with expertise in providing perinatal mental health support in line with the NICE guideline on caesarean birth . \n\nFor a woman with persistent subthreshold symptoms of anxiety in pregnancy or the postnatal period, consider facilitated self‑help. This should consist of use of CBT‑based self‑help materials over 2 to 3\xa0months with support (either face to face or by telephone) for a total of 2 to 3\xa0hours over 6\xa0sessions. \n\nFor a woman with an anxiety disorder in pregnancy or the postnatal period, offer a low-intensity psychological intervention (for example, facilitated self‑help) or a high‑intensity psychological intervention (for example, CBT) as initial treatment in line with the recommendations set out in the NICE guideline for the specific mental health problem and be aware that:\n\nonly high‑intensity psychological interventions are recommended for post‑traumatic stress disorder\n\nhigh‑intensity psychological interventions are recommended for the initial treatment of social anxiety disorder\n\nprogress should be closely monitored and a high‑intensity psychological intervention offered within 2\xa0weeks if symptoms have not improved. \n\nIf a woman who is taking a TCA, SSRI or (S)NRI for an anxiety disorder becomes pregnant, discuss with her the following options:\n\nstopping the medication gradually and switching to a high‑intensity psychological intervention (for example, CBT)\n\ncontinuing with medication if she understands the risks associated with the medication and the mental health problem in pregnancy and the postnatal period and:\n\n\n\nhas expressed a preference for medication or\n\ndeclines psychological interventions or\n\nher symptoms have not responded to psychological interventions\n\n\n\nchanging medication if there is a drug that is effective for her with a lower risk of adverse effects\n\ncombining medication with a high‑intensity psychological intervention (for example, CBT) if the woman understands the risks associated with the medication and the mental health problem in pregnancy and the postnatal period and there is no response, or a limited response, to a high‑intensity psychological intervention alone. \n\n## Psychological interventions for eating disorders\n\nFor a woman with an eating disorder in pregnancy or the postnatal period:\n\noffer a psychological intervention in line with the NICE guideline on eating disorders\n\nmonitor the woman's condition carefully throughout pregnancy and the postnatal period\n\nassess the need for fetal growth scans\n\ndiscuss the importance of healthy eating during pregnancy and the postnatal period in line with the NICE guideline on maternal and child nutrition\n\nadvise her about feeding the baby in line with the NICE guideline on maternal and child nutrition and support her with this. \n\n## Interventions for alcohol and drug misuse\n\nIf hazardous drug or alcohol misuse is identified in pregnancy or the postnatal period, refer or offer brief interventions in line with section 1.3.1 of the NICE guideline on drug misuse in over 16s: psychosocial interventions or the NICE guideline on alcohol-use disorders: prevention. \n\nIf harmful or dependent drug or alcohol misuse is identified in pregnancy or the postnatal period, refer the woman to a specialist substance misuse service for advice and treatment. \n\nOffer assisted alcohol withdrawal in collaboration with specialist mental health and alcohol services (preferably in an inpatient setting) to pregnant women who are dependent on alcohol. Work with a woman who does not want assisted alcohol withdrawal to help her reduce her alcohol intake. \n\nOffer detoxification in collaboration with specialist mental health and substance misuse services to pregnant women who are dependent on opioids. Monitor closely after completion of detoxification. Work with a woman who does not want detoxification to help her reduce her opioid intake. Recognise the risk of accidental overdose in women who stop or reduce drug misuse in pregnancy but start misusing again after childbirth. \n\n## Interventions for severe mental illness\n\nConsider psychological interventions for women with bipolar disorder. This includes:\n\nCBT, IPT and behavioural couples therapy for bipolar depression\n\nstructured individual, group and family interventions designed for bipolar disorder to reduce the risk of relapse, particularly when medication is changed or stopped. \n\nIf a pregnant woman develops mania or psychosis and is not taking psychotropic medication, offer an antipsychotic. \n\nConsider psychological interventions (CBT or family intervention) delivered as described in the section on how to deliver psychological interventions in the NICE guideline on psychosis and schizophrenia in adults, for a woman with psychosis or schizophrenia who becomes pregnant and is at risk of relapse arising from:\n\nstress associated with pregnancy or the postnatal period\n\na change in medication, including stopping antipsychotic medication. \n\nOffer an antipsychotic in line with recommendations 1.5.3 and 1.5.4 of the NICE guideline on bipolar disorder as prophylactic medication if a woman with bipolar disorder:\n\nbecomes pregnant and is stopping lithium, or\n\nplans to breastfeed. \n\nIf a pregnant woman with bipolar disorder develops mania while taking prophylactic medication:\n\ncheck the dose of the prophylactic medication and adherence\n\nincrease the dose if the prophylactic medication is an antipsychotic\n\nsuggest changing to an antipsychotic if she is taking another type of prophylactic medication\n\nconsider lithium if there is no response to an increase in dose or change of drug and the woman has severe mania\n\nconsider electroconvulsive therapy (ECT) if there has been no response to lithium. \n\n## Interventions for sleep problems\n\nAdvise pregnant women who have a sleep problem about sleep hygiene (including having a healthy bedtime routine, avoiding caffeine and reducing activity before sleep). For women with a severe or chronic sleep problem, consider promethazine. In December 2014, this was an off-label use of promethazine. See NICE's information on prescribing medicines. \n\n## Electroconvulsive therapy\n\nConsider electroconvulsive therapy (ECT) for pregnant women with severe depression, severe mixed affective states or mania, or catatonia, whose physical health or that of the fetus is at serious risk. \n\n## Rapid tranquillisation\n\nA pregnant woman requiring rapid tranquillisation should be treated according to the NICE guidelines on the short-term management of violence and aggression, psychosis and schizophrenia and bipolar disorder (see our topic page on mental health and wellbeing for details), except that:\n\nshe should not be secluded after rapid tranquillisation\n\nrestraint procedures should be adapted to avoid possible harm to the fetus\n\nwhen choosing an agent for rapid tranquillisation in a pregnant woman, an antipsychotic or a benzodiazepine with a short half‑life should be considered; if an antipsychotic is used, it should be at the minimum effective dose because of neonatal extrapyramidal symptoms; if a benzodiazepine is used, the risks of floppy baby syndrome should be taken into account\n\nduring the perinatal period, the woman's care should be managed in close collaboration with a paediatrician and an anaesthetist. \n\n# Considerations for women and their babies in the postnatal period\n\n## Reviewing treatment for women with severe mental illness\n\nAfter childbirth, review and assess the need for starting, restarting or adjusting psychotropic medication as soon as a woman with a past or present severe mental illness is medically stable. \n\n## Monitoring babies for effects of psychotropic medication taken in pregnancy\n\nIf a woman has taken psychotropic medication during pregnancy, carry out a full neonatal assessment of the newborn baby, bearing in mind:\n\nthe variation in the onset of adverse effects of psychotropic medication\n\nthe need for further monitoring\n\nthe need to inform relevant healthcare professionals and the woman and her partner, family or carer of any further monitoring, particularly if the woman has been discharged early. \n\n## Care of women and their babies if there has been alcohol or drug misuse in pregnancy\n\nIf there has been alcohol or drug misuse in pregnancy, offer treatment and support after childbirth to both the woman and the baby, including:\n\na full neonatal assessment for any congenital abnormalities or neonatal adaptation syndrome\n\ncontinuing psychological treatment and support for the woman\n\nmonitoring of the baby. \n\n## Traumatic birth, stillbirth and miscarriage\n\nOffer advice and support to women who have had a traumatic birth or miscarriage and wish to talk about their experience. Take into account the effect of the birth or miscarriage on the partner and encourage them to accept support from family and friends. \n\nOffer women who have post‑traumatic stress disorder, which has resulted from a traumatic birth, miscarriage, stillbirth or neonatal death, a high-intensity psychological intervention (trauma‑focused CBT or eye movement desensitisation and reprocessing [EMDR]) in line with the NICE guideline on post-traumatic stress disorder. \n\nDo not offer single‑session high‑intensity psychological interventions with an explicit focus on 're‑living' the trauma to women who have a traumatic birth. \n\nDiscuss with a woman whose baby is stillborn or dies soon after birth, and her partner and family, the option of 1\xa0or more of the following:\n\nseeing a photograph of the baby\n\nhaving mementos of the baby\n\nseeing the baby\n\nholding the baby.This should be facilitated by an experienced practitioner and the woman and her partner and family should be offered a follow‑up appointment in primary or secondary care. If it is known that the baby has died in utero, this discussion should take place before the delivery, and continue after delivery if needed. \n\n## Psychotropic medication and breastfeeding\n\nEncourage women with a mental health problem to breastfeed, unless they are taking carbamazepine, clozapine or lithium (valproate is not recommended to treat a mental health problem in women or girls of childbearing potential – see the MHRA safety advice on valproate use by women and girls). However, support each woman in the choice of feeding method that best suits her and her family. [amended 2020]\n\nWhen assessing the risks and benefits of TCAs, SSRIs or (S)NRIs for women who are breastfeeding, take into account:\n\nthe limited data about the safety of these drugs and\n\nthe risks associated with switching from a previously effective medication. Seek advice from a specialist (preferably from a specialist perinatal mental health service) if needed for specific drugs. See also the UK Drugs in Lactation Advisory Service for information on the use of specific drugs. \n\nWhen assessing the risks and benefits of antipsychotic medication for women who are breastfeeding, take into account:\n\nthe limited data on the safety of these drugs and\n\nthe level of antipsychotic medication in breast milk depends on the drug. \n\nIf a woman is taking psychotropic medication while breastfeeding, monitor the baby for adverse effects. \n\n## The mother–baby relationship\n\nRecognise that some women with a mental health problem may experience difficulties with the mother–baby relationship. Assess the nature of this relationship, including verbal interaction, emotional sensitivity and physical care, at all postnatal contacts. Discuss any concerns that the woman has about her relationship with her baby and provide information and treatment for the mental health problem. \n\nConsider further intervention to improve the mother–baby relationship if any problems in the relationship have not resolved. \n\n# The organisation of services\n\nWomen who need inpatient care for a mental health problem within 12\xa0months of childbirth should normally be admitted to a specialist mother and baby unit, unless there are specific reasons for not doing so. \n\nManagers and senior healthcare professionals responsible for perinatal mental health services (including those working in maternity and primary care services) should ensure that:\n\nthere are clearly specified care pathways so that all primary and secondary healthcare professionals involved in the care of women during pregnancy and the postnatal period know how to access assessment and treatment\n\nstaff have supervision and training, covering mental health problems, assessment methods and referral routes, to allow them to follow the care pathways. \n\nClinical networks should be established for perinatal mental health services, managed by a coordinating board of healthcare professionals, commissioners, managers, and service users and carers. These networks should provide:\n\na specialist multidisciplinary perinatal service in each locality, which provides direct services, consultation and advice to maternity services, other mental health services and community services; in areas of high morbidity these services may be provided by separate specialist perinatal teams\n\naccess to specialist expert advice on the risks and benefits of psychotropic medication during pregnancy and breastfeeding\n\nclear referral and management protocols for services across all levels of the existing stepped‑care frameworks for mental health problems, to ensure effective transfer of information and continuity of care\n\npathways of care for service users, with defined roles and competencies for all professional groups involved. \n\nEach managed perinatal mental health network should have designated specialist inpatient services and cover a population where there are between 25,000 and 50,000 live births a year, depending on the local psychiatric morbidity rates. \n\nSpecialist perinatal inpatient services should:\n\nprovide facilities designed specifically for mothers and babies (typically with 6 to 12\xa0beds)\n\nbe staffed by specialist perinatal mental health staff\n\nbe staffed to provide appropriate care for babies\n\nhave effective liaison with general medical and mental health services\n\nhave available the full range of therapeutic services\n\nbe closely integrated with community‑based mental health services to ensure continuity of care and minimum length of stay. \n\n# Terms used in this guideline\n\n## Anxiety disorders\n\nThese include generalised anxiety disorder, panic disorder, obsessive‑compulsive disorder, phobias, post‑traumatic stress disorder and social anxiety disorder.\n\n## Baby\n\nRefers to an infant aged between 0 and 12\xa0months.\n\n## High‑intensity psychological intervention\n\nA formal psychological intervention usually delivered face to face (either in a group or individually) by a qualified therapist who has specific training in the delivery of the intervention.\n\n## Low‑intensity intervention\n\nA psychological or psychosocial intervention delivered by a trained coach or facilitator (rather than a therapist) to enable use of self‑help materials.\n\n## Postnatal period\n\nThis is defined in this guideline as up to 1\xa0year after childbirth.\n\n## Postpartum psychosis\n\nPsychosis often with mania and/or depressive symptoms in the immediate postnatal period, which can become very severe extremely quickly.\n\n## Psychotropic medication\n\nThis is defined in this guideline as all medication used to treat mental health problems.\n\n## Severe mental illness\n\nThis is defined in this guideline as severe and incapacitating depression, psychosis, schizophrenia, bipolar disorder, schizoaffective disorder and postpartum psychosis.\n\n## Traumatic birth\n\nThis includes births, whether preterm or full term, which are physically traumatic (for example, instrumental or assisted deliveries or emergency caesarean sections, severe perineal tears, postpartum haemorrhage) and births that are experienced as traumatic, even when the delivery is obstetrically straightforward.\n\n## Valproate\n\nRefers to 3\xa0formulations of valproate available in the UK: sodium valproate and valproic acid (licensed for the treatment of epilepsy) and semi‑sodium valproate (licensed for the treatment of acute mania and continuation treatment in people whose mania responds to treatment). Both semi‑sodium and sodium valproate are metabolised to valproic acid (also known as valproate), which is the pharmacologically active component. Valproate must not be used in pregnancy, and only used in girls and women when there is no alternative and a pregnancy prevention plan is in place. This is because of the risk of malformations and developmental abnormalities in the baby. See update information for important safety advice from the MHRA on the use of valproate.\n\n## Woman/women\n\nRefer(s) to female(s) of childbearing potential, including girls and young women under 18\xa0years.", 'Recommendations for research': "The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. The Guideline Development Group's full set of recommendations for research are detailed in the full guideline.\n\n# Preventing postpartum psychosis\n\nWhat methods can improve the identification of women at high risk of postpartum psychosis and reduce this risk?\n\n## Why this is important\n\nPostpartum psychosis is a severe mental illness with a rapid onset and a major impact on the woman and her ability to care for her baby. It is associated with an increased risk of mortality in both the woman and her baby. Prophylactic treatment can be effective for women who are known to be at high risk, but for some women postpartum psychosis may be their first episode of severe mental illness. Better identification of women at high risk and a greater understanding of prophylactic and acute treatment would have a significant impact on maternal and child welfare, and on service costs.\n\nThe question should be addressed by a programme of research into the prevention, treatment and management of postpartum psychosis comprising:\n\nThe development of a tool for routine clinical use to improve the identification of women at high risk of developing postpartum psychosis. This should be tested in a prospective cohort study.\n\nThe development of a set of interventions intended to prevent the onset of postpartum psychosis and a method for their effective and efficient delivery.\n\nThe testing of the clinical and cost effectiveness of the interventions in a large scale randomised controlled trial.\n\nThe development and testing of a programme for the implementation of an effective strategy for preventing and identifying postpartum psychosis.\n\n# The safety of drugs for bipolar disorder in pregnancy and the postnatal period\n\nHow safe are drugs used to treat bipolar disorder in pregnancy and the postnatal period?\n\n## Why this is important\n\nDrugs are effective for the acute treatment of bipolar disorder and for preventing relapse. All drugs used to treat mental health problems may carry some risk for the woman, fetus and baby. For some drugs such as sodium valproate these risks are well described, but the data are drawn from epilepsy case registers. For others such as lithium, the data are very limited. In addition, the prevalence of adverse outcomes for the woman, fetus or baby in untreated bipolar disorder is not well described.\n\nThe question should be addressed by establishing a long‑term register of women with bipolar disorder to provide data on:\n\nthe drugs used for treating bipolar disorder in pregnancy\n\nthe following outcomes (by drug type and for women who had no treatment for bipolar disorder in pregnancy):\n\n\n\nmaternal outcomes (for example, episodes of mood disorder in pregnancy and the postnatal period, miscarriage, preterm delivery)\n\ncongenital malformations (for example, spinal cord and cardiac malformation)\n\nbaby outcomes (for example, mortality, birthweight)\n\nchildhood outcomes (for example, cognitive development).\n\n\n\n# Psychological interventions focused on the mother‑baby relationship\n\nAre interventions designed to improve the quality of the mother–baby relationship in the first year after childbirth effective in women with a diagnosed mental health problem?\n\n## Why this is important\n\nProblems in the mother–baby relationship in the first year after childbirth may increase maternal mental health problems and are associated with a range of problems for the baby, including delayed cognitive and emotional development. A number of interventions are effective in improving the interaction between women and their babies, but it is not known if these are effective in women with a diagnosed mental health problem.\n\nThe question should be addressed in a randomised controlled trial comparing an intervention (proven to be effective in improving the quality of mother–baby interactions in women without a diagnosed mental health problem) against standard care. The trial should report the following outcomes, with a follow‑up period of at least 2\xa0years:\n\nthe mental health of the woman\n\nthe emotional and cognitive development of the baby\n\nthe quality of the interaction.\n\nThe trial should also examine the cost effectiveness of the intervention.\n\n# Structured clinical management for moderate to severe personality disorders in pregnancy and the postnatal period\n\nIs structured clinical management for moderate to severe personality disorders in pregnancy and the postnatal period effective at improving outcomes for women and their babies?\n\n## Why this is important\n\nPersonality disorders are associated with poor engagement with maternity services and perinatal mental health services and this leads to poor mental and physical health outcomes for the woman, fetus and baby. The complex psychological interventions that are effective for treating personality disorder may present problems for engagement even in those motivated to seek treatment. Structured clinical management is a psychologically informed model of case management, which is effective for treating personality disorder and may have greater flexibility and capacity to engage women with personality disorder in pregnancy and the postnatal period.\n\nThe question should be addressed in a randomised controlled trial comparing structured clinical management of personality disorder in pregnancy and the postnatal period against standard care. The trial should report the following outcomes, with a follow‑up period of at least 2\xa0years:\n\nthe mental and physical health of the woman\n\nthe physical health of the fetus\n\nthe mental and physical health of the baby\n\nthe quality of the mother–baby relationship.\n\nThe trial should also examine the cost effectiveness of the intervention.\n\n# Psychological interventions for moderate to severe anxiety disorders in pregnancy\n\nAre psychological interventions effective for treating moderate to severe anxiety disorders (including obsessive‑compulsive disorder, panic disorder, post‑traumatic stress disorder and social anxiety disorder) in pregnancy?\n\n## Why this is important\n\nAnxiety disorders are often not identified or treated in pregnancy. In addition, many women who are taking medication for such problems stop taking it when they are pregnant. The development of effective psychological interventions is therefore important. Although there are effective psychological interventions for anxiety disorders, there is limited evidence about their effectiveness in pregnancy and how these interventions might be adapted for use in pregnant women.\n\nThe question should be addressed by a programme of research evaluating psychological interventions (including individual and group approaches) for moderate to severe anxiety disorders in pregnancy, comprising:\n\na development programme to establish the adaptations to effective interventions (for example, mode of delivery, duration, content, and intensity of treatment) that are needed for use in pregnancy\n\nthe testing of the adapted interventions in a series of pilot studies\n\nthe testing of the clinical and cost effectiveness of the adapted interventions in large‑scale randomised controlled trials\n\nthe development and testing of a programme for the implementation of psychological interventions for moderate to severe anxiety disorders."}
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https://www.nice.org.uk/guidance/cg192
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This guideline covers recognising, assessing and treating mental health problems in women who are planning to have a baby, are pregnant, or have had a baby or been pregnant in the past year. It covers depression, anxiety disorders, eating disorders, drug- and alcohol-use disorders and severe mental illness (such as psychosis, bipolar disorder and schizophrenia). It promotes early detection and good management of mental health problems to improve women’s quality of life during pregnancy and in the year after giving birth.
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49a919706a79ecc6fa605c4b7603d11e89ec2847
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nice
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Leg ulcer infection: antimicrobial prescribing
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Leg ulcer infection: antimicrobial prescribing
This guideline sets out an antimicrobial prescribing strategy for adults with leg ulcer infection. It aims to optimise antibiotic use and reduce antibiotic resistance.
# Recommendations
# Managing leg ulcer infection in adults
## Treatment
Be aware that:
there are many causes of leg ulcers: underlying conditions, such as venous insufficiency and oedema, should be managed to promote healing
most leg ulcers are not clinically infected but are likely to be colonised with bacteria
antibiotics do not help to promote healing when a leg ulcer is not clinically infected.
Do not take a sample for microbiological testing from a leg ulcer at initial presentation, even if it might be infected.
Only offer an antibiotic for adults with a leg ulcer when there are symptoms or signs of infection (for example, redness or swelling spreading beyond the ulcer, localised warmth, increased pain or fever). When choosing an antibiotic (see the recommendations on choice of antibiotic) take account of:
the severity of symptoms or signs
the risk of developing complications
previous antibiotic use.
Give oral antibiotics if the person can take oral medicines, and the severity of their condition does not require intravenous antibiotics.
If intravenous antibiotics are given, review by 48 hours and consider switching to oral antibiotics if possible.
For a short explanation of why the committee made these recommendations, see the rationale section on treatment .
For more details, see the summary of the evidence on antibiotics and topical antiseptics.
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## Advice
When prescribing antibiotics for an infected leg ulcer in adults, give advice to seek medical help if symptoms or signs of the infection worsen rapidly or significantly at any time, or do not start to improve within 2 to 3 days of starting treatment.
## Reassessment
Reassess an infected leg ulcer in adults if:
symptoms or signs of the infection worsen rapidly or significantly at any time, or do not start to improve within 2 to 3 days
the person becomes systemically unwell or has severe pain out of proportion to the infection.
When reassessing an infected leg ulcer in adults, take account of previous antibiotic use, which may have led to resistant bacteria.
Be aware that it will take some time for a leg ulcer infection to resolve, with full resolution not expected until after the antibiotic course is completed.
Consider sending a sample from the leg ulcer (after cleaning) for microbiological testing if symptoms or signs of the infection are worsening or have not improved as expected.
When microbiological results are available:
review the choice of antibiotic(s) and
change the antibiotic(s) according to results if symptoms or signs of the infection are not improving, using a narrow-spectrum antibiotic if possible.
For a short explanation of why the committee made these recommendations, see the rationale section on reassessment .
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## Referral or seeking specialist advice
Refer adults with an infected leg ulcer to hospital if they have any symptoms or signs suggesting a more serious illness or condition, such as sepsis, necrotising fasciitis or osteomyelitis.
Consider referring or seeking specialist advice for adults with an infected leg ulcer if they:
have a higher risk of complications because of comorbidities, such as diabetes or immunosuppression
have lymphangitis
have spreading infection that is not responding to oral antibiotics
cannot take oral antibiotics (exploring locally available options for giving intravenous or intramuscular antibiotics at home or in the community, rather than in hospital, where appropriate).
For a short explanation of why the committee made these recommendations, see the rationale section on referral or seeking specialist advice .
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# Choice of antibiotic
When prescribing antibiotics for an infected leg ulcer in adults aged 18 years and over, follow the recommendations in table 1.
Treatment
Antibiotic, dosage and course length
First-choice oral antibiotic
Flucloxacillin:
mg to 1 g four times a day for 7 days
(In February 2020, 1 g four times a day was off label. See NICE's information on prescribing medicines.)
Alternative first-choice oral antibiotics for penicillin allergy or if flucloxacillin unsuitable
Doxycycline:
mg on the first day, then 100 mg once a day (can be increased to 200 mg daily) for 7 days in total
Clarithromycin:
mg twice a day for 7 days
Erythromycin (in pregnancy):
mg four times a day for 7 days
Second-choice oral antibiotics (guided by microbiological results when available)
Co‑amoxiclav:
/125 mg three times a day for 7 days
Co‑trimoxazole (in penicillin allergy):
mg twice a day for 7 days
(In February 2020, co‑trimoxazole was off label for leg ulcer infection. See NICE's information on prescribing medicines. See the BNF for information on monitoring.)
First-choice antibiotics if severely unwell (guided by microbiological results if available)
Flucloxacillin:
g to 2 g four times a day intravenously
with or without
Gentamicin:
Initially, 5 mg/kg to 7 mg/kg once daily intravenously, subsequent doses if needed according to serum gentamicin concentration (see the BNF for information on monitoring)
and/or
Metronidazole:
mg three times a day orally or 500 mg three times a day intravenously
Co‑amoxiclav:
g three times a day intravenously
with or without
Gentamicin:
Initially, 5 mg/kg to 7 mg/kg once daily intravenously, subsequent doses if needed according to serum gentamicin concentration (see the BNF for information on monitoring)
Co‑trimoxazole (in penicillin allergy):
mg twice a day intravenously (increased to 1.44 g twice a day if severe infection)
(In February 2020, co‑trimoxazole was off label for leg ulcer infection. See NICE's information on prescribing medicines. See the BNF for information on monitoring.)
with or without
Gentamicin:
Initially, 5 mg/kg to 7 mg/kg once daily intravenously, subsequent doses if needed according to serum gentamicin concentration (see the BNF for information on monitoring)
and/or
Metronidazole:
mg three times a day orally or 500 mg three times a day intravenously
Second-choice antibiotics if severely unwell (guided by microbiological results when available or following specialist advice)
Piperacillin with tazobactam:
g three times a day intravenously (increased to 4.5 g four times a day if severe infection)
Ceftriaxone:
g once a day intravenously
with or without
Metronidazole:
mg three times a day orally or 500 mg three times a day intravenously
Antibiotics to be added if meticillin-resistant
Staphylococcus aureus
infection is suspected or confirmed (combination therapy with antibiotics listed above)
Vancomycin:
mg/kg to 20 mg/kg two or three times a day intravenously (maximum 2 g per dose), adjusted according to serum vancomycin concentration (see the BNF for information on monitoring)
Teicoplanin:
Initially 6 mg/kg every 12 hours for three doses, then 6 mg/kg once a day intravenously (see the BNF for information on monitoring)
Linezolid (if vancomycin or teicoplanin cannot be used; specialist advice only):
mg twice a day orally or intravenously (see the BNF for information on monitoring)
See the BNF for appropriate use and dosing in specific populations, for example, people with hepatic or renal impairment, in pregnancy and breastfeeding, and when administering intravenous (or, where appropriate, intramuscular) antibiotics.
Review intravenous antibiotics by 48 hours and consider switching to oral antibiotics if possible.
Erythromycin is preferred if a macrolide is needed in pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. See the Medicines and Healthcare products Regulatory Agency (MHRA) Public Assessment Report on the safety of macrolide antibiotics in pregnancy.
For a short explanation of why the committee made the recommendation, see the rationale section on choice of antibiotic .
For more detail, see the summary of the evidence on choice of antibiotic.
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# Terms used in the guideline
## Leg ulcer
A leg ulcer is a long-lasting (chronic) open wound that takes more than 4 to 6 weeks to heal. Leg ulcers usually develop on the lower leg, between the shin and the ankle.
## Necrotising fasciitis
This is a rare but serious bacterial infection that affects the tissue beneath the skin and surrounding muscles and organs (fascia). Early symptoms can include intense pain that is out of proportion to any damage to the skin, and fever. The most common cause is group A streptococcus.
## Osteomyelitis
This is an infection of the bone. It can be very painful and most commonly occurs in the long bones of the leg. It can also occur in other bones, such as those in the back or arms. Anyone can develop osteomyelitis, but certain people are more at risk, including people with diabetes and those with a weakened immune system.# Recommendation for research
The guideline committee has made the following recommendation for research.
# Topical treatments for infected leg ulcer
What is the clinical effectiveness of topical treatments (antibiotics and antiseptics) compared with oral antibiotics for the treatment of infected leg ulcer?
For a short explanation of why the committee made the recommendation for research, see the rationale on treatment .
For more details, see the summary of the evidence on antibiotics and topical antiseptics.
Loading. Please wait.# Rationales
The recommendations in this guideline are for adults and are based on the evidence identified and the experience of the committee. No evidence was found for children with leg ulcers and recommendations were made for adults only.
# Treatment
## Why the committee made the recommendations
Recommendations 1.1.1 to 1.1.5
The committee agreed that health professionals should be aware that there are many causes of leg ulcers and that, although most leg ulcers are colonised by bacteria, few are infected. They discussed that it is important to ensure that underlying conditions, such as venous insufficiency and oedema, are managed appropriately.
The committee discussed that antibiotics should only be offered for adults with a leg ulcer when there are symptoms or signs of infection. They agreed that there was no difference in outcomes between treatment with antibiotics and standard care in people with uninfected leg ulcers (although this was from a small, very low-quality study with no details reported on dosage or route of administration).
Evidence showed no difference in complete healing of the leg ulcer with antibiotics compared with standard care or placebo. However, in all but 1 study, the ulcer was either uninfected or the infection status was unclear. No study stated that children and young people (under 18 years) were included. The committee agreed that this age group are very unlikely to develop a leg ulcer and if they do the cause is likely to be from a condition that needs specialist management. Therefore, it was not appropriate to extrapolate evidence for adults to children and young people and so the committee made recommendations for adults only.
The committee agreed that antibiotics should be offered to all adults with a leg ulcer if there are symptoms or signs of an infection, because untreated infection causes delays in ulcer healing, affecting quality of life and sometimes resulting in hospital admission. The committee discussed that studies did not use consistent criteria for identifying infection in ulcers, and some signs of infection (such as localised redness, discharge and unpleasant smell) could be present in all leg ulcers, regardless of infection status, especially once compression is removed. Therefore, they agreed that the symptoms or signs to use to determine if the ulcer is infected may include redness or swelling spreading beyond the ulcer, localised warmth, increased pain or fever. The committee noted that healthcare professionals should be aware that redness, 1 of the signs of infection, may be less visible on darker skin tones.
Based on experience, the committee agreed that antibiotic choice will depend on the severity of symptoms or signs of infection (for example, how rapidly the infection is progressing or expanding), the person's risk of complications (possibly because of comorbidities, such as diabetes or immunosuppression) and any previous antibiotic use (which may have led to antimicrobial resistance).
In line with the NICE guideline on antimicrobial stewardship: systems and processes for effective antimicrobial medicine use and Public Health England's antimicrobial stewardship: start smart – then focus toolkit, oral antibiotics should be given first if the person can take them, and if the severity of their infection does not require intravenous antibiotics. The use of intravenous antibiotics should be reviewed by 48 hours (taking into account the person's response to treatment and any microbiological results) and switched to oral treatment where possible.
The committee discussed and agreed that samples for microbiological testing should not routinely be taken from a leg ulcer at initial presentation, whether it is thought to be infected or not. Most leg ulcers are colonised by bacteria, and bacterial growth from a sample is likely regardless of infection status. Universal sampling could lead to inappropriate antibiotic prescribing. If the leg ulcer is clinically infected, the most likely causative organism is Staphylococcus aureus, which would be covered by empirical treatment with flucloxacillin.
Evidence comparing antibiotics with povidone-iodine (an antiseptic) for leg ulcer infection was limited by small sample size. Most of the evidence was in adults with unclear infection status or uninfected leg ulcer.
There was some evidence of effect for cadexomer‑iodine and silver dressings in people with infected leg ulcer (compared with standard care and non-adherent foam dressing respectively). But there were severe limitations, including an unclear definition of 'infection' (1 being reliant on laboratory growth and the other stating that inflammation was the only symptom required). For the comparison of silver dressings and foam dressings, the only sign of infection required was inflammation, there were very wide confidence intervals, and both study arms had the option to use antibiotics (and the number of people taking systemic antibiotics was not reported). Silver dressings can be expensive and could have considerable resource impact. Therefore, because of the inadequate definition of infection, the confounding issue of antibiotic use, the uncertainty of the effect estimate and the potential cost, the committee agreed not to recommend silver dressings.
The committee were also concerned about the adverse effects with cadexomer‑iodine. These were mainly local skin irritation, rash and pain, all of which can make leg ulcers worse. No adverse effects were reported for silver dressings, but this may have been because of the small sample size. The committee were also aware of issues with the availability of iodine-based preparations, particularly in community settings.
In clinical practice, topical antiseptics are used for leg ulcers, often to manage minor, localised infections. However, the committee agreed that they could not make any recommendations on the use topical antiseptics for treating infected leg ulcers because of the limitations of the evidence and the unclear benefit. The inability to differentiate between a more localised or widespread infection both in the evidence and in clinical practice makes it difficult to define any place in therapy for topical antiseptics. The committee decided that it was appropriate to make a research recommendation on the effectiveness of topical treatments (antiseptics and antibiotics) compared with oral antibiotics.
For more details, see the summary of the evidence on antibiotics and topical antiseptics.
Return to recommendations
# Reassessment
## Why the committee made the recommendations
Recommendations 1.1.7 to 1.1.11
Based on experience, the committee agreed when adults with an infected leg ulcer should be reassessed. If symptoms of the infection worsen rapidly or significantly at any time, or do not start to improve within 2 to 3 days, this may indicate that the person has a more serious illness requiring referral, or a resistant infection (possibly because of previous antibiotic use). People with leg ulcers have routine reviews, often by nurses. However, this review and any decision on the need for further antibiotics should take into account the fact that a leg ulcer infection will take some time to resolve even after a course of effective antibiotics.
The committee agreed that adults should be reassessed if they have severe pain out of proportion to the infection because this can be a symptom of necrotising fasciitis, which is a rare but serious bacterial infection.
Although microbiological sampling is not required at initial presentation, the committee agreed that it is appropriate to consider this if symptoms or signs of the infection are worsening or have not improved as expected. This will guide future antibiotic choice if the person has a resistant infection. The committee agreed that before microbiological sampling the wound should be cleaned to remove surface contaminants, slough or necrotic tissue, in line with Public Health England's guidance on venous leg ulcers: infection diagnosis and microbiological investigation guide for primary care.
When microbiological results are available, the choice of antibiotic should be reviewed and changed according to results if symptoms or signs of the infection are not improving, using a narrow-spectrum antibiotic if appropriate to minimise the risk of antimicrobial resistance.
Return to recommendations
# Referral or seeking specialist advice
## Why the committee made the recommendations
Recommendations 1.1.12 and 1.1.13
Based on experience, the committee agreed that adults with symptoms or signs suggesting a more serious illness or condition should be referred to hospital. Some people may have an infected leg ulcer that is more difficult to treat, for example, because they have a higher risk of complications or other underlying conditions, or they have a resistant infection. In these cases, referral or specialist advice should be considered (which may include giving intravenous antibiotics or adopting other non-antimicrobial management strategies).
Return to recommendations
# Choice of antibiotic
Recommendation 1.2.1
## Why the committee made the recommendations
There was very limited evidence on the choice of antibiotics in adults with an infected leg ulcer. Only 1 study compared antibiotics with standard care, and this was limited by the criteria for diagnosing infection. It was unclear whether wounds had symptoms and signs of clinical infection at baseline or whether they were just colonised with bacteria.
Based on experience, current practice and resistance data, the committee agreed that the first-choice oral antibiotic in adults with an infected leg ulcer is flucloxacillin (a penicillin). This is a relatively narrow-spectrum penicillin, which has good penetration for skin and soft tissue infections and is effective against gram‑positive organisms, including the most common causative organism Staphylococcus aureus.
The alternative first-choice antibiotics in adults with penicillin allergy or in whom flucloxacillin is unsuitable are doxycycline (a tetracycline), or clarithromycin or erythromycin (in pregnancy), which are macrolides. These all have a similar spectrum of activity to flucloxacillin. The committee agreed that the doses provided in the prescribing table were suitable for people with poor vascular flow.
The committee discussed the MHRA Public Assessment Report on the safety of macrolide antibiotics in pregnancy. This found that the available evidence is insufficient to confirm with certainty whether there is a small increased risk of birth defects or miscarriage when macrolides are taken in early pregnancy. They agreed with the UK Teratology Information Service monograph on the use of macrolides in pregnancy. They decided that there should be an informed discussion of the potential benefits and harms of treatment. Then, after such a discussion, macrolides can be used if there is a compelling clinical need and there are no suitable alternatives with adequate pregnancy safety data. Erythromycin is the preferred choice if a macrolide is needed during pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. This is because there is more documented experience of its use than for other macrolides.
The committee agreed that the second-choice oral antibiotics if the first-choice oral antibiotics are not effective (guided by microbiological results when available) are the broader-spectrum antibiotics co-amoxiclav (a penicillin with a beta-lactamase inhibitor) or co‑trimoxazole (in penicillin allergy). These are more active against gram-negative organisms. The presence of gram‑negative organisms may be a reason why an infected leg ulcer is not healing; these antibiotics are therefore appropriate second-choice antibiotics. However, the committee noted that it is important to only use broad-spectrum antibiotics if first-choice antibiotics are not effective. Broad-spectrum antibiotics can create a selective advantage for bacteria resistant to these agents, allowing such strains to proliferate and spread. By disrupting normal flora, broad-spectrum antibiotics can also leave people susceptible to harmful bacteria such as Clostridium difficile in community settings. The committee discussed that cephalosporins are not an appropriate option as a second-choice oral antibiotic because they do not provide adequate cover for anaerobes.
Oral antibiotics should be given first line if possible. But based on experience and resistance data, the committee agreed that several intravenous antibiotics (or combinations of antibiotics) can be used for adults who are severely unwell or unable to take oral antibiotics. This enables antibiotics to be selected based on individual patient factors, likely pathogens, and antibiotic susceptibilities from microbiological results (if known).
In people who are severely unwell, broader antimicrobial cover is needed because both anaerobes and gram-negative bacteria may be present. However, in line with the principles of antimicrobial stewardship, narrower-spectrum antibiotics should be used where possible.
For adults with an infected leg ulcer who require intravenous antibiotics, the committee agreed that flucloxacillin was the most appropriate first choice, with or without the addition of gentamicin (a broad-spectrum aminoglycoside) and/or metronidazole.
The committee agreed that additional choices would be:
co-amoxiclav with or without gentamicin
co-trimoxazole with or without gentamicin and/or metronidazole (if penicillin allergy).
The committee discussed that metronidazole (which is used for anaerobic bacteria) may be useful for people with leg ulcers related to arterial disease or diabetes. These people may have a reduced blood supply that can encourage anaerobic bacterial growth. Because metronidazole has good oral bioavailability, this could be given orally instead of intravenously if people were able to take oral antibiotics.
Second choice intravenous antibiotics (guided by microbiological results when available or following specialist advice) are:
piperacillin with tazobactam (a penicillin with a beta-lactamase inhibitor) or
ceftriaxone (a third-generation cephalosporin) with metronidazole.
The committee discussed that intravenous ceftriaxone may be given as an outpatient without the need for hospital admission.
Meticillin‑resistant Staphylococcus aureus (MRSA) may be found on swabbing, but the current likelihood of MRSA infection is very low. The committee agreed that if MRSA infection is suspected or confirmed, 1 of the following intravenous antibiotics with activity against MRSA should be added to the treatment regimen:
vancomycin (a glycopeptide) or
teicoplanin or
linezolid (an oxazolidinone; if vancomycin or teicoplanin cannot be used, following specialist advice only).
There was very little evidence on antibiotic dosage, course length and route of administration. Therefore, recommendations were based on the committee's experience of current practice. Flucloxacillin has poor oral bioavailability and in people with an infected leg ulcer who could have impaired circulation, a higher (off‑label dose) of up to 1 g, 4 times a day orally, may be needed to adequately treat the infection.
The committee agreed that the shortest course that is likely to be effective should be prescribed to minimise adverse effects and reduce the risk of antimicrobial resistance, but that this should be balanced against the need for a course length that provides effective treatment.
In the absence of evidence for optimum course length, the committee agreed, based on experience and extrapolation of evidence from people with cellulitis and diabetic foot infection, that a course of 7 days is appropriate for most people with an infected leg ulcer. They discussed that a decision for a longer course of antibiotics may be made on review if the infection is not improving, particularly for people with poor healing and a higher risk of complications because of comorbidities. However, 7 days should be adequate for most people if their wound and any underlying condition is being managed appropriately. Any decision on the need for further antibiotics should take into account the fact that a leg ulcer infection will take some time to resolve, even after a course of effective antibiotics.
The committee also discussed safety concerns around longer courses of flucloxacillin or co-amoxiclav, particularly in older people, because of the risk of cholestatic jaundice or hepatitis.
In line with the NICE guideline on antimicrobial stewardship and Public Heath England's antimicrobial stewardship: start smart – then focus toolkit, oral antibiotics should be given first line if the person can take them, and the severity of their condition does not require intravenous antibiotics. The use of intravenous antibiotics should be reviewed by 48 hours (taking into account the person's response to treatment and any microbiological results) and switched to oral treatment where possible.
For more detail, see the summary of the evidence on choice of antibiotic.
Return to recommendation# Context
A leg ulcer is a long-lasting (chronic) open wound that takes more than 4 to 6 weeks to heal. Leg ulcers usually develop on the lower leg, between the shin and the ankle.
Studies suggest that 80% to 100% of leg ulcers may have bacteria (usually Staphylococcus aureus or Pseudomonas aeruginosa) present in the wound, but this does not necessarily mean the wound is infected.# Summary of the evidence
This is a summary of the evidence. For full details see the evidence review and expert testimony.
The review protocol included a population of adults, young people and children with infected leg ulcers. There was minimal evidence for this population (2 small studies), therefore the population was expanded to people with leg ulcers that had an unclear infection status or were not infected. For antiseptic and antibiotics, the results have been presented separately for people with:
an infected leg ulcer
a leg ulcer with unclear infection status
an uninfected leg ulcer.
All the evidence is based on 1 systematic review of antibiotics and antiseptics for venous leg ulcers (O'Meara et al. 2014), which included 45 randomised controlled trials (RCTs). Nine of these were not included in the review because 8 contained ineligible interventions and 1 study was withdrawn from publication. Seven RCTs included people exclusively with leg ulcer infection (however 5 of these RCTs had an uncertain definition of infection); 14 RCTs included people with leg ulcers of unclear infection status and 15 studies included people with leg ulcers that were not infected.
No studies included in the review stated that they included children. The committee discussed that leg ulcer infection in children and young people is extremely rare, and usually a result of an underlying illness that requires specialist management. Therefore, they agreed not to extrapolate the evidence to children and young people.
Standard care is the care given in addition to the intervention and/or the control. The included studies were limited because the definition of standard care for each study varied widely, full details of what composed standard care is noted in the GRADE tables (appendix H of the evidence review).
# Topical antiseptics
## Iodine-based preparations
In a single RCT, cadexomer-iodine was significantly better than standard care at reducing the average size of the ulcers, the amount of pain experienced from the ulcers and reducing or eliminating the presence of Staphylococcus aureus at 6 weeks.
There was no significant difference for:
cadexomer-iodine compared with silver dressing for the frequency of complete healing at 12 weeks and for participant satisfaction (neither group reported any adverse effects)
povidone-iodine plus compression compared with moist or foam dressings plus compression for complete healing at 4 months.
Cadexomer-iodine (topical application) was significantly better than standard care (varied by RCT) for the frequency of complete healing at 4 to 12 weeks, mean percentage change ulcer area and mean rate of ulcer healing. However, adverse events were significantly more common in the cadexomer-iodine group.
Cadexomer-iodine was not significantly different from hydrocolloid dressing or paraffin gauze for the frequency of complete healing at 12 weeks, neither group reported any adverse effects.
Povidone-iodine plus compression was not significantly different from hydrocolloid plus compression for the frequency of complete healing at 4 months.
Povidone-iodine 10% solution plus compression was significantly better for time to healing than hydrocolloid plus compression.
## Peroxide-based preparations
Benzoyl peroxide (10% and 20%) was significantly better than a saline dressing for reducing average ulcer size at 42 days. Data on adverse effects were limited and poorly reported.
Hydrogen peroxide 1% cream was significantly better for median decrease in ulcer area compared with placebo cream at 10-day follow up. Data on adverse effects were limited and poorly reported.
## Honey-based preparations
Honey (calcium alginate dressing impregnated with Manuka honey) was not significantly different from standard care for:
complete healing at 12 weeks
incidence of ulcer infection during 12 weeks of treatment.
There were significantly more adverse effects in the honey group than the standard care group.
Honey (topical Manuka honey) was not significantly different from hydrogel (3 g/20 cm2 applied weekly) for the eradication of meticillin-resistant Staphylococcus aureus (MRSA) at 4 weeks.
## Silver-based preparations
Silver dressing plus compression was significantly better than non‑adhesive plus compression dressing for:
complete healing at 9 weeks
proportion of adults who were pain free at the end of the trial.
Silver dressings were not significantly different from non-adhesive dressings for adverse effects.
There was no significant difference between the following comparisons for complete healing (4 to 12 weeks):
silver sulfadiazine (1% cream) plus compression compared with non-adherent dressing plus compression
silver impregnated dressings (with or without compression) compared with non-antimicrobial dressings (with or without compression)
silver-impregnated polyurethane foam dressing plus compression compared with 5-layer silver impregnated dressing plus compression.
Silver dressings were not significantly different from non-antimicrobial dressings for adverse effects.
There was no significant difference for:
silver sulfadiazine (1% cream) with non-adhesive foam dressing and compression compared with placebo cream with non-adherent dressing and compression for complete healing at 4 weeks
silver sulfadiazine (1% cream) compared with standard care for median time to healing
silver dressing plus compression compared with low-adherent dressing for complete healing at 4 to 12 weeks, 6 months or 12 months, or for ulcer recurrence within 12 months
silver dressings compared with non-antimicrobial dressings for adverse effects.
Silver dressing plus compression was significantly better than non-antimicrobial dressings plus compression for reducing ulcer surface area when measured using square centimetres at 4 weeks, but was not significantly different when measured as a percentage change. The healing rate (cm2 per day) in these 2 RCTs was not significantly different.
# Antibiotics
## Antibiotics compared with standard care or placebo
Ciprofloxacin was not significantly different from standard care for the frequency of complete healing, emergence of antibiotic-resistant strains or bacterial eradication at 3 months.
For the frequency of complete healing (unclear follow-up time), there was no significant difference between:
ciprofloxacin and placebo or
trimethoprim and placebo.
Emergence of resistance was significantly higher with ciprofloxacin than with placebo, but there was no significant difference in the emergence of resistance with trimethoprim compared with placebo.
There was no significant difference between:
systemic antibiotics (co-trimoxazole, gentamicin or amikacin according to sensitivities) and standard care for the outcomes of complete healing at 3 weeks, complete eventual healing or bacterial eradication
topical mupirocin compared with standard care for frequency of complete healing at 12 weeks or for the eradication of gram-positive bacteria.
Data on adverse effects were limited and poorly reported.
## Antibiotics compared with antiseptics
Amoxicillin with compression was not significantly different from povidone-iodine alone or with compression for complete healing at 12 weeks in people with an infected leg ulcer.
No data on adverse effects were reported.
# Choice of antibiotic
## Unclear leg ulcer infection status
Ciprofloxacin was not significantly different from trimethoprim for the frequency of complete healing.
Limited data on adverse effects were reported. However, ciprofloxacin and trimethoprim increased the emergence of antimicrobial resistance compared with standard care or placebo. This finding was statistically significant for ciprofloxacin, but did not reach significance for trimethoprim.
# Antibiotic course length, dosage and route of administration
No evidence from systematic reviews or RCTs was identified.# Other considerations
# Medicines safety
Antibiotic-associated diarrhoea is estimated to occur in 2% to 25% of people taking antibiotics, depending on the antibiotic used (NICE clinical knowledge summary on diarrhoea – antibiotic associated).
About 10% of the general population claim to have a penicillin allergy; this is often because of a skin rash that occurred while taking a course of penicillin as a child. Fewer than 10% of people who think they are allergic to penicillin are truly allergic. See the NICE guideline on drug allergy: diagnosis and management for more information.
Cholestatic jaundice and hepatitis can occur with flucloxacillin up to 2 months after stopping treatment, with risk factors being increasing age and use for more than 14 days (British national formulary flucloxacillin). Cholestatic jaundice can also occur with co-amoxiclav, and is more common in people over 65 years and in men; treatment should not usually exceed 14 days (BNF co-amoxiclav).
People with a history of immediate hypersensitivity to penicillin may also react to cephalosporins and other beta-lactam antibiotics (BNF phenoxymethylpenicillin).
Macrolides (for example, clarithromycin) should be used with caution in people with a predisposition to QT interval prolongation. Nausea, vomiting, abdominal discomfort, and diarrhoea are the most common side effects of macrolides. These are less frequent with clarithromycin than with erythromycin (BNF erythromycin).
Tetracyclines (for example, doxycycline) can deposit in growing bone and teeth (by binding to calcium) causing staining and occasionally dental hypoplasia. They should not be given to pregnant women or women who are breastfeeding, and use in children under 12 years is either contraindicated or cautioned for use in severe or life-threatening infections where there are no alternatives. People should be advised to avoid exposure to sunlight or sun lamps because of photosensitivity reactions (BNF doxycycline).
Co-trimoxazole is associated with rare but serious side effects, including blood disorders and Stevens−Johnson syndrome. It is cautioned for use in older people because there is an increased risk of serious side effects, and in those with a predisposition to hyperkalaemia. Monitoring of blood counts is recommended with prolonged treatment (BNF co-trimoxazole).
Aminoglycoside (for example, gentamicin) doses are based on body weight and renal function. Ototoxicity and nephrotoxicity are important side effects to consider, and whenever possible treatment should not exceed 7 days (BNF gentamicin).
Glycopeptide (for example, vancomycin and teicoplanin) doses are based on body weight. Therapeutic drug monitoring and monitoring of various patient parameters, including blood count, urinalysis, auditory function, hepatic function and renal function, is recommended, depending on the particular glycopeptide (BNF vancomycin).
Severe optic neuropathy can occur with linezolid, particularly if used for longer than 28 days. Blood disorders have also been reported, and weekly full blood counts are recommended (BNF linezolid).
See the electronic medicines compendium's summaries of product characteristics for information on contraindications, cautions and adverse effects of individual medicines.
# Medicines adherence
Medicines adherence may be a problem for some people taking antibiotics that need frequent dosing or longer treatment duration (see the NICE clinical guideline on medicines adherence).
# Resource implications
Recommended antibiotics are available as generic formulations. See NHS Drug tariff and BNF for costs.
See the evidence review for more information.
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{'Recommendations': "# Managing leg ulcer infection in adults\n\n## Treatment\n\nBe aware that:\n\nthere are many causes of leg ulcers: underlying conditions, such as venous insufficiency and oedema, should be managed to promote healing\n\nmost leg ulcers are not clinically infected but are likely to be colonised with bacteria\n\nantibiotics do not help to promote healing when a leg ulcer is not clinically infected.\n\nDo not take a sample for microbiological testing from a leg ulcer at initial presentation, even if it might be infected.\n\nOnly offer an antibiotic for adults with a leg ulcer when there are symptoms or signs of infection (for example, redness or swelling spreading beyond the ulcer, localised warmth, increased pain or fever). When choosing an antibiotic (see the recommendations on choice of antibiotic) take account of:\n\nthe severity of symptoms or signs\n\nthe risk of developing complications\n\nprevious antibiotic use.\n\nGive oral antibiotics if the person can take oral medicines, and the severity of their condition does not require intravenous antibiotics.\n\nIf intravenous antibiotics are given, review by 48\xa0hours and consider switching to oral antibiotics if possible.\n\nFor a short explanation of why the committee made these recommendations, see the rationale section on treatment\xa0.\n\nFor more details, see the summary of the evidence on antibiotics and topical antiseptics.\n\nLoading. Please wait.\n\n## Advice\n\nWhen prescribing antibiotics for an infected leg ulcer in adults, give advice to seek medical help if symptoms or signs of the infection worsen rapidly or significantly at any time, or do not start to improve within 2 to 3\xa0days of starting treatment.\n\n## Reassessment\n\nReassess an infected leg ulcer in adults if:\n\nsymptoms or signs of the infection worsen rapidly or significantly at any time, or do not start to improve within 2 to 3\xa0days\n\nthe person becomes systemically unwell or has severe pain out of proportion to the infection.\n\nWhen reassessing an infected leg ulcer in adults, take account of previous antibiotic use, which may have led to resistant bacteria.\n\nBe aware that it will take some time for a leg ulcer infection to resolve, with full resolution not expected until after the antibiotic course is completed.\n\nConsider sending a sample from the leg ulcer (after cleaning) for microbiological testing if symptoms or signs of the infection are worsening or have not improved as expected.\n\nWhen microbiological results are available:\n\nreview the choice of antibiotic(s) and\n\nchange the antibiotic(s) according to results if symptoms or signs of the infection are not improving, using a narrow-spectrum antibiotic if possible.\n\nFor a short explanation of why the committee made these recommendations, see the rationale section on reassessment\xa0.\n\nLoading. Please wait.\n\n## Referral or seeking specialist advice\n\nRefer adults with an infected leg ulcer to hospital if they have any symptoms or signs suggesting a more serious illness or condition, such as sepsis, necrotising fasciitis or osteomyelitis.\n\nConsider referring or seeking specialist advice for adults with an infected leg ulcer if they:\n\nhave a higher risk of complications because of comorbidities, such as diabetes or immunosuppression\n\nhave lymphangitis\n\nhave spreading infection that is not responding to oral antibiotics\n\ncannot take oral antibiotics (exploring locally available options for giving intravenous or intramuscular antibiotics at home or in the community, rather than in hospital, where appropriate).\n\nFor a short explanation of why the committee made these recommendations, see the rationale section on referral or seeking specialist advice\xa0.\n\nLoading. Please wait.\n\n# Choice of antibiotic\n\nWhen prescribing antibiotics for an infected leg ulcer in adults aged 18\xa0years and over, follow the recommendations in table\xa01.\n\nTreatment\n\nAntibiotic, dosage and course length\n\nFirst-choice oral antibiotic\n\nFlucloxacillin:\n\nmg to 1\xa0g four times a day for 7\xa0days\n\n(In February 2020, 1\xa0g four times a day was off label. See NICE's information on prescribing medicines.)\n\nAlternative first-choice oral antibiotics for penicillin allergy or if flucloxacillin unsuitable\n\nDoxycycline:\n\nmg on the first day, then 100\xa0mg once a day (can be increased to 200\xa0mg daily) for 7\xa0days in total\n\n\n\nClarithromycin:\n\nmg twice a day for 7\xa0days\n\n\n\nErythromycin (in pregnancy):\n\nmg four times a day for 7\xa0days\n\nSecond-choice oral antibiotics (guided by microbiological results when available)\n\nCo‑amoxiclav:\n\n/125\xa0mg three times a day for 7\xa0days\n\n\n\nCo‑trimoxazole (in penicillin allergy):\n\nmg twice a day for 7\xa0days\n\n(In February 2020, co‑trimoxazole was off label for leg ulcer infection. See NICE's information on prescribing medicines. See the BNF for information on monitoring.)\n\nFirst-choice antibiotics if severely unwell (guided by microbiological results if available)\n\nFlucloxacillin:\n\ng to 2\xa0g four times a day intravenously\n\nwith or without\n\nGentamicin:\n\nInitially, 5\xa0mg/kg to 7\xa0mg/kg once daily intravenously, subsequent doses if needed according to serum gentamicin concentration (see the BNF for information on monitoring)\n\nand/or\n\nMetronidazole:\n\nmg three times a day orally or 500\xa0mg three times a day intravenously\n\n\n\nCo‑amoxiclav:\n\ng three times a day intravenously\n\nwith or without\n\nGentamicin:\n\nInitially, 5\xa0mg/kg to 7\xa0mg/kg once daily intravenously, subsequent doses if needed according to serum gentamicin concentration (see the BNF for information on monitoring)\n\n\n\nCo‑trimoxazole (in penicillin allergy):\n\nmg twice a day intravenously (increased to 1.44\xa0g twice a day if severe infection)\n\n(In February 2020, co‑trimoxazole was off label for leg ulcer infection. See NICE's information on prescribing medicines. See the BNF for information on monitoring.)\n\nwith or without\n\nGentamicin:\n\nInitially, 5\xa0mg/kg to 7\xa0mg/kg once daily intravenously, subsequent doses if needed according to serum gentamicin concentration (see the BNF for information on monitoring)\n\nand/or\n\nMetronidazole:\n\nmg three times a day orally or 500\xa0mg three times a day intravenously\n\nSecond-choice antibiotics if severely unwell (guided by microbiological results when available or following specialist advice)\n\nPiperacillin with tazobactam:\n\ng three times a day intravenously (increased to 4.5\xa0g four times a day if severe infection)\n\n\n\nCeftriaxone:\n\ng once a day intravenously\n\nwith or without\n\nMetronidazole:\n\nmg three times a day orally or 500\xa0mg three times a day intravenously\n\nAntibiotics to be added if meticillin-resistant \n \n Staphylococcus aureus\n \n infection is suspected or confirmed (combination therapy with antibiotics listed above)\n\nVancomycin:\n\nmg/kg to 20\xa0mg/kg two or three times a day intravenously (maximum 2\xa0g per dose), adjusted according to serum vancomycin concentration (see the BNF for information on monitoring)\n\n\n\nTeicoplanin:\n\nInitially 6\xa0mg/kg every 12\xa0hours for three\xa0doses, then 6\xa0mg/kg once a day intravenously (see the BNF for information on monitoring)\n\n\n\nLinezolid (if vancomycin or teicoplanin cannot be used; specialist advice only):\n\nmg twice a day orally or intravenously (see the BNF for information on monitoring)\n\nSee the BNF for appropriate use and dosing in specific populations, for example, people with hepatic or renal impairment, in pregnancy and breastfeeding, and when administering intravenous (or, where appropriate, intramuscular) antibiotics.\n\nReview intravenous antibiotics by 48\xa0hours and consider switching to oral antibiotics if possible.\n\nErythromycin is preferred if a macrolide is needed in pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. See the Medicines and Healthcare products Regulatory Agency (MHRA) Public Assessment Report on the safety of macrolide antibiotics in pregnancy.\n\nFor a short explanation of why the committee made the recommendation, see the rationale section on choice of antibiotic\xa0.\n\nFor more detail, see the summary of the evidence on choice of antibiotic.\n\nLoading. Please wait.\n\n# Terms used in the guideline\n\n## Leg ulcer\n\nA leg ulcer is a long-lasting (chronic) open wound that takes more than 4 to 6\xa0weeks to heal. Leg ulcers usually develop on the lower leg, between the shin and the ankle.\n\n## Necrotising fasciitis\n\nThis is a rare but serious bacterial infection that affects the tissue beneath the skin and surrounding muscles and organs (fascia). Early symptoms can include intense pain that is out of proportion to any damage to the skin, and fever. The most common cause is group A streptococcus.\n\n## Osteomyelitis\n\nThis is an infection of the bone. It can be very painful and most commonly occurs in the long bones of the leg. It can also occur in other bones, such as those in the back or arms. Anyone can develop osteomyelitis, but certain people are more at risk, including people with diabetes and those with a weakened immune system.", 'Recommendation for research': 'The guideline committee has made the following recommendation for research.\n\n# Topical treatments for infected leg ulcer\n\nWhat is the clinical effectiveness of topical treatments (antibiotics and antiseptics) compared with oral antibiotics for the treatment of infected leg ulcer?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on treatment\xa0.\n\nFor more details, see the summary of the evidence on antibiotics and topical antiseptics.\n\nLoading. Please wait.', 'Rationales': "The recommendations in this guideline are for adults and are based on the evidence identified and the experience of the committee. No evidence was found for children with leg ulcers and recommendations were made for adults only.\n\n# Treatment\n\n## Why the committee made the recommendations\n\nRecommendations 1.1.1 to 1.1.5\n\nThe committee agreed that health professionals should be aware that there are many causes of leg ulcers and that, although most leg ulcers are colonised by bacteria, few are infected. They discussed that it is important to ensure that underlying conditions, such as venous insufficiency and oedema, are managed appropriately.\n\nThe committee discussed that antibiotics should only be offered for adults with a leg ulcer when there are symptoms or signs of infection. They agreed that there was no difference in outcomes between treatment with antibiotics and standard care in people with uninfected leg ulcers (although this was from a small, very low-quality study with no details reported on dosage or route of administration).\n\nEvidence showed no difference in complete healing of the leg ulcer with antibiotics compared with standard care or placebo. However, in all but 1 study, the ulcer was either uninfected or the infection status was unclear. No study stated that children and young people (under 18\xa0years) were included. The committee agreed that this age group are very unlikely to develop a leg ulcer and if they do the cause is likely to be from a condition that needs specialist management. Therefore, it was not appropriate to extrapolate evidence for adults to children and young people and so the committee made recommendations for adults only.\n\nThe committee agreed that antibiotics should be offered to all adults with a leg ulcer if there are symptoms or signs of an infection, because untreated infection causes delays in ulcer healing, affecting quality of life and sometimes resulting in hospital admission. The committee discussed that studies did not use consistent criteria for identifying infection in ulcers, and some signs of infection (such as localised redness, discharge and unpleasant smell) could be present in all leg ulcers, regardless of infection status, especially once compression is removed. Therefore, they agreed that the symptoms or signs to use to determine if the ulcer is infected may include redness or swelling spreading beyond the ulcer, localised warmth, increased pain or fever. The committee noted that healthcare professionals should be aware that redness, 1 of the signs of infection, may be less visible on darker skin tones.\n\nBased on experience, the committee agreed that antibiotic choice will depend on the severity of symptoms or signs of infection (for example, how rapidly the infection is progressing or expanding), the person's risk of complications (possibly because of comorbidities, such as diabetes or immunosuppression) and any previous antibiotic use (which may have led to antimicrobial resistance).\n\nIn line with the NICE guideline on antimicrobial stewardship: systems and processes for effective antimicrobial medicine use and Public Health England's antimicrobial stewardship: start smart – then focus toolkit, oral antibiotics should be given first if the person can take them, and if the severity of their infection does not require intravenous antibiotics. The use of intravenous antibiotics should be reviewed by 48\xa0hours (taking into account the person's response to treatment and any microbiological results) and switched to oral treatment where possible.\n\nThe committee discussed and agreed that samples for microbiological testing should not routinely be taken from a leg ulcer at initial presentation, whether it is thought to be infected or not. Most leg ulcers are colonised by bacteria, and bacterial growth from a sample is likely regardless of infection status. Universal sampling could lead to inappropriate antibiotic prescribing. If the leg ulcer is clinically infected, the most likely causative organism is Staphylococcus aureus, which would be covered by empirical treatment with flucloxacillin.\n\nEvidence comparing antibiotics with povidone-iodine (an antiseptic) for leg ulcer infection was limited by small sample size. Most of the evidence was in adults with unclear infection status or uninfected leg ulcer.\n\nThere was some evidence of effect for cadexomer‑iodine and silver dressings in people with infected leg ulcer (compared with standard care and non-adherent foam dressing respectively). But there were severe limitations, including an unclear definition of 'infection' (1 being reliant on laboratory growth and the other stating that inflammation was the only symptom required). For the comparison of silver dressings and foam dressings, the only sign of infection required was inflammation, there were very wide confidence intervals, and both study arms had the option to use antibiotics (and the number of people taking systemic antibiotics was not reported). Silver dressings can be expensive and could have considerable resource impact. Therefore, because of the inadequate definition of infection, the confounding issue of antibiotic use, the uncertainty of the effect estimate and the potential cost, the committee agreed not to recommend silver dressings.\n\nThe committee were also concerned about the adverse effects with cadexomer‑iodine. These were mainly local skin irritation, rash and pain, all of which can make leg ulcers worse. No adverse effects were reported for silver dressings, but this may have been because of the small sample size. The committee were also aware of issues with the availability of iodine-based preparations, particularly in community settings.\n\nIn clinical practice, topical antiseptics are used for leg ulcers, often to manage minor, localised infections. However, the committee agreed that they could not make any recommendations on the use topical antiseptics for treating infected leg ulcers because of the limitations of the evidence and the unclear benefit. The inability to differentiate between a more localised or widespread infection both in the evidence and in clinical practice makes it difficult to define any place in therapy for topical antiseptics. The committee decided that it was appropriate to make a research recommendation on the effectiveness of topical treatments (antiseptics and antibiotics) compared with oral antibiotics.\n\nFor more details, see the summary of the evidence on antibiotics and topical antiseptics.\n\nReturn to recommendations\n\n# Reassessment\n\n## Why the committee made the recommendations\n\nRecommendations 1.1.7 to 1.1.11\n\nBased on experience, the committee agreed when adults with an infected leg ulcer should be reassessed. If symptoms of the infection worsen rapidly or significantly at any time, or do not start to improve within 2 to 3\xa0days, this may indicate that the person has a more serious illness requiring referral, or a resistant infection (possibly because of previous antibiotic use). People with leg ulcers have routine reviews, often by nurses. However, this review and any decision on the need for further antibiotics should take into account the fact that a leg ulcer infection will take some time to resolve even after a course of effective antibiotics.\n\nThe committee agreed that adults should be reassessed if they have severe pain out of proportion to the infection because this can be a symptom of necrotising fasciitis, which is a rare but serious bacterial infection.\n\nAlthough microbiological sampling is not required at initial presentation, the committee agreed that it is appropriate to consider this if symptoms or signs of the infection are worsening or have not improved as expected. This will guide future antibiotic choice if the person has a resistant infection. The committee agreed that before microbiological sampling the wound should be cleaned to remove surface contaminants, slough or necrotic tissue, in line with Public Health England's guidance on venous leg ulcers: infection diagnosis and microbiological investigation guide for primary care.\n\nWhen microbiological results are available, the choice of antibiotic should be reviewed and changed according to results if symptoms or signs of the infection are not improving, using a narrow-spectrum antibiotic if appropriate to minimise the risk of antimicrobial resistance.\n\nReturn to recommendations\n\n# Referral or seeking specialist advice\n\n## Why the committee made the recommendations\n\nRecommendations 1.1.12 and 1.1.13\n\nBased on experience, the committee agreed that adults with symptoms or signs suggesting a more serious illness or condition should be referred to hospital. Some people may have an infected leg ulcer that is more difficult to treat, for example, because they have a higher risk of complications or other underlying conditions, or they have a resistant infection. In these cases, referral or specialist advice should be considered (which may include giving intravenous antibiotics or adopting other non-antimicrobial management strategies).\n\nReturn to recommendations\n\n# Choice of antibiotic\n\nRecommendation 1.2.1\n\n## Why the committee made the recommendations\n\nThere was very limited evidence on the choice of antibiotics in adults with an infected leg ulcer. Only 1\xa0study compared antibiotics with standard care, and this was limited by the criteria for diagnosing infection. It was unclear whether wounds had symptoms and signs of clinical infection at baseline or whether they were just colonised with bacteria.\n\nBased on experience, current practice and resistance data, the committee agreed that the first-choice oral antibiotic in adults with an infected leg ulcer is flucloxacillin (a penicillin). This is a relatively narrow-spectrum penicillin, which has good penetration for skin and soft tissue infections and is effective against gram‑positive organisms, including the most common causative organism Staphylococcus aureus.\n\nThe alternative first-choice antibiotics in adults with penicillin allergy or in whom flucloxacillin is unsuitable are doxycycline (a tetracycline), or clarithromycin or erythromycin (in pregnancy), which are macrolides. These all have a similar spectrum of activity to flucloxacillin. The committee agreed that the doses provided in the prescribing table were suitable for people with poor vascular flow.\n\nThe committee discussed the MHRA Public Assessment Report on the safety of macrolide antibiotics in pregnancy. This found that the available evidence is insufficient to confirm with certainty whether there is a small increased risk of birth defects or miscarriage when macrolides are taken in early pregnancy. They agreed with the UK Teratology Information Service monograph on the use of macrolides in pregnancy. They decided that there should be an informed discussion of the potential benefits and harms of treatment. Then, after such a discussion, macrolides can be used if there is a compelling clinical need and there are no suitable alternatives with adequate pregnancy safety data. Erythromycin is the preferred choice if a macrolide is needed during pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. This is because there is more documented experience of its use than for other macrolides.\n\nThe committee agreed that the second-choice oral antibiotics if the first-choice oral antibiotics are not effective (guided by microbiological results when available) are the broader-spectrum antibiotics co-amoxiclav (a penicillin with a beta-lactamase inhibitor) or co‑trimoxazole (in penicillin allergy). These are more active against gram-negative organisms. The presence of gram‑negative organisms may be a reason why an infected leg ulcer is not healing; these antibiotics are therefore appropriate second-choice antibiotics. However, the committee noted that it is important to only use broad-spectrum antibiotics if first-choice antibiotics are not effective. Broad-spectrum antibiotics can create a selective advantage for bacteria resistant to these agents, allowing such strains to proliferate and spread. By disrupting normal flora, broad-spectrum antibiotics can also leave people susceptible to harmful bacteria such as Clostridium difficile in community settings. The committee discussed that cephalosporins are not an appropriate option as a second-choice oral antibiotic because they do not provide adequate cover for anaerobes.\n\nOral antibiotics should be given first line if possible. But based on experience and resistance data, the committee agreed that several intravenous antibiotics (or combinations of antibiotics) can be used for adults who are severely unwell or unable to take oral antibiotics. This enables antibiotics to be selected based on individual patient factors, likely pathogens, and antibiotic susceptibilities from microbiological results (if known).\n\nIn people who are severely unwell, broader antimicrobial cover is needed because both anaerobes and gram-negative bacteria may be present. However, in line with the principles of antimicrobial stewardship, narrower-spectrum antibiotics should be used where possible.\n\nFor adults with an infected leg ulcer who require intravenous antibiotics, the committee agreed that flucloxacillin was the most appropriate first choice, with or without the addition of gentamicin (a broad-spectrum aminoglycoside) and/or metronidazole.\n\nThe committee agreed that additional choices would be:\n\nco-amoxiclav with or without gentamicin\n\nco-trimoxazole with or without gentamicin and/or metronidazole (if penicillin allergy).\n\nThe committee discussed that metronidazole (which is used for anaerobic bacteria) may be useful for people with leg ulcers related to arterial disease or diabetes. These people may have a reduced blood supply that can encourage anaerobic bacterial growth. Because metronidazole has good oral bioavailability, this could be given orally instead of intravenously if people were able to take oral antibiotics.\n\nSecond choice intravenous antibiotics (guided by microbiological results when available or following specialist advice) are:\n\npiperacillin with tazobactam (a penicillin with a beta-lactamase inhibitor) or\n\nceftriaxone (a third-generation cephalosporin) with metronidazole.\n\nThe committee discussed that intravenous ceftriaxone may be given as an outpatient without the need for hospital admission.\n\nMeticillin‑resistant Staphylococcus aureus (MRSA) may be found on swabbing, but the current likelihood of MRSA infection is very low. The committee agreed that if MRSA infection is suspected or confirmed, 1 of the following intravenous antibiotics with activity against MRSA should be added to the treatment regimen:\n\nvancomycin (a glycopeptide) or\n\nteicoplanin or\n\nlinezolid (an oxazolidinone; if vancomycin or teicoplanin cannot be used, following specialist advice only).\n\nThere was very little evidence on antibiotic dosage, course length and route of administration. Therefore, recommendations were based on the committee's experience of current practice. Flucloxacillin has poor oral bioavailability and in people with an infected leg ulcer who could have impaired circulation, a higher (off‑label dose) of up to 1\xa0g, 4\xa0times a day orally, may be needed to adequately treat the infection.\n\nThe committee agreed that the shortest course that is likely to be effective should be prescribed to minimise adverse effects and reduce the risk of antimicrobial resistance, but that this should be balanced against the need for a course length that provides effective treatment.\n\nIn the absence of evidence for optimum course length, the committee agreed, based on experience and extrapolation of evidence from people with cellulitis and diabetic foot infection, that a course of 7\xa0days is appropriate for most people with an infected leg ulcer. They discussed that a decision for a longer course of antibiotics may be made on review if the infection is not improving, particularly for people with poor healing and a higher risk of complications because of comorbidities. However, 7\xa0days should be adequate for most people if their wound and any underlying condition is being managed appropriately. Any decision on the need for further antibiotics should take into account the fact that a leg ulcer infection will take some time to resolve, even after a course of effective antibiotics.\n\nThe committee also discussed safety concerns around longer courses of flucloxacillin or co-amoxiclav, particularly in older people, because of the risk of cholestatic jaundice or hepatitis.\n\nIn line with the NICE guideline on antimicrobial stewardship and Public Heath England's antimicrobial stewardship: start smart – then focus toolkit, oral antibiotics should be given first line if the person can take them, and the severity of their condition does not require intravenous antibiotics. The use of intravenous antibiotics should be reviewed by 48\xa0hours (taking into account the person's response to treatment and any microbiological results) and switched to oral treatment where possible.\n\nFor more detail, see the summary of the evidence on choice of antibiotic.\n\nReturn to recommendation", 'Context ': 'A leg ulcer is a long-lasting (chronic) open wound that takes more than 4 to 6\xa0weeks to heal. Leg ulcers usually develop on the lower leg, between the shin and the ankle.\n\nStudies suggest that 80% to 100% of leg ulcers may have bacteria (usually Staphylococcus aureus or Pseudomonas aeruginosa) present in the wound, but this does not necessarily mean the wound is infected.', 'Summary of the evidence': "This is a summary of the evidence. For full details see the evidence review and expert testimony.\n\nThe review protocol included a population of adults, young people and children with infected leg ulcers. There was minimal evidence for this population (2 small studies), therefore the population was expanded to people with leg ulcers that had an unclear infection status or were not infected. For antiseptic and antibiotics, the results have been presented separately for people with:\n\nan infected leg ulcer\n\na leg ulcer with unclear infection status\n\nan uninfected leg ulcer.\n\nAll the evidence is based on 1 systematic review of antibiotics and antiseptics for venous leg ulcers (O'Meara et al. 2014), which included 45 randomised controlled trials (RCTs). Nine of these were not included in the review because 8 contained ineligible interventions and 1 study was withdrawn from publication. Seven RCTs included people exclusively with leg ulcer infection (however 5 of these RCTs had an uncertain definition of infection); 14 RCTs included people with leg ulcers of unclear infection status and 15 studies included people with leg ulcers that were not infected.\n\nNo studies included in the review stated that they included children. The committee discussed that leg ulcer infection in children and young people is extremely rare, and usually a result of an underlying illness that requires specialist management. Therefore, they agreed not to extrapolate the evidence to children and young people.\n\nStandard care is the care given in addition to the intervention and/or the control. The included studies were limited because the definition of standard care for each study varied widely, full details of what composed standard care is noted in the GRADE tables (appendix\xa0H of the evidence review).\n\n# Topical antiseptics\n\n## Iodine-based preparations\n\nIn a single RCT, cadexomer-iodine was significantly better than standard care at reducing the average size of the ulcers, the amount of pain experienced from the ulcers and reducing or eliminating the presence of Staphylococcus aureus at 6\xa0weeks.\n\nThere was no significant difference for:\n\ncadexomer-iodine compared with silver dressing for the frequency of complete healing at 12\xa0weeks and for participant satisfaction (neither group reported any adverse effects)\n\npovidone-iodine plus compression compared with moist or foam dressings plus compression for complete healing at 4\xa0months.\n\nCadexomer-iodine (topical application) was significantly better than standard care (varied by RCT) for the frequency of complete healing at 4 to 12\xa0weeks, mean percentage change ulcer area and mean rate of ulcer healing. However, adverse events were significantly more common in the cadexomer-iodine group.\n\nCadexomer-iodine was not significantly different from hydrocolloid dressing or paraffin gauze for the frequency of complete healing at 12\xa0weeks, neither group reported any adverse effects.\n\nPovidone-iodine plus compression was not significantly different from hydrocolloid plus compression for the frequency of complete healing at 4\xa0months.\n\nPovidone-iodine 10% solution plus compression was significantly better for time to healing than hydrocolloid plus compression.\n\n## Peroxide-based preparations\n\nBenzoyl peroxide (10% and 20%) was significantly better than a saline dressing for reducing average ulcer size at 42\xa0days. Data on adverse effects were limited and poorly reported.\n\nHydrogen peroxide 1% cream was significantly better for median decrease in ulcer area compared with placebo cream at 10-day follow up. Data on adverse effects were limited and poorly reported.\n\n## Honey-based preparations\n\nHoney (calcium alginate dressing impregnated with Manuka honey) was not significantly different from standard care for:\n\ncomplete healing at 12\xa0weeks\n\nincidence of ulcer infection during 12\xa0weeks of treatment.\n\nThere were significantly more adverse effects in the honey group than the standard care group.\n\nHoney (topical Manuka honey) was not significantly different from hydrogel (3\xa0g/20\xa0cm2 applied weekly) for the eradication of meticillin-resistant Staphylococcus aureus (MRSA) at 4\xa0weeks.\n\n## Silver-based preparations\n\nSilver dressing plus compression was significantly better than non‑adhesive plus compression dressing for:\n\ncomplete healing at 9\xa0weeks\n\nproportion of adults who were pain free at the end of the trial.\n\nSilver dressings were not significantly different from non-adhesive dressings for adverse effects.\n\nThere was no significant difference between the following comparisons for complete healing (4 to 12\xa0weeks):\n\nsilver sulfadiazine (1% cream) plus compression compared with non-adherent dressing plus compression\n\nsilver impregnated dressings (with or without compression) compared with non-antimicrobial dressings (with or without compression)\n\nsilver-impregnated polyurethane foam dressing plus compression compared with 5-layer silver impregnated dressing plus compression.\n\nSilver dressings were not significantly different from non-antimicrobial dressings for adverse effects.\n\nThere was no significant difference for:\n\nsilver sulfadiazine (1% cream) with non-adhesive foam dressing and compression compared with placebo cream with non-adherent dressing and compression for complete healing at 4\xa0weeks\n\nsilver sulfadiazine (1% cream) compared with standard care for median time to healing\n\nsilver dressing plus compression compared with low-adherent dressing for complete healing at 4 to 12\xa0weeks, 6\xa0months or 12\xa0months, or for ulcer recurrence within 12\xa0months\n\nsilver dressings compared with non-antimicrobial dressings for adverse effects.\n\nSilver dressing plus compression was significantly better than non-antimicrobial dressings plus compression for reducing ulcer surface area when measured using square centimetres at 4\xa0weeks, but was not significantly different when measured as a percentage change. The healing rate (cm2 per day) in these 2 RCTs was not significantly different.\n\n# Antibiotics\n\n## Antibiotics compared with standard care or placebo\n\nCiprofloxacin was not significantly different from standard care for the frequency of complete healing, emergence of antibiotic-resistant strains or bacterial eradication at 3\xa0months.\n\nFor the frequency of complete healing (unclear follow-up time), there was no significant difference between:\n\nciprofloxacin and placebo or\n\ntrimethoprim and placebo.\n\nEmergence of resistance was significantly higher with ciprofloxacin than with placebo, but there was no significant difference in the emergence of resistance with trimethoprim compared with placebo.\n\nThere was no significant difference between:\n\nsystemic antibiotics (co-trimoxazole, gentamicin or amikacin according to sensitivities) and standard care for the outcomes of complete healing at 3\xa0weeks, complete eventual healing or bacterial eradication\n\ntopical mupirocin compared with standard care for frequency of complete healing at 12\xa0weeks or for the eradication of gram-positive bacteria.\n\nData on adverse effects were limited and poorly reported.\n\n## Antibiotics compared with antiseptics\n\nAmoxicillin with compression was not significantly different from povidone-iodine alone or with compression for complete healing at 12\xa0weeks in people with an infected leg ulcer.\n\nNo data on adverse effects were reported.\n\n# Choice of antibiotic\n\n## Unclear leg ulcer infection status\n\nCiprofloxacin was not significantly different from trimethoprim for the frequency of complete healing.\n\nLimited data on adverse effects were reported. However, ciprofloxacin and trimethoprim increased the emergence of antimicrobial resistance compared with standard care or placebo. This finding was statistically significant for ciprofloxacin, but did not reach significance for trimethoprim.\n\n# Antibiotic course length, dosage and route of administration\n\nNo evidence from systematic reviews or RCTs was identified.", 'Other considerations': "# Medicines safety\n\nAntibiotic-associated diarrhoea is estimated to occur in 2% to 25% of people taking antibiotics, depending on the antibiotic used (NICE clinical knowledge summary on diarrhoea – antibiotic associated).\n\nAbout 10% of the general population claim to have a penicillin allergy; this is often because of a skin rash that occurred while taking a course of penicillin as a child. Fewer than 10% of people who think they are allergic to penicillin are truly allergic. See the NICE guideline on drug allergy: diagnosis and management for more information.\n\nCholestatic jaundice and hepatitis can occur with flucloxacillin up to 2\xa0months after stopping treatment, with risk factors being increasing age and use for more than 14\xa0days (British national formulary [BNF] flucloxacillin). Cholestatic jaundice can also occur with co-amoxiclav, and is more common in people over 65\xa0years and in men; treatment should not usually exceed 14\xa0days (BNF co-amoxiclav).\n\nPeople with a history of immediate hypersensitivity to penicillin may also react to cephalosporins and other beta-lactam antibiotics (BNF phenoxymethylpenicillin).\n\nMacrolides (for example, clarithromycin) should be used with caution in people with a predisposition to QT interval prolongation. Nausea, vomiting, abdominal discomfort, and diarrhoea are the most common side effects of macrolides. These are less frequent with clarithromycin than with erythromycin (BNF erythromycin).\n\nTetracyclines (for example, doxycycline) can deposit in growing bone and teeth (by binding to calcium) causing staining and occasionally dental hypoplasia. They should not be given to pregnant women or women who are breastfeeding, and use in children under 12\xa0years is either contraindicated or cautioned for use in severe or life-threatening infections where there are no alternatives. People should be advised to avoid exposure to sunlight or sun lamps because of photosensitivity reactions (BNF doxycycline).\n\nCo-trimoxazole is associated with rare but serious side effects, including blood disorders and Stevens−Johnson syndrome. It is cautioned for use in older people because there is an increased risk of serious side effects, and in those with a predisposition to hyperkalaemia. Monitoring of blood counts is recommended with prolonged treatment (BNF co-trimoxazole).\n\nAminoglycoside (for example, gentamicin) doses are based on body weight and renal function. Ototoxicity and nephrotoxicity are important side effects to consider, and whenever possible treatment should not exceed 7\xa0days (BNF gentamicin).\n\nGlycopeptide (for example, vancomycin and teicoplanin) doses are based on body weight. Therapeutic drug monitoring and monitoring of various patient parameters, including blood count, urinalysis, auditory function, hepatic function and renal function, is recommended, depending on the particular glycopeptide (BNF vancomycin).\n\nSevere optic neuropathy can occur with linezolid, particularly if used for longer than 28\xa0days. Blood disorders have also been reported, and weekly full blood counts are recommended (BNF linezolid).\n\nSee the electronic medicines compendium's summaries of product characteristics for information on contraindications, cautions and adverse effects of individual medicines.\n\n# Medicines adherence\n\nMedicines adherence may be a problem for some people taking antibiotics that need frequent dosing or longer treatment duration (see the NICE clinical guideline on medicines adherence).\n\n# Resource implications\n\nRecommended antibiotics are available as generic formulations. See NHS Drug tariff and BNF for costs.\n\nSee the evidence review for more information."}
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https://www.nice.org.uk/guidance/ng152
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This guideline sets out an antimicrobial prescribing strategy for adults with leg ulcer infection. It aims to optimise antibiotic use and reduce antibiotic resistance.
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a6d8ae0ecc5170b66ae4c606aac58f37a09e7fb6
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nice
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Episcissors-60 for mediolateral episiotomy
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Episcissors-60 for mediolateral episiotomy
Evidence-based recommendations on Episcissors-60 for mediolateral episiotomy.
# Recommendations
Episcissors‑60 show promise for mediolateral episiotomy. But there is currently not enough evidence to support the case for routine adoption in the NHS.
Research is recommended to address uncertainties about the efficacy and safety of using Episcissors‑60. This research should:
determine if using Episcissors‑60 in addition to other care bundle measures is more effective in achieving an optimal episiotomy angle and in preventing episiotomy-related obstetric anal sphincter injuries (OASI) than standard episiotomy scissors
include patient-reported outcome measures
address potential equality considerations by ensuring patients at greatest risk of OASI are recruited
determine the relative cost of using Episcissors‑60 compared with standard episiotomy scissors.
Why the committee made these recommendations
Episcissors‑60 are adapted surgical scissors. They are used to guide and make a cut between the vagina and anus (episiotomy) at an optimal angle (45 to 60 degrees to the midline, according to NICE's guideline on intrapartum care for healthy women and babies) during delivery. This is called a guided mediolateral episiotomy.
Cutting at the optimal angle is important to reduce the chance of OASI, which can have severe long-term effects, such as faecal incontinence.
Because not much good evidence is available, it is recommended that new studies are done to determine with more certainty whether Episcissors‑60 are better than standard scissors, when used with other best-practice care measures to prevent OASI (such as the Royal College of Obstetricians and Gynaecologists OASI care bundle).# The technology
# Technology
Episcissors‑60 are adapted surgical scissors used to perform an incision for mediolateral episiotomies. The scissors have 5 cm long blades with a guide limb mounted at the blade pivot point and angled at 60 degrees from the blades. A cutting angle of 60 degrees is ensured by pointing the guide limb towards the anus in the vertical perineal midline.
Episcissors-60 are available in reusable and single-use disposable versions (available from June 2019).
# Innovative aspects
Episcissors‑60 are designed to achieve a mediolateral cut at 60 degrees to the perineal midline, so preventing inaccurate visual estimation of the cutting angle. The device aims to reduce the incidence of obstetric anal sphincter injuries (OASI). Episcissors‑60 are an alternative to current standard episiotomy scissors when visual estimation of the cutting angle is required.
# Intended use
Episcissors‑60 are intended for use in women who have a clinical need for an episiotomy, such as for instrumental deliveries or in cases of suspected fetal compromise.
Episcissors‑60 are intended to be used by obstetricians or midwives. The use of Episcissors‑60 does not need any special training measures.
# Costs
The cost of single-use disposable Episcissors‑60 is £16 (excluding VAT). The reusable Episcissors‑60 were priced at £320 (excluding VAT).
For more details, see the website for Episcissors-60.# Evidence
# Clinical evidence
## The evidence for Episcissors-60 is limited in quality and quantity and relates only to the reusable Episcissors-60
The clinical evidence for reusable Episcissors‑60 comprises 8 published studies and 3 unpublished studies:
systematic review and meta-analysis (Divakova et al. 2019; included studies are van Roon et al. 2015, Sawant et al. 2015, Lou et al. 2016 and Mohiudin et al. 2018)
systematic review (Cole et al. 2019; included studies are Freeman et al. 2014, Patel et al. 2014, van Roon et al. 2015, Sawant et al. 2015 and Mohiudin et al. 2018)
proof of concept study (Freeman et al. 2014)
case series (Patel et al. 2014)
cohort study (Sawant et al. 2015)
before and after studies (van Roon et al. 2015, Mohiudin et al. 2018, Ayuk et al. 2019)
abstracts (Farnworth et al. 2019, Condell et al. 2017)
-bservational study (Lou et al. 2016).The evidence includes patients who had a mediolateral episiotomy with reusable Episcissors-60 or standard episiotomy scissors. Two studies introduced reusable Episcissors‑60 with other care measures (see sections 4.3 and 4.4), which makes it difficult to ascertain the impact of reusable Episcissors‑60 alone on the rate of obstetric anal sphincter injuries (OASI). All of the studies used only the reusable version of Episcissors‑60, so there is no evidence evaluating the single-use disposable version of Episcissors‑60. For full details of the clinical evidence, see section 3 of the external assessment centre's (EAC) assessment report in the supporting documents – committee papers.
## The evidence base is limited to a small number of non-comparative studies and before and after studies with a high risk of bias
The EAC assessed the quality of the evidence base as very low. This is primarily because there are no randomised trials, only observational studies, 3 of which had no comparator group or information on the comparator. There is a high risk of bias because outcomes were measured differently across the studies, and most studies did not report the 'before' data for accurate comparison. In addition, not all studies reported who carried out the episiotomies and suturing after delivery.
## The studies suggest that using reusable Episcissors-60 results in reliable post-delivery suture angles
Four studies reported a median or mean post-delivery suture angle within a 40 to 60 degree range with reusable Episcissors‑60. In one before and after study (van Roon et al. 2015) it was reported that 100% of midwives and 86% of doctors achieved a post-delivery suture angle between 40 and 60 degrees when using reusable Episcissors‑60. However, this is based on only 76 episiotomies, limiting its reliability. Furthermore, no comparable data were reported for the 'before' period so no comment can be made on whether this outcome represented a significant change from previous practice with standard scissors.
## Episcissors-60 as part of a care bundle may reduce OASI rates in women who have an episiotomy
Pooled analysis suggests no significant reduction in OASI rates in women who had an episiotomy with reusable Episcissors‑60 compared with standard episiotomy scissors. However, pooled results of 2 studies that included using reusable Episcissors‑60 with a care bundle showed a significant reduction in OASI rates in women with an episiotomy.
## Studies suggest that Episcissors-60 may result in more episiotomies
Pooled analysis suggests that rates of episiotomies could increase by between 1% and 4% (absolute increase) with using Episcissors‑60. However the result was not statistically significant.
## Episcissors-60 may result in a larger incision and increased blood loss in some patients
One study (Sawant et al. 2015) reported that the episiotomy incision was longer with reusable Episcissors‑60 than with standard scissors. One study (Ayuk et al. 2019) reported an increase in the estimated mean delivery blood loss by approximately 50 ml after reusable Episcissors‑60 were introduced. For full details of the adverse events, see section 3.7 of the EAC's assessment report in the supporting documents – committee papers.
## The evidence for reusable Episcissors-60 is broadly generalisable to NHS practice
Most studies were done in the UK, providing directly applicable evidence for using reusable Episcissors‑60 in the NHS. Two studies, a comparative cohort study and a non-comparative case series study, were in Indian hospitals. The EAC stated that women of Asian family origin may be at higher risk of OASI because of a shorter perineal body length, so those studies may also be applicable to the UK.
# Cost evidence
## The company's cost model shows that using Episcissors-60 is cost saving on a cost per birth basis in an all-births population
The company created a de novo cost analysis using a simple decision tree model. The model had a single decision node: using Episcissors‑60 or standard scissors, leading to 2 outcomes: an OASI repair or no OASI repair. The time horizon was 1 year. The company's model showed that using Episcissors‑60 saves £20.67 per birth based on all births. Costs were based on the cost of single-use disposable standard episiotomy scissors and a cost per use of reusable Episcissors‑60. For full details of the cost evidence, see section 4 of the EAC's assessment report in the supporting documents – committee papers).
## The EAC's revised model also shows Episcissors-60 as cost saving in an episiotomy-only population
The EAC agreed with the company's model structure, but did not agree with all the model inputs. The EAC suggested that the population should be confined to those having an episiotomy as opposed to all births, and the incidence of OASI should be for episiotomy births and not all births. The EAC's revised model shows that using Episcissors‑60 saves £30.70 per patient.
## Sensitivity analyses suggest that any cost savings with Episcissors-60 are driven by the baseline OASI rate
Assuming reduced OASI rates with Episcissors‑60 compared with standard scissors, the EAC's sensitivity analysis showed that the cost analysis was most sensitive to the rate of OASI in the comparator (standard scissors) arm. The lower the baseline OASI rate, the less effect Episcissors‑60 have on OASI rates and the lower the expected cost savings. The EAC base case comparator OASI rate was 5.1%. If the OASI rate in the comparator group is reduced in the model to 4%, then Episcissors‑60 are cost incurring by £1.81 per patient per birth by episiotomy. If the OASI rate in the comparator group is increased in the model to 7%, Episcissors‑60 are cost saving by £63.21.
It was uncertain whether or not additional length of stay attributed to OASI should be included in the cost model. Additional analysis assessed the impact of including length of stay or not on the difference in total costs. Excluding the cost of an excess length of stay attributable to OASI from the cost model results in reduced cost savings associated with Episcissors‑60.# Committee discussion
# Clinical-effectiveness overview
## Evidence for the clinical effectiveness of reusable Episcissors-60 is uncertain
The committee noted that the evidence for clinical benefit with reusable Episcissors‑60 is uncertain. Published evidence and the opinions of experts indicate that they are easy to use. But their impact on the incidence of obstetric anal sphincter injuries (OASI) after episiotomy is uncertain. The clinical experts explained that several factors make an injury more likely. The committee noted that some of the studies introduced reusable Episcissors‑60 at the same time as a care bundle of other measures of optimal care to reduce the risk of OASI. The evidence shows that when these studies are excluded from a pooled analysis, there was no difference in the incidence of OASI between women who had episiotomies using reusable Episcissors‑60 and standard scissors. Given this, as well as the low quality and heterogenous nature of the studies available, the committee concluded that the impact of reusable Episcissors‑60 alone on OASI rates could not be determined with certainty on the basis of the current evidence, and further research is needed.
## Evidence on using the single-use disposable version of Episcissors-60 is needed
The committee noted that all of the published studies used the reusable Episcissors‑60. The company stated that the differences between the 2 versions are that reusable Episcissors-60 have gold handles and tungsten carbide blades. These components are not in the single-use disposable version. The committee considered that the evidence cannot be extrapolated to the single-use disposable version. The committee concluded, therefore, that further evidence assessing the relative merits of the single-use disposable Episcissors‑60 compared with standard scissors is also needed.
## More evidence is needed to assess the impact of Episcissors-60 over and above standard bundles of care
The clinical experts explained that the Royal College of Midwives and the Royal College of Obstetricians and Gynaecologists (RCOG) published a list of evidence-based measures in 2017 to reduce the risk of OASI (the OASI care bundle). These have been incorporated since then across the NHS as part of routine care. These measures are instituted before, during and after birth and include:
providing antenatal information to women
performing a mediolateral episiotomy when indicated at 60 degrees at crowning
using manual perineal protection during all vaginal births
doing a perineal examination (including a per rectum examination) after childbirth.
The RCOG's Third- and fourth-degree perineal tears, management (green-top guideline no. 29) provides different evidence-based guidance to aid good clinical practice in the diagnosis, management and treatment of OASI, including:
providing information to women that the evidence for the protective effect of episiotomy is conflicting
considering the use of mediolateral episiotomy in instrumental deliveries
performing mediolateral episiotomies at 60 degrees away from the midline when the perineum is distended. The guidance also states that perineal protection at crowning can be protective and warm compression during the second stage of labour reduces the risk of OASI.
The experts explained that, if implemented, Episcissors‑60 would be used for the episiotomy as part of the standard RCOG OASI care bundle to reduce the incidence of OASI. The committee proposed that further evidence exploring the possible benefits of using Episcissors‑60 compared with standard episiotomy scissors, in addition to the standard bundle of care, is needed to identify any additional incremental clinical benefits.
# Side effects and adverse events
## Episcissors-60 may result in a longer episiotomy cut
The external assessment centre (EAC) considered that the evidence reporting a longer episiotomy cut with reusable Episcissors‑60 than with standard scissors is limited and of poor quality. The company stated that reusable and single-use disposable Episcissors‑60 have a blade length of 5 cm, and this is the same as for standard scissors. The clinical experts noted that the length of cut using standard scissors may be reduced by using less of the blade, allowing clinicians to make as small a cut as is needed. The experts were unsure if this would also be possible in a reliable way using Episcissors‑60, and stated that the ability to alter the length of the cut may depend on clinical experience. The committee concluded that the length of the episiotomy incision should be addressed in future studies.
## Episcissors-60 may result in increased blood loss
One study reported an increase in estimated delivery blood loss of approximately 50 ml per use after reusable Episcissors‑60 were introduced. One clinical expert, who was involved in the trial, explained that this outcome was added to the study after anecdotal reports from clinicians that using reusable Episcissors‑60 appeared to be associated with an increase in blood loss and a need for earlier suturing in some cases to seal bleeding points. The clinical expert was unsure about the clinical significance of this level of increased blood loss. The clinical expert also explained that estimating blood loss under these clinical circumstances is difficult and that the different centres involved in the study measured it differently. The EAC noted that this was not a predetermined outcome in the study in question and that blood loss is not reported as an outcome in any of the other studies. The committee concluded therefore that this finding should be interpreted with caution but is something that could be explored further in future studies.
## The episiotomy angle alone is not a good surrogate marker for the likely risk or outcome of an OASI
The clinical experts explained that angle of incision to the midline at the time of delivery does not always correlate closely with the post-delivery suture angle because of the anatomical distension that results from the passage of the baby at the time of the episiotomy. Furthermore, they explained that in addition to the episiotomy angle, there are a number of other important factors which influence the rate of OASI. These include the timing and speed of delivery, the perineal body length, and whether the mother has given birth before. The committee concluded therefore that the post-delivery suture angle alone cannot be regarded as a reliable surrogate for either the risk or outcome of an OASI.
## Diagnosing an OASI can be difficult and may be subjective
The clinical experts explained that, although there is a clear written definition of different levels of OASI, in practice it is subjective and often difficult to determine. The clinical experts highlighted that it is particularly difficult to differentiate between a 3b and 3c degree tear. This may be one compounding factor that influences the heterogenous rates of OASI in different populations and studies.
# Other patient benefits or issues
## The risk of OASI is determined by a number of factors that raise important equalities considerations
A number of equalities considerations are relevant to the risk of OASI. Older women, women with a short perineal body length (such as those of Asian family origin), and women who have undergone female genital mutilation may be at increased risk of OASI (although the last is uncertain from the evidence available). The clinical experts explained that women at higher risk of OASI may need an earlier episiotomy. Age, sex, pregnancy, race and disability are protected characteristics under the Equality Act 2010. The committee concluded that research is needed in those at greatest risk to address potential equality considerations.
## There are no data on patient-reported outcome measures
There is currently no evidence reporting the experiences of women who have had an episiotomy using Episcissors‑60, even though OASI repair may impact sexual function and quality of life. The committee concluded that patient-reported outcome measures, including patient-reported experience measures to assess the impact of the process of care on the patient's experience, should be included in future research to assess the impact of Episcissors‑60.
# NHS considerations overview
## Using single-use disposable Episcissors-60 may have an environmental impact
The company stated that disposable Episcissors‑60 are discarded after a single use and cannot be recycled. Because of this the committee and experts raised concern about the sustainability of the technology and a possible negative environmental impact.
The clinical experts said there may be wastage when Episcissors‑60 are opened in preparation for an episiotomy but not then used. Experts estimated that wastage of Episcissors‑60 is most likely with midwife-supervised spontaneous vaginal deliveries. Experts thought that if Episcissors‑60 were opened for all spontaneous births in preparation for a possible episiotomy, but the women delivered spontaneously, then wastage would result. On the other hand, the need for an episiotomy is more predictable when an obstetrician performs an operative vaginal delivery, meaning that wastage may be less likely. The EAC stated that the problem of wastage is more relevant with single-use disposable Episcissors‑60 (which would need to be thrown away once opened) rather than reusable Episcissors-60 (which could then be resterilised).
# Training
## Using Episcissors-60 alongside a training package has increased midwives' confidence in doing episiotomies
In one clinical expert's hospital, a training package was delivered at the same time as introducing Episcissors‑60, which included doing episiotomies on a dummy. Experts stated that this training increased midwives' confidence in doing episiotomies. The experts emphasised, however, the importance of focusing training on optimal episiotomy practice in the context of a wider bundle of measures to minimise the risk of OASIs.
## Ease of use of Episcissors-60 is uncertain
Two studies report favourable data on how easy it is to use reusable Episcissors‑60, but they are poor quality. The clinical experts were divided on their experiences and those of their colleagues about how easy it is to use Episcissors‑60. Midwives were identified by some as the most supportive professional group of Episcissors‑60 but opinion among obstetricians is mixed.
# Service implications
## Episcissors-60 may increase the rate of episiotomy
There is some evidence to suggest that introducing Episcissors‑60 may increase the rate of episiotomy, but the quality of this evidence is poor. The clinical experts explained that, if episiotomy rates are increased, this may be because of increased staff confidence in doing episiotomies, and because of introducing the OASI care bundle. The clinical experts acknowledged that there is no consensus on what best-practice episiotomy rates should be either in spontaneous or operative vaginal delivery.
## The impact on length of hospital stay with Episcissors-60 is uncertain
The clinical experts said it was difficult to be certain about how an OASI affects length of hospital stay. They explained that there are several factors that affect length of stay after delivery, including the method of delivery and severity of OASI, as well as those relating to establishing feeding and wellbeing for the newborn baby and mother. Experts explained that women with fourth-degree tears stay in hospital longer than those with third-degree tears. One expert stated that women who have a spontaneous vaginal delivery and an OASI stay overnight, whereas women with uncomplicated spontaneous vaginal deliveries are normally discharged the same day. Women who have had an operative vaginal delivery normally stay in hospital overnight even in the absence of an OASI, so an increase in length of stay may not be a consequence of the OASI itself in these women.
# Cost modelling overview
## The EAC's updated model is acceptable but uncertainties remain
The committee considered that, because of the uncertainties about the possible clinical benefit of Episcissors‑60, it was difficult to draw firm conclusions about any cost benefits. The committee concluded that further evidence is needed to show if reusable and single-use disposable Episcissors‑60 lead to cost savings when compared with using standard scissors.
# Main cost drivers
## The OASI rate is a key driver in the model
The committee considered the factors that are likely to be important in determining the cost impact of Episcissors‑60. The EAC identified the key driver in the cost model to be the OASI rate in the comparator, standard scissors arm. The lower the rate of baseline OASI, the less of an impact introducing Episcissors‑60 can have on the rates of OASI, and the potential for cost savings. The clinical experts discussed how the rate of OASI varies depending on the population studied and its different demographics. The committee concluded that more robust evidence is needed that includes these important considerations to better understand the cost impact of using single-use disposable Episcissors‑60 in the NHS.
# Cost savings
## Cost modelling for Episcissors-60 has limitations but cost savings are likely if Episcissors-60 reduce the OASI rate
The EAC's revised cost model showed that over 1 year, compared with standard episiotomy scissors (based on a cost per use of reusable episiotomy scissors), Episcissors‑60 are associated with a cost saving of around £30.70 per patient. In an EAC scenario analysis, the cost of standard scissors was increased to reflect a possible higher cost of single-use disposable standard scissors. This increased the incremental cost saving to £34.44 per patient. The cost of standard scissors cannot be reported because this cost is considered confidential by NHS Supply Chain. Further detail can be obtained by contacting NHS Supply Chain.
The clinical experts said that uncertainties in the evidence and the higher cost of reusable Episcissors‑60 compared with standard scissors have affected the adoption of the device. The committee considered that the EAC may have underestimated the cost of an OASI repair in their model. The EAC confirmed that NHS reference costs for perineal trauma were used, but long-term costs associated with OASI, including managing faecal incontinence, are not accounted for in the EAC's model. The EAC and experts agree that there may be additional long-term costs to the NHS of managing patients with OASI including the need for additional therapies and social care. The committee suggested that the time horizon for future studies and cost estimates should be sufficiently long to capture these important aspects of holistic care. One clinical expert thought that the cost of a caesarean section should also be included because some women may elect to have this as an alternative to accepting the possible consequences of an OASI complication of a vaginal delivery.
# Further research
## Further research is needed to address the uncertainty in the safety and efficacy of Episcissors-60
The committee concluded that further research is needed to address uncertainties about the safety and efficacy of Episcissors‑60. This research should be sufficiently robust in design and implementation to determine if Episcissors‑60, in addition to an OASI care bundle, adds clinical value compared with using standard episiotomy scissors and visual assessment of the cutting angle in addition to an OASI care bundle. It was the opinion of the experts that a randomised controlled trial would be ethical and feasible to do. Trials would need to ensure that optimal bundles of clinical care to reduce OASI risk were defined and applied equally to both intervention and comparator arms and that OASI rates, length of hospital stay, incision length and blood loss, patient-reported outcome measures, and cost analysis were included. Studies should include women who have not given birth before, women having an operative vaginal delivery, and women of Asian family origin to ensure that equalities considerations are addressed. The research should provide data to inform cost modelling and should be designed within a timeframe to provide useful information before this guidance is reviewed.
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{'Recommendations': "Episcissors‑60 show promise for mediolateral episiotomy. But there is currently not enough evidence to support the case for routine adoption in the NHS.\n\nResearch is recommended to address uncertainties about the efficacy and safety of using Episcissors‑60. This research should:\n\ndetermine if using Episcissors‑60 in addition to other care bundle measures is more effective in achieving an optimal episiotomy angle and in preventing episiotomy-related obstetric anal sphincter injuries (OASI) than standard episiotomy scissors\n\ninclude patient-reported outcome measures\n\naddress potential equality considerations by ensuring patients at greatest risk of OASI are recruited\n\ndetermine the relative cost of using Episcissors‑60 compared with standard episiotomy scissors.\n\nWhy the committee made these recommendations\n\nEpiscissors‑60 are adapted surgical scissors. They are used to guide and make a cut between the vagina and anus (episiotomy) at an optimal angle (45\xa0to\xa060\xa0degrees to the midline, according to NICE's guideline on intrapartum care for healthy women and babies) during delivery. This is called a guided mediolateral episiotomy.\n\nCutting at the optimal angle is important to reduce the chance of OASI, which can have severe long-term effects, such as faecal incontinence.\n\nBecause not much good evidence is available, it is recommended that new studies are done to determine with more certainty whether Episcissors‑60 are better than standard scissors, when used with other best-practice care measures to prevent OASI (such as the Royal College of Obstetricians and Gynaecologists OASI care bundle).", 'The technology': '# Technology\n\nEpiscissors‑60 are adapted surgical scissors used to perform an incision for mediolateral episiotomies. The scissors have 5\xa0cm long blades with a guide limb mounted at the blade pivot point and angled at 60\xa0degrees from the blades. A cutting angle of 60\xa0degrees is ensured by pointing the guide limb towards the anus in the vertical perineal midline.\n\nEpiscissors-60 are available in reusable and single-use disposable versions (available from June\xa02019).\n\n# Innovative aspects\n\nEpiscissors‑60 are designed to achieve a mediolateral cut at 60\xa0degrees to the perineal midline, so preventing inaccurate visual estimation of the cutting angle. The device aims to reduce the incidence of obstetric anal sphincter injuries (OASI). Episcissors‑60 are an alternative to current standard episiotomy scissors when visual estimation of the cutting angle is required.\n\n# Intended use\n\nEpiscissors‑60 are intended for use in women who have a clinical need for an episiotomy, such as for instrumental deliveries or in cases of suspected fetal compromise.\n\nEpiscissors‑60 are intended to be used by obstetricians or midwives. The use of Episcissors‑60 does not need any special training measures.\n\n# Costs\n\nThe cost of single-use disposable Episcissors‑60 is £16 (excluding VAT). The reusable Episcissors‑60 were priced at £320 (excluding VAT).\n\nFor more details, see the website for Episcissors-60.', 'Evidence': "# Clinical evidence\n\n## The evidence for Episcissors-60 is limited in quality and quantity and relates only to the reusable Episcissors-60\n\nThe clinical evidence for reusable Episcissors‑60 comprises 8 published studies and 3 unpublished studies:\n\nsystematic review and meta-analysis (Divakova et al. 2019; included studies are van Roon et al. 2015, Sawant et al. 2015, Lou et al. 2016 and Mohiudin et al. 2018)\n\nsystematic review (Cole et al. 2019; included studies are Freeman et al. 2014, Patel et al. 2014, van Roon et al. 2015, Sawant et al. 2015 and Mohiudin et al. 2018)\n\nproof of concept study (Freeman et al. 2014)\n\ncase series (Patel et al. 2014)\n\ncohort study (Sawant et al. 2015)\n\nbefore and after studies (van Roon et al. 2015, Mohiudin et al. 2018, Ayuk et al. 2019)\n\nabstracts (Farnworth et al. 2019, Condell et al. 2017)\n\nobservational study (Lou et al. 2016).The evidence includes patients who had a mediolateral episiotomy with reusable Episcissors-60 or standard episiotomy scissors. Two studies introduced reusable Episcissors‑60 with other care measures (see sections 4.3 and 4.4), which makes it difficult to ascertain the impact of reusable Episcissors‑60 alone on the rate of obstetric anal sphincter injuries (OASI). All of the studies used only the reusable version of Episcissors‑60, so there is no evidence evaluating the single-use disposable version of Episcissors‑60. For full details of the clinical evidence, see section 3 of the external assessment centre's (EAC) assessment report in the supporting documents – committee papers.\n\n## The evidence base is limited to a small number of non-comparative studies and before and after studies with a high risk of bias\n\nThe EAC assessed the quality of the evidence base as very low. This is primarily because there are no randomised trials, only observational studies, 3 of which had no comparator group or information on the comparator. There is a high risk of bias because outcomes were measured differently across the studies, and most studies did not report the 'before' data for accurate comparison. In addition, not all studies reported who carried out the episiotomies and suturing after delivery.\n\n## The studies suggest that using reusable Episcissors-60 results in reliable post-delivery suture angles\n\nFour studies reported a median or mean post-delivery suture angle within a 40 to 60\xa0degree range with reusable Episcissors‑60. In one before and after study (van Roon et al. 2015) it was reported that 100% of midwives and 86% of doctors achieved a post-delivery suture angle between 40 and 60\xa0degrees when using reusable Episcissors‑60. However, this is based on only 76 episiotomies, limiting its reliability. Furthermore, no comparable data were reported for the 'before' period so no comment can be made on whether this outcome represented a significant change from previous practice with standard scissors.\n\n## Episcissors-60 as part of a care bundle may reduce OASI rates in women who have an episiotomy\n\nPooled analysis suggests no significant reduction in OASI rates in women who had an episiotomy with reusable Episcissors‑60 compared with standard episiotomy scissors. However, pooled results of 2 studies that included using reusable Episcissors‑60 with a care bundle showed a significant reduction in OASI rates in women with an episiotomy.\n\n## Studies suggest that Episcissors-60 may result in more episiotomies\n\nPooled analysis suggests that rates of episiotomies could increase by between 1% and 4% (absolute increase) with using Episcissors‑60. However the result was not statistically significant.\n\n## Episcissors-60 may result in a larger incision and increased blood loss in some patients\n\nOne study (Sawant et al. 2015) reported that the episiotomy incision was longer with reusable Episcissors‑60 than with standard scissors. One study (Ayuk et al. 2019) reported an increase in the estimated mean delivery blood loss by approximately 50\xa0ml after reusable Episcissors‑60 were introduced. For full details of the adverse events, see section 3.7 of the EAC's assessment report in the supporting documents – committee papers.\n\n## The evidence for reusable Episcissors-60 is broadly generalisable to NHS practice\n\nMost studies were done in the UK, providing directly applicable evidence for using reusable Episcissors‑60 in the NHS. Two studies, a comparative cohort study and a non-comparative case series study, were in Indian hospitals. The EAC stated that women of Asian family origin may be at higher risk of OASI because of a shorter perineal body length, so those studies may also be applicable to the UK.\n\n# Cost evidence\n\n## The company's cost model shows that using Episcissors-60 is cost saving on a cost per birth basis in an all-births population\n\nThe company created a de novo cost analysis using a simple decision tree model. The model had a single decision node: using Episcissors‑60 or standard scissors, leading to 2 outcomes: an OASI repair or no OASI repair. The time horizon was 1\xa0year. The company's model showed that using Episcissors‑60 saves £20.67 per birth based on all births. Costs were based on the cost of single-use disposable standard episiotomy scissors and a cost per use of reusable Episcissors‑60. For full details of the cost evidence, see section 4 of the EAC's assessment report in the supporting documents – committee papers).\n\n## The EAC's revised model also shows Episcissors-60 as cost saving in an episiotomy-only population\n\nThe EAC agreed with the company's model structure, but did not agree with all the model inputs. The EAC suggested that the population should be confined to those having an episiotomy as opposed to all births, and the incidence of OASI should be for episiotomy births and not all births. The EAC's revised model shows that using Episcissors‑60 saves £30.70 per patient.\n\n## Sensitivity analyses suggest that any cost savings with Episcissors-60 are driven by the baseline OASI rate\n\nAssuming reduced OASI rates with Episcissors‑60 compared with standard scissors, the EAC's sensitivity analysis showed that the cost analysis was most sensitive to the rate of OASI in the comparator (standard scissors) arm. The lower the baseline OASI rate, the less effect Episcissors‑60 have on OASI rates and the lower the expected cost savings. The EAC base case comparator OASI rate was 5.1%. If the OASI rate in the comparator group is reduced in the model to 4%, then Episcissors‑60 are cost incurring by £1.81 per patient per birth by episiotomy. If the OASI rate in the comparator group is increased in the model to 7%, Episcissors‑60 are cost saving by £63.21.\n\nIt was uncertain whether or not additional length of stay attributed to OASI should be included in the cost model. Additional analysis assessed the impact of including length of stay or not on the difference in total costs. Excluding the cost of an excess length of stay attributable to OASI from the cost model results in reduced cost savings associated with Episcissors‑60.", 'Committee discussion': "# Clinical-effectiveness overview\n\n## Evidence for the clinical effectiveness of reusable Episcissors-60 is uncertain\n\nThe committee noted that the evidence for clinical benefit with reusable Episcissors‑60 is uncertain. Published evidence and the opinions of experts indicate that they are easy to use. But their impact on the incidence of obstetric anal sphincter injuries (OASI) after episiotomy is uncertain. The clinical experts explained that several factors make an injury more likely. The committee noted that some of the studies introduced reusable Episcissors‑60 at the same time as a care bundle of other measures of optimal care to reduce the risk of OASI. The evidence shows that when these studies are excluded from a pooled analysis, there was no difference in the incidence of OASI between women who had episiotomies using reusable Episcissors‑60 and standard scissors. Given this, as well as the low quality and heterogenous nature of the studies available, the committee concluded that the impact of reusable Episcissors‑60 alone on OASI rates could not be determined with certainty on the basis of the current evidence, and further research is needed.\n\n## Evidence on using the single-use disposable version of Episcissors-60 is needed\n\nThe committee noted that all of the published studies used the reusable Episcissors‑60. The company stated that the differences between the 2 versions are that reusable Episcissors-60 have gold handles and tungsten carbide blades. These components are not in the single-use disposable version. The committee considered that the evidence cannot be extrapolated to the single-use disposable version. The committee concluded, therefore, that further evidence assessing the relative merits of the single-use disposable Episcissors‑60 compared with standard scissors is also needed.\n\n## More evidence is needed to assess the impact of Episcissors-60 over and above standard bundles of care\n\nThe clinical experts explained that the Royal College of Midwives and the Royal College of Obstetricians and Gynaecologists (RCOG) published a list of evidence-based measures in 2017 to reduce the risk of OASI (the OASI care bundle). These have been incorporated since then across the NHS as part of routine care. These measures are instituted before, during and after birth and include:\n\nproviding antenatal information to women\n\nperforming a mediolateral episiotomy when indicated at 60\xa0degrees at crowning\n\nusing manual perineal protection during all vaginal births\n\ndoing a perineal examination (including a per rectum examination) after childbirth.\n\nThe RCOG's Third- and fourth-degree perineal tears, management (green-top guideline no. 29) provides different evidence-based guidance to aid good clinical practice in the diagnosis, management and treatment of OASI, including:\n\nproviding information to women that the evidence for the protective effect of episiotomy is conflicting\n\nconsidering the use of mediolateral episiotomy in instrumental deliveries\n\nperforming mediolateral episiotomies at 60\xa0degrees away from the midline when the perineum is distended. The guidance also states that perineal protection at crowning can be protective and warm compression during the second stage of labour reduces the risk of OASI.\n\nThe experts explained that, if implemented, Episcissors‑60 would be used for the episiotomy as part of the standard RCOG OASI care bundle to reduce the incidence of OASI. The committee proposed that further evidence exploring the possible benefits of using Episcissors‑60 compared with standard episiotomy scissors, in addition to the standard bundle of care, is needed to identify any additional incremental clinical benefits.\n\n# Side effects and adverse events\n\n## Episcissors-60 may result in a longer episiotomy cut\n\nThe external assessment centre (EAC) considered that the evidence reporting a longer episiotomy cut with reusable Episcissors‑60 than with standard scissors is limited and of poor quality. The company stated that reusable and single-use disposable Episcissors‑60 have a blade length of 5\xa0cm, and this is the same as for standard scissors. The clinical experts noted that the length of cut using standard scissors may be reduced by using less of the blade, allowing clinicians to make as small a cut as is needed. The experts were unsure if this would also be possible in a reliable way using Episcissors‑60, and stated that the ability to alter the length of the cut may depend on clinical experience. The committee concluded that the length of the episiotomy incision should be addressed in future studies.\n\n## Episcissors-60 may result in increased blood loss\n\nOne study reported an increase in estimated delivery blood loss of approximately 50\xa0ml per use after reusable Episcissors‑60 were introduced. One clinical expert, who was involved in the trial, explained that this outcome was added to the study after anecdotal reports from clinicians that using reusable Episcissors‑60 appeared to be associated with an increase in blood loss and a need for earlier suturing in some cases to seal bleeding points. The clinical expert was unsure about the clinical significance of this level of increased blood loss. The clinical expert also explained that estimating blood loss under these clinical circumstances is difficult and that the different centres involved in the study measured it differently. The EAC noted that this was not a predetermined outcome in the study in question and that blood loss is not reported as an outcome in any of the other studies. The committee concluded therefore that this finding should be interpreted with caution but is something that could be explored further in future studies.\n\n## The episiotomy angle alone is not a good surrogate marker for the likely risk or outcome of an OASI\n\nThe clinical experts explained that angle of incision to the midline at the time of delivery does not always correlate closely with the post-delivery suture angle because of the anatomical distension that results from the passage of the baby at the time of the episiotomy. Furthermore, they explained that in addition to the episiotomy angle, there are a number of other important factors which influence the rate of OASI. These include the timing and speed of delivery, the perineal body length, and whether the mother has given birth before. The committee concluded therefore that the post-delivery suture angle alone cannot be regarded as a reliable surrogate for either the risk or outcome of an OASI.\n\n## Diagnosing an OASI can be difficult and may be subjective\n\nThe clinical experts explained that, although there is a clear written definition of different levels of OASI, in practice it is subjective and often difficult to determine. The clinical experts highlighted that it is particularly difficult to differentiate between a 3b and 3c\xa0degree tear. This may be one compounding factor that influences the heterogenous rates of OASI in different populations and studies.\n\n# Other patient benefits or issues\n\n## The risk of OASI is determined by a number of factors that raise important equalities considerations\n\nA number of equalities considerations are relevant to the risk of OASI. Older women, women with a short perineal body length (such as those of Asian family origin), and women who have undergone female genital mutilation may be at increased risk of OASI (although the last is uncertain from the evidence available). The clinical experts explained that women at higher risk of OASI may need an earlier episiotomy. Age, sex, pregnancy, race and disability are protected characteristics under the Equality Act 2010. The committee concluded that research is needed in those at greatest risk to address potential equality considerations.\n\n## There are no data on patient-reported outcome measures\n\nThere is currently no evidence reporting the experiences of women who have had an episiotomy using Episcissors‑60, even though OASI repair may impact sexual function and quality of life. The committee concluded that patient-reported outcome measures, including patient-reported experience measures to assess the impact of the process of care on the patient's experience, should be included in future research to assess the impact of Episcissors‑60.\n\n# NHS considerations overview\n\n## Using single-use disposable Episcissors-60 may have an environmental impact\n\nThe company stated that disposable Episcissors‑60 are discarded after a single use and cannot be recycled. Because of this the committee and experts raised concern about the sustainability of the technology and a possible negative environmental impact.\n\nThe clinical experts said there may be wastage when Episcissors‑60 are opened in preparation for an episiotomy but not then used. Experts estimated that wastage of Episcissors‑60 is most likely with midwife-supervised spontaneous vaginal deliveries. Experts thought that if Episcissors‑60 were opened for all spontaneous births in preparation for a possible episiotomy, but the women delivered spontaneously, then wastage would result. On the other hand, the need for an episiotomy is more predictable when an obstetrician performs an operative vaginal delivery, meaning that wastage may be less likely. The EAC stated that the problem of wastage is more relevant with single-use disposable Episcissors‑60 (which would need to be thrown away once opened) rather than reusable Episcissors-60 (which could then be resterilised).\n\n# Training\n\n## Using Episcissors-60 alongside a training package has increased midwives' confidence in doing episiotomies\n\nIn one clinical expert's hospital, a training package was delivered at the same time as introducing Episcissors‑60, which included doing episiotomies on a dummy. Experts stated that this training increased midwives' confidence in doing episiotomies. The experts emphasised, however, the importance of focusing training on optimal episiotomy practice in the context of a wider bundle of measures to minimise the risk of OASIs.\n\n## Ease of use of Episcissors-60 is uncertain\n\nTwo studies report favourable data on how easy it is to use reusable Episcissors‑60, but they are poor quality. The clinical experts were divided on their experiences and those of their colleagues about how easy it is to use Episcissors‑60. Midwives were identified by some as the most supportive professional group of Episcissors‑60 but opinion among obstetricians is mixed.\n\n# Service implications\n\n## Episcissors-60 may increase the rate of episiotomy\n\nThere is some evidence to suggest that introducing Episcissors‑60 may increase the rate of episiotomy, but the quality of this evidence is poor. The clinical experts explained that, if episiotomy rates are increased, this may be because of increased staff confidence in doing episiotomies, and because of introducing the OASI care bundle. The clinical experts acknowledged that there is no consensus on what best-practice episiotomy rates should be either in spontaneous or operative vaginal delivery.\n\n## The impact on length of hospital stay with Episcissors-60 is uncertain\n\nThe clinical experts said it was difficult to be certain about how an OASI affects length of hospital stay. They explained that there are several factors that affect length of stay after delivery, including the method of delivery and severity of OASI, as well as those relating to establishing feeding and wellbeing for the newborn baby and mother. Experts explained that women with fourth-degree tears stay in hospital longer than those with third-degree tears. One expert stated that women who have a spontaneous vaginal delivery and an OASI stay overnight, whereas women with uncomplicated spontaneous vaginal deliveries are normally discharged the same day. Women who have had an operative vaginal delivery normally stay in hospital overnight even in the absence of an OASI, so an increase in length of stay may not be a consequence of the OASI itself in these women.\n\n# Cost modelling overview\n\n## The EAC's updated model is acceptable but uncertainties remain\n\nThe committee considered that, because of the uncertainties about the possible clinical benefit of Episcissors‑60, it was difficult to draw firm conclusions about any cost benefits. The committee concluded that further evidence is needed to show if reusable and single-use disposable Episcissors‑60 lead to cost savings when compared with using standard scissors.\n\n# Main cost drivers\n\n## The OASI rate is a key driver in the model\n\nThe committee considered the factors that are likely to be important in determining the cost impact of Episcissors‑60. The EAC identified the key driver in the cost model to be the OASI rate in the comparator, standard scissors arm. The lower the rate of baseline OASI, the less of an impact introducing Episcissors‑60 can have on the rates of OASI, and the potential for cost savings. The clinical experts discussed how the rate of OASI varies depending on the population studied and its different demographics. The committee concluded that more robust evidence is needed that includes these important considerations to better understand the cost impact of using single-use disposable Episcissors‑60 in the NHS.\n\n# Cost savings\n\n## Cost modelling for Episcissors-60 has limitations but cost savings are likely if Episcissors-60 reduce the OASI rate\n\nThe EAC's revised cost model showed that over 1\xa0year, compared with standard episiotomy scissors (based on a cost per use of reusable episiotomy scissors), Episcissors‑60 are associated with a cost saving of around £30.70 per patient. In an EAC scenario analysis, the cost of standard scissors was increased to reflect a possible higher cost of single-use disposable standard scissors. This increased the incremental cost saving to £34.44 per patient. The cost of standard scissors cannot be reported because this cost is considered confidential by NHS Supply Chain. Further detail can be obtained by contacting NHS Supply Chain.\n\nThe clinical experts said that uncertainties in the evidence and the higher cost of reusable Episcissors‑60 compared with standard scissors have affected the adoption of the device. The committee considered that the EAC may have underestimated the cost of an OASI repair in their model. The EAC confirmed that NHS reference costs for perineal trauma were used, but long-term costs associated with OASI, including managing faecal incontinence, are not accounted for in the EAC's model. The EAC and experts agree that there may be additional long-term costs to the NHS of managing patients with OASI including the need for additional therapies and social care. The committee suggested that the time horizon for future studies and cost estimates should be sufficiently long to capture these important aspects of holistic care. One clinical expert thought that the cost of a caesarean section should also be included because some women may elect to have this as an alternative to accepting the possible consequences of an OASI complication of a vaginal delivery.\n\n# Further research\n\n## Further research is needed to address the uncertainty in the safety and efficacy of Episcissors-60\n\nThe committee concluded that further research is needed to address uncertainties about the safety and efficacy of Episcissors‑60. This research should be sufficiently robust in design and implementation to determine if Episcissors‑60, in addition to an OASI care bundle, adds clinical value compared with using standard episiotomy scissors and visual assessment of the cutting angle in addition to an OASI care bundle. It was the opinion of the experts that a randomised controlled trial would be ethical and feasible to do. Trials would need to ensure that optimal bundles of clinical care to reduce OASI risk were defined and applied equally to both intervention and comparator arms and that OASI rates, length of hospital stay, incision length and blood loss, patient-reported outcome measures, and cost analysis were included. Studies should include women who have not given birth before, women having an operative vaginal delivery, and women of Asian family origin to ensure that equalities considerations are addressed. The research should provide data to inform cost modelling and should be designed within a timeframe to provide useful information before this guidance is reviewed."}
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https://www.nice.org.uk/guidance/mtg47
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Evidence-based recommendations on Episcissors-60 for mediolateral episiotomy.
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c6bbf71eb7116919138f54aba5952b2bc7e60216
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nice
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Fetoscopic prenatal repair for open neural tube defects in the fetus
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Fetoscopic prenatal repair for open neural tube defects in the fetus
Evidence-based recommendations on fetoscopic prenatal repair of open neural tube defects in the fetus. This involves keyhole surgery through the woman’s abdomen to close the gap in the baby’s spine.
# Recommendations
Evidence on the safety and efficacy of fetoscopic prenatal repair of open neural tube defects in the fetus is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research. This could be in the form of randomised controlled trials or published registry data. Find out what only in research means on the NICE interventional procedures guidance page.
The procedure is technically challenging and should only be done in specialised centres, and only by clinicians and teams with specific training and experience in fetoscopic prenatal repair.
Patient selection should only be done by a multidisciplinary team, which should include a consultant in fetal medicine, an obstetric surgeon, a paediatric neurosurgeon, a radiologist with experience in fetal imaging and an anaesthetist.
Further research should report details of risks to the mother (including her subsequent pregnancies), risks to the fetus (including the need for further surgery), and long-term disability after birth.# The condition, current treatments and procedure
# The condition
Neural tube defects happen because the neural tube does not fuse during early embryonic development. Open neural tube defects are those in which the affected region of the neural tube is exposed on the body's surface. The most common neural tube defect is spina bifida where the defect is in the spine. Myelomeningocele (open spina bifida) is the most severe type of spina bifida, in which the baby's spinal canal remains open along several vertebrae in the back. The spinal cord and protective membranes around it push out and form a sac which is exposed on the baby's back. Children born with myelomeningocele may experience motor neurological deficits including muscle weakness and paralysis of the lower limbs, sensory deficit, bowel, bladder and sexual dysfunctions and learning difficulties. The condition can be associated with Chiari II malformation (hindbrain herniation) and hydrocephalus.
# Current treatments
Conventional treatment for myelomeningocele (open spina bifida) is immediate surgical repair of the defect within days of birth to prevent further damage to nervous tissue and reduce the risk of central nervous system infection. The immediate management may also include ventricular-peritoneal shunt placement to relieve hydrocephalus. The condition can also be treated prenatally with the aim of decreasing morbidity in the child.
# The procedure
Fetoscopic prenatal repair is typically done before 26 weeks of pregnancy. It is done using general anaesthesia and with partial CO2 insufflation of the uterine cavity. Under ultrasound guidance an endoscope is introduced through a port followed by the introduction of additional ports to allow the passage of instruments. Once the fetus is positioned adequately, the skin around the fetal neural placode/elements is dissected. Occasionally a biocellulose patch may be placed between the neural elements (defect) and the skin. Myofascial flaps are created and sutured on top of the biocellulose patch. The skin is then sutured using interrupted stitches over the patch or, for a large defect, a dermal regeneration patch substitute can be used for repair.
A number of variations to the procedure have been described and the technique is still evolving.
|
{'Recommendations': 'Evidence on the safety and efficacy of fetoscopic prenatal repair of open neural tube defects in the fetus is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research. This could be in the form of randomised controlled trials or published registry data. Find out what only in research means on the NICE interventional procedures guidance page.\n\nThe procedure is technically challenging and should only be done in specialised centres, and only by clinicians and teams with specific training and experience in fetoscopic prenatal repair.\n\nPatient selection should only be done by a multidisciplinary team, which should include a consultant in fetal medicine, an obstetric surgeon, a paediatric neurosurgeon, a radiologist with experience in fetal imaging and an anaesthetist.\n\nFurther research should report details of risks to the mother (including her subsequent pregnancies), risks to the fetus (including the need for further surgery), and long-term disability after birth.', 'The condition, current treatments and procedure': "# The condition\n\nNeural tube defects happen because the neural tube does not fuse during early embryonic development. Open neural tube defects are those in which the affected region of the neural tube is exposed on the body's surface. The most common neural tube defect is spina bifida where the defect is in the spine. Myelomeningocele (open spina bifida) is the most severe type of spina bifida, in which the baby's spinal canal remains open along several vertebrae in the back. The spinal cord and protective membranes around it push out and form a sac which is exposed on the baby's back. Children born with myelomeningocele may experience motor neurological deficits including muscle weakness and paralysis of the lower limbs, sensory deficit, bowel, bladder and sexual dysfunctions and learning difficulties. The condition can be associated with Chiari\xa0II malformation (hindbrain herniation) and hydrocephalus.\n\n# Current treatments\n\nConventional treatment for myelomeningocele (open spina bifida) is immediate surgical repair of the defect within days of birth to prevent further damage to nervous tissue and reduce the risk of central nervous system infection. The immediate management may also include ventricular-peritoneal shunt placement to relieve hydrocephalus. The condition can also be treated prenatally with the aim of decreasing morbidity in the child.\n\n# The procedure\n\nFetoscopic prenatal repair is typically done before 26\xa0weeks of pregnancy. It is done using general anaesthesia and with partial CO2 insufflation of the uterine cavity. Under ultrasound guidance an endoscope is introduced through a port followed by the introduction of additional ports to allow the passage of instruments. Once the fetus is positioned adequately, the skin around the fetal neural placode/elements is dissected. Occasionally a biocellulose patch may be placed between the neural elements (defect) and the skin. Myofascial flaps are created and sutured on top of the biocellulose patch. The skin is then sutured using interrupted stitches over the patch or, for a large defect, a dermal regeneration patch substitute can be used for repair.\n\nA number of variations to the procedure have been described and the technique is still evolving."}
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https://www.nice.org.uk/guidance/ipg667
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Evidence-based recommendations on fetoscopic prenatal repair of open neural tube defects in the fetus. This involves keyhole surgery through the woman’s abdomen to close the gap in the baby’s spine.
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d08ea1684bd84c86cae6e468775473a06cc28d18
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nice
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Open prenatal repair for open neural tube defects in the fetus
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Open prenatal repair for open neural tube defects in the fetus
Evidence-based recommendations on open prenatal repair of open neural tube defects in the fetus. This involves open surgery through the woman’s abdomen to close the gap in the baby’s spine.
# Recommendations
Evidence on the efficacy of open prenatal repair of open neural tube defects in the fetus is adequate in quantity and quality. However, evidence on its safety shows serious but well recognised safety concerns for the mother and fetus. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.
Clinicians wishing to do open prenatal repair of open neural tube defects in the fetus should:
Inform the clinical governance leads in their NHS trusts.
Give parents clear written information to support shared decision making, including NICE's information for the public.
Ensure that parents understand the procedure's safety and efficacy, as well as any uncertainties about these.
Audit and review clinical outcomes of everyone having the procedure. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).
The procedure is technically challenging and should only be done in specialised centres, and only by clinicians and teams with specific training and experience in open prenatal repair.
Patient selection should only be done by a multidisciplinary team, which should include a consultant in fetal medicine, an obstetric surgeon, a paediatric neurosurgeon, a radiologist with experience in fetal imaging and an anaesthetist.
Further research should report details of risks to the mother (including her subsequent pregnancies), risks to the fetus (including the need for further surgery) and long-term disability after birth.# The condition, current treatments and procedure
# The condition
Neural tube defects happen because the neural tube does not fuse during early embryonic development. Open neural tube defects are those in which the affected region of the neural tube is exposed on the body's surface. The most common neural tube defect is spina bifida, where the defect is in the spine. Myelomeningocele (open spina bifida) is the most severe type of spina bifida, in which the baby's spinal canal remains open along several vertebrae in the back. The spinal cord and protective membranes around it push out and form a sac, which is exposed on the baby's back. Children born with myelomeningocele may experience motor neurological deficits including muscle weakness and paralysis of the lower limbs, sensory deficit, bowel, bladder and sexual dysfunctions, and learning difficulties. The condition can be associated with Chiari II malformation (hindbrain herniation) and hydrocephalus.
# Current treatments
Conventional treatment for myelomeningocele (open spina bifida) is immediate surgical repair of the defect within days of birth to prevent further damage to nervous tissue and reduce the risk of central nervous system infection. The immediate management may also include ventricular-peritoneal shunt placement to relieve hydrocephalus. The condition can also be treated prenatally with the aim of decreasing morbidity in the child.
# The procedure
Open prenatal repair for open neural tube defects is typically done before 26 weeks of pregnancy. Using general anaesthesia, a low transverse laparotomy incision is done and the gravid uterus is exposed and exteriorised. The fetus and placenta are visualised by ultrasound, and the fetus is manually positioned to allow a uterine incision (hysterotomy) over the centre of the myelomeningocele sac. The hysterotomy location is either anterior, fundal or posterior depending on the location of the placenta. The hysterotomy is made large enough to allow the neural tissue in the meningomyelocele to be dissected from surrounding tissue so that it can drop into the spinal canal. The defect is then closed. If there is insufficient dura or skin for closure, occasionally a biocellulose and dermal regeneration patch substitute may be used for repair. The uterine incision is closed and a sodium lactate solution with antibiotics is added to the uterus until the amniotic fluid index is normal. The maternal abdominal wound is then closed.
A number of variations to the procedure have been described and the technique is still evolving.
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{'Recommendations': "Evidence on the efficacy of open prenatal repair of open neural tube defects in the fetus is adequate in quantity and quality. However, evidence on its safety shows serious but well recognised safety concerns for the mother and fetus. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wishing to do open prenatal repair of open neural tube defects in the fetus should:\n\nInform the clinical governance leads in their NHS trusts.\n\nGive parents clear written information to support shared decision making, including NICE's information for the public.\n\nEnsure that parents understand the procedure's safety and efficacy, as well as any uncertainties about these.\n\nAudit and review clinical outcomes of everyone having the procedure. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).\n\nThe procedure is technically challenging and should only be done in specialised centres, and only by clinicians and teams with specific training and experience in open prenatal repair.\n\nPatient selection should only be done by a multidisciplinary team, which should include a consultant in fetal medicine, an obstetric surgeon, a paediatric neurosurgeon, a radiologist with experience in fetal imaging and an anaesthetist.\n\nFurther research should report details of risks to the mother (including her subsequent pregnancies), risks to the fetus (including the need for further surgery) and long-term disability after birth.", 'The condition, current treatments and procedure': "# The condition\n\nNeural tube defects happen because the neural tube does not fuse during early embryonic development. Open neural tube defects are those in which the affected region of the neural tube is exposed on the body's surface. The most common neural tube defect is spina bifida, where the defect is in the spine. Myelomeningocele (open spina bifida) is the most severe type of spina bifida, in which the baby's spinal canal remains open along several vertebrae in the back. The spinal cord and protective membranes around it push out and form a sac, which is exposed on the baby's back. Children born with myelomeningocele may experience motor neurological deficits including muscle weakness and paralysis of the lower limbs, sensory deficit, bowel, bladder and sexual dysfunctions, and learning difficulties. The condition can be associated with Chiari\xa0II malformation (hindbrain herniation) and hydrocephalus.\n\n# Current treatments\n\nConventional treatment for myelomeningocele (open spina bifida) is immediate surgical repair of the defect within days of birth to prevent further damage to nervous tissue and reduce the risk of central nervous system infection. The immediate management may also include ventricular-peritoneal shunt placement to relieve hydrocephalus. The condition can also be treated prenatally with the aim of decreasing morbidity in the child.\n\n# The procedure\n\nOpen prenatal repair for open neural tube defects is typically done before 26\xa0weeks of pregnancy. Using general anaesthesia, a low transverse laparotomy incision is done and the gravid uterus is exposed and exteriorised. The fetus and placenta are visualised by ultrasound, and the fetus is manually positioned to allow a uterine incision (hysterotomy) over the centre of the myelomeningocele sac. The hysterotomy location is either anterior, fundal or posterior depending on the location of the placenta. The hysterotomy is made large enough to allow the neural tissue in the meningomyelocele to be dissected from surrounding tissue so that it can drop into the spinal canal. The defect is then closed. If there is insufficient dura or skin for closure, occasionally a biocellulose and dermal regeneration patch substitute may be used for repair. The uterine incision is closed and a sodium lactate solution with antibiotics is added to the uterus until the amniotic fluid index is normal. The maternal abdominal wound is then closed.\n\nA number of variations to the procedure have been described and the technique is still evolving."}
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https://www.nice.org.uk/guidance/ipg668
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Evidence-based recommendations on open prenatal repair of open neural tube defects in the fetus. This involves open surgery through the woman’s abdomen to close the gap in the baby’s spine.
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6b6adc10a62308e4c6e31ae101be650549c80bbe
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nice
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Reducing the risk of transmission of Creutzfeldt–Jakob disease (CJD) from surgical instruments used for interventional procedures on high-risk tissues
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Reducing the risk of transmission of Creutzfeldt–Jakob disease (CJD) from surgical instruments used for interventional procedures on high-risk tissues
Evidence-based recommendations on reducing the risk of transmission of Creutzfeldt–Jakob disease (CJD) from surgical instruments used for interventional procedures on high-risk tissues. These procedures on high-risk tissues are intradural surgery on the brain (including the pituitary gland) and spinal cord, neuroendoscopy, and surgery on the retina or optic nerve.
# This guidance is for high-risk tissues
This guidance is for interventional procedures on tissues considered at high risk of transmitting Creutzfeldt–Jakob disease (CJD). These procedures on high-risk tissues are intradural surgery on the brain (including the pituitary gland) and spinal cord, neuroendoscopy, and surgery on the retina or optic nerve (see appendix D for a complete list).
Note that the abbreviation 'CJD' is used for both sporadic and variant CJD (vCJD), including surgically transmitted CJD (stCJD), unless otherwise specified.
The recommendations do not apply to any interventional procedures done on patients already known to have or thought to be at increased risk of CJD as previously defined by the Advisory Committee on Dangerous Pathogens' Transmissible Spongiform Encephalopathies subgroup. For these patients and patients in whom the risk of CJD cannot be ascertained by questioning them, or when a diagnosis of CJD cannot be excluded, the Advisory Committee on Dangerous Pathogens' guidance on transmissible spongiform encephalopathy agents: safe working and the prevention of infection must be followed.# Recommendations
# Decontamination
All surgical instruments that come into contact with high-risk tissues during an interventional procedure must be kept moist and separated from other instruments until they are cleaned, and then disinfected and sterilised (decontaminated). This improves the efficacy of the decontamination process and is highly cost effective.
# Set integrity and tracking
Surgical instruments that come into contact with high-risk tissues must not be moved from one set to another and must remain within their individual sets. Maintaining set integrity reduces the risks associated with instrument migration (including infection) and makes it easier to trace instruments back to the patients they were used on.
# Supplementary instruments
Supplementary instruments that come into contact with high-risk tissues must remain within the individual set to which they have been introduced. Supplementary instruments are those that are not part of a specific instrument set. If supplementary instruments are used with different sets, this would compromise set traceability and increases the risks associated with instrument migration.
# Neuroendoscopy
Rigid neuroendoscopes (rather than flexible neuroendoscopes) should be used if possible. They should be of a type that can be steam sterilised and must be thoroughly cleaned and steam sterilised after each use.
# Single-use instruments
The evidence on cost effectiveness does not support using sets of single-use instruments to reduce the risk of Creutzfeldt–Jakob disease (CJD) transmission.
# Systems specifically for people born after 1996
The evidence on cost effectiveness does not support introducing systems to maintain separate sets of neuroendoscopes and reusable surgical instruments for use on high-risk tissues for people born after 1996.
Removing the requirement to use different instruments on high-risk tissues for people born after 1996 would not markedly increase the risk of surgical transmission of CJD.
# Other relevant guidance
This guidance should be used with:
the Advisory Committee on Dangerous Pathogens' Transmissible Spongiform Encephalopathies subgroup's previous guidance on transmissible spongiform encephalopathy agents: safe working and the prevention of Infection
the Department of Health and Social Care's Health Technical Memorandum (HTM) 01-01: decontamination of surgical instruments (2016) and corresponding guidance in the devolved administrations' areas.
# Further research
NICE may update this guidance after 3 years or sooner if important new information becomes available, including evidence on:
the epidemiology of CJD, including data on the prevalence of CJD and its infectivity in the UK population
the transmission of CJD by surgical instruments, including cases of CJD in which surgery is a possible route of transmission
the cost effectiveness of single-use instruments for use in interventional procedures on high-risk tissues
commercially available decontamination methods that are safe and cost effective against prions
the systems for, and cost effectiveness of, maintaining set integrity and traceability of instruments.# Indication
# The condition
Creutzfeldt–Jakob disease (CJD) is a progressive, fatal neurological disease affecting the brain. It is caused by pathological accumulation of a transmissible form of protein called a prion. CJD belongs to a wider group of neurodegenerative disorders known as transmissible spongiform encephalopathies (TSEs) that affect both humans and animals. People with CJD typically present with rapidly progressive dementia, usually accompanied by myoclonus and cerebellar ataxia. Most people die within 4 months of disease onset, in a mute and immobile state.
# Epidemiology of CJD
The incidence of any type of CJD (based on published surveillance studies) is 1 to 2 cases per million of the population worldwide. There are 4 aetiological CJD categories:
Sporadic CJD (sCJD) accounts for 85% to 90% of cases worldwide. The aetiology is not known. It has an annual incidence of 1 to 2 deaths per million of population per year. The general rate of age-adjusted detection of sCJD is increasing in the UK. Reasons for this include improved case ascertainment and an ageing population (in which there is a higher incidence).
Inherited (genetic or familial) CJD accounts for 5% to 15% of cases or about 10 deaths in the UK per year. It is associated with pathogenic mutations in the prion protein gene.
Variant CJD (vCJD) is a novel form of human prion disease, first recognised in the UK in 1996. It is believed to result from consumption of food derived from cattle infected with bovine spongiform encephalopathy (BSE), a fatal neurodegenerative disease that causes sponge-like changes in the brain. vCJD is characterised by extensive lymphoreticular tissue involvement and a young age at onset (the mean age at death is 28 years, compared with 66 years for sCJD). The clinical course of vCJD is distinct from that of sCJD. People with vCJD frequently present with sensory and psychiatric symptoms that are uncommon in people with sCJD. They develop progressive neurological signs such as gait disturbance, ataxia and tremor. The median duration of illness is longer than for sCJD (14 months compared with 4 months). By 2016 there had been 178 cases of vCJD in the UK. Three cases are considered to have occurred through blood transfusion and 175 cases were related to dietary exposure to BSE. The prevalence of non-clinical vCJD (abnormal prion accumulation in tissues without clinical symptoms) in the general UK population is estimated to be 240 per million, based on retrospective analyses of appendix specimens. In the UK, between 1988 and 1996, a series of measures were put in place to reduce the risk of people being exposed to BSE. Over the past 8 years there have been 0 or 1 deaths per year in the UK attributed to vCJD.
Iatrogenic CJD (iCJD) accounts for less than 1% of cases each year. It is the transmission of prions through surgical or medical procedures (especially from tissues with the highest concentration of prions, such as brain and posterior eye tissue) or human-derived products (growth hormone, gonadotropin, dura mater grafts and packed red blood cells). Surgically transmitted CJD (stCJD) is theoretically possible through prion-contaminated instruments that have been previously used on patients with CJD. This includes patients who are asymptomatic but infectious because neural tissue has a high infectious load, and there are difficulties in eradicating prions from surgical instruments. The most common causes of iCJD are historic use of human growth hormone and dura mater grafts, according to a review of worldwide iCJD cases published in 2012. In the UK, 85 iCJD cases were identified between 1970 and 2016. Eight were from dura mater grafts, 1 was from human gonadotrophin and 76 were from human growth hormone. There were 4 cases of possible stCJD through contaminated neurosurgical instruments between 1952 and 1974; 3 in the UK and 1 in France. The University of Sheffield's School of Health and Related Research (ScHARR) systematic review indicates that the risk of stCJD is currently low and no cases were reported between 2005 and 2018. However, there is uncertainty about the future risk of stCJD because of the potentially long incubation period of CJD, difficulties in eradicating prions from surgical instruments, the presumed subclinical prevalence in the general population, and high levels of infectivity in the brain. Neurosurgical instruments used on people who are possibly carriers of CJD are handled in accordance with the Advisory Committee on Dangerous Pathogens' Transmissible Spongiform Encephalopathies risk management subgroup's guidance on safe working and the prevention of infection.
The National CJD Research and Surveillance Unit report the number of deaths per year in the UK attributed to the 4 categories of CJD.
# Incubation periods
Evidence from retrospective data in the ScHARR systematic review shows that the incubation period of iatrogenic CJD ranges from 1 to 42 years with durations towards the shorter end of the range reported in cases of stCJD. Incubation times might be affected by the recipient's genotype and the infecting prion strain or subtype of CJD.
# Infectivity
The infectivity of CJD is likely to be moderated by a number of factors including the recipient's genotype, the infecting prion strain, and the route of transmission. There are limited data about infectious dose or infectious titre in humans. The ID50 is the dose that would give the person receiving it a 50% chance of becoming infected. High values are expressed in log or factor-of-10 terms. For example, 1 g of brain tissue can have an ID50 of 108 (8 log). This means it carries a dose of 100,000,000 ID50. The model assumes that intracranial transfer of 0.01 micrograms of such brain tissue would result in the recipient having a 50% chance of becoming infected with CJD.# Appendix B: Contributors
These organisations provided specialist advice and comments:
CJD Support Network
Child Growth Foundation# Appendix C: Related advisory groups
A number of advisory committees, expert groups and academic units are addressing issues related to Creutzfeldt–Jakob disease (CJD) including developing the scientific basis of our understanding of the disease, improving decontamination practices across the NHS and minimising the risk of transmission. NICE has made every effort to coordinate with these groups to ensure that this guidance takes account of, and builds on, their work. Some members of the CJD advisory subcommittee are also members of other CJD committees, working groups and academic units. NICE has been represented on some of these groups.
The following is a list of some of the organisations in the UK that either fund surveillance, study or provide advice on the public health aspect of CJD:
Department of Health and Social Care
Medical Research Council Prion Unit at University College London Hospitals' National Prion Clinic
University of Edinburgh National CJD Research & Surveillance Unit
Public Health England
Health Protection Scotland# Appendix D: High-risk procedures
The OPCS‑4 codes for intradural operations on the brain and spinal cord are shown below.
# Neurosurgery
This list may not be comprehensive.
All purposeful intradural brain and spinal cord surgery are regarded as high-risk and this guidance applies wherever there is contact with or possible contamination by brain or spinal cord tissue.
Extradural surgery, even in the presence of a cerebrospinal fluid leak, is not high risk and this guidance does not apply.
A01 Major excision of tissue of brain
A02 Excision of lesion of tissue of brain
A03 Stereotactic ablation of tissue of brain
A04 Open biopsy of lesion of tissue of brain
A05 Drainage of lesion of tissue of brain
A07 Other open operations on tissue of brain
A08 Other biopsy of lesion of tissue of brain
A09 Neurostimulation of brain
A10 Other operations on tissue of brain
A12 Creation of connection from ventricle of brain
A13 Attention to component of connection from ventricle of brain
A14 Other operation on connection from ventricle of brain
A16 Other open operations on ventricle of brain
A20 Other operations on ventricle of brain
A22 Operations on subarachnoid space of brain
A24 Graft to cranial nerve
A25 Intracranial transection of cranial nerve
A26 Other intracranial destruction of cranial nerve
A29 Excision of lesion of cranial nerve
A30 Repair of cranial nerve
A31 Intracranial stereotactic release of cranial nerve
A32 Other decompression of cranial nerve
A33 Neurostimulation of cranial nerve
A34 Exploration of cranial nerve
A36 Other operations on cranial nerve
A38 Extirpation of lesion of meninges of brain
A39 Repair of dura
A42 Other operations on meninges of brain
B01 Excision of pituitary gland
B02 Destruction of pituitary gland
B04 Other operations on pituitary gland
B06 Operations on the pineal gland
L33 Operations on aneurysm of cerebral artery
L34 Other open operations on cerebral artery
A44.1 Chordectomy of spinal cord
A44.2 Extirpation of lesion of spinal cord NEC
A44.3 Excision of lesion of intradural intramedullary spinal cord
A44.5 Excision of lesion of intradural extramedullary spinal cord
A44.8 Other specified partial extirpation of spinal cord
A44.9 Unspecified partial extirpation of spinal cord
A45.1 Stereotactic chordotomy of spinal cord
A45.2 Open chordotomy of spinal cord NEC
A45.3 Myelotomy of spinal cord
A45.4 Open biopsy of lesion of spinal cord
A45.5 Removal of foreign body from spinal cord
A45.6 Open aspiration of lesion of spinal cord
A45.8 Other specified other open operations on spinal cord
A47.1 Needle destruction of substantia gelatinosa of cervical spinal cord
A47.2 Radiofrequency controlled thermal destruction of spinothalamic tract
A47.3 Percutaneous chordotomy of spinal cord
A47.8 Other specified other destruction of spinal cord
A48.1 Biopsy of lesion of spinal cord NEC
A48.2 Aspiration of lesion of spinal cord
A48.3 Insertion of neurostimulator adjacent to spinal cord
A48.4 Attention to neurostimulator adjacent to spinal cord NEC
A48.6 Removal of neurostimulator adjacent to spinal cord
A48.7 Insertion of neurostimulator electrodes into the spinal cord
A48.8 Other specified other operations on spinal cord
A49.1 Freeing of spinal tether NEC
A49.2 Closure of spinal myelomeningocele
A49.3 Closure of spinal meningocele
A49.4 Complex freeing of spinal tether
A49.8 Other specified repair of spina bifida
A49.9 Unspecified repair of spina bifida
A51.1 Extirpation of lesion of meninges of spinal cord
A51.2 Freeing of adhesions of meninges of spinal cord
A51.3 Biopsy of lesion of meninges of spinal cord
A51.8 Other specified other operations on meninges of spinal cord
A51.9 Unspecified other operations on meninges of spinal cord
A53.1 Cerebrospinal syringostomy
A53.3 Creation of syringoperitoneal shunt
A57.1 Extirpation of lesion of spinal nerve root
A57.6 Reimplantation of spinal nerves into spinal cord
# Posterior eye surgical procedures that are regarded as high-risk posterior segment eye surgery
## Orbit (C01 to C08)
C01 Excision of eye
C03 Insertion of prosthesis of eye
C04 Attention to prosthesis of eye
These orbital operations are only included if the surgery or implant is likely to come into contact with the optic nerve or retinal tissue (for example, evisceration of the eye and intra-orbital implant).
## Operations on optic nerve (A29.1 to A36.4)
A29.1 Excision of lesion of optic nerve
A30.1 Repair of optic nerve
A32.1 Decompression of optic nerve
A34.1 Exploration of optic nerve
A36.4 Radial Optic Neurotomy
# Sclera and iris (C52 to C65)
C54 Buckling operations for attachment of retina
# Retina, other parts of eye and anaesthetics (C79 to C90)
C79 Operations on vitreous body, only when this involves potential contact with the posterior hyaloid face. For example:
Code C7910 for vitrectomy via anterior approach and code C7923 for intravitreal injections are specifically excluded because they are unlikely to come into contact with the posterior hyaloid face.
Code C7920 and code C7922, which potentially could come into contact with the hyaloid face, are included.
C80 Operations on retinal membrane
C81 Photocoagulation of retina for detachment, only when the retina is handled directly
C82 Destruction of lesion of retina, only when the retina is handled directly
Code C82.4 for insertion of radiotherapy plaques is specifically excluded.
C83 Translocation of retina
C84 Other operations on retina
C85 Fixation of retina
C86 Other operations on eye
C88 Destruction of subretinal lesion
C89 Operations on posterior segment of eye
ISBN: 978-1-4731-3605-2
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{'This guidance is for high-risk tissues': "This guidance is for interventional procedures on tissues considered at high risk of transmitting Creutzfeldt–Jakob disease (CJD). These procedures on high-risk tissues are intradural surgery on the brain (including the pituitary gland) and spinal cord, neuroendoscopy, and surgery on the retina or optic nerve (see appendix\xa0D for a complete list).\n\nNote that the abbreviation 'CJD' is used for both sporadic and variant CJD (vCJD), including surgically transmitted CJD (stCJD), unless otherwise specified.\n\nThe recommendations do not apply to any interventional procedures done on patients already known to have or thought to be at increased risk of CJD as previously defined by the Advisory Committee on Dangerous Pathogens' Transmissible Spongiform Encephalopathies subgroup. For these patients and patients in whom the risk of CJD cannot be ascertained by questioning them, or when a diagnosis of CJD cannot be excluded, the Advisory Committee on Dangerous Pathogens' guidance on transmissible spongiform encephalopathy agents: safe working and the prevention of infection must be followed.", 'Recommendations': "# Decontamination\n\nAll surgical instruments that come into contact with high-risk tissues during an interventional procedure must be kept moist and separated from other instruments until they are cleaned, and then disinfected and sterilised (decontaminated). This improves the efficacy of the decontamination process and is highly cost effective.\n\n# Set integrity and tracking\n\nSurgical instruments that come into contact with high-risk tissues must not be moved from one\xa0set to another and must remain within their individual sets. Maintaining set integrity reduces the risks associated with instrument migration (including infection) and makes it easier to trace instruments back to the patients they were used on.\n\n# Supplementary instruments\n\nSupplementary instruments that come into contact with high-risk tissues must remain within the individual set to which they have been introduced. Supplementary instruments are those that are not part of a specific instrument set. If supplementary instruments are used with different sets, this would compromise set traceability and increases the risks associated with instrument migration.\n\n# Neuroendoscopy\n\nRigid neuroendoscopes (rather than flexible neuroendoscopes) should be used if possible. They should be of a type that can be steam sterilised and must be thoroughly cleaned and steam sterilised after each use.\n\n# Single-use instruments\n\nThe evidence on cost effectiveness does not support using sets of single-use instruments to reduce the risk of Creutzfeldt–Jakob disease (CJD) transmission.\n\n# Systems specifically for people born after 1996\n\nThe evidence on cost effectiveness does not support introducing systems to maintain separate sets of neuroendoscopes and reusable surgical instruments for use on high-risk tissues for people born after 1996.\n\nRemoving the requirement to use different instruments on high-risk tissues for people born after 1996 would not markedly increase the risk of surgical transmission of CJD.\n\n# Other relevant guidance\n\nThis guidance should be used with:\n\nthe Advisory Committee on Dangerous Pathogens' Transmissible Spongiform Encephalopathies subgroup's previous guidance on transmissible spongiform encephalopathy agents: safe working and the prevention of Infection\n\nthe Department of Health and Social Care's Health Technical Memorandum (HTM) 01-01: decontamination of surgical instruments (2016) and corresponding guidance in the devolved administrations' areas.\n\n# Further research\n\nNICE may update this guidance after 3\xa0years or sooner if important new information becomes available, including evidence on:\n\nthe epidemiology of CJD, including data on the prevalence of CJD and its infectivity in the UK population\n\nthe transmission of CJD by surgical instruments, including cases of CJD in which surgery is a possible route of transmission\n\nthe cost effectiveness of single-use instruments for use in interventional procedures on high-risk tissues\n\ncommercially available decontamination methods that are safe and cost effective against prions\n\nthe systems for, and cost effectiveness of, maintaining set integrity and traceability of instruments.", 'Indication': "# The condition\n\nCreutzfeldt–Jakob disease (CJD) is a progressive, fatal neurological disease affecting the brain. It is caused by pathological accumulation of a transmissible form of protein called a prion. CJD belongs to a wider group of neurodegenerative disorders known as transmissible spongiform encephalopathies (TSEs) that affect both humans and animals. People with CJD typically present with rapidly progressive dementia, usually accompanied by myoclonus and cerebellar ataxia. Most people die within 4\xa0months of disease onset, in a mute and immobile state.\n\n# Epidemiology of CJD\n\nThe incidence of any type of CJD (based on published surveillance studies) is 1\xa0to 2\xa0cases per million of the population worldwide. There are 4\xa0aetiological CJD categories:\n\nSporadic CJD (sCJD) accounts for 85%\xa0to\xa090% of cases worldwide. The aetiology is not known. It has an annual incidence of 1\xa0to 2\xa0deaths per million of population per year. The general rate of age-adjusted detection of sCJD is increasing in the UK. Reasons for this include improved case ascertainment and an ageing population (in which there is a higher incidence).\n\nInherited (genetic or familial) CJD accounts for 5%\xa0to\xa015% of cases or about 10\xa0deaths in the UK per year. It is associated with pathogenic mutations in the prion protein gene.\n\nVariant CJD (vCJD) is a novel form of human prion disease, first recognised in the UK in 1996. It is believed to result from consumption of food derived from cattle infected with bovine spongiform encephalopathy (BSE), a fatal neurodegenerative disease that causes sponge-like changes in the brain. vCJD is characterised by extensive lymphoreticular tissue involvement and a young age at onset (the mean age at death is 28\xa0years, compared with 66\xa0years for sCJD). The clinical course of vCJD is distinct from that of sCJD. People with vCJD frequently present with sensory and psychiatric symptoms that are uncommon in people with sCJD. They develop progressive neurological signs such as gait disturbance, ataxia and tremor. The median duration of illness is longer than for sCJD (14\xa0months compared with 4\xa0months). By 2016 there had been 178\xa0cases of vCJD in the UK. Three cases are considered to have occurred through blood transfusion and 175\xa0cases were related to dietary exposure to BSE. The prevalence of non-clinical vCJD (abnormal prion accumulation in tissues without clinical symptoms) in the general UK population is estimated to be 240\xa0per million, based on retrospective analyses of appendix specimens. In the UK, between 1988 and 1996, a series of measures were put in place to reduce the risk of people being exposed to BSE. Over the past 8\xa0years there have been 0\xa0or 1\xa0deaths per year in the UK attributed to vCJD.\n\nIatrogenic CJD (iCJD) accounts for less than 1% of cases each year. It is the transmission of prions through surgical or medical procedures (especially from tissues with the highest concentration of prions, such as brain and posterior eye tissue) or human-derived products (growth hormone, gonadotropin, dura mater grafts and packed red blood cells). Surgically transmitted CJD (stCJD) is theoretically possible through prion-contaminated instruments that have been previously used on patients with CJD. This includes patients who are asymptomatic but infectious because neural tissue has a high infectious load, and there are difficulties in eradicating prions from surgical instruments. The most common causes of iCJD are historic use of human growth hormone and dura mater grafts, according to a review of worldwide iCJD cases published in 2012. In the UK, 85\xa0iCJD cases were identified between 1970 and 2016. Eight were from dura mater grafts, 1\xa0was from human gonadotrophin and 76\xa0were from human growth hormone. There were 4\xa0cases of possible stCJD through contaminated neurosurgical instruments between 1952 and 1974; 3\xa0in the UK and 1\xa0in France. The University of Sheffield's School of Health and Related Research (ScHARR) systematic review indicates that the risk of stCJD is currently low and no cases were reported between 2005 and 2018. However, there is uncertainty about the future risk of stCJD because of the potentially long incubation period of CJD, difficulties in eradicating prions from surgical instruments, the presumed subclinical prevalence in the general population, and high levels of infectivity in the brain. Neurosurgical instruments used on people who are possibly carriers of CJD are handled in accordance with the Advisory Committee on Dangerous Pathogens' Transmissible Spongiform Encephalopathies risk management subgroup's guidance on safe working and the prevention of infection.\n\nThe National CJD Research and Surveillance Unit report the number of deaths per year in the UK attributed to the 4\xa0categories of CJD.\n\n# Incubation periods\n\nEvidence from retrospective data in the ScHARR systematic review shows that the incubation period of iatrogenic CJD ranges from 1\xa0to 42\xa0years with durations towards the shorter end of the range reported in cases of stCJD. Incubation times might be affected by the recipient's genotype and the infecting prion strain or subtype of CJD.\n\n# Infectivity\n\nThe infectivity of CJD is likely to be moderated by a number of factors including the recipient's genotype, the infecting prion strain, and the route of transmission. There are limited data about infectious dose or infectious titre in humans. The ID50 is the dose that would give the person receiving it a 50%\xa0chance of becoming infected. High values are expressed in log or factor-of-10 terms. For example, 1\xa0g of brain tissue can have an ID50 of 108 (8\xa0log). This means it carries a dose of 100,000,000\xa0ID50. The model assumes that intracranial transfer of 0.01\xa0micrograms of such brain tissue would result in the recipient having a 50%\xa0chance of becoming infected with CJD.", 'Appendix B: Contributors': 'These organisations provided specialist advice and comments:\n\nCJD Support Network\n\nChild Growth Foundation', 'Appendix C: Related advisory groups': "A number of advisory committees, expert groups and academic units are addressing issues related to Creutzfeldt–Jakob disease (CJD) including developing the scientific basis of our understanding of the disease, improving decontamination practices across the NHS and minimising the risk of transmission. NICE has made every effort to coordinate with these groups to ensure that this guidance takes account of, and builds on, their work. Some members of the CJD advisory subcommittee are also members of other CJD committees, working groups and academic units. NICE has been represented on some of these groups.\n\nThe following is a list of some of the organisations in the UK that either fund surveillance, study or provide advice on the public health aspect of CJD:\n\nDepartment of Health and Social Care\n\nMedical Research Council Prion Unit at University College London Hospitals' National Prion Clinic\n\nUniversity of Edinburgh National CJD Research & Surveillance Unit\n\nPublic Health England\n\nHealth Protection Scotland", 'Appendix D: High-risk procedures': 'The OPCS‑4\xa0codes for intradural operations on the brain and spinal cord are shown below.\n\n# Neurosurgery\n\nThis list may not be comprehensive.\n\nAll purposeful intradural brain and spinal cord surgery are regarded as high-risk and this guidance applies wherever there is contact with or possible contamination by brain or spinal cord tissue.\n\nExtradural surgery, even in the presence of a cerebrospinal fluid leak, is not high risk and this guidance does not apply.\n\nA01 Major excision of tissue of brain\n\nA02 Excision of lesion of tissue of brain\n\nA03 Stereotactic ablation of tissue of brain\n\nA04 Open biopsy of lesion of tissue of brain\n\nA05 Drainage of lesion of tissue of brain\n\nA07 Other open operations on tissue of brain\n\nA08 Other biopsy of lesion of tissue of brain\n\nA09 Neurostimulation of brain\n\nA10 Other operations on tissue of brain\n\nA12 Creation of connection from ventricle of brain\n\nA13 Attention to component of connection from ventricle of brain\n\nA14 Other operation on connection from ventricle of brain\n\nA16 Other open operations on ventricle of brain\n\nA20 Other operations on ventricle of brain\n\nA22 Operations on subarachnoid space of brain\n\nA24 Graft to cranial nerve\n\nA25 Intracranial transection of cranial nerve\n\nA26 Other intracranial destruction of cranial nerve\n\nA29 Excision of lesion of cranial nerve\n\nA30 Repair of cranial nerve\n\nA31 Intracranial stereotactic release of cranial nerve\n\nA32 Other decompression of cranial nerve\n\nA33 Neurostimulation of cranial nerve\n\nA34 Exploration of cranial nerve\n\nA36 Other operations on cranial nerve\n\nA38 Extirpation of lesion of meninges of brain\n\nA39 Repair of dura\n\nA42 Other operations on meninges of brain\n\nB01 Excision of pituitary gland\n\nB02 Destruction of pituitary gland\n\nB04 Other operations on pituitary gland\n\nB06 Operations on the pineal gland\n\nL33 Operations on aneurysm of cerebral artery\n\nL34 Other open operations on cerebral artery\n\nA44.1 Chordectomy of spinal cord\n\nA44.2 Extirpation of lesion of spinal cord NEC\n\nA44.3 Excision of lesion of intradural intramedullary spinal cord\n\nA44.5 Excision of lesion of intradural extramedullary spinal cord\n\nA44.8 Other specified partial extirpation of spinal cord\n\nA44.9 Unspecified partial extirpation of spinal cord\n\nA45.1 Stereotactic chordotomy of spinal cord\n\nA45.2 Open chordotomy of spinal cord NEC\n\nA45.3 Myelotomy of spinal cord\n\nA45.4 Open biopsy of lesion of spinal cord\n\nA45.5 Removal of foreign body from spinal cord\n\nA45.6 Open aspiration of lesion of spinal cord\n\nA45.8 Other specified other open operations on spinal cord\n\nA47.1 Needle destruction of substantia gelatinosa of cervical spinal cord\n\nA47.2 Radiofrequency controlled thermal destruction of spinothalamic tract\n\nA47.3 Percutaneous chordotomy of spinal cord\n\nA47.8 Other specified other destruction of spinal cord\n\nA48.1 Biopsy of lesion of spinal cord NEC\n\nA48.2 Aspiration of lesion of spinal cord\n\nA48.3 Insertion of neurostimulator adjacent to spinal cord\n\nA48.4 Attention to neurostimulator adjacent to spinal cord NEC\n\nA48.6 Removal of neurostimulator adjacent to spinal cord\n\nA48.7 Insertion of neurostimulator electrodes into the spinal cord\n\nA48.8 Other specified other operations on spinal cord\n\nA49.1 Freeing of spinal tether NEC\n\nA49.2 Closure of spinal myelomeningocele\n\nA49.3 Closure of spinal meningocele\n\nA49.4 Complex freeing of spinal tether\n\nA49.8 Other specified repair of spina bifida\n\nA49.9 Unspecified repair of spina bifida\n\nA51.1 Extirpation of lesion of meninges of spinal cord\n\nA51.2 Freeing of adhesions of meninges of spinal cord\n\nA51.3 Biopsy of lesion of meninges of spinal cord\n\nA51.8 Other specified other operations on meninges of spinal cord\n\nA51.9 Unspecified other operations on meninges of spinal cord\n\nA53.1 Cerebrospinal syringostomy\n\nA53.3 Creation of syringoperitoneal shunt\n\nA57.1 Extirpation of lesion of spinal nerve root\n\nA57.6 Reimplantation of spinal nerves into spinal cord\n\n# Posterior eye surgical procedures that are regarded as high-risk posterior segment eye surgery\n\n## Orbit (C01\xa0to\xa0C08)\n\nC01 Excision of eye\n\nC03 Insertion of prosthesis of eye\n\nC04 Attention to prosthesis of eye\n\nThese orbital operations are only included if the surgery or implant is likely to come into contact with the optic nerve or retinal tissue (for example, evisceration of the eye and intra-orbital implant).\n\n## Operations on optic nerve (A29.1\xa0to\xa0A36.4)\n\nA29.1 Excision of lesion of optic nerve\n\nA30.1 Repair of optic nerve\n\nA32.1 Decompression of optic nerve\n\nA34.1 Exploration of optic nerve\n\nA36.4 Radial Optic Neurotomy\n\n# Sclera and iris (C52\xa0to\xa0C65)\n\nC54 Buckling operations for attachment of retina\n\n# Retina, other parts of eye and anaesthetics (C79\xa0to\xa0C90)\n\nC79 Operations on vitreous body, only when this involves potential contact with the posterior hyaloid face. For example:\n\n\n\nCode\xa0C7910 for vitrectomy via anterior approach and code\xa0C7923 for intravitreal injections are specifically excluded because they are unlikely to come into contact with the posterior hyaloid face.\n\nCode\xa0C7920 and code\xa0C7922, which potentially could come into contact with the hyaloid face, are included.\n\n\n\nC80 Operations on retinal membrane\n\nC81 Photocoagulation of retina for detachment, only when the retina is handled directly\n\nC82 Destruction of lesion of retina, only when the retina is handled directly\n\n\n\nCode C82.4 for insertion of radiotherapy plaques is specifically excluded.\n\n\n\nC83 Translocation of retina\n\nC84 Other operations on retina\n\nC85 Fixation of retina\n\nC86 Other operations on eye\n\nC88 Destruction of subretinal lesion\n\nC89 Operations on posterior segment of eye\n\nISBN: 978-1-4731-3605-2'}
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https://www.nice.org.uk/guidance/ipg666
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Evidence-based recommendations on reducing the risk of transmission of Creutzfeldt–Jakob disease (CJD) from surgical instruments used for interventional procedures on high-risk tissues. These procedures on high-risk tissues are intradural surgery on the brain (including the pituitary gland) and spinal cord, neuroendoscopy, and surgery on the retina or optic nerve.
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05349a5df55abfe48d1bd7fd6d939fea88440196
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nice
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Supporting adult carers
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Supporting adult carers
This guideline covers support for adults (aged 18 and over) who provide unpaid care for anyone aged 16 or over with health or social care needs. It aims to improve the lives of carers by helping health and social care practitioners identify people who are caring for someone and give them the right information and support. It covers carers’ assessments, practical, emotional and social support and training, and support for carers providing end of life care.
# Context
The 2011 Census indicated that there were around 6.5 million unpaid carers in the UK, with 1.3 million being over 65. Most carers were aged between 50 and 64 but people aged 65 and over made up a higher proportion of carers (19%) than in the population as a whole.
Carers UK (2015) estimated that the number of carers will increase to 9 million by 2037. This rise is linked with a number of factors, not least the increasing number of people aged over 85 (the group most likely to need care and support), which is expected to increase to 1.9 million by 2020 (Office for National Statistics). Other pressures include the continued closure of care and nursing homes and the increased use of care at home (The state of health care and adult social care in England 2018/19, Care Quality Commission). In addition, according to a survey conducted by Dying Matters, 70% of people expressed a wish to stay in their own home, and to die at home rather than in hospital or a nursing home. This is likely to further increase reliance on family members and friends.
Despite the recognised pressures, both Carers UK's State of caring report 2019 and the Government response to the 2016 carers call for evidence (in advance of the Carers action plan 2018 to 2020) report clear evidence that many carers did not feel adequately supported and that although caring can be immensely rewarding, many found that they did not feel respected, valued and supported for the contribution they made. Guidelines on supporting carers are therefore urgently needed.
Caring for someone can take its toll on a person's health and wellbeing. According to Carers UK (Juggling work and unpaid care), almost 1 in 10 UK adults have given up work or reduced their hours to accommodate care. Leaving or reducing work affects carers' own independence and wellbeing and their contribution to the economy. This may also have a substantial effect on their former employers' productivity and lead to high costs in recruitment and training.
Carers may also give up other activities and may face isolation; they may report feelings of depression and a reduced quality of life. Good quality, consistent support helps to address this, providing benefits for the health, wellbeing and resilience of unpaid carers. It can also enhance the life of the person being supported and help to reduce admissions to hospital and support earlier discharge. However, the amount and quality of support available to unpaid carers varies widely across the UK. Even where it is available, it may be neither appropriate nor affordable and complex local systems can be difficult to navigate with little guidance and direction (Government response to the 2016 carers call for evidence).
A key barrier to the provision of appropriate support to carers is that they are often not identified. Many carers do not think of themselves as carers or are not identified by health and social care practitioners as such (so called 'hidden carers') and do not know about the support available. The Care Act 2014 and Department of Health and Social Care's Care and support statutory guidance attempted to address this, substantially strengthening the rights and recognition of adult carers within the social care system. The Act entitles carers to assessment in their own right, together with information and advice to help them make the best choices about support for their own health and wellbeing. The Care Act defines a carer as an adult, aged 18 or over, who provides, or intends to provide, care for another adult who needs care because of a disability, health condition, frailty, mental health problem, addiction or other health or care needs. It excludes those who provide paid care or do so as voluntary work.
The Care Act introduces carer support plans setting out how identified and eligible needs may be met, including personal budgets and the option of direct payments. These duties reflect the emphasis on universal personalised support for carers as set out in the NHS long term plan (NHS England). However, it is still the case that only a small proportion (in one area estimated as 7%) are identified as unpaid carers by social care and health organisations, so many are missing out on help and support.
This guideline provides action-orientated recommendations for good practice, aimed at improving outcomes for adult carers. The guideline is based on the best available evidence of effectiveness, including cost effectiveness, as well as evidence on the views and experiences of carers, people using services and practitioners. It identifies good practice in providing support that enhances the wellbeing, resilience and life experience of adult carers.
The guideline covers information and support for carers; identifying carers and assessing their needs; helping carers stay in, enter or return to employment and training; providing community support, training, psychological and emotional support for carers; and providing support during changes to the caring role and during the end of life period of the cared-for person.
The guideline complements statutory duties and good practice as set out in relevant legislation and guidance. The recommendations cross-refer to legislation and other guidance where appropriate. In particular, the guideline takes account of the relationship between the Children and Families Act 2014 and the Care Act 2014, recognising that many young carers will transition into adult caring roles and that many parent carers will similarly transition into caring roles for their adult children. It also takes account of NHS England's Carers toolkit, the latest National carers strategy and the Carers action plan 2018 to 2020, and the Care and support statutory guidance.
Most carers will need support from a number of different services, including the NHS. The NHS long term plan emphasises the vital contribution of carers and the need for more integrated and personalised support (including greater use of personal health budgets). The Care Act 2014 expects the NHS and social care to work together and where possible to integrate services and support. The Care Quality Commission has introduced Quality Markers in Primary Care (usually the first means of identifying carers) and the Association of Directors of Adult Social Services (ADASS) Carers Policy Network reports encouraging evidence of greater cooperation between health and social care in their regularly updated Guide to efficient and effective interventions for implementing the Care Act. Similarly, principles of co-production and interventions such as Think Local Act Personal (TLAP)'s 'Make it real' offer new approaches to more actively engaging carers as 'experts by experience' and co-designing their own care and support.
NICE guidelines provide recommendations on what works. This may include details on who should carry out interventions and where. NICE guidelines do not routinely describe how services are funded or commissioned, unless this has been formally requested by the Department of Health and Social Care.# Recommendations
People have the right to be involved in discussions and make informed decisions about their care as described in your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity) and safeguarding.
# Information and support for carers: overarching principles
## The right to information and support
Local authorities should provide information to carers to support them in their caring role. Information provision must meet the requirements of the Care Act 2014.
Practitioners in health and social care (including healthcare professionals in primary and secondary care, social care practitioners, care and support workers and personal assistants) should use every opportunity to tell carers they have a right to information and support and how to get it (see section 1.2).
Information for carers should be up to date and cover:
the range of support and advice recommended in this guideline
how to access social and community support for carers (see section 1.5)
useful further sources of information and support such as carer groups and forums.
For a short explanation of why the committee made these recommendations see the rationale and impact section on the right to information and support .
Full details of the evidence and the committee's discussion are in evidence review B: providing information and advice about caring to carers in the UK.
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## Sharing information with carers
Discuss information with carers as well as giving them written materials. When providing information:
ensure it is plainly worded, clearly presented and free of jargon
be aware that smaller, more manageable chunks of information are easier to remember, and that visual aids or pictures can be useful
encourage the carer to ask questions
ensure that information is consistent.
Make information available in a range of formats to meet carers' needs and preferences, for example written leaflets, links to online and digital resources (including local and national websites and forums and social media) and information in accessible formats or different languages. For more about accessible communication see NHS England's Accessible Information Standard.
Take into account that carers' information needs will change over time and whenever their circumstances or caring role change. Provide information and advice that addresses the carer's individual needs at the time when they need it and that helps them plan and prepare.
Offer to revisit discussions or provide the same information several times if needed, for example if there is a lot of complicated information to digest or the carer is experiencing emotional stress.
Practitioners responsible for providing and discussing information with carers should have the knowledge, time and communication skills to do so.
Primary care providers and primary care networks should explore ways of offering and promoting services to carers, including through partnership working (for example, working with local carer support services or nominating carer champions).
For a short explanation of why the committee made the recommendations on sharing information with carers and how they might affect practice see the rationale and impact on sharing information with carers .
Full details of the evidence and the committee's discussion are in evidence review B: providing information and advice about caring to carers in the UK and evidence review D: work, education and training. Other supporting evidence and discussion can be found in evidence review A: identifying carers as defined by the Care Act 2014 and evidence review F: providing practical support for adult carers.
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## Working with and involving carers
Health and social care organisations should promote ways of working with carers that acknowledge them as expert partners in care and value their skills and knowledge about the person they care for. These approaches should be incorporated into formal policies and processes.
Health and social care practitioners should work in partnership with carers and treat them as a valued member of the care team around the person being cared for, with the person's consent. This should include involving carers in decision making and care planning and keeping them up to date.
During discussions with carers about the person they are caring for:
take into account the mental capacity of the person being cared for and their wishes around confidentiality (see NICE's guideline on decision making and mental capacity)
share with carers the information they need to provide care effectively and safely while respecting confidentiality (explain to them the constraints of confidentiality).
Be open and honest with carers about the health condition, disability or needs of the person they care for (with the person's consent), including when information is difficult or upsetting. Explain how it is likely to progress so that carers understand how their caring role might change in the future.
For a short explanation of why the committee made the recommendations on working with and involving carers and how they might affect practice see the rationale and impact section on working with and involving carers .
Full details of the evidence and the committee's discussion are in evidence review A: identifying carers as defined by the Care Act 2014 and evidence review B: providing information and advice about caring to carers in the UK.
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# Identifying carers
## Recommendations for health and social care practitioners
Actively seek to identify carers (in line with the requirements of the Care Act 2014) and ensure that they know:
about their right to a carer's assessment, what this is and the benefits of having one
how to obtain a carer's assessment
that some support may be means tested
that they can still access community support without formal assessment.
Use every opportunity to identify carers, including GP appointments, flu jab appointments, home visits, outpatient appointments, social care and other needs assessments, including admission and discharge assessments and planning meetings. Record details about carers you have identified (with the carer's consent).
Take into account that carers themselves may not ask for support from certain professionals, for example GPs, because they may not view support for carers as being part of that professional's role.
When identifying carers, be aware that some people may not view themselves as a carer because:
becoming a carer can be a gradual process, and carers may not recognise the changing nature of their relationship with the person they support
carers may prefer to continue identifying primarily as a husband, wife, partner, sibling, parent, child or friend rather than as a carer
carers often become engulfed by competing demands, including working and caring, and as a result may overlook their own needs as a carer and may not seek support
the person being supported may not accept that they have care and support needs
the carer does not live with the person or the person has moved away from home, for example into supported living or residential care.
Encourage carers to recognise their caring role and seek support, explaining the benefits for both them and the person they care for, including:
the carer's role and contribution can be acknowledged and their support needs addressed and
carers can share valuable knowledge about the person they care for, which helps practitioners provide the right care and support.
Ask people with care and support needs whether anyone gives them help or support, apart from paid practitioners. Avoid making assumptions about who might be providing their care. Take into account that:
-ther people offering help or support may not be family members or may not live with the person
there may be more than 1 person involved in caring.
Practitioners involved in transferring people to and from hospital should seek to identify carers and refer them to appropriate services.
Follow recommendations on support for families, parents and carers throughout admission in NICE's guideline on transition between inpatient mental health settings and community or care home settings and
Follow recommendations on discharge from hospital in NICE's guideline on transition between inpatient hospital settings and community or care home settings for adults with social care needs.
Offer carers the opportunity to have confidential conversations about their own needs as carers separately from the person they are supporting.
If a person who has care and support needs is also identified as having caring responsibilities, their care and support needs assessment should take account of this. They should also be offered a carer's assessment to identify their needs as a carer. Assessments must meet the requirements of the Care Act 2014.
Ensure that carers who don't want or need a statutory carer's assessment are still offered information about how to access support.
For a short explanation of why the committee made the recommendations for health and social care practitioners on identifying carers and how they might affect practice see the rationale and impact section on identifying carers: recommendations for health and social care practitioners .
Full details of the evidence and the committee's discussion are in evidence review A: identifying carers as defined by the Care Act 2014. Other supporting evidence and discussion is in evidence review H: support needs of adult carers who are caring for people at the end of life and evidence review I: supporting carers during changes to the caring role.
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## Recommendations for health and social care organisations
Health and social care organisations should encourage people to recognise their role and rights as carers through:
publicity campaigns involving local community services, for example posters and leaflets in GP surgeries, libraries and pharmacies
digital communications, social media and online forums that engage with carers
partnerships with community pharmacies, local carer support organisations and carer groups, for example in hospital settings
partnerships with local community organisations who can help disseminate information more widely, such as further education colleges, sports centres and supermarkets.Use descriptions that carers will relate to and include details of where to find further information and advice.
Consider nominating a carer champion to help implement the recommendations in this guideline and Care Act 2014 requirements in relation to identifying carers.
Health and social care organisations should ensure their policies and systems encourage the identification of carers, including by developing formal processes to help them do so.
Ensure that all staff likely to come into contact with carers understand their responsibilities under the Care Act 2014 in relation to identifying carers.
For a short explanation of why the committee made the recommendations for health and social care organisations on identifying carers and how they might affect practice see the rationale and impact section on identifying carers: recommendations for health and social care organisations .
Full details of the evidence and the committee's discussion are in evidence review A: identifying carers as defined by the Care Act 2014.
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# Assessing carers' needs
## Carers' assessments
Local authorities, and social care organisations delegated by local authorities to carry out carers' assessments, should make arrangements for and carry out assessments in cooperation with other relevant health and social care organisations (in accordance with the Care Act 2014 and associated Care and support statutory guidance and the Children and Families Act 2014).
Practitioners from health and social care carrying out or contributing to carers' assessments should work together to ensure that:
the assessment covers all relevant aspects of health, wellbeing and social care needs and
details of the assessment are shared with other practitioners and organisations who are involved in the assessment.
Health and social care organisations should ensure that practitioners who carry out or contribute to carers' assessments have training and skills in that role and access to specialist advice.
The carer's assessment should be jointly produced with the carer and reflect what matters most to the carer and what might help them achieve this.
Be aware that a well-conducted carer's assessment may in itself be a therapeutic intervention or a means of preventing future problems.
For a short explanation of why the committee made the recommendations on carers' assessments and how they might affect practice, see the rationale and impact section on carers' assessments .
Full details of the evidence and the committee's discussion are in evidence review C: assessment of carers as defined by the Care Act 2014.
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## Preparing for and carrying out a carer's assessment
Arrange the timing of the carer's assessment according to the carer's preferences and the urgency of their need for support. For example, take into account:
whether the person they care for is near the end of life
the level of stress the carer is experiencing
the timing of hospital discharge
changes to the caring role
any negative impact of delays on the health and wellbeing of the carer.
Provide flexibility in how, when and where carers' assessments are carried out, taking into account individual preferences and accommodating their caring responsibilities, working patterns and other circumstances.
Ensure that the assessment process is accessible, easy to navigate and complete, and tailored to individual needs, with information provided in a format that carers can understand.
Before a carer's assessment takes place, share information with the carer that helps them prepare.
Discuss caring in the context of the carer's own family and support networks, for example whether they share caring responsibilities with other people and whether they care for more than 1 person.
Discuss with carers the option to combine or link their assessment with the assessment of the person they care for, if they both choose to do this.
Do not make assumptions about the willingness and the ability of carers to carry out caring tasks when completing assessments for the carer or the person they care for.
If a carer's needs have been identified during a hospital-based assessment:
inform the local authority (and/or any delegated care organisation) that a carer's needs have been identified
ensure an effective process is in place to link the hospital-based carer's assessment with the community-based statutory assessment, to avoid duplication and so that meaningful support for carers is provided during transfer from hospital (including during a crisis).
Ensure that replacement care is discussed as part of carers' assessments, including planning for any emergency replacement care that might be needed, for example if the carer becomes suddenly unwell.
For a short explanation of why the committee made the recommendations on preparing for and carrying out a carer's assessment and how they might affect practice see the rationale and impact section on preparing for and carrying out a carer's assessment .
Full details of the evidence and the committee's discussion are in evidence review C: assessment of carers as defined by the Care Act 2014 and evidence review D: work, education and training.
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## Work, education and training
Discuss education, training and employment with carers during their carer's assessment. Explore the options and the support they need to remain in, start or return to work, training or education. This could include providing replacement care at home.
Ensure that practitioners carrying out carers' assessments have the necessary skills, knowledge and understanding of potential opportunities for returning to, or remaining in work, education and training.
Give carers tailored information about community services and support that could help them remain in, start or return to work.
For a short explanation of why the committee made the recommendations on work, education and training and how they might affect practice see the rationale and impact section on work, education and training .
Full details of the evidence and the committee's discussion are in evidence review D: work, education and training.
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## After a carer's assessment
Ensure there are clearly identified outcomes for the carer after their assessment.
After an assessment:
ensure the carer understands the actions that have been agreed and what the next steps will be and
share information (as appropriate) with other practitioners and organisations involved with the carer and the person they care for.
If a carer support plan is developed as a result of a carer's assessment, ensure it is monitored and reviewed regularly.
For a short explanation of why the committee made the recommendations on after a carer's assessment and how they might affect practice see the rationale and impact section on after a carer's assessment .
Full details of the evidence and the committee's discussion are in evidence review C: assessment of carers as defined by the Care Act 2014 and evidence review D: work, education and training.
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# Helping carers stay in, enter or return to work, education and training
## Advice and support
Local authorities should ensure carers have access to tailored advice about balancing work, education or training with caring, including associated benefits and welfare advice.
Services providing welfare rights advice or back-to-work or education training should develop a good understanding of carer needs, for example by appointing a named carer champion who can provide knowledgeable, expert advice and train other practitioners in the service.
Services providing welfare rights advice or back-to-work or education training should help carers recognise that the skills they have gained through caring are transferable, and support them to describe their skills in a way that will appeal to employers.
Workplaces should make information available to their staff about ways in which they can support employees who need to balance caring responsibilities with work. See NICE's guideline on workplace health.
For a short explanation of why the committee made the recommendations on advice and support for helping carers stay in, enter or return to work, education and training and how they might affect practice see the rationale and impact section on helping carers stay in, enter or return to work, education and training: advice and support .
Full details of the evidence and the committee's discussion are in evidence review D: work, education and training. Other supporting evidence and discussion can be found in evidence review A: identifying carers as defined by the Care Act 2014.
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## Flexibilities to support employment
Practitioners should encourage carers to discuss supportive working arrangements with their employers, including adjustments to make caring possible. Examples might include flexible hours, fixed hours or shifts, carers' leave, permission to use a mobile phone, technology to allow flexible working, or providing a private space to take personal phone calls.
Workplaces should offer flexible working arrangements to enable staff to balance caring responsibilities with work, and other initiatives that support mental wellbeing for carers in line with the NICE guidelines on workplace health and mental wellbeing at work.
Workplaces should ensure that staff with caring responsibilities have equal access to career development. At a minimum, workplaces must meet the requirements set out in the Equality Act 2010 in relation to people with caring responsibilities.
Health and social care organisations should offer flexibility when arranging appointments for working carers and the person they care for. Examples include workplace surgeries, carer appointments outside of office hours, digital access and telephone appointments.
Carer support services should work closely with employers and employee assistance programmes to make advice and information for carers available within the workplace.
For a short explanation of why the committee made the recommendations on flexibilities to support employment and how they might affect practice see the rationale and impact section on flexibilities to support employment .
Full details of the evidence and the committee's discussion are in evidence review D: work, education and training.
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## Replacement care
Commissioners should be aware of the benefits of replacement care for supporting carers to stay in, enter or return to work, education and training when designing and delivering support services for carers.
Commissioners should ensure that replacement care services are available locally for carers who need to access them to stay in, enter or return to work, education or training, including for those who fund their own support.
Ensure that replacement care is flexible and provides a choice of options to meet all levels of carer need, including for those who care for more than 1 person or who care for over 20 hours a week.
Review replacement care often enough to respond to changes in people's working patterns and career development.
For a short explanation of why the committee made the recommendations on replacement care and how they might affect practice see the rationale and impact section on replacement care .
Full details of the evidence and the committee's discussion are in evidence review D: work, education and training.
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# Social and community support for carers
## Community information, advice and support
Local authorities should ensure carers are kept regularly informed about available community services and other sources of support and advice and how to access them, for example:
local carer support services
self-help groups
community and faith groups
specialist benefits, financial and legal advice
financial support
advice about self-care
where to find reliable information about the health condition of the person they are caring for.
For a short explanation of why the committee made the recommendation on community information, advice and support and how it might affect practice see the rationale and impact section on community information, advice and support .
Full details of the evidence and the committee's discussion are in evidence review F: providing practical support for adult carers
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## Carers' breaks
Health and social care practitioners should regularly discuss with carers the value of having a break from their caring role and explain the options available.
Carers' breaks should:
meet carers' needs for a break, for example in duration, timing, frequency and type of break
be arranged in a way that provides reliable and consistent support to the carer (such as avoiding last-minute changes that could lead to additional stress for the carer).
For a short explanation of why the committee made the recommendations on carers' breaks and how they might affect practice see the rationale and impact section on carers' breaks .
Full details of the evidence and the committee's discussion are in evidence review F: providing practical support for adult carers.
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## Peer support
Tell carers about peer support and how to access it locally. Explain that peer support can help reduce a sense of isolation, provide empathy and social and emotional support, and enable them to share information.
## Support for former carers
Consider extending support services for people when their caring role is finished, including through peer support groups.
For a short explanation of why the committee made the recommendations on peer support and support for former carers and how they might affect practice see the rationale and impact section on peer support and support for former carers .
Full details of the evidence and the committee's discussion are in evidence review F: providing practical support for adult carers.
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## Advocacy
Local authorities should provide information to carers about how to access advocacy support services. Access to advocacy services should meet the requirements of the Care Act 2014 and the Mental Capacity Act 2005.
If carers choose to have an advocate or representative to support them, health and social care practitioners should recognise this person's contribution and include them in discussions.
For a short explanation of why the committee made the recommendations on advocacy and how they might affect practice see the rationale and impact section on advocacy .
Full details of the evidence and the committee's discussion are in evidence review F: providing practical support for adult carers.
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# Training to provide care and support
Offer training to enable carers to provide care safely. Training could include structured programmes or one-to-one guidance from a practitioner.
Commissioners and those involved in planning local carer support services should ensure that the provision of carer training meets local needs.
Involve carers in the design and delivery of carer training to ensure it covers skills and expertise relevant to them.
## Carer training programmes
Offer carer training programmes that are:
designed to improve carers' knowledge and coping skills
accessible and available in a variety of formats, including printed or online materials or face to face
tailored to the needs of carers
delivered by practitioners with relevant knowledge and skills.
Training programmes for carers should include the following components, as relevant:
general education about the health condition, disability or needs of the person they care for
skills training to help them provide care, including how to understand and respond to changes in mood and behaviour
principles of self-care
training in communication skills to improve interactions with the person they care for
advice on planning enjoyable and meaningful activities with the person they care for
information about relevant services and how to access them
future planning, including preparing for transitions.
Consider including the following in carer training programmes, as relevant:
managing medicines
managing diet and nutrition
maintaining personal hygiene
managing behaviour that challenges
use of digital and assistive technology
specific information that carers need to enable them to remain safe in their caring role.
Ensure that training programmes for carers are inclusive and address the needs and preferences of diverse groups, such as lesbian, gay, bisexual and transgender carers, and carers from diverse ethnic, religious and cultural backgrounds.
Training programmes for carers should provide a balance between learning, enjoyment, a chance to meet other carers and opportunities for peer support.
Encourage carers to keep in touch with each other after they have attended a training programme and suggest ways they could do this.
For a short explanation of why the committee made the recommendations on training to provide care and support, including carer training programmes, and how they might affect practice see the rationale and impact section on training to provide care and support .
Full details of the evidence and the committee's discussion are in evidence review E: providing training for carers to provide practical support.
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## Use of equipment and adaptations, and moving and handling
Health and social care practitioners should involve carers during assessments for equipment and adaptations.
Health and social care practitioners should ensure carers have access to advice, guidance and training about appropriate use of equipment and adaptations, and safe moving and handling techniques.
For a short explanation of why the committee made the recommendations on use of equipment and adaptations, and moving and handling, and how they might affect practice see the rationale and impact section on use of equipment and adaptations, and moving and handling .
Full details of the evidence and the committee's discussion are in evidence review E: providing training for carers to provide practical support
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# Psychological and emotional support for carers
## Psychosocial and psychoeducational support
Consider providing carers with psychosocial and psychoeducational support, which should include:
developing personalised strategies and building carer skills
advice on how to look after their own physical and mental health, and their emotional and spiritual wellbeing
information about emotional support services and psychological therapies for carers and how to access them.
Ensure that the range of psychosocial and psychoeducational support offered to carers includes group-based options.
Recognise that psychosocial and psychoeducational support may be needed at different stages of the caring experience and ask carers regularly whether they feel they would benefit from it.
Arrange the timing of psychosocial or psychoeducational support to suit carers' circumstances, taking into account other commitments such as work or other caring and family responsibilities.
When providing psychosocial or psychoeducational support to carers, take into account:
the carer's preferred location
whether they need support to attend (for example a practitioner to go with them)
physical accessibility (such as help needed with transport)
if replacement care is needed
the carer's preferred format
the cultural appropriateness of the intervention
what follow-up will be needed.
For a short explanation of why the committee made the recommendations on psychosocial and psychoeducational support for carers and how they might affect practice see the rationale and impact section on psychosocial and psychoeducational support for carers .
Full details of the evidence and the committee's discussion are in evidence review G: providing psychological and emotional support to adult carers.
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## Psychotherapy and counselling
If a carer has an identified mental health problem, consider:
psychotherapy and counselling interventions in line with existing NICE guidance (see NICE's topic page for mental health and behavioural conditions) or
referral to a GP or mental health professional who can provide interventions in line with existing NICE guidance.
For a short explanation of why the committee made the recommendation on psychotherapy and counselling and how it might affect practice see the rationale and impact section on psychotherapy and counselling .
Full details of the evidence and the committee's discussion are in evidence review G: providing psychological and emotional support to adult carers
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# Support during changes to the caring role
Be aware that caring responsibilities may not end when the person being cared for moves away from home, for example into a residential care home.
Provide information and emotional and practical support to help carers prepare for and adjust to changes in their role, for example if the person they care for:
becomes an adult
makes the transition to adult services (see NICE's guideline on transitions from children's to adults' services)
moves away from home
has a significant change in their health
becomes terminally ill or needs end of life care (for recommendations on care near the end of life see NICE's guideline on care of dying adults in the last days of life)
dies unexpectedly.
Provide information and emotional and practical support to carers when their circumstances change, for example when they:
start or go back to work
move from being a young carer to an adult carer
have a change in benefits or financial circumstances
go through personal changes (such as divorce)
take on another caring role
go into hospital
are bereaved
become less able to care as they get older.
For recommendations about support and training for carers during transitions between hospital and home, see NICE's guideline on transition between inpatient hospital settings and community or care home settings for adults with social care needs, in particular:
recommendations on communication and information sharing
and
recommendations on support and training for carers.
For a short explanation of why the committee made the recommendations on support during changes to the caring role and how they might affect practice, see the rationale and impact section on support during changes to the caring role .
Full details of the evidence and the committee's discussion are in evidence review I: supporting carers during changes to the caring role.
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# Support for carers during end of life care and after the person dies
## Information and support
Offer carers frequent opportunities for discussion and help them to understand information about the diagnosis and prognosis of the person they care for (with the person's consent). Use a sensitive manner during these discussions and avoid jargon.
Health and social care practitioners involved in providing end of life care should be competent to have conversations with carers about death and dying.
Practitioners should establish early contact with carers involved in providing end of life care. Discuss with carers how best to support them, taking into account that unsatisfactory early contact with health and social care services can have a long-lasting negative impact on carers involved in providing end of life care.
Health and social care practitioners, including home care workers, should recognise that carers can find it hard to accept help at home when they are providing end of life care and can find it invasive.
Provide continuity during end of life care with the same professional care staff wherever possible, so that the carer and the person they care for can build a relationship with the staff supporting them.
Encourage carers who are caring for someone near the end of their life to think about ways they can get support from their family, friends, employer and wider social network.
## Advance care planning
Involve carers in advance care planning if the person being cared for consents to this. For recommendations about involving carers in advance care plans for people who may lack mental capacity, see NICE's guideline on decision making and mental capacity.
When making an advance care plan that includes responsibilities for carers, consider the wishes of any current or future carers who have been named in the plan.
Ensure the carer has a clear understanding of their role as part of the advance care plan. Share advance care plans in a clear and simple format with everyone involved in the person's care.
## Providing care at the end of life
When managing medication and other care at the end of life, follow the principles of involving carers and the dying person described in NICE's guideline on care of dying adults in the last days of life.
During a structured medication review, as described in recommendations on medication review in NICE's guideline on medicines optimisation, take into account:
the person's, and their family members' or carers' where appropriate, views and understanding about their medicines
the person's, and their family members' or carers' where appropriate, concerns, questions or problems with the medicines.
Help carers who are providing end of life care at home to access local services that could support them, including from local hospices. This could include:
replacement care
palliative home care
practical support, for example to use equipment and adaptations
additional help in the home.
Provide privacy and dignity for people dying in hospital and their carers. This could include offering them a private room or, if this is not possible, alternatives such as:
private space
space to keep personal possessions from home
flexible visiting times and tailored arrangements for carers
comfortable seating for the carer
access to refreshments.
Give carers of people at the end of life up-to-date and accurate information and advice about financial, legal and logistical issues they need to address when preparing for or following the death of the person they care for.
Take account of the changing information and support needs of carers in planning for their own future when the person they care for dies. This should include discussing with carers how to address their own support needs after the death of a mutual carer.
For a short explanation of why the committee made the recommendations on support for carers during end of life care and after the person dies and how they might affect practice see the rationale and impact section on support for carers during end of life care and after the person dies .
Full details of the evidence and the committee's discussion are in evidence review H: support needs of adult carers who are caring for people at the end of life.
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# Terms used in this guideline
## Carers
In this guideline, a carer is an adult (aged 18 or over) who provides unpaid care and support to a family member, partner or friend (aged 16 or over) because of a disability, health condition, frailty, mental health problem, addiction or other health or social care need.
## Carer champion
A designated member of staff (for example in a GP surgery, hospital, workplace, leisure or similar setting) who is given the task of supporting and speaking up for carers. They can act as a key contact for carer information and advice in that setting, providing knowledgeable, expert advice as well as training other practitioners working within the service.
## Carer support plan
If a carer is identified as having eligible needs following an assessment under the Care Act 2014, the local authority must provide a support plan that sets out how those needs will be met. The support plan must be developed in partnership with the carer and should set out the outcomes the carer hopes to achieve, including their wishes around providing care and accessing work, education and leisure. The support plan must be regularly reviewed.
## Carer's assessment
Anyone who is an unpaid carer for a family member or friend has the right to discuss their own needs with their local authority, separate to the needs of the person they care for. This is a statutory requirement under the Care Act 2014. Carers can discuss anything they think would help with their own health and wellbeing or with managing other aspects of their life, including their caring role. The local authority uses this information to decide what help it can offer.
## Carers' breaks
These services, which would include respite care, give carers a break by providing short-term care for the person with care needs in their own home or in a residential setting. This can mean a few hours during the day or evening, overnight, or a longer-term break. Carers' breaks may be one-off or more regular arrangements. They can also benefit the person with care needs by giving them the chance to try new activities and meet new people.
## Peer support
Peer support involves carers sharing experiences, practical advice and emotional support and improving their understanding of the options available to them and the person they care for. Peer support can take a number of different forms, including one-to-one friendships and support based on lived experience and contact through third sector organisations, support groups or online networks. Peer support is often but not always provided by volunteers, for example volunteer befrienders.
## Replacement care
Care that replaces the care normally given by a regular carer. It may be needed either on a planned basis or in an emergency. Replacement care may be offered by the local authority, if the person needing care has had an assessment and is entitled to care and support services, or if the carer is entitled to help. Otherwise, people may have to pay for it.
These definitions are based on Think Local, Act Personal's care and support jargon buster. See the jargon buster for other social care terms used in this guideline.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Key recommendations for research
## Whole family approach to carer's assessment
What is the effectiveness, cost effectiveness and acceptability of the whole family approach to carers' assessments?
For a short explanation of why the committee made the research recommendation on whole family approach to carers' assessment see the rationale and impact section on carers' assessments .
Full details of the research recommendation are in evidence review C: assessment of carers as defined by the Care Act 2014.
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## Support for carers to return to work, employment or training
What is the effectiveness of personal health and social care budgets in supporting carers to return to work, education or training?
For a short explanation of why the committee made the research recommendation about support for carers to return to work, employment or training see the rationale and impact section on helping carers stay in, enter or return to work, education and training: advice and support .
Full details of the research recommendation are in evidence review D: work, education and training.
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## Training for carers to reduce caring-related incidents
What training, support or interventions help to reduce caring-related accidents or incidents?
For a short explanation of why the committee made the research recommendation about training for carers to reduce caring-related incidents see the rationale and impact section on training to provide care and support .
Full details of the research recommendation are in evidence review E: providing training for carers to provide practical support.
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## Practical support through carer passport schemes
What is the effectiveness, cost effectiveness and acceptability of carer passport schemes?
For a short explanation of why the committee made the research recommendation about practical support through carer passport schemes see the rationale and impact section on carers' breaks .
Full details of the research recommendation are in evidence review F: providing practical support for adult carers.
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## Practical support for carers through social prescribing
What is the effectiveness, cost effectiveness and acceptability of social prescribing for carers?
For a short explanation of why the committee made the research recommendation about practical support for carers through social prescribing see the rationale and impact section on peer support and support for former carers .
Full details of the research recommendation are in evidence review F: providing practical support for adult carers.
Loading. Please wait.# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.
# The right to information and support
Recommendations 1.1.1 to 1.1.3
## Why the committee made the recommendations
The committee used themes in the qualitative evidence to build on statutory guidance about the key principles of providing information and support to carers. Under the Care Act 2014, local authorities must establish and maintain a service for providing people with information and advice relating to support for carers. However, many carers are unaware of the advice and services available, or they may not have time to search for them. The committee wanted to emphasise the importance of signposting carers to useful local services and up-to-date sources of information and that health and social care practitioners should pass this information to carers whenever they get the chance.
## How the recommendations might affect practice
Information provision varies, so in some areas additional training and review of current information provision may be needed. Providing information is a statutory requirement, and giving carers the right information, advice and support at the right time can help them continue caring while managing other aspects of their lives. Any costs would be outweighed by the benefits of helping to avoid crisis situations such as unplanned hospital admissions and carer health problems.
Full details of the evidence and the committee's discussion are in evidence review B: providing information and advice about caring to carers in the UK.
Return to recommendations
# Sharing information with carers
Recommendations 1.1.4 to 1.1.9
## Why the committee made the recommendations
There was good quality evidence from carers about how information sharing could be improved. This evidence guided recommendations about the way in which information should be delivered, including its format, style and timing of delivery and how to tailor it to what each carer needs and prefers.
One strong theme suggested that carers often receive information from multiple sources around the same time, emphasising the importance of professionals in different services working together to make sure they are giving consistent advice.
There was some limited evidence that primary care practitioners would like to promote care services to carers and are interested in formalising ways to do it. However only 1 example was identified for how this might be done within GP surgeries. The committee discussed this and reached the consensus that developing partnerships with other carer-related services and using carer 'champions' within teams are 2 ways they could do this.
## How the recommendations might affect practice
Following these recommendations would make information easier for carers to understand and retain, improve their experience and wellbeing, and their ability to give effective care. They may call for refinements to existing practice but do not imply any costly changes or radical new provision.
Details of the evidence and the committee's discussion are in evidence review B: providing information and advice about caring to carers in the UK and evidence review D: work, education and training. Other supporting evidence and discussion can be found in evidence review A: identifying carers as defined by the Care Act 2014 and evidence review F: providing practical support for adult carers.
Return to recommendations
# Working with and involving carers
Recommendations 1.1.10 to 1.1.13
## Why the committee made the recommendations
There was evidence that carers value being recognised and respected as core members of the team around the person they care for and that carers have valuable information to contribute to care planning and assessment. They are often key to understanding the person's needs and preferences, so these recommendations were made to promote their involvement. This approach should be incorporated in formal policies and processes to ensure it is consistent across organisations.
The evidence showed that to provide effective care, carers need sufficient information about the person they are caring for. However, in many cases this can clash with the person's right to confidentiality. The committee made a recommendation to address this issue and balance the different concerns.
There was strong evidence that carers value being kept up to date, even with difficult news about the condition of the person they care for. However, the evidence suggested that professionals are sometimes vague, euphemistic or evasive with difficult news, which carers don't find helpful. They prefer to have time to process and understand any new information, and to properly prepare for possible changes to their caring role in the future.
## How the recommendations might affect practice
The committee acknowledged that a little additional time may be needed for practitioners to keep carers up to date and well informed. However, the benefits include ensuring that care planning is based on accurate and detailed information, encouraging the carer in their role and respecting them as a core team member to help sustain the caring arrangement.
Details of the evidence and the committee's discussion are in evidence review A: identifying carers as defined by the Care Act 2014 and evidence review B: providing information and advice about caring to carers in the UK.
Return to the recommendations
# Identifying carers: recommendations for health and social care practitioners
Recommendations 1.2.1 to 1.2.10
## Why the committee made the recommendations
It is a requirement of the Care Act 2014 for local authorities to have due regard to the importance of identifying carers who may have support needs and explain the advice and support available to them. The quality of the evidence was fairly low but it found specific barriers to identifying carers, so the committee drew on these along with their own experience to recommend how to improve identification of carers. This included setting out a range of potential opportunities for practitioners to identify carers and record details about them – providing the carer gives consent.
In the committee's experience, there are many reasons why people may not identify as a carer and, even if people recognise they are in a caring role, they are still more likely to see their primary role in relation to that person as a family member or friend. Practitioners should take this into account in the way they communicate and work with carers.
There may be more than 1 person involved in a person's care and support, and the committee agreed that it is important that health and social care practitioners seek to identify all carers and to understand the context of their caring situation. This enables advice, support and assessments to be more likely to meet each carer's needs.
The committee agreed that recording information about carers as part of routine assessments can help to identify carers, especially when this information is shared with other health and social care practitioners, and there was evidence to support this.
The evidence also suggested that carers value discussions with practitioners where their caring is recognised and they are offered support. However, it can be challenging to have open conversations with carers about their own needs, especially with the person receiving the support present.
Carers may also have care needs of their own due to long-term health conditions or disability. Where this is the case, an assessment of both their own care and support needs and their carer support needs should take place in line with the requirements of the Care Act 2014.
Finally, the committee agreed that not all carers would want or need a formal statutory carers assessment, for example if they were managing well at that time, so it was important to give those carers information about how and where to access carer support services if they need them.
## How the recommendations might affect practice
The recommendations should have limited cost implications because they involve using existing opportunities to help identify carers. There may be some costs associated with improving how information about carers is recorded and used to improve identification and support. The committee recognised that as more people identify as carers and seek information and support, local authorities, together with partner organisations in health and social care, will need to consider how resources are best used to benefit as many carers as possible, as well as those most in need.
Full details of the evidence and the committee's discussion are in evidence review A: identifying carers as defined by the Care Act 2014. Other supporting evidence and discussion is in evidence review H: support needs of adult carers who are caring for people at the end of life and evidence review I: supporting carers during changes to the caring rolev.
Return to recommendations
# Identifying carers: recommendations for health and social care organisations
Recommendations 1.2.11 to 1.2.14
## Why the committee made the recommendations
The committee agreed that health and social care organisations need to be proactive about promoting carers' roles and rights to help more people to self-identify as carers and seek support – this would help them meet Care Act 2014 requirements. There was little evidence to support the recommendations, but in the committee's own experience, people would be more likely to identify as carers if they are presented with images and language that are directly relatable to their changing perceptions of themselves and their own needs as carers.
Qualitative evidence showed that practitioners welcomed both informal and formal systems and processes to help them better identify and subsequently support carers and the committee agreed that carers were likely to benefit from these initiatives.
Practitioners coming into contact with carers need to have good knowledge of their responsibilities under the Care Act 2014 in relation to identifying carers. By consensus, the committee agreed that one possible way to achieve this was for organisations to consider nominating 'carer champions' within their workforce to help other staff understand their responsibilities in this area.
## How the recommendations might affect practice
The recommendations could result in more carers seeking advice and support, which could lead to a higher demand for carers' support services. But they may also improve coordination between local authorities and other health and social care organisations in identifying carers and giving them support, leading to better care in turn for the person they care for.
Full details of the evidence and the committee's discussion are in evidence review A: identifying carers as defined by the Care Act 2014.
Return to recommendations
# Carers' assessments
Recommendations 1.3.1 to 1.3.5
## Why the committee made the recommendations
Recommendations were drafted to complement the Care Act 2014, other associated care and support statutory guidance, and the Children and Families Act 2014. These set out legal duties for local authorities, or social care organisations delegated by local authorities, to arrange and carry out carers' assessments.
The evidence that underpinned the recommendations was of variable quality but it found that:
carers find out about carers' assessments from various sources, but still have trouble understanding the process and getting an assessment
a lack of coordination across multiple services (for example between hospitals and community services) is an obstacle to the assessment process
practitioners from teams across health and social care need to work together on carers' assessments, but they do not always have the relevant skills and training
properly conducted, a carer's assessment provides carers with psychosocial and emotional benefits and may be thought of as a therapeutic intervention in itself.
The evidence was most limited on collaborative working and on carers' assessments as a therapeutic intervention, so for these recommendations the committee supplemented the evidence with their own experience and expertise.
The committee thought it was important that carers feel that they have co-produced the assessment and that it reflects what is most important to them. They also agreed it was important that practitioners carrying out carers' assessments should have access to specialist advice, for example about particular aspects of care and treatment of the person they care for, because this might influence the support needs of the carer.
There was no evidence on whether using the lead professional approach or the whole family approach can make collaborative working easier and more effective. The committee agreed to make a research recommendation on the whole family approach to carers' assessments (see research recommendation 1).
## How the recommendations might affect practice
The impact of the recommendations is likely to vary depending on how much local services already collaborate with each other and train their staff to take the initiative with assessments. Additional training or reviewing of service coordination may be needed in some areas, but because such assessments are statutory requirements, they should not introduce additional financial implications.
Full details of the evidence and the committee's discussion are in evidence review C: assessment of carers as defined by the Care Act 2014.
Return to recommendations
# Preparing for and carrying out a carer's assessment
Recommendations 1.3.6 to 1.3.14
## Why the committee made the recommendations
The quality of the evidence was mixed, so the committee supplemented the evidence with their own knowledge and experience.
Qualitative evidence reported that some carers found the assessment process difficult to follow. Some carers also struggled to understand what being 'entitled to an assessment' actually meant. The committee agreed that practitioners need to give carers a clear explanation of what a carer's assessment involves and provide information in advance so that carers are better prepared and have time to reflect on their needs as carers. The committee also used the themes reported in the evidence to suggest ways of making assessments more positive for carers by making them more accessible and person-centred.
Expert testimony suggested the context in which caring takes place may be complicated, for example someone may be caring for more than 1 person or may be sharing their care responsibilities with other people, and so the committee agreed assessors should take account of this.
According to the evidence, carers' assessments are sometimes carried out in conjunction with those of the person they care for, which in some cases can mean the carer's own needs are not separately assessed. This was also supported by expert testimony. The committee agreed on the importance of making sure the carer's needs are considered independently, while providing an option to link with the cared-for person's assessments.
The Care Act 2014 states that carers' assessments must include an assessment of the ability and willingness of the carer to provide care, so assessors must not make assumptions about how willing or able a carer is to perform any given caring tasks.
If an assessment is done in hospital, it needs to be forward-looking and connected to the completion of a statutory assessment by community staff. This helps to ensure meaningful support for carers during transfer from hospital, because the evidence showed that assessments by different services can be fragmented.
The evidence suggested that the provision of replacement care enables carers to return to or remain in work. Therefore, the committee agreed that replacement care should always be discussed during assessments.
## How the recommendations might affect practice
Carers' assessments are already statutory, so the implementation of these recommendations may only involve minor changes to existing practice. Some costs may be associated with retraining, or with implementing more flexible and individualised assessments, but the committee agreed these were implicit to what is an adequate assessment as required by the Care Act 2014. The committee considered that sharing information with carers in advance of the assessment so that they are prepared would not have significant complications. It could be facilitated by the creation of a frequently asked questions resource, for example.
Full details of the evidence and the committee's discussion are in evidence review C: assessment of carers as defined by the Care Act 2014 and evidence review D: work, education and training.
Return to recommendations
# Work, education and training
Recommendations 1.3.15 to 1.3.17
## Why the committee made the recommendations
Although there was no high-quality evidence, the committee was able to make recommendations in areas where the lower-quality evidence aligned with their own experience. Some qualitative evidence showed that carers valued being offered services, practical support and financial support to stay in work, education and training. Evidence also suggested there may not be enough opportunities presented during carers' assessments to encourage their use and uptake. This chimed with the committee's concern that practitioners carrying out assessments often overlook carers' wishes about work, education and training.
The committee agreed that it was important for assessing practitioners to have good local knowledge about these types of opportunities for carers, as well as the community support options available (such as replacement care) to help carers take up these opportunities if they wish.
## How the recommendations might affect practice
The recommendations might involve some changes to existing training and practice for practitioners carrying out assessments to make sure that work, education and training is covered routinely. They could also lead to changes in the levels of support needed by carers, and greater demand for services like replacement care. However, access to this support is a statutory right under the Care Act 2014, and any costs would be offset by the economic benefits to carers and wider society.
Full details of the evidence and the committee's discussion are in evidence review D: work, education and training.
Return to recommendations
# After a carer's assessment
Recommendations 1.3.18 to 1.3.20
## Why the committee made the recommendations
There was some evidence that after an assessment, carers don't always feel that they have received helpful information or advice. Although this evidence was low in quality, having mostly come from survey studies with uncontrolled and potentially biased participant samples, it was supported by the combined experience of the committee. They agreed that practitioners should always make sure an assessment leads to clear outcomes and practical benefits for the carer. This means ensuring good communication with other practitioners and organisations and carrying out any agreed actions.
The committee agreed that if a carer's support plan is prepared as a result of an assessment, it should be monitored and reviewed regularly to ensure it achieves outcomes that are important to the carer.
## How the recommendations might affect practice
The cost of implementing the actions identified as part of assessment will vary from case to case and will be informed by local eligibility requirements for funded support and on local arrangements for sharing information about carers' support requirements as well as monitoring and review. They should not have large cost implications and do not represent a significant change in practice.
Full details of the evidence and the committee's discussion are in evidence review C: assessment of carers as defined by the Care Act 2014 and evidence review D: work, education and training.
Return to recommendations
# Helping carers stay in, enter or return to work, education and training: advice and support
Recommendations 1.4.1 to 1.4.4
## Why the committee made the recommendations
The Care Act 2014 mandates providing information for carers on work, education and training, and the committee used a combination of evidence and expert consensus to build on that legal requirement. There was some evidence that a lack of information and advice, combined with the fragmented nature of local support services, often acted as barriers to carers remaining in, returning to or entering work, education and training. The committee agreed it was important to make widely available person-centred advice and information specifically for carers. This was supported by evidence that carers welcomed advice and information from practitioners who understood the particular challenges they face in combining work and caring, including associated benefits and welfare advice. One way that the committee proposed services may do this is by designating a 'carer champion' to offer expert advice when needed and to assist in training other practitioners working in the service about carers' needs and rights under the Care Act 2014.
There was some limited evidence showing the disadvantages experienced by young adult carers striving to balance work or education with caring. The committee also noted the difficulties often experienced by older carers wishing to retain or return to employment after the end of their caring roles. They agreed that carers may lack confidence about finding work, especially if they have spent years caring at the expense of education or training. They agreed by consensus that it was relevant for all carers to be encouraged to recognise their value to employers using the skills they have built up during caring.
There was a lack of evidence about the effectiveness of particular tools or approaches for supporting carers to return to work, education or training. Supported by expert testimony, the committee agreed that there was potential in further exploring whether the use of personal budgets, either for the person being cared for or the carer in their own right, might have positive outcomes for the carer. So the committee agreed to make a research recommendation about the effectiveness of personal health and social care budgets in supporting carers to return to work, education or training (see research recommendation 2).
## How the recommendations might affect practice
These recommendations reinforce legislation and should help to improve consistency of best practice. Changes needed to current practice will depend on the availability of carers' work-related support services in each area. Providing tailored advice of this kind may require some additional local investment, but this would be offset by substantial benefits for carers from being supported to continue working or learning alongside caring, leading to cost savings in the long term.
Full details of the evidence and the committee's discussion are in evidence review D: work, education and training. Other supporting evidence and discussion can be found in evidence review A: identifying carers as defined by the Care Act 2014.
Return to recommendations
# Flexibilities to support employment
Recommendations 1.4.5 to 1.4.9
## Why the committee made the recommendations
There was evidence that even small adjustments to working practices can have positive benefits for carers balancing paid work with caring responsibilities. Carers also reported that they often avoid discussing caring-related problems with employers for fear of negative attitudes from managers, feeling a burden, or being excluded from opportunities to develop their careers.
It is a requirement of the Equality Act 2010 for employers to actively promote a positive culture towards people with caring responsibilities. The committee agreed that this could include promoting opportunities for flexible working practices and use of employee assistance programmes that can provide advice and support for working carers, as well as ensuring that staff with caring responsibilities have equal access to career development opportunities.
Using expert witness testimony, the committee incorporated some specific examples of adjustments in the workplace that would benefit carers.
## How the recommendations might affect practice
The recommendations reinforce carers' statutory rights and best current practice. Changes needed to current practice will depend on the availability of carers' work-related support services in each area.
Providing flexibility for working carers may incur additional costs for employers (for example, if it's not possible to reorganise work among other staff) and for policymakers and commissioners (for example, costs of enforcing legislation). However, the committee also recognised that flexible working could assist with staff retention, bringing potentially large cost savings.
Full details of the evidence and the committee's discussion are in evidence review D: work, education and training.
Return to recommendations
# Replacement care
Recommendations 1.4.10 to 1.4.13
## Why the committee made the recommendations
Some limited evidence showed that carers valued being able to use replacement care locally so they could work or take part in education or training, and the committee's own experience supported this. Furthermore, economic evidence suggested that the gains from increased labour market participation could outweigh the costs of replacement care. Those gains would come in the form of generating increased taxation, reducing social welfare payments and increasing economic output.
The recommendations are consistent with the Care Act 2014, which includes a duty for local authorities to promote individual wellbeing, including through participation in work or education.
The committee agreed that replacement care should be responsive and flexible and provide a choice of options. Providing choice would benefit the person being cared for as well as the carer themselves. This was supported by evidence suggesting that the attitude of the person being cared for could sometimes discourage carers from pursuing opportunities for work and education because of concerns about the quality of their replacement care, especially when their care and support needs were complex.
## How the recommendations might affect practice
The recommendations reinforce carers' statutory rights and best current practice. Changes needed to practice will depend on whether replacement care services are available in each area. The recommendations should encourage commissioners to develop local markets so that replacement care is available to purchase, through either local authority or self-funding.
Providing working carers with replacement care will help them to remain in work, so the additional costs of replacement care would be offset by the benefits of keeping carers in the workforce.
Full details of the evidence and the committee's discussion are in evidence review D: work, education and training.
Return to recommendations
# Community information, advice and support
Recommendation 1.5.1
## Why the committee made the recommendation
The committee used the evidence along with their own experience to complement the legal requirements of the Care Act 2014 about providing information on community services to carers. They noted that the exact provision may vary by region and not all services will be available to everybody, so carers should be made aware of what is available to them and the ways in which they can access different types of support.
The committee suggested the kinds of information that carers would find useful, based on the evidence. They also wanted to emphasise that information giving should be ongoing to meet the changing circumstances of carers. This echoes recommendations elsewhere that carers' information and support needs should be revisited frequently (see the section on sharing information with carers about providing tailored information for carers).
## How the recommendation might affect practice
Providing information to carers is mandated by the Care Act 2014 so this recommendation should not have a significant impact on practice, other than to improve the consistency of implementation of legislative requirements.
Full details of the evidence and the committee's discussion are in evidence review F: providing practical support for adult carers.
Return to recommendations
# Carers' breaks
Recommendations 1.5.2 and 1.5.3
## Why the committee made the recommendations
There was a lack of evidence on effectiveness or cost effectiveness to support a recommendation about the circumstances in which carers' breaks should or shouldn't be offered. Instead, the committee based their recommendations on qualitative evidence showing that many carers struggle to maintain their own wellbeing and often overlook their own needs because of their caring responsibilities. This makes it important for practitioners to remind them regularly of the value of taking a break, including a break from their usual routines associated with caring.
The evidence showed that carers' breaks were often limited in nature, availability, quality and flexibility. This can cause stress to the carer that undermines the benefits when they are offered. The committee drafted recommendations to improve how breaks are provided when they are offered or accessed by carers.
No evidence was found about carers' passports as a means of improving support for carers, so the committee made a research recommendation to establish their effectiveness and to understand people's views and experiences of them (see research recommendation 4).
## How the recommendations might affect practice
The committee did not anticipate that these recommendations would have a significant impact on practice or resource implications. However, it is not consistent practice for practitioners to discuss carers' breaks with carers so this recommendation could have a positive effect and may represent a change to the quality of discussions between practitioners and carers.
Full details of the evidence and the committee's discussion are in evidence review F: providing practical support for adult carers.
Return to recommendations
# Peer support and support for former carers
Recommendations 1.5.4 and 1.5.5
## Why the committee made the recommendations
There was some evidence suggesting the benefits of peer support for carers, either through individual befriending arrangements or support groups. These include reducing social isolation and providing empathy and mutual emotional support. The benefits described in the studies resonated with the committee's own experiences, so they used this evidence to recommend encouraging carers to use peer support and explaining why it can be helpful.
Low quality evidence from 1 study suggested some perceived benefits of support for former carers (for example, reducing social isolation). Given the limitations of this evidence, the committee could only recommend considering the possibility of extending support services to people after their caring role had ended (in place of a stronger recommendation).
The committee agreed that signposting and social prescribing could potentially promote better access to peer support for carers, but there was no evidence so they could not recommend them. Evidence is emerging about the effectiveness of social prescribing more generally, so the committee made a research recommendation about its effectiveness and acceptability specifically for carers (see research recommendation 5).
## How the recommendations might affect practice
Peer support for carers is available but may be configured differently in different places. There may be an increased demand for and uptake of peer support locally, which may affect coordination and training costs for voluntary services.
The committee did not think that continuing to offer support to former carers would have resource implications because for most carers this support would only be needed for a short time after their caring role ended.
Full details of the evidence and the committee's discussion are in evidence review F: providing practical support for adult carers.
Return to recommendations
# Advocacy
Recommendations 1.5.6 and 1.5.7
## Why the committee made the recommendations
There was no evidence in this area, but there is a legal responsibility on local authorities to provide access to independent advocacy, in line with the Care Act 2014 and the Mental Capacity Act 2005. The committee agreed by consensus that it was important to inform carers about their right to support from advocacy services and the circumstances in which they would apply. To build on this and ensure that advocates (or other representatives) can give meaningful support to carers, the committee agreed that practitioners should recognise the voice and role of advocates. In the committee's view this does not always happen in practice.
The committee also noted the important role of advocacy as set out in the Mental Capacity Act 2005.
## How the recommendations might affect practice
These recommendations underline existing legal requirements and should not impact on practice.
Full details of the evidence and the committee's discussion are in evidence review F: providing practical support for adult carers.
Return to recommendations
# Training to provide care and support
Recommendations 1.6.1 to 1.6.9
## Why the committee made the recommendations
Qualitative evidence suggested that carers often lacked confidence or felt overwhelmed in their caring role. There was also a wide range of evidence suggesting that training containing a variety of components can improve carers' skills and confidence in caring, and their understanding of the health condition, disability or needs of the person they care for, so the committee recommended carer-specific training programmes.
The committee used the evidence to pinpoint the common features of effective, cost-effective and acceptable carer training programmes. Tailoring programmes means their exact content would depend on the training needs of different carers but, based on the evidence, the committee recommended some core components to include. Those elements related to psychological and emotional wellbeing are included in the psychological and emotional support section of this guideline.
By consensus, the committee also agreed to add some additional components in recommendation 1.6.6 that they felt were valuable, based on their knowledge and experience, but which did not have specific support from the evidence.
Qualitative evidence suggested that some carers have insufficient information about medication management and the use and maintenance of equipment to administer medication. Therefore, the committee recommended that training programmes could include managing medicines. For guidance on managing medicines in the community, see NICE's guideline on managing medicines for adults receiving social care in the community.
The committee agreed by consensus that training could be delivered in a number of ways, in groups or one-to-one, and that it was important to acknowledge the range of skills and specific expertise needed by trainers. The committee also agreed that trainers should seek input directly from people who have been carers when designing and delivering carer training so that training programmes are based on real and recent lived experiences of caring.
From the evidence it was clear that many carers value the chance during training to meet other carers with similar experiences or circumstances, as well as the opportunity to have a break from caring. Moderate quality evidence suggested that training programmes reduced carers' sense of isolation, helped them interact with each other, discuss and resolve issues they are facing, and provide informal emotional support. Based on this evidence and their own expertise, the committee agreed that training programmes should provide a balance between learning and social and emotional support, and opportunities to explore different ways of continuing to offer support and advice to each other (peer support).
Evidence showed positive feedback from minority groups (in this case lesbian, gay, bisexual and transgender carers) that training groups which are inclusive or specific to them were valued and allowed them to meet others from that community. Therefore, the committee agreed to make a recommendation to ensure that training programmes are designed with a particular focus on being inclusive and supporting diverse groups.
There was no evidence on the impact of training for carers on caring-related accidents or incidents (involving either the carer or the person they care for), including failure to take prescribed medicine and falls. The committee therefore made a research recommendation to identify what training, support or other interventions aimed at carers help to reduce caring-related accidents or incidents (see research recommendation 3). The committee noted that it would be helpful if any new research were able to identify the association between increased accidents and specific factors such as the carer's age and their physical and mental health.
## How the recommendations might affect practice
The recommendations reinforce best practice. The way services deliver carer training programmes varies across the UK, so the recommendations will help to improve consistency.
Providing multicomponent training programmes may involve initial additional costs. First, there may be an increase in the number of requests for training. Training may also be needed for practitioners to deliver the training. However, the components in recommendation 1.6.5 were based on the elements of the START (Strategies for Relatives) training programme. The economic evidence suggested that START was cost effective for carers of people with dementia and the committee agreed that it was reasonable to extrapolate this to all carers. Therefore, any additional costs of providing the programmes would be worth the benefits in carers' wellbeing and quality of life.
Full details of the evidence and the committee's discussion are in evidence review E: providing training for carers to provide practical support.
Return to recommendations
# Use of equipment and adaptations, and moving and handling
Recommendations 1.6.10 to 1.6.11
## Why the committee made the recommendations
The quality of evidence was mixed but, based on both the evidence and their own expertise, the committee agreed that involving people's carers when they are having needs assessments for equipment and adaptations would help the carer understand the options available and how they can help the person they care for. To address challenges in using equipment that were reported in the qualitative evidence, carers should also be offered advice, guidance and training in using it safely and confidently.
No evidence was identified about the effectiveness and acceptability of training for carers in moving and handling. However, the committee agreed this was an important area for carers' own safety and wellbeing as well as for the person they care for. This is in line with current NHS and social care practice.
## How the recommendations might affect practice
The recommendations reinforce legislation and should improve consistency of best practice. The way services support carers with moving and handling is variable, and changes to practice will depend on the availability of services in each area. Providing advice and guidance for carers in using equipment and adaptations and in moving and handling could involve additional costs. There may be an increase in the number of carers seeking this advice or guidance, and training may be needed for the practitioners who are delivering it.
Full details of the evidence and the committee's discussion are in evidence review E: providing training for carers to provide practical support.
Return to recommendations
# Psychosocial and psychoeducational support for carers
Recommendations 1.7.1 to 1.7.5
## Why the committee made the recommendations
The evidence suggested that psychosocial and psychoeducational support was important to carers, and helped improve their knowledge, skills and confidence about caring as well as improving emotional support, mental wellbeing and stress management. Overall, the quality of the quantitative evidence was low so the committee agreed that psychosocial and psychoeducational support should only be considered as an option for carers rather than be offered routinely. They used the qualitative evidence and their own expertise to agree the important elements that should be included as part of this support. Some of the components included in recommendation 1.6.5 (training and skills for carers) are derived from the same evidence and also contribute to mental wellbeing and stress management. They are considered as complementary to the components here.
The evidence for group interventions was more convincing than for one-to-one interventions. Group-based opportunities, where people had a chance to meet other carers and share experiences, were particularly valuable in building self-esteem, understanding and expectations of the caring role.
There was some qualitative evidence suggesting that carers see the timing of the support being offered as important. They believed psychological support would be most helpful at the earlier stages of becoming a carer, or soon after any times when the caring situation had changed or escalated. The committee agreed it was important to check regularly whether carers' needs and circumstances have changed and they need psychological support.
The committee also considered the timing of support in terms of carers' other commitments and responsibilities and drafted a recommendation to be mindful of their schedule and weekly circumstances.
The committee agreed by consensus that it was also important for practitioners to think about the way in which such support was provided. This might determine whether carers choose (or are able) to take up this intervention. They made a recommendation about other factors to consider, including location and accessibility, health and support needs of the carer, cultural factors and the availability of replacement care while they are away.
## How the recommendations might affect practice
There is considerable regional variation in the psychosocial and psychoeducational support available for carers, so these recommendations may lead to an increase in demand from carers. In most cases, funding for support of this kind would only be considered as part of an assessment of the carer's needs by the local authority.
These programmes are likely to help reduce mental health problems in the carer that could otherwise significantly impact on the person's ability to continue caring and on the health and wellbeing of the person being cared for, as well as on demand for mental health services.
Full details of the evidence and the committee's discussion are in evidence review G: providing psychological and emotional support to adult carers.
Return to recommendations
# Psychotherapy and counselling
Recommendation 1.7.6
## Why the committee made the recommendation
The evidence on the effectiveness of psychotherapy and counselling was conflicting and was limited to cognitive behavioural therapy for carers of people living with dementia. There was not enough evidence to recommend these interventions for carers generally but the committee agreed on the importance of providing psychotherapy and counselling interventions for carers with mental health problems, in line with existing NICE guidance on mental health and behavioural conditions.
## How the recommendation might affect practice
Because the provision of psychotherapy and counselling interventions to people with mental health problems is in line with existing NICE guidelines, the recommendation should not have a marked impact on practice except to highlight the importance of providing this support to adult carers.
Full details of the evidence and the committee's discussion are in evidence review G: providing psychological and emotional support to adult carers.
Return to recommendations
# Support during changes to the caring role
Recommendations 1.8.1 to 1.8.4
## Why the committee made the recommendations
Although there was no strong evidence in this area, the committee was able to use their own experience to support studies in some areas and make recommendations by consensus in other areas that they felt were too important to be overlooked.
The evidence was specific to transitions to a care home, but the committee agreed to highlight other changes carers might find difficult that mean they need support, for example, when a cared-for person experiences major changes in their health, becomes terminally ill or moves out of their home. The committee also recognised that significant emotional and practical support would be needed if the person being cared for dies unexpectedly. By consensus, the committee also highlighted times when support might be needed when the carer's own life changes.
The committee used evidence from the information and advice section of the guideline to support recommending that carers need information and support when their needs and circumstances evolve, as they do at times of transition.
## How the recommendations might affect practice
Some services and practitioners will need to adjust their practice to improve their information and consideration of carers during times of transition, but any changes would fit into existing routines of providing care so should not have any significant cost implications.
Full details of the evidence and the committee's discussion are in evidence review I: supporting carers during changes to the caring rolev.
Return to recommendations
# Support for carers during end of life care and after the person dies
Recommendations 1.9.1 to 1.9.15
## Why the committee made the recommendations
The quality of the evidence varied, but the evidence helped the committee to identify the information needs that carers have when they are caring for someone near the end of life. This included the need to be kept informed about the person's developing condition, and to be given information to meet their own practical and emotional needs.
The committee agreed with the finding that all practitioners (including non-specialist staff) need to know how to communicate sensitively with carers. Failing to do this can add to the carer's distress and may even put them off from seeking support from services in future.
There was good evidence that carers can find it very difficult to accept help at home and may rearrange their lives to avoid this. The committee agreed that practitioners going into carers' homes need to know that carers might find outside help invasive so they can incorporate this into their approach to working with the carer.
A small amount of evidence found that carers of people who may lack capacity believe advanced care planning is important but can find the process uncomfortable. The committee referred to existing NICE guidance on this topic and also agreed to emphasise the importance of involving any current or potential future carers during advance care planning.
Evidence suggested that carers often had worries about care at the end of life, especially medication, including pain relief and its potential side effects. To help address these, the committee referred to NICE's guidelines about medication optimisation and the care of dying adults.
The committee drew on the evidence to suggest important considerations for practitioners supporting carers who are caring for someone at home at the end of life, as well as how to improve carers' experiences in hospitals, hospices or care units. There was strong qualitative evidence that carers value good quality care and support when they're providing end of life care at home, so the committee suggested examples of the support that would benefit them. For people dying in hospital, the committee recognised that some hospitals might struggle to always provide private rooms, so added some alternative considerations to give carers and the person dying as much dignity, privacy and personal space as possible.
The committee used some limited evidence together with their own expert knowledge to recommend support, information, advice and signposting in preparation for and after the person dies. Practitioners especially need to consider the specific issues for mutual carers when one of them dies.
## How the recommendations might affect practice
The recommendations on information provision and communication will help to improve consistency of best practice and should not have significant implications for training or cost. The way that care at home is provided, and the amount of resources allocated to make it accessible, varies from region to region. Recommendation 1.9.12 was intended to improve the consistency of good support for people who are caring from someone at home so that they know about and can use local services.
The recommendation on dignity and privacy for people dying in hospitals or care units and their carers should promote and reinforce good practice without adding any significant resource impact. The committee provided a range of suggestions to improve patients' and carers' experiences even if space or resources are scarce.
Full details of the evidence and the committee's discussion are in evidence review H: support needs of adult carers who are caring for people at the end of life.
Return to recommendations
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{'Context': "The 2011 Census indicated that there were around 6.5\xa0million unpaid carers in the UK, with 1.3\xa0million being over 65. Most carers were aged between 50 and 64 but people aged 65 and over made up a higher proportion of carers (19%) than in the population as a whole.\n\nCarers UK (2015) estimated that the number of carers will increase to 9\xa0million by 2037. This rise is linked with a number of factors, not least the increasing number of people aged over 85 (the group most likely to need care and support), which is expected to increase to 1.9\xa0million by 2020 (Office for National Statistics). Other pressures include the continued closure of care and nursing homes and the increased use of care at home (The state of health care and adult social care in England 2018/19, Care Quality Commission). In addition, according to a survey conducted by Dying Matters, 70% of people expressed a wish to stay in their own home, and to die at home rather than in hospital or a nursing home. This is likely to further increase reliance on family members and friends.\n\nDespite the recognised pressures, both Carers UK's State of caring report 2019 and the Government response to the 2016 carers call for evidence (in advance of the Carers action plan 2018 to 2020) report clear evidence that many carers did not feel adequately supported and that although caring can be immensely rewarding, many found that they did not feel respected, valued and supported for the contribution they made. Guidelines on supporting carers are therefore urgently needed.\n\nCaring for someone can take its toll on a person's health and wellbeing. According to Carers UK (Juggling work and unpaid care), almost 1\xa0in\xa010 UK adults have given up work or reduced their hours to accommodate care. Leaving or reducing work affects carers' own independence and wellbeing and their contribution to the economy. This may also have a substantial effect on their former employers' productivity and lead to high costs in recruitment and training.\n\nCarers may also give up other activities and may face isolation; they may report feelings of depression and a reduced quality of life. Good quality, consistent support helps to address this, providing benefits for the health, wellbeing and resilience of unpaid carers. It can also enhance the life of the person being supported and help to reduce admissions to hospital and support earlier discharge. However, the amount and quality of support available to unpaid carers varies widely across the UK. Even where it is available, it may be neither appropriate nor affordable and complex local systems can be difficult to navigate with little guidance and direction (Government response to the 2016 carers call for evidence).\n\nA key barrier to the provision of appropriate support to carers is that they are often not identified. Many carers do not think of themselves as carers or are not identified by health and social care practitioners as such (so called 'hidden carers') and do not know about the support available. The Care Act 2014 and Department of Health and Social Care's Care and support statutory guidance attempted to address this, substantially strengthening the rights and recognition of adult carers within the social care system. The Act entitles carers to assessment in their own right, together with information and advice to help them make the best choices about support for their own health and wellbeing. The Care Act defines a carer as an adult, aged 18 or over, who provides, or intends to provide, care for another adult who needs care because of a disability, health condition, frailty, mental health problem, addiction or other health or care needs. It excludes those who provide paid care or do so as voluntary work.\n\nThe Care Act introduces carer support plans setting out how identified and eligible needs may be met, including personal budgets and the option of direct payments. These duties reflect the emphasis on universal personalised support for carers as set out in the NHS long term plan (NHS England). However, it is still the case that only a small proportion (in one area estimated as 7%) are identified as unpaid carers by social care and health organisations, so many are missing out on help and support.\n\nThis guideline provides action-orientated recommendations for good practice, aimed at improving outcomes for adult carers. The guideline is based on the best available evidence of effectiveness, including cost effectiveness, as well as evidence on the views and experiences of carers, people using services and practitioners. It identifies good practice in providing support that enhances the wellbeing, resilience and life experience of adult carers.\n\nThe guideline covers information and support for carers; identifying carers and assessing their needs; helping carers stay in, enter or return to employment and training; providing community support, training, psychological and emotional support for carers; and providing support during changes to the caring role and during the end of life period of the cared-for person.\n\nThe guideline complements statutory duties and good practice as set out in relevant legislation and guidance. The recommendations cross-refer to legislation and other guidance where appropriate. In particular, the guideline takes account of the relationship between the Children and Families Act 2014 and the Care Act 2014, recognising that many young carers will transition into adult caring roles and that many parent carers will similarly transition into caring roles for their adult children. It also takes account of NHS England's Carers toolkit, the latest National carers strategy and the Carers action plan 2018 to 2020, and the Care and support statutory guidance.\n\nMost carers will need support from a number of different services, including the NHS. The NHS long term plan emphasises the vital contribution of carers and the need for more integrated and personalised support (including greater use of personal health budgets). The Care Act 2014 expects the NHS and social care to work together and where possible to integrate services and support. The Care Quality Commission has introduced Quality Markers in Primary Care (usually the first means of identifying carers) and the Association of Directors of Adult Social Services (ADASS) Carers Policy Network reports encouraging evidence of greater cooperation between health and social care in their regularly updated Guide to efficient and effective interventions for implementing the Care Act. Similarly, principles of co-production and interventions such as Think Local Act Personal (TLAP)'s 'Make it real' offer new approaches to more actively engaging carers as 'experts by experience' and co-designing their own care and support.\n\nNICE guidelines provide recommendations on what works. This may include details on who should carry out interventions and where. NICE guidelines do not routinely describe how services are funded or commissioned, unless this has been formally requested by the Department of Health and Social Care.", 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care as described in your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity) and safeguarding.\n\n# Information and support for carers: overarching principles\n\n## The right to information and support\n\nLocal authorities should provide information to carers to support them in their caring role. Information provision must meet the requirements of the Care Act 2014.\n\nPractitioners in health and social care (including healthcare professionals in primary and secondary care, social care practitioners, care and support workers and personal assistants) should use every opportunity to tell carers they have a right to information and support and how to get it (see section 1.2).\n\nInformation for carers should be up to date and cover:\n\nthe range of support and advice recommended in this guideline\n\nhow to access social and community support for carers (see section 1.5)\n\nuseful further sources of information and support such as carer groups and forums.\n\nFor a short explanation of why the committee made these recommendations see the rationale and impact section on the right to information and support\xa0.\n\nFull details of the evidence and the committee's discussion are in\xa0evidence review B: providing information and advice about caring to carers in the UK.\n\nLoading. Please wait.\n\n## Sharing information with carers\n\nDiscuss information with carers as well as giving them written materials. When providing information:\n\nensure it is plainly worded, clearly presented and free of jargon\n\nbe aware that smaller, more manageable chunks of information are easier to remember, and that visual aids or pictures can be useful\n\nencourage the carer to ask questions\n\nensure that information is consistent.\n\nMake information available in a range of formats to meet carers' needs and preferences, for example written leaflets, links to online and digital resources (including local and national websites and forums and social media) and information in accessible formats or different languages. For more about accessible communication see NHS England's Accessible Information Standard.\n\nTake into account that carers' information needs will change over time and whenever their circumstances or caring role change. Provide information and advice that addresses the carer's individual needs at the time when they need it and that helps them plan and prepare.\n\nOffer to revisit discussions or provide the same information several times if needed, for example if there is a lot of complicated information to digest or the carer is experiencing emotional stress.\n\nPractitioners responsible for providing and discussing information with carers should have the knowledge, time and communication skills to do so.\n\nPrimary care providers and primary care networks should explore ways of offering and promoting services to carers, including through partnership working (for example, working with local carer support services or nominating carer champions).\n\nFor a short explanation of why the committee made the recommendations on sharing information with carers and how they might affect practice see the rationale and impact on sharing information with carers\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B: providing information and advice about caring to carers in the UK and evidence review D: work, education and training. Other supporting evidence and discussion can be found in evidence review A: identifying carers as defined by the Care Act 2014 and evidence review F: providing practical support for adult carers.\n\nLoading. Please wait.\n\n## Working with and involving carers\n\nHealth and social care organisations should promote ways of working with carers that acknowledge them as expert partners in care and value their skills and knowledge about the person they care for. These approaches should be incorporated into formal policies and processes.\n\nHealth and social care practitioners should work in partnership with carers and treat them as a valued member of the care team around the person being cared for, with the person's consent. This should include involving carers in decision making and care planning and keeping them up to date.\n\nDuring discussions with carers about the person they are caring for:\n\ntake into account the mental capacity of the person being cared for and their wishes around confidentiality (see NICE's guideline on decision making and mental capacity)\n\nshare with carers the information they need to provide care effectively and safely while respecting confidentiality (explain to them the constraints of confidentiality).\n\nBe open and honest with carers about the health condition, disability or needs of the person they care for (with the person's consent), including when information is difficult or upsetting. Explain how it is likely to progress so that carers understand how their caring role might change in the future.\n\nFor a short explanation of why the committee made the recommendations on working with and involving carers and how they might affect practice see the rationale and impact section on working with and involving carers\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: identifying carers as defined by the Care Act 2014 and evidence review B: providing information and advice about caring to carers in the UK.\n\nLoading. Please wait.\n\n\n\n# Identifying carers\n\n## Recommendations for health and social care practitioners\n\nActively seek to identify carers (in line with the requirements of the Care Act 2014) and ensure that they know:\n\nabout their right to a carer's assessment, what this is and the benefits of having one\n\nhow to obtain a carer's assessment\n\nthat some support may be means tested\n\nthat they can still access community support without formal assessment.\n\nUse every opportunity to identify carers, including GP appointments, flu jab appointments, home visits, outpatient appointments, social care and other needs assessments, including admission and discharge assessments and planning meetings. Record details about carers you have identified (with the carer's consent).\n\nTake into account that carers themselves may not ask for support from certain professionals, for example GPs, because they may not view support for carers as being part of that professional's role.\n\nWhen identifying carers, be aware that some people may not view themselves as a carer because:\n\nbecoming a carer can be a gradual process, and carers may not recognise the changing nature of their relationship with the person they support\n\ncarers may prefer to continue identifying primarily as a husband, wife, partner, sibling, parent, child or friend rather than as a carer\n\ncarers often become engulfed by competing demands, including working and caring, and as a result may overlook their own needs as a carer and may not seek support\n\nthe person being supported may not accept that they have care and support needs\n\nthe carer does not live with the person or the person has moved away from home, for example into supported living or residential care.\n\nEncourage carers to recognise their caring role and seek support, explaining the benefits for both them and the person they care for, including:\n\nthe carer's role and contribution can be acknowledged and their support needs addressed and\n\ncarers can share valuable knowledge about the person they care for, which helps practitioners provide the right care and support.\n\nAsk people with care and support needs whether anyone gives them help or support, apart from paid practitioners. Avoid making assumptions about who might be providing their care. Take into account that:\n\nother people offering help or support may not be family members or may not live with the person\n\nthere may be more than 1\xa0person involved in caring.\n\nPractitioners involved in transferring people to and from hospital should seek to identify carers and refer them to appropriate services.\n\nFollow recommendations on support for families, parents and carers throughout admission in NICE's guideline on transition between inpatient mental health settings and community or care home settings and\n\nFollow recommendations on discharge from hospital in NICE's guideline on transition between inpatient hospital settings and community or care home settings for adults with social care needs.\n\nOffer carers the opportunity to have confidential conversations about their own needs as carers separately from the person they are supporting.\n\nIf a person who has care and support needs is also identified as having caring responsibilities, their care and support needs assessment should take account of this. They should also be offered a carer's assessment to identify their needs as a carer. Assessments must meet the requirements of the Care Act 2014.\n\nEnsure that carers who don't want or need a statutory carer's assessment are still offered information about how to access support.\n\nFor a short explanation of why the committee made the recommendations for health and social care practitioners on identifying carers and how they might affect practice see the rationale and impact section on identifying carers: recommendations for health and social care practitioners\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: identifying carers as defined by the Care Act 2014. Other supporting evidence and discussion is in evidence review H: support needs of adult carers who are caring for people at the end of life and evidence review I: supporting carers during changes to the caring role.\n\nLoading. Please wait.\n\n## Recommendations for health and social care organisations\n\nHealth and social care organisations should encourage people to recognise their role and rights as carers through:\n\npublicity campaigns involving local community services, for example posters and leaflets in GP surgeries, libraries and pharmacies\n\ndigital communications, social media and online forums that engage with carers\n\npartnerships with community pharmacies, local carer support organisations and carer groups, for example in hospital settings\n\npartnerships with local community organisations who can help disseminate information more widely, such as further education colleges, sports centres and supermarkets.Use descriptions that carers will relate to and include details of where to find further information and advice.\n\nConsider nominating a carer champion to help implement the recommendations in this guideline and Care Act 2014 requirements in relation to identifying carers.\n\nHealth and social care organisations should ensure their policies and systems encourage the identification of carers, including by developing formal processes to help them do so.\n\nEnsure that all staff likely to come into contact with carers understand their responsibilities under the Care Act 2014 in relation to identifying carers.\n\nFor a short explanation of why the committee made the recommendations for health and social care organisations on identifying carers and how they might affect practice see the rationale and impact section on identifying carers: recommendations for health and social care organisations\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: identifying carers as defined by the Care Act 2014.\n\nLoading. Please wait.\n\n# Assessing carers' needs\n\n## Carers' assessments\n\nLocal authorities, and social care organisations delegated by local authorities to carry out carers' assessments, should make arrangements for and carry out assessments in cooperation with other relevant health and social care organisations (in accordance with the Care Act 2014 and associated Care and support statutory guidance and the Children and Families Act 2014).\n\nPractitioners from health and social care carrying out or contributing to carers' assessments should work together to ensure that:\n\nthe assessment covers all relevant aspects of health, wellbeing and social care needs and\n\ndetails of the assessment are shared with other practitioners and organisations who are involved in the assessment.\n\nHealth and social care organisations should ensure that practitioners who carry out or contribute to carers' assessments have training and skills in that role and access to specialist advice.\n\nThe carer's assessment should be jointly produced with the carer and reflect what matters most to the carer and what might help them achieve this.\n\nBe aware that a well-conducted carer's assessment may in itself be a therapeutic intervention or a means of preventing future problems.\n\nFor a short explanation of why the committee made the recommendations on carers' assessments and how they might affect practice, see the rationale and impact section on carers' assessments\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: assessment of carers as defined by the Care Act 2014.\n\nLoading. Please wait.\n\n## Preparing for and carrying out a carer's assessment\n\nArrange the timing of the carer's assessment according to the carer's preferences and the urgency of their need for support. For example, take into account:\n\nwhether the person they care for is near the end of life\n\nthe level of stress the carer is experiencing\n\nthe timing of hospital discharge\n\nchanges to the caring role\n\nany negative impact of delays on the health and wellbeing of the carer.\n\nProvide flexibility in how, when and where carers' assessments are carried out, taking into account individual preferences and accommodating their caring responsibilities, working patterns and other circumstances.\n\nEnsure that the assessment process is accessible, easy to navigate and complete, and tailored to individual needs, with information provided in a format that carers can understand.\n\nBefore a carer's assessment takes place, share information with the carer that helps them prepare.\n\nDiscuss caring in the context of the carer's own family and support networks, for example whether they share caring responsibilities with other people and whether they care for more than 1\xa0person.\n\nDiscuss with carers the option to combine or link their assessment with the assessment of the person they care for, if they both choose to do this.\n\nDo not make assumptions about the willingness and the ability of carers to carry out caring tasks when completing assessments for the carer or the person they care for.\n\nIf a carer's needs have been identified during a hospital-based assessment:\n\ninform the local authority (and/or any delegated care organisation) that a carer's needs have been identified\n\nensure an effective process is in place to link the hospital-based carer's assessment with the community-based statutory assessment, to avoid duplication and so that meaningful support for carers is provided during transfer from hospital (including during a crisis).\n\nEnsure that replacement care is discussed as part of carers' assessments, including planning for any emergency replacement care that might be needed, for example if the carer becomes suddenly unwell.\n\nFor a short explanation of why the committee made the recommendations on preparing for and carrying out a carer's assessment and how they might affect practice see the rationale and impact section on preparing for and carrying out a carer's assessment\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: assessment of carers as defined by the Care Act 2014 and evidence review D: work, education and training.\n\nLoading. Please wait.\n\n## Work, education and training\n\nDiscuss education, training and employment with carers during their carer's assessment. Explore the options and the support they need to remain in, start or return to work, training or education. This could include providing replacement care at home.\n\nEnsure that practitioners carrying out carers' assessments have the necessary skills, knowledge and understanding of potential opportunities for returning to, or remaining in work, education and training.\n\nGive carers tailored information about community services and support that could help them remain in, start or return to work.\n\nFor a short explanation of why the committee made the recommendations on work, education and training and how they might affect practice see the rationale and impact section on work, education and training\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: work, education and training.\n\nLoading. Please wait.\n\n## After a carer's assessment\n\nEnsure there are clearly identified outcomes for the carer after their assessment.\n\nAfter an assessment:\n\nensure the carer understands the actions that have been agreed and what the next steps will be and\n\nshare information (as appropriate) with other practitioners and organisations involved with the carer and the person they care for.\n\nIf a carer support plan is developed as a result of a carer's assessment, ensure it is monitored and reviewed regularly.\n\nFor a short explanation of why the committee made the recommendations on after a carer's assessment and how they might affect practice see the rationale and impact section on after a carer's assessment\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: assessment of carers as defined by the Care Act 2014 and evidence review D: work, education and training.\n\nLoading. Please wait.\n\n# Helping carers stay in, enter or return to work, education and training\n\n## Advice and support\n\nLocal authorities should ensure carers have access to tailored advice about balancing work, education or training with caring, including associated benefits and welfare advice.\n\nServices providing welfare rights advice or back-to-work or education training should develop a good understanding of carer needs, for example by appointing a named carer champion who can provide knowledgeable, expert advice and train other practitioners in the service.\n\nServices providing welfare rights advice or back-to-work or education training should help carers recognise that the skills they have gained through caring are transferable, and support them to describe their skills in a way that will appeal to employers.\n\nWorkplaces should make information available to their staff about ways in which they can support employees who need to balance caring responsibilities with work. See NICE's guideline on workplace health.\n\nFor a short explanation of why the committee made the recommendations on advice and support for helping carers stay in, enter or return to work, education and training and how they might affect practice see the rationale and impact section on helping carers stay in, enter or return to work, education and training: advice and support\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: work, education and training. Other supporting evidence and discussion can be found in evidence review A: identifying carers as defined by the Care Act 2014.\n\nLoading. Please wait.\n\n## Flexibilities to support employment\n\nPractitioners should encourage carers to discuss supportive working arrangements with their employers, including adjustments to make caring possible. Examples might include flexible hours, fixed hours or shifts, carers' leave, permission to use a mobile phone, technology to allow flexible working, or providing a private space to take personal phone calls.\n\nWorkplaces should offer flexible working arrangements to enable staff to balance caring responsibilities with work, and other initiatives that support mental wellbeing for carers in line with the NICE guidelines on workplace health and mental wellbeing at work.\n\nWorkplaces should ensure that staff with caring responsibilities have equal access to career development. At a minimum, workplaces must meet the requirements set out in the Equality Act 2010 in relation to people with caring responsibilities.\n\nHealth and social care organisations should offer flexibility when arranging appointments for working carers and the person they care for. Examples include workplace surgeries, carer appointments outside of office hours, digital access and telephone appointments.\n\nCarer support services should work closely with employers and employee assistance programmes to make advice and information for carers available within the workplace.\n\nFor a short explanation of why the committee made the recommendations on flexibilities to support employment and how they might affect practice see the rationale and impact section on flexibilities to support employment\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: work, education and training.\n\nLoading. Please wait.\n\n## Replacement care\n\nCommissioners should be aware of the benefits of replacement care for supporting carers to stay in, enter or return to work, education and training when designing and delivering support services for carers.\n\nCommissioners should ensure that replacement care services are available locally for carers who need to access them to stay in, enter or return to work, education or training, including for those who fund their own support.\n\nEnsure that replacement care is flexible and provides a choice of options to meet all levels of carer need, including for those who care for more than 1\xa0person or who care for over 20\xa0hours a week.\n\nReview replacement care often enough to respond to changes in people's working patterns and career development.\n\nFor a short explanation of why the committee made the recommendations on replacement care and how they might affect practice see the rationale and impact section on replacement care\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: work, education and training.\n\nLoading. Please wait.\n\n# Social and community support for carers\n\n## Community information, advice and support\n\nLocal authorities should ensure carers are kept regularly informed about available community services and other sources of support and advice and how to access them, for example:\n\nlocal carer support services\n\nself-help groups\n\ncommunity and faith groups\n\nspecialist benefits, financial and legal advice\n\nfinancial support\n\nadvice about self-care\n\nwhere to find reliable information about the health condition of the person they are caring for.\n\nFor a short explanation of why the committee made the recommendation on community information, advice and support and how it might affect practice see the rationale and impact section on community information, advice and support\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review F: providing practical support for adult carers\n\nLoading. Please wait.\n\n## Carers' breaks\n\nHealth and social care practitioners should regularly discuss with carers the value of having a break from their caring role and explain the options available.\n\nCarers' breaks should:\n\nmeet carers' needs for a break, for example in duration, timing, frequency and type of break\n\nbe arranged in a way that provides reliable and consistent support to the carer (such as avoiding last-minute changes that could lead to additional stress for the carer).\n\nFor a short explanation of why the committee made the recommendations on carers' breaks and how they might affect practice see the rationale and impact section on carers' breaks\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review F: providing practical support for adult carers.\n\nLoading. Please wait.\n\n## Peer support\n\nTell carers about peer support and how to access it locally. Explain that peer support can help reduce a sense of isolation, provide empathy and social and emotional support, and enable them to share information.\n\n## Support for former carers\n\nConsider extending support services for people when their caring role is finished, including through peer support groups.\n\nFor a short explanation of why the committee made the recommendations on peer support and support for former carers and how they might affect practice see the rationale and impact section on peer support and support for former carers\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review F: providing practical support for adult carers.\n\nLoading. Please wait.\n\n## Advocacy\n\nLocal authorities should provide information to carers about how to access advocacy support services. Access to advocacy services should meet the requirements of the Care Act 2014 and the Mental Capacity Act 2005.\n\nIf carers choose to have an advocate or representative to support them, health and social care practitioners should recognise this person's contribution and include them in discussions.\n\nFor a short explanation of why the committee made the recommendations on advocacy and how they might affect practice see the rationale and impact section on advocacy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review F: providing practical support for adult carers.\n\nLoading. Please wait.\n\n# Training to provide care and support\n\nOffer training to enable carers to provide care safely. Training could include structured programmes or one-to-one guidance from a practitioner.\n\nCommissioners and those involved in planning local carer support services should ensure that the provision of carer training meets local needs.\n\nInvolve carers in the design and delivery of carer training to ensure it covers skills and expertise relevant to them.\n\n## Carer training programmes\n\nOffer carer training programmes that are:\n\ndesigned to improve carers' knowledge and coping skills\n\naccessible and available in a variety of formats, including printed or online materials or face to face\n\ntailored to the needs of carers\n\ndelivered by practitioners with relevant knowledge and skills.\n\nTraining programmes for carers should include the following components, as relevant:\n\ngeneral education about the health condition, disability or needs of the person they care for\n\nskills training to help them provide care, including how to understand and respond to changes in mood and behaviour\n\nprinciples of self-care\n\ntraining in communication skills to improve interactions with the person they care for\n\nadvice on planning enjoyable and meaningful activities with the person they care for\n\ninformation about relevant services and how to access them\n\nfuture planning, including preparing for transitions.\n\nConsider including the following in carer training programmes, as relevant:\n\nmanaging medicines\n\nmanaging diet and nutrition\n\nmaintaining personal hygiene\n\nmanaging behaviour that challenges\n\nuse of digital and assistive technology\n\nspecific information that carers need to enable them to remain safe in their caring role.\n\nEnsure that training programmes for carers are inclusive and address the needs and preferences of diverse groups, such as lesbian, gay, bisexual and transgender carers, and carers from diverse ethnic, religious and cultural backgrounds.\n\nTraining programmes for carers should provide a balance between learning, enjoyment, a chance to meet other carers and opportunities for peer support.\n\nEncourage carers to keep in touch with each other after they have attended a training programme and suggest ways they could do this.\n\nFor a short explanation of why the committee made the recommendations on training to provide care and support, including carer training programmes, and how they might affect practice see the rationale and impact section on training to provide care and support\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review E: providing training for carers to provide practical support.\n\nLoading. Please wait.\n\n## Use of equipment and adaptations, and moving and handling\n\nHealth and social care practitioners should involve carers during assessments for equipment and adaptations.\n\nHealth and social care practitioners should ensure carers have access to advice, guidance and training about appropriate use of equipment and adaptations, and safe moving and handling techniques.\n\nFor a short explanation of why the committee made the recommendations on use of equipment and adaptations, and moving and handling, and how they might affect practice see the rationale and impact section on use of equipment and adaptations, and moving and handling\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review E: providing training for carers to provide practical support\n\nLoading. Please wait.\n\n# Psychological and emotional support for carers\n\n## Psychosocial and psychoeducational support\n\nConsider providing carers with psychosocial and psychoeducational support, which should include:\n\ndeveloping personalised strategies and building carer skills\n\nadvice on how to look after their own physical and mental health, and their emotional and spiritual wellbeing\n\ninformation about emotional support services and psychological therapies for carers and how to access them.\n\nEnsure that the range of psychosocial and psychoeducational support offered to carers includes group-based options.\n\nRecognise that psychosocial and psychoeducational support may be needed at different stages of the caring experience and ask carers regularly whether they feel they would benefit from it.\n\nArrange the timing of psychosocial or psychoeducational support to suit carers' circumstances, taking into account other commitments such as work or other caring and family responsibilities.\n\nWhen providing psychosocial or psychoeducational support to carers, take into account:\n\nthe carer's preferred location\n\nwhether they need support to attend (for example a practitioner to go with them)\n\nphysical accessibility (such as help needed with transport)\n\nif replacement care is needed\n\nthe carer's preferred format\n\nthe cultural appropriateness of the intervention\n\nwhat follow-up will be needed.\n\nFor a short explanation of why the committee made the recommendations on psychosocial and psychoeducational support for carers and how they might affect practice see the rationale and impact section on psychosocial and psychoeducational support for carers\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review G: providing psychological and emotional support to adult carers.\n\nLoading. Please wait.\n\n## Psychotherapy and counselling\n\nIf a carer has an identified mental health problem, consider:\n\npsychotherapy and counselling interventions in line with existing NICE guidance (see NICE's topic page for mental health and behavioural conditions) or\n\nreferral to a GP or mental health professional who can provide interventions in line with existing NICE guidance.\n\nFor a short explanation of why the committee made the recommendation on psychotherapy and counselling and how it might affect practice see the rationale and impact section on psychotherapy and counselling\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review G: providing psychological and emotional support to adult carers\n\nLoading. Please wait.\n\n# Support during changes to the caring role\n\nBe aware that caring responsibilities may not end when the person being cared for moves away from home, for example into a residential care home.\n\nProvide information and emotional and practical support to help carers prepare for and adjust to changes in their role, for example if the person they care for:\n\nbecomes an adult\n\nmakes the transition to adult services (see NICE's guideline on transitions from children's to adults' services)\n\nmoves away from home\n\nhas a significant change in their health\n\nbecomes terminally ill or needs end of life care (for recommendations on care near the end of life see NICE's guideline on care of dying adults in the last days of life)\n\ndies unexpectedly.\n\nProvide information and emotional and practical support to carers when their circumstances change, for example when they:\n\nstart or go back to work\n\nmove from being a young carer to an adult carer\n\nhave a change in benefits or financial circumstances\n\ngo through personal changes (such as divorce)\n\ntake on another caring role\n\ngo into hospital\n\nare bereaved\n\nbecome less able to care as they get older.\n\nFor recommendations about support and training for carers during transitions between hospital and home, see NICE's guideline on transition between inpatient hospital settings and community or care home settings for adults with social care needs, in particular:\n\nrecommendations on communication and information sharing\n and\n\nrecommendations on support and training for carers.\n\nFor a short explanation of why the committee made the recommendations on support during changes to the caring role and how they might affect practice, see the rationale and impact section on support during changes to the caring role\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review I: supporting carers during changes to the caring role.\n\nLoading. Please wait.\n\n# Support for carers during end of life care and after the person dies\n\n## Information and support\n\nOffer carers frequent opportunities for discussion and help them to understand information about the diagnosis and prognosis of the person they care for (with the person's consent). Use a sensitive manner during these discussions and avoid jargon.\n\nHealth and social care practitioners involved in providing end of life care should be competent to have conversations with carers about death and dying.\n\nPractitioners should establish early contact with carers involved in providing end of life care. Discuss with carers how best to support them, taking into account that unsatisfactory early contact with health and social care services can have a long-lasting negative impact on carers involved in providing end of life care.\n\nHealth and social care practitioners, including home care workers, should recognise that carers can find it hard to accept help at home when they are providing end of life care and can find it invasive.\n\nProvide continuity during end of life care with the same professional care staff wherever possible, so that the carer and the person they care for can build a relationship with the staff supporting them.\n\nEncourage carers who are caring for someone near the end of their life to think about ways they can get support from their family, friends, employer and wider social network.\n\n## Advance care planning\n\nInvolve carers in advance care planning if the person being cared for consents to this. For recommendations about involving carers in advance care plans for people who may lack mental capacity, see NICE's guideline on decision making and mental capacity.\n\nWhen making an advance care plan that includes responsibilities for carers, consider the wishes of any current or future carers who have been named in the plan.\n\nEnsure the carer has a clear understanding of their role as part of the advance care plan. Share advance care plans in a clear and simple format with everyone involved in the person's care.\n\n## Providing care at the end of life\n\nWhen managing medication and other care at the end of life, follow the principles of involving carers and the dying person described in NICE's guideline on care of dying adults in the last days of life.\n\nDuring a structured medication review, as described in recommendations on medication review in NICE's guideline on medicines optimisation, take into account:\n\nthe person's, and their family members' or carers' where appropriate, views and understanding about their medicines\n\nthe person's, and their family members' or carers' where appropriate, concerns, questions or problems with the medicines.\n\nHelp carers who are providing end of life care at home to access local services that could support them, including from local hospices. This could include:\n\nreplacement care\n\npalliative home care\n\npractical support, for example to use equipment and adaptations\n\nadditional help in the home.\n\nProvide privacy and dignity for people dying in hospital and their carers. This could include offering them a private room or, if this is not possible, alternatives such as:\n\nprivate space\n\nspace to keep personal possessions from home\n\nflexible visiting times and tailored arrangements for carers\n\ncomfortable seating for the carer\n\naccess to refreshments.\n\nGive carers of people at the end of life up-to-date and accurate information and advice about financial, legal and logistical issues they need to address when preparing for or following the death of the person they care for.\n\nTake account of the changing information and support needs of carers in planning for their own future when the person they care for dies. This should include discussing with carers how to address their own support needs after the death of a mutual carer.\n\nFor a short explanation of why the committee made the recommendations on support for carers during end of life care and after the person dies and how they might affect practice see the rationale and impact section on support for carers during end of life care and after the person dies\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review H: support needs of adult carers who are caring for people at the end of life.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\n## Carers\n\nIn this guideline, a carer is an adult (aged 18 or over) who provides unpaid care and support to a family member, partner or friend (aged 16 or over) because of a disability, health condition, frailty, mental health problem, addiction or other health or social care need.\n\n## Carer champion\n\nA designated member of staff (for example in a GP surgery, hospital, workplace, leisure or similar setting) who is given the task of supporting and speaking up for carers. They can act as a key contact for carer information and advice in that setting, providing knowledgeable, expert advice as well as training other practitioners working within the service.\n\n## Carer support plan\n\nIf a carer is identified as having eligible needs following an assessment under the Care Act 2014, the local authority must provide a support plan that sets out how those needs will be met. The support plan must be developed in partnership with the carer and should set out the outcomes the carer hopes to achieve, including their wishes around providing care and accessing work, education and leisure. The support plan must be regularly reviewed.\n\n## Carer's assessment\n\nAnyone who is an unpaid carer for a family member or friend has the right to discuss their own needs with their local authority, separate to the needs of the person they care for. This is a statutory requirement under the Care Act 2014. Carers can discuss anything they think would help with their own health and wellbeing or with managing other aspects of their life, including their caring role. The local authority uses this information to decide what help it can offer.\n\n## Carers' breaks\n\nThese services, which would include respite care, give carers a break by providing short-term care for the person with care needs in their own home or in a residential setting. This can mean a few hours during the day or evening, overnight, or a longer-term break. Carers' breaks may be one-off or more regular arrangements. They can also benefit the person with care needs by giving them the chance to try new activities and meet new people.\n\n## Peer support\n\nPeer support involves carers sharing experiences, practical advice and emotional support and improving their understanding of the options available to them and the person they care for. Peer support can take a number of different forms, including one-to-one friendships and support based on lived experience and contact through third sector organisations, support groups or online networks. Peer support is often but not always provided by volunteers, for example volunteer befrienders.\n\n## Replacement care\n\nCare that replaces the care normally given by a regular carer. It may be needed either on a planned basis or in an emergency. Replacement care may be offered by the local authority, if the person needing care has had an assessment and is entitled to care and support services, or if the carer is entitled to help. Otherwise, people may have to pay for it.\n\nThese definitions are based on Think Local, Act Personal's care and support jargon buster. See the jargon buster for other social care terms used in this guideline.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Whole family approach to carer's assessment\n\nWhat is the effectiveness, cost effectiveness and acceptability of the whole family approach to carers' assessments?\n\nFor a short explanation of why the committee made the research recommendation on whole family approach to carers' assessment see the rationale and impact section on carers' assessments\xa0.\n\nFull details of the research recommendation are in evidence review C: assessment of carers as defined by the Care Act 2014.\n\nLoading. Please wait.\n\n## Support for carers to return to work, employment or training\n\nWhat is the effectiveness of personal health and social care budgets in supporting carers to return to work, education or training?\n\nFor a short explanation of why the committee made the research recommendation about support for carers to return to work, employment or training see the rationale and impact section on helping carers stay in, enter or return to work, education and training: advice and support\xa0.\n\nFull details of the research recommendation are in evidence review D: work, education and training.\n\nLoading. Please wait.\n\n## Training for carers to reduce caring-related incidents\n\nWhat training, support or interventions help to reduce caring-related accidents or incidents?\n\nFor a short explanation of why the committee made the research recommendation about training for carers to reduce caring-related incidents see the rationale and impact section on training to provide care and support\xa0.\n\nFull details of the research recommendation are in evidence review E: providing training for carers to provide practical support.\n\nLoading. Please wait.\n\n## Practical support through carer passport schemes\n\nWhat is the effectiveness, cost effectiveness and acceptability of carer passport schemes?\n\nFor a short explanation of why the committee made the research recommendation about practical support through carer passport schemes see the rationale and impact section on carers' breaks\xa0.\n\nFull details of the research recommendation are in evidence review F: providing practical support for adult carers.\n\nLoading. Please wait.\n\n## Practical support for carers through social prescribing\n\nWhat is the effectiveness, cost effectiveness and acceptability of social prescribing for carers?\n\nFor a short explanation of why the committee made the research recommendation about practical support for carers through social prescribing see the rationale and impact section on peer support and support for former carers\xa0.\n\nFull details of the research recommendation are in evidence review F: providing practical support for adult carers.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.\n\n# The right to information and support\n\nRecommendations 1.1.1 to 1.1.3\n\n## Why the committee made the recommendations\n\nThe committee used themes in the qualitative evidence to build on statutory guidance about the key principles of providing information and support to carers. Under the Care Act 2014, local authorities must establish and maintain a service for providing people with information and advice relating to support for carers. However, many carers are unaware of the advice and services available, or they may not have time to search for them. The committee wanted to emphasise the importance of signposting carers to useful local services and up-to-date sources of information and that health and social care practitioners should pass this information to carers whenever they get the chance.\n\n## How the recommendations might affect practice\n\nInformation provision varies, so in some areas additional training and review of current information provision may be needed. Providing information is a statutory requirement, and giving carers the right information, advice and support at the right time can help them continue caring while managing other aspects of their lives. Any costs would be outweighed by the benefits of helping to avoid crisis situations such as unplanned hospital admissions and carer health problems.\n\nFull details of the evidence and the committee's discussion are in evidence review B: providing information and advice about caring to carers in the UK.\n\nReturn to recommendations\n\n# Sharing information with carers\n\nRecommendations 1.1.4 to 1.1.9\n\n## Why the committee made the recommendations\n\nThere was good quality evidence from carers about how information sharing could be improved. This evidence guided recommendations about the way in which information should be delivered, including its format, style and timing of delivery and how to tailor it to what each carer needs and prefers.\n\nOne strong theme suggested that carers often receive information from multiple sources around the same time, emphasising the importance of professionals in different services working together to make sure they are giving consistent advice.\n\nThere was some limited evidence that primary care practitioners would like to promote care services to carers and are interested in formalising ways to do it. However only 1 example was identified for how this might be done within GP surgeries. The committee discussed this and reached the consensus that developing partnerships with other carer-related services and using carer 'champions' within teams are 2 ways they could do this.\n\n## How the recommendations might affect practice\n\nFollowing these recommendations would make information easier for carers to understand and retain, improve their experience and wellbeing, and their ability to give effective care. They may call for refinements to existing practice but do not imply any costly changes or radical new provision.\n\nDetails of the evidence and the committee's discussion are in evidence review B: providing information and advice about caring to carers in the UK and evidence review D: work, education and training. Other supporting evidence and discussion can be found in evidence review A: identifying carers as defined by the Care Act 2014 and evidence review F: providing practical support for adult carers.\n\nReturn to recommendations\n\n# Working with and involving carers\n\nRecommendations 1.1.10 to 1.1.13\n\n## Why the committee made the recommendations\n\nThere was evidence that carers value being recognised and respected as core members of the team around the person they care for and that carers have valuable information to contribute to care planning and assessment. They are often key to understanding the person's needs and preferences, so these recommendations were made to promote their involvement. This approach should be incorporated in formal policies and processes to ensure it is consistent across organisations.\n\nThe evidence showed that to provide effective care, carers need sufficient information about the person they are caring for. However, in many cases this can clash with the person's right to confidentiality. The committee made a recommendation to address this issue and balance the different concerns.\n\nThere was strong evidence that carers value being kept up to date, even with difficult news about the condition of the person they care for. However, the evidence suggested that professionals are sometimes vague, euphemistic or evasive with difficult news, which carers don't find helpful. They prefer to have time to process and understand any new information, and to properly prepare for possible changes to their caring role in the future.\n\n## How the recommendations might affect practice\n\nThe committee acknowledged that a little additional time may be needed for practitioners to keep carers up to date and well informed. However, the benefits include ensuring that care planning is based on accurate and detailed information, encouraging the carer in their role and respecting them as a core team member to help sustain the caring arrangement.\n\nDetails of the evidence and the committee's discussion are in evidence review A: identifying carers as defined by the Care Act 2014 and evidence review B: providing information and advice about caring to carers in the UK.\n\nReturn to the recommendations\n\n# Identifying carers: recommendations for health and social care practitioners\n\nRecommendations 1.2.1 to 1.2.10\n\n## Why the committee made the recommendations\n\nIt is a requirement of the Care Act 2014 for local authorities to have due regard to the importance of identifying carers who may have support needs and explain the advice and support available to them. The quality of the evidence was fairly low but it found specific barriers to identifying carers, so the committee drew on these along with their own experience to recommend how to improve identification of carers. This included setting out a range of potential opportunities for practitioners to identify carers and record details about them – providing the carer gives consent.\n\nIn the committee's experience, there are many reasons why people may not identify as a carer and, even if people recognise they are in a caring role, they are still more likely to see their primary role in relation to that person as a family member or friend. Practitioners should take this into account in the way they communicate and work with carers.\n\nThere may be more than 1\xa0person involved in a person's care and support, and the committee agreed that it is important that health and social care practitioners seek to identify all carers and to understand the context of their caring situation. This enables advice, support and assessments to be more likely to meet each carer's needs.\n\nThe committee agreed that recording information about carers as part of routine assessments can help to identify carers, especially when this information is shared with other health and social care practitioners, and there was evidence to support this.\n\nThe evidence also suggested that carers value discussions with practitioners where their caring is recognised and they are offered support. However, it can be challenging to have open conversations with carers about their own needs, especially with the person receiving the support present.\n\nCarers may also have care needs of their own due to long-term health conditions or disability. Where this is the case, an assessment of both their own care and support needs and their carer support needs should take place in line with the requirements of the Care Act 2014.\n\nFinally, the committee agreed that not all carers would want or need a formal statutory carers assessment, for example if they were managing well at that time, so it was important to give those carers information about how and where to access carer support services if they need them.\n\n## How the recommendations might affect practice\n\nThe recommendations should have limited cost implications because they involve using existing opportunities to help identify carers. There may be some costs associated with improving how information about carers is recorded and used to improve identification and support. The committee recognised that as more people identify as carers and seek information and support, local authorities, together with partner organisations in health and social care, will need to consider how resources are best used to benefit as many carers as possible, as well as those most in need.\n\nFull details of the evidence and the committee's discussion are in evidence review A: identifying carers as defined by the Care Act 2014. Other supporting evidence and discussion is in evidence review H: support needs of adult carers who are caring for people at the end of life and evidence review I: supporting carers during changes to the caring rolev.\n\nReturn to recommendations\n\n# Identifying carers: recommendations for health and social care organisations\n\nRecommendations 1.2.11 to 1.2.14\n\n## Why the committee made the recommendations\n\nThe committee agreed that health and social care organisations need to be proactive about promoting carers' roles and rights to help more people to self-identify as carers and seek support – this would help them meet Care Act 2014 requirements. There was little evidence to support the recommendations, but in the committee's own experience, people would be more likely to identify as carers if they are presented with images and language that are directly relatable to their changing perceptions of themselves and their own needs as carers.\n\nQualitative evidence showed that practitioners welcomed both informal and formal systems and processes to help them better identify and subsequently support carers and the committee agreed that carers were likely to benefit from these initiatives.\n\nPractitioners coming into contact with carers need to have good knowledge of their responsibilities under the Care Act 2014 in relation to identifying carers. By consensus, the committee agreed that one possible way to achieve this was for organisations to consider nominating 'carer champions' within their workforce to help other staff understand their responsibilities in this area.\n\n## How the recommendations might affect practice\n\nThe recommendations could result in more carers seeking advice and support, which could lead to a higher demand for carers' support services. But they may also improve coordination between local authorities and other health and social care organisations in identifying carers and giving them support, leading to better care in turn for the person they care for.\n\nFull details of the evidence and the committee's discussion are in evidence review A: identifying carers as defined by the Care Act 2014.\n\nReturn to recommendations\n\n# Carers' assessments\n\nRecommendations 1.3.1 to 1.3.5\n\n## Why the committee made the recommendations\n\nRecommendations were drafted to complement the Care Act 2014, other associated care and support statutory guidance, and the Children and Families Act 2014. These set out legal duties for local authorities, or social care organisations delegated by local authorities, to arrange and carry out carers' assessments.\n\nThe evidence that underpinned the recommendations was of variable quality but it found that:\n\ncarers find out about carers' assessments from various sources, but still have trouble understanding the process and getting an assessment\n\na lack of coordination across multiple services (for example between hospitals and community services) is an obstacle to the assessment process\n\npractitioners from teams across health and social care need to work together on carers' assessments, but they do not always have the relevant skills and training\n\nproperly conducted, a carer's assessment provides carers with psychosocial and emotional benefits and may be thought of as a therapeutic intervention in itself.\n\nThe evidence was most limited on collaborative working and on carers' assessments as a therapeutic intervention, so for these recommendations the committee supplemented the evidence with their own experience and expertise.\n\nThe committee thought it was important that carers feel that they have co-produced the assessment and that it reflects what is most important to them. They also agreed it was important that practitioners carrying out carers' assessments should have access to specialist advice, for example about particular aspects of care and treatment of the person they care for, because this might influence the support needs of the carer.\n\nThere was no evidence on whether using the lead professional approach or the whole family approach can make collaborative working easier and more effective. The committee agreed to make a research recommendation on the whole family approach to carers' assessments (see research recommendation 1).\n\n## How the recommendations might affect practice\n\nThe impact of the recommendations is likely to vary depending on how much local services already collaborate with each other and train their staff to take the initiative with assessments. Additional training or reviewing of service coordination may be needed in some areas, but because such assessments are statutory requirements, they should not introduce additional financial implications.\n\nFull details of the evidence and the committee's discussion are in evidence review C: assessment of carers as defined by the Care Act 2014.\n\nReturn to recommendations\n\n# Preparing for and carrying out a carer's assessment\n\nRecommendations 1.3.6 to 1.3.14\n\n## Why the committee made the recommendations\n\nThe quality of the evidence was mixed, so the committee supplemented the evidence with their own knowledge and experience.\n\nQualitative evidence reported that some carers found the assessment process difficult to follow. Some carers also struggled to understand what being 'entitled to an assessment' actually meant. The committee agreed that practitioners need to give carers a clear explanation of what a carer's assessment involves and provide information in advance so that carers are better prepared and have time to reflect on their needs as carers. The committee also used the themes reported in the evidence to suggest ways of making assessments more positive for carers by making them more accessible and person-centred.\n\nExpert testimony suggested the context in which caring takes place may be complicated, for example someone may be caring for more than 1\xa0person or may be sharing their care responsibilities with other people, and so the committee agreed assessors should take account of this.\n\nAccording to the evidence, carers' assessments are sometimes carried out in conjunction with those of the person they care for, which in some cases can mean the carer's own needs are not separately assessed. This was also supported by expert testimony. The committee agreed on the importance of making sure the carer's needs are considered independently, while providing an option to link with the cared-for person's assessments.\n\nThe Care Act 2014 states that carers' assessments must include an assessment of the ability and willingness of the carer to provide care, so assessors must not make assumptions about how willing or able a carer is to perform any given caring tasks.\n\nIf an assessment is done in hospital, it needs to be forward-looking and connected to the completion of a statutory assessment by community staff. This helps to ensure meaningful support for carers during transfer from hospital, because the evidence showed that assessments by different services can be fragmented.\n\nThe evidence suggested that the provision of replacement care enables carers to return to or remain in work. Therefore, the committee agreed that replacement care should always be discussed during assessments.\n\n## How the recommendations might affect practice\n\nCarers' assessments are already statutory, so the implementation of these recommendations may only involve minor changes to existing practice. Some costs may be associated with retraining, or with implementing more flexible and individualised assessments, but the committee agreed these were implicit to what is an adequate assessment as required by the Care Act 2014. The committee considered that sharing information with carers in advance of the assessment so that they are prepared would not have significant complications. It could be facilitated by the creation of a frequently asked questions resource, for example.\n\nFull details of the evidence and the committee's discussion are in evidence review C: assessment of carers as defined by the Care Act 2014 and evidence review D: work, education and training.\n\nReturn to recommendations\n\n# Work, education and training\n\nRecommendations 1.3.15 to 1.3.17\n\n## Why the committee made the recommendations\n\nAlthough there was no high-quality evidence, the committee was able to make recommendations in areas where the lower-quality evidence aligned with their own experience. Some qualitative evidence showed that carers valued being offered services, practical support and financial support to stay in work, education and training. Evidence also suggested there may not be enough opportunities presented during carers' assessments to encourage their use and uptake. This chimed with the committee's concern that practitioners carrying out assessments often overlook carers' wishes about work, education and training.\n\nThe committee agreed that it was important for assessing practitioners to have good local knowledge about these types of opportunities for carers, as well as the community support options available (such as replacement care) to help carers take up these opportunities if they wish.\n\n## How the recommendations might affect practice\n\nThe recommendations might involve some changes to existing training and practice for practitioners carrying out assessments to make sure that work, education and training is covered routinely. They could also lead to changes in the levels of support needed by carers, and greater demand for services like replacement care. However, access to this support is a statutory right under the Care Act 2014, and any costs would be offset by the economic benefits to carers and wider society.\n\nFull details of the evidence and the committee's discussion are in evidence review D: work, education and training.\n\nReturn to recommendations\n\n# After a carer's assessment\n\nRecommendations 1.3.18 to 1.3.20\n\n## Why the committee made the recommendations\n\nThere was some evidence that after an assessment, carers don't always feel that they have received helpful information or advice. Although this evidence was low in quality, having mostly come from survey studies with uncontrolled and potentially biased participant samples, it was supported by the combined experience of the committee. They agreed that practitioners should always make sure an assessment leads to clear outcomes and practical benefits for the carer. This means ensuring good communication with other practitioners and organisations and carrying out any agreed actions.\n\nThe committee agreed that if a carer's support plan is prepared as a result of an assessment, it should be monitored and reviewed regularly to ensure it achieves outcomes that are important to the carer.\n\n## How the recommendations might affect practice\n\nThe cost of implementing the actions identified as part of assessment will vary from case to case and will be informed by local eligibility requirements for funded support and on local arrangements for sharing information about carers' support requirements as well as monitoring and review. They should not have large cost implications and do not represent a significant change in practice.\n\nFull details of the evidence and the committee's discussion are in evidence review C: assessment of carers as defined by the Care Act 2014 and evidence review D: work, education and training.\n\nReturn to recommendations\n\n# Helping carers stay in, enter or return to work, education and training: advice and support\n\nRecommendations 1.4.1 to 1.4.4\n\n## Why the committee made the recommendations\n\nThe Care Act 2014 mandates providing information for carers on work, education and training, and the committee used a combination of evidence and expert consensus to build on that legal requirement. There was some evidence that a lack of information and advice, combined with the fragmented nature of local support services, often acted as barriers to carers remaining in, returning to or entering work, education and training. The committee agreed it was important to make widely available person-centred advice and information specifically for carers. This was supported by evidence that carers welcomed advice and information from practitioners who understood the particular challenges they face in combining work and caring, including associated benefits and welfare advice. One way that the committee proposed services may do this is by designating a 'carer champion' to offer expert advice when needed and to assist in training other practitioners working in the service about carers' needs and rights under the Care Act 2014.\n\nThere was some limited evidence showing the disadvantages experienced by young adult carers striving to balance work or education with caring. The committee also noted the difficulties often experienced by older carers wishing to retain or return to employment after the end of their caring roles. They agreed that carers may lack confidence about finding work, especially if they have spent years caring at the expense of education or training. They agreed by consensus that it was relevant for all carers to be encouraged to recognise their value to employers using the skills they have built up during caring.\n\nThere was a lack of evidence about the effectiveness of particular tools or approaches for supporting carers to return to work, education or training. Supported by expert testimony, the committee agreed that there was potential in further exploring whether the use of personal budgets, either for the person being cared for or the carer in their own right, might have positive outcomes for the carer. So the committee agreed to make a research recommendation about the effectiveness of personal health and social care budgets in supporting carers to return to work, education or training (see research recommendation 2).\n\n## How the recommendations might affect practice\n\nThese recommendations reinforce legislation and should help to improve consistency of best practice. Changes needed to current practice will depend on the availability of carers' work-related support services in each area. Providing tailored advice of this kind may require some additional local investment, but this would be offset by substantial benefits for carers from being supported to continue working or learning alongside caring, leading to cost savings in the long term.\n\nFull details of the evidence and the committee's discussion are in evidence review D: work, education and training. Other supporting evidence and discussion can be found in evidence review A: identifying carers as defined by the Care Act 2014.\n\nReturn to recommendations\n\n# Flexibilities to support employment\n\nRecommendations 1.4.5 to 1.4.9\n\n## Why the committee made the recommendations\n\nThere was evidence that even small adjustments to working practices can have positive benefits for carers balancing paid work with caring responsibilities. Carers also reported that they often avoid discussing caring-related problems with employers for fear of negative attitudes from managers, feeling a burden, or being excluded from opportunities to develop their careers.\n\nIt is a requirement of the Equality Act 2010 for employers to actively promote a positive culture towards people with caring responsibilities. The committee agreed that this could include promoting opportunities for flexible working practices and use of employee assistance programmes that can provide advice and support for working carers, as well as ensuring that staff with caring responsibilities have equal access to career development opportunities.\n\nUsing expert witness testimony, the committee incorporated some specific examples of adjustments in the workplace that would benefit carers.\n\n## How the recommendations might affect practice\n\nThe recommendations reinforce carers' statutory rights and best current practice. Changes needed to current practice will depend on the availability of carers' work-related support services in each area.\n\nProviding flexibility for working carers may incur additional costs for employers (for example, if it's not possible to reorganise work among other staff) and for policymakers and commissioners (for example, costs of enforcing legislation). However, the committee also recognised that flexible working could assist with staff retention, bringing potentially large cost savings.\n\nFull details of the evidence and the committee's discussion are in evidence review D: work, education and training.\n\nReturn to recommendations\n\n# Replacement care\n\nRecommendations 1.4.10 to 1.4.13\n\n## Why the committee made the recommendations\n\nSome limited evidence showed that carers valued being able to use replacement care locally so they could work or take part in education or training, and the committee's own experience supported this. Furthermore, economic evidence suggested that the gains from increased labour market participation could outweigh the costs of replacement care. Those gains would come in the form of generating increased taxation, reducing social welfare payments and increasing economic output.\n\nThe recommendations are consistent with the Care Act 2014, which includes a duty for local authorities to promote individual wellbeing, including through participation in work or education.\n\nThe committee agreed that replacement care should be responsive and flexible and provide a choice of options. Providing choice would benefit the person being cared for as well as the carer themselves. This was supported by evidence suggesting that the attitude of the person being cared for could sometimes discourage carers from pursuing opportunities for work and education because of concerns about the quality of their replacement care, especially when their care and support needs were complex.\n\n## How the recommendations might affect practice\n\nThe recommendations reinforce carers' statutory rights and best current practice. Changes needed to practice will depend on whether replacement care services are available in each area. The recommendations should encourage commissioners to develop local markets so that replacement care is available to purchase, through either local authority or self-funding.\n\nProviding working carers with replacement care will help them to remain in work, so the additional costs of replacement care would be offset by the benefits of keeping carers in the workforce.\n\nFull details of the evidence and the committee's discussion are in evidence review D: work, education and training.\n\nReturn to recommendations\n\n# Community information, advice and support\n\nRecommendation 1.5.1\n\n## Why the committee made the recommendation\n\nThe committee used the evidence along with their own experience to complement the legal requirements of the Care Act 2014 about providing information on community services to carers. They noted that the exact provision may vary by region and not all services will be available to everybody, so carers should be made aware of what is available to them and the ways in which they can access different types of support.\n\nThe committee suggested the kinds of information that carers would find useful, based on the evidence. They also wanted to emphasise that information giving should be ongoing to meet the changing circumstances of carers. This echoes recommendations elsewhere that carers' information and support needs should be revisited frequently (see the section on sharing information with carers about providing tailored information for carers).\n\n## How the recommendation might affect practice\n\nProviding information to carers is mandated by the Care Act 2014 so this recommendation should not have a significant impact on practice, other than to improve the consistency of implementation of legislative requirements.\n\nFull details of the evidence and the committee's discussion are in evidence review F: providing practical support for adult carers.\n\nReturn to recommendations\n\n# Carers' breaks\n\nRecommendations 1.5.2 and 1.5.3\n\n## Why the committee made the recommendations\n\nThere was a lack of evidence on effectiveness or cost effectiveness to support a recommendation about the circumstances in which carers' breaks should or shouldn't be offered. Instead, the committee based their recommendations on qualitative evidence showing that many carers struggle to maintain their own wellbeing and often overlook their own needs because of their caring responsibilities. This makes it important for practitioners to remind them regularly of the value of taking a break, including a break from their usual routines associated with caring.\n\nThe evidence showed that carers' breaks were often limited in nature, availability, quality and flexibility. This can cause stress to the carer that undermines the benefits when they are offered. The committee drafted recommendations to improve how breaks are provided when they are offered or accessed by carers.\n\nNo evidence was found about carers' passports as a means of improving support for carers, so the committee made a research recommendation to establish their effectiveness and to understand people's views and experiences of them (see research recommendation 4).\n\n## How the recommendations might affect practice\n\nThe committee did not anticipate that these recommendations would have a significant impact on practice or resource implications. However, it is not consistent practice for practitioners to discuss carers' breaks with carers so this recommendation could have a positive effect and may represent a change to the quality of discussions between practitioners and carers.\n\nFull details of the evidence and the committee's discussion are in evidence review F: providing practical support for adult carers.\n\nReturn to recommendations\n\n# Peer support and support for former carers\n\nRecommendations 1.5.4 and 1.5.5\n\n## Why the committee made the recommendations\n\nThere was some evidence suggesting the benefits of peer support for carers, either through individual befriending arrangements or support groups. These include reducing social isolation and providing empathy and mutual emotional support. The benefits described in the studies resonated with the committee's own experiences, so they used this evidence to recommend encouraging carers to use peer support and explaining why it can be helpful.\n\nLow quality evidence from 1\xa0study suggested some perceived benefits of support for former carers (for example, reducing social isolation). Given the limitations of this evidence, the committee could only recommend considering the possibility of extending support services to people after their caring role had ended (in place of a stronger recommendation).\n\nThe committee agreed that signposting and social prescribing could potentially promote better access to peer support for carers, but there was no evidence so they could not recommend them. Evidence is emerging about the effectiveness of social prescribing more generally, so the committee made a research recommendation about its effectiveness and acceptability specifically for carers (see research recommendation 5).\n\n## How the recommendations might affect practice\n\nPeer support for carers is available but may be configured differently in different places. There may be an increased demand for and uptake of peer support locally, which may affect coordination and training costs for voluntary services.\n\nThe committee did not think that continuing to offer support to former carers would have resource implications because for most carers this support would only be needed for a short time after their caring role ended.\n\nFull details of the evidence and the committee's discussion are in evidence review F: providing practical support for adult carers.\n\nReturn to recommendations\n\n# Advocacy\n\nRecommendations 1.5.6 and 1.5.7\n\n## Why the committee made the recommendations\n\nThere was no evidence in this area, but there is a legal responsibility on local authorities to provide access to independent advocacy, in line with the Care Act 2014 and the Mental Capacity Act 2005. The committee agreed by consensus that it was important to inform carers about their right to support from advocacy services and the circumstances in which they would apply. To build on this and ensure that advocates (or other representatives) can give meaningful support to carers, the committee agreed that practitioners should recognise the voice and role of advocates. In the committee's view this does not always happen in practice.\n\nThe committee also noted the important role of advocacy as set out in the Mental Capacity Act 2005.\n\n## How the recommendations might affect practice\n\nThese recommendations underline existing legal requirements and should not impact on practice.\n\nFull details of the evidence and the committee's discussion are in evidence review F: providing practical support for adult carers.\n\nReturn to recommendations\n\n# Training to provide care and support\n\nRecommendations 1.6.1 to 1.6.9\n\n## Why the committee made the recommendations\n\nQualitative evidence suggested that carers often lacked confidence or felt overwhelmed in their caring role. There was also a wide range of evidence suggesting that training containing a variety of components can improve carers' skills and confidence in caring, and their understanding of the health condition, disability or needs of the person they care for, so the committee recommended carer-specific training programmes.\n\nThe committee used the evidence to pinpoint the common features of effective, cost-effective and acceptable carer training programmes. Tailoring programmes means their exact content would depend on the training needs of different carers but, based on the evidence, the committee recommended some core components to include. Those elements related to psychological and emotional wellbeing are included in the psychological and emotional support section of this guideline.\n\nBy consensus, the committee also agreed to add some additional components in recommendation 1.6.6 that they felt were valuable, based on their knowledge and experience, but which did not have specific support from the evidence.\n\nQualitative evidence suggested that some carers have insufficient information about medication management and the use and maintenance of equipment to administer medication. Therefore, the committee recommended that training programmes could include managing medicines. For guidance on managing medicines in the community, see NICE's guideline on managing medicines for adults receiving social care in the community.\n\nThe committee agreed by consensus that training could be delivered in a number of ways, in groups or one-to-one, and that it was important to acknowledge the range of skills and specific expertise needed by trainers. The committee also agreed that trainers should seek input directly from people who have been carers when designing and delivering carer training so that training programmes are based on real and recent lived experiences of caring.\n\nFrom the evidence it was clear that many carers value the chance during training to meet other carers with similar experiences or circumstances, as well as the opportunity to have a break from caring. Moderate quality evidence suggested that training programmes reduced carers' sense of isolation, helped them interact with each other, discuss and resolve issues they are facing, and provide informal emotional support. Based on this evidence and their own expertise, the committee agreed that training programmes should provide a balance between learning and social and emotional support, and opportunities to explore different ways of continuing to offer support and advice to each other (peer support).\n\nEvidence showed positive feedback from minority groups (in this case lesbian, gay, bisexual and transgender carers) that training groups which are inclusive or specific to them were valued and allowed them to meet others from that community. Therefore, the committee agreed to make a recommendation to ensure that training programmes are designed with a particular focus on being inclusive and supporting diverse groups.\n\nThere was no evidence on the impact of training for carers on caring-related accidents or incidents (involving either the carer or the person they care for), including failure to take prescribed medicine and falls. The committee therefore made a research recommendation to identify what training, support or other interventions aimed at carers help to reduce caring-related accidents or incidents (see research recommendation 3). The committee noted that it would be helpful if any new research were able to identify the association between increased accidents and specific factors such as the carer's age and their physical and mental health.\n\n## How the recommendations might affect practice\n\nThe recommendations reinforce best practice. The way services deliver carer training programmes varies across the UK, so the recommendations will help to improve consistency.\n\nProviding multicomponent training programmes may involve initial additional costs. First, there may be an increase in the number of requests for training. Training may also be needed for practitioners to deliver the training. However, the components in recommendation 1.6.5 were based on the elements of the START (Strategies for Relatives) training programme. The economic evidence suggested that START was cost effective for carers of people with dementia and the committee agreed that it was reasonable to extrapolate this to all carers. Therefore, any additional costs of providing the programmes would be worth the benefits in carers' wellbeing and quality of life.\n\nFull details of the evidence and the committee's discussion are in evidence review E: providing training for carers to provide practical support.\n\nReturn to recommendations\n\n# Use of equipment and adaptations, and moving and handling\n\nRecommendations 1.6.10 to 1.6.11\n\n## Why the committee made the recommendations\n\nThe quality of evidence was mixed but, based on both the evidence and their own expertise, the committee agreed that involving people's carers when they are having needs assessments for equipment and adaptations would help the carer understand the options available and how they can help the person they care for. To address challenges in using equipment that were reported in the qualitative evidence, carers should also be offered advice, guidance and training in using it safely and confidently.\n\nNo evidence was identified about the effectiveness and acceptability of training for carers in moving and handling. However, the committee agreed this was an important area for carers' own safety and wellbeing as well as for the person they care for. This is in line with current NHS and social care practice.\n\n## How the recommendations might affect practice\n\nThe recommendations reinforce legislation and should improve consistency of best practice. The way services support carers with moving and handling is variable, and changes to practice will depend on the availability of services in each area. Providing advice and guidance for carers in using equipment and adaptations and in moving and handling could involve additional costs. There may be an increase in the number of carers seeking this advice or guidance, and training may be needed for the practitioners who are delivering it.\n\nFull details of the evidence and the committee's discussion are in evidence review E: providing training for carers to provide practical support.\n\nReturn to recommendations\n\n# Psychosocial and psychoeducational support for carers\n\nRecommendations 1.7.1 to 1.7.5\n\n## Why the committee made the recommendations\n\nThe evidence suggested that psychosocial and psychoeducational support was important to carers, and helped improve their knowledge, skills and confidence about caring as well as improving emotional support, mental wellbeing and stress management. Overall, the quality of the quantitative evidence was low so the committee agreed that psychosocial and psychoeducational support should only be considered as an option for carers rather than be offered routinely. They used the qualitative evidence and their own expertise to agree the important elements that should be included as part of this support. Some of the components included in recommendation 1.6.5 (training and skills for carers) are derived from the same evidence and also contribute to mental wellbeing and stress management. They are considered as complementary to the components here.\n\nThe evidence for group interventions was more convincing than for one-to-one interventions. Group-based opportunities, where people had a chance to meet other carers and share experiences, were particularly valuable in building self-esteem, understanding and expectations of the caring role.\n\nThere was some qualitative evidence suggesting that carers see the timing of the support being offered as important. They believed psychological support would be most helpful at the earlier stages of becoming a carer, or soon after any times when the caring situation had changed or escalated. The committee agreed it was important to check regularly whether carers' needs and circumstances have changed and they need psychological support.\n\nThe committee also considered the timing of support in terms of carers' other commitments and responsibilities and drafted a recommendation to be mindful of their schedule and weekly circumstances.\n\nThe committee agreed by consensus that it was also important for practitioners to think about the way in which such support was provided. This might determine whether carers choose (or are able) to take up this intervention. They made a recommendation about other factors to consider, including location and accessibility, health and support needs of the carer, cultural factors and the availability of replacement care while they are away.\n\n## How the recommendations might affect practice\n\nThere is considerable regional variation in the psychosocial and psychoeducational support available for carers, so these recommendations may lead to an increase in demand from carers. In most cases, funding for support of this kind would only be considered as part of an assessment of the carer's needs by the local authority.\n\nThese programmes are likely to help reduce mental health problems in the carer that could otherwise significantly impact on the person's ability to continue caring and on the health and wellbeing of the person being cared for, as well as on demand for mental health services.\n\nFull details of the evidence and the committee's discussion are in evidence review G: providing psychological and emotional support to adult carers.\n\nReturn to recommendations\n\n# Psychotherapy and counselling\n\nRecommendation 1.7.6\n\n## Why the committee made the recommendation\n\nThe evidence on the effectiveness of psychotherapy and counselling was conflicting and was limited to cognitive behavioural therapy for carers of people living with dementia. There was not enough evidence to recommend these interventions for carers generally but the committee agreed on the importance of providing psychotherapy and counselling interventions for carers with mental health problems, in line with existing NICE guidance on mental health and behavioural conditions.\n\n## How the recommendation might affect practice\n\nBecause the provision of psychotherapy and counselling interventions to people with mental health problems is in line with existing NICE guidelines, the recommendation should not have a marked impact on practice except to highlight the importance of providing this support to adult carers.\n\nFull details of the evidence and the committee's discussion are in evidence review G: providing psychological and emotional support to adult carers.\n\nReturn to recommendations\n\n# Support during changes to the caring role\n\nRecommendations 1.8.1 to 1.8.4\n\n## Why the committee made the recommendations\n\nAlthough there was no strong evidence in this area, the committee was able to use their own experience to support studies in some areas and make recommendations by consensus in other areas that they felt were too important to be overlooked.\n\nThe evidence was specific to transitions to a care home, but the committee agreed to highlight other changes carers might find difficult that mean they need support, for example, when a cared-for person experiences major changes in their health, becomes terminally ill or moves out of their home. The committee also recognised that significant emotional and practical support would be needed if the person being cared for dies unexpectedly. By consensus, the committee also highlighted times when support might be needed when the carer's own life changes.\n\nThe committee used evidence from the information and advice section of the guideline to support recommending that carers need information and support when their needs and circumstances evolve, as they do at times of transition.\n\n## How the recommendations might affect practice\n\nSome services and practitioners will need to adjust their practice to improve their information and consideration of carers during times of transition, but any changes would fit into existing routines of providing care so should not have any significant cost implications.\n\nFull details of the evidence and the committee's discussion are in evidence review I: supporting carers during changes to the caring rolev.\n\nReturn to recommendations\n\n# Support for carers during end of life care and after the person dies\n\nRecommendations 1.9.1 to 1.9.15\n\n## Why the committee made the recommendations\n\nThe quality of the evidence varied, but the evidence helped the committee to identify the information needs that carers have when they are caring for someone near the end of life. This included the need to be kept informed about the person's developing condition, and to be given information to meet their own practical and emotional needs.\n\nThe committee agreed with the finding that all practitioners (including non-specialist staff) need to know how to communicate sensitively with carers. Failing to do this can add to the carer's distress and may even put them off from seeking support from services in future.\n\nThere was good evidence that carers can find it very difficult to accept help at home and may rearrange their lives to avoid this. The committee agreed that practitioners going into carers' homes need to know that carers might find outside help invasive so they can incorporate this into their approach to working with the carer.\n\nA small amount of evidence found that carers of people who may lack capacity believe advanced care planning is important but can find the process uncomfortable. The committee referred to existing NICE guidance on this topic and also agreed to emphasise the importance of involving any current or potential future carers during advance care planning.\n\nEvidence suggested that carers often had worries about care at the end of life, especially medication, including pain relief and its potential side effects. To help address these, the committee referred to NICE's guidelines about medication optimisation and the care of dying adults.\n\nThe committee drew on the evidence to suggest important considerations for practitioners supporting carers who are caring for someone at home at the end of life, as well as how to improve carers' experiences in hospitals, hospices or care units. There was strong qualitative evidence that carers value good quality care and support when they're providing end of life care at home, so the committee suggested examples of the support that would benefit them. For people dying in hospital, the committee recognised that some hospitals might struggle to always provide private rooms, so added some alternative considerations to give carers and the person dying as much dignity, privacy and personal space as possible.\n\nThe committee used some limited evidence together with their own expert knowledge to recommend support, information, advice and signposting in preparation for and after the person dies. Practitioners especially need to consider the specific issues for mutual carers when one of them dies.\n\n## How the recommendations might affect practice\n\nThe recommendations on information provision and communication will help to improve consistency of best practice and should not have significant implications for training or cost. The way that care at home is provided, and the amount of resources allocated to make it accessible, varies from region to region. Recommendation 1.9.12 was intended to improve the consistency of good support for people who are caring from someone at home so that they know about and can use local services.\n\nThe recommendation on dignity and privacy for people dying in hospitals or care units and their carers should promote and reinforce good practice without adding any significant resource impact. The committee provided a range of suggestions to improve patients' and carers' experiences even if space or resources are scarce.\n\nFull details of the evidence and the committee's discussion are in evidence review H: support needs of adult carers who are caring for people at the end of life.\n\nReturn to recommendations"}
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https://www.nice.org.uk/guidance/ng150
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This guideline covers support for adults (aged 18 and over) who provide unpaid care for anyone aged 16 or over with health or social care needs. It aims to improve the lives of carers by helping health and social care practitioners identify people who are caring for someone and give them the right information and support. It covers carers’ assessments, practical, emotional and social support and training, and support for carers providing end of life care.
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4ede50dd7e518315e4dd3591541b2c60a15d4082
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nice
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Virtual Touch Quantification to diagnose and monitor liver fibrosis in chronic hepatitis B and C
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Virtual Touch Quantification to diagnose and monitor liver fibrosis in chronic hepatitis B and C
Evidence-based recommendations on Virtual Touch Quantification to diagnose and monitor liver fibrosis in chronic hepatitis B and C.
# Recommendations
NICE medical technologies guidance addresses specific technologies notified to NICE by companies. The 'case for adoption' is based on the claimed advantages of introducing the specific technology compared with current management of the condition. This case is reviewed against the evidence submitted and expert advice. If the case for adopting the technology is supported, then the technology has been found to offer advantages to patients and the NHS. The specific recommendations on individual technologies are not intended to limit use of other relevant technologies which may offer similar advantages.
The case for adopting Virtual Touch Quantification (VTq) software to diagnose and monitor liver fibrosis is supported by the evidence. VTq is as accurate as transient elastography in diagnosing and staging liver fibrosis, and may offer other benefits in terms of imaging the liver and sampling selected areas to assess fibrosis and identify associated pathologies. By avoiding liver biopsies, it may also benefit people whose liver fibrosis needs monitoring. Cost savings through adopting VTq will be greater in hospitals in which liver biopsy is the primary method for diagnosing and monitoring liver fibrosis.
VTq should be considered as an option for people with chronic hepatitis B or C who need assessment of liver fibrosis.
Cost modelling suggests that using VTq is cost saving compared with transient elastography and liver biopsy, whether or not a compatible Siemens ultrasound machine needs to be purchased. Compared with transient elastography, the estimated overall cost saving for VTq is around £53 per person. This saving assumes that 10% of the ultrasound machine capacity would be used for VTq measurements, leaving 90% to be applied to other uses. Compared with liver biopsy, the corresponding saving is around £434 per person.# The technology
# Description of the technology
The Virtual Touch Quantification (VTq; Siemens) software application uses acoustic radiation force impulse (ARFI) imaging technology to measure the elasticity of liver tissue. VTq is used in combination with a Siemens Acuson S2000 or S3000 ultrasound platform. Liver tissue can be damaged by inflammation, causing high levels of collagen to be deposited in the liver cells (fibrosis), which become stiff. ARFI imaging involves generating a shear wave by applying an acoustic 'push pulse' lateral to the area of interest identified during a conventional ultrasound scan. The speed of the shear wave is proportional to the stiffness of the tissue.
The VTq investigation comprises multiple measurements and is both non‑invasive and painless. The software generates a report which includes a statistical summary of the median and mean shear‑wave velocities. The reliability of VTq measurements is usually confirmed by calculating the ratio of the interquartile range to median, which should be less than 0.30. VTq is indicated for adults or children needing assessment of liver fibrosis.
This evaluation focuses on the use of VTq to diagnose and monitor liver fibrosis in adults and children with chronic hepatitis B or C. The use of VTq to assess liver fibrosis associated with other conditions was outside the scope and so is not considered here.
The cost of the VTq software stated in the company's submission is £4,415. A compatible Siemens Acuson S2000 ultrasound system costs from £50,000 with annual maintenance costs, starting in year 2, from £2,000. The cost varies with the system configuration; the cost model includes typical values of £59,700 for the ultrasound system and £2,246 for the annual maintenance costs. All costs are excluding VAT.
The claimed benefits of VTq as presented by the company are as follows:
VTq is painless and may be safer than liver biopsy as the standard of care.
No hospital stay or post‑procedure monitoring is needed with VTq because it can be done in an outpatient setting.
VTq may avoid the need for serial biopsies over several years to monitor fibrosis progression, improving quality of life and reducing procedure costs (if fibrosis progression is monitored with VTq).
VTq provides a more complete assessment of the liver; during the procedure, a sonogram allows visualization of the liver parenchyma, portal and hepatic veins, portal and hepatic venous and arterial blood flow measurements, and the biliary tree for possible obstructions.
Hepatic cellular carcinoma surveillance is included during the sonogram in patients with cirrhosis.
Early identification of fibrosis in people with viral hepatitis may allow earlier intervention with antiviral drugs, which can reverse the course of early disease.
Potential for increased capacity because the VTq procedure does not need to be done by a consultant.
Reduced resource costs because no hospital admission or stay is needed for VTq measurements in an outpatient setting.
# Current management
The NICE Pathway for chronic hepatitis B indicates that initial assessment usually takes place in primary care, through blood tests. All patients who test positive for hepatitis B surface antigen are then referred to a hepatologist, gastroenterologist or infectious diseases specialist with an interest in hepatology (children are referred to a similar paediatric specialist in a secondary or tertiary centre).
In secondary or tertiary care patients are provided with information on disease progress, long‑term prognosis, transmission and antiviral treatment options. Adults are then offered transient elastography as an initial test for chronic liver disease. Transient elastography (using, for example, the FibroScan device) is a non‑invasive method of assessing liver fibrosis by measuring liver stiffness based on a mechanical wave generated by vibration. Children and young people are offered liver biopsy to determine the need for antiviral therapy, with appropriate information provided on biopsy limitations and risks.
NICE's guideline on hepatitis B recommends:
Transient elastography as the initial test for chronic liver disease, offering antiviral treatment (without a liver biopsy) to patients with a transient elastography score of 11 kPa or above.
Considering liver biopsy in patients with a transient elastography score of 6–10 kPa.
Offering liver biopsy to patients with a transient elastography score of less than 6 kPa if they are younger than 30 years of age and have hepatitis B virus DNA of more than 2000 IU/ml and abnormal alanine aminotransferase (ALT) on 2 consecutive tests conducted months apart.
Annual reassessment of patients who are not taking antiviral treatment.
The therapy pathway for people with hepatitis C is described in NICE's clinical knowledge summary on hepatitis C. Presently, patients who test hepatitis C virus RNA‑positive on a blood test are referred to a hepatology clinic. The degree of fibrosis is assessed and treatment options then depend on specific patient characteristics and the severity of their liver disease. There is a NICE guideline on the management and assessment of cirrhosis.
Liver biopsy is considered to be the gold standard for assessing liver fibrosis for both hepatitis B and C. Histological assessment uses the METAVIR score, based on an assessment of fibrosis and the degree of liver architecture disorganisation, and classifies the severity of liver disease from none (F0), through mild, moderate and severe (F1–F3), to cirrhosis (F4).# Clinical evidence
# Summary of clinical evidence
The key clinical outcomes for Virtual Touch Quantification (VTq) presented in the decision problem were:
correlation in assessment of stage of liver disease and stage of fibrosis using METAVIR score
sensitivity and specificity (using area under receiver operating characteristic curve) in assessment of liver fibrosis
use of antiviral drugs
quality of life measures
hospital bed usage and length of stay
need for liver biopsy
device‑related adverse events.
The company identified 23 published papers as suitable for full‑text review. No unpublished studies were identified. After review, the company excluded 12 papers which were conference abstracts with insufficient information. Of the remaining 11 papers presented as the clinical evidence for VTq, 10 reported case‑control observational studies and 1 was a meta‑analysis of 8 studies.
The External Assessment Centre reviewed the literature presented by the company in its submission. It considered that 8 of the 11 papers included by the company should be excluded from further assessment because they reported on studies with overlapping cohorts. The External Assessment Centre carried out a further literature search using revised search terms and found an additional 7 papers; in total, it considered 10 papers to be relevant to this evaluation.
Seven of the papers evaluated VTq in people with hepatitis C and 3 evaluated VTq in people with hepatitis B. Five studies compared VTq with transient elastography and liver biopsy and 5 compared it with liver biopsy only. Optimal cut‑off values for VTq measurements were calculated to classify fibrosis stages by METAVIR score. Most studies describe VTq as acoustic radiation force impulse (ARFI) imaging carried out on a Siemens Acuson S2000 ultrasound machine.
Chen et al. (2012) carried out a prospective observational study evaluating ARFI (VTq) to measure fibrosis in 127 people with chronic hepatitis C attending a liver centre in Taiwan. ARFI measurements were compared with liver biopsy and blood tests (FibroTest) for staging of fibrosis. Necro‑inflammatory activity was also measured. Histological fibrosis staging was done using METAVIR scoring by a pathologist blinded to the ARFI and FibroTest results. The Spearman correlation coefficient between ARFI and liver biopsy was 0.696 (p<0.001). The AUROC curve measures for ARFI were: 0.847 for F1 compared with F2–4 (95% confidence interval 0.779 to 0.914); 0.902 for F1–2 compared with F3–4 (95% CI 0.835 to 0.97); and 0.831 for F1–3 compared with F4 (95% CI 0.723 to 0.939). The authors reported that the degree of necro‑inflammatory activity artificially raised the severity of fibrosis detected by ARFI, but concluded that ARFI was a promising alternative technology to measure liver stiffness.
The paper by Friedrich‑Rust et al. (2014) is a published abstract from a conference poster presentation reporting findings from a prospective international multicentre study. The study examined the use of ARFI (VTq) compared with transient elastography for fibrosis staging in 253 people with chronic hepatitis C, using liver biopsy as a reference method. Each person had ARFI, transient elastography and blood tests. The extent of fibrosis was staged from liver histology using METAVIR scoring by a single pathologist. The authors did an intention‑to‑diagnose analysis including 247 people and a per‑protocol analysis including 182 people. They reported that both ARFI and transient elastography correlated significantly with the histological fibrosis staging and that no statistically significant differences were found between ARFI and transient elastography for identifying fibrosis at stage F2 or higher in the per‑protocol analysis. The authors concluded that ARFI and transient elastography are comparable methods for non‑invasive fibrosis staging.
Friedrich‑Rust et al. (2013) report findings from a prospective, international multicentre study examining ARFI (VTq) used to assess liver fibrosis in people with chronic hepatitis B. In the study, 131 people attending hospitals in 3 European centres were recruited consecutively and tested with ARFI to assess the extent of fibrosis. Of the 131 people, 105 also had transient elastography (FibroScan). Liver biopsy was used as a reference method for histological assessment using METAVIR scoring, and blood tests were taken to confirm the diagnosis of chronic hepatitis B. Following exclusions because of invalid biopsy or ARFI measurements, data from 114 people were included in the final analysis. Of those, 92 also had transient elastography and were included in an intention‑to‑diagnose analysis. A per‑protocol analysis was done using data for 88 people who had valid ARFI and transient elastography measurements. Diagnostic accuracy was determined by AUROC curves. Both ARFI and transient elastography correlated significantly with liver biopsy results; the Spearman correlation coefficient was 0.415 (p<0.001) for ARFI and 0.556 (p<0.001) for transient elastography. The diagnostic accuracy of ARFI was 0.66 for mild fibrosis (F1), 0.73 for moderate fibrosis (F2), 0.94 for severe fibrosis (F3) and 0.97 for liver cirrhosis (F4). No statistically significant differences were found between ARFI and transient elastography in either the intention‑to‑diagnose or per‑protocol analyses.
Kuroda et al. (2010) carried out a prospective diagnostic accuracy study for ARFI (VTq) used in 70 people in Japan; 30 with chronic hepatitis C, 30 with liver cirrhosis and hepatitis C, and 10 healthy controls. The assessment of fibrosis by ARFI was compared with blood tests for serum markers of liver function. Liver biopsy for METAVIR staging was done for 19 patients. Mean shear‑wave velocity was 2.67±1.18 m/s in the liver cirrhosis group, 1.33±0.54 m/s in the chronic hepatitis C group and 0.99±0.21 m/s in the control group. The authors reported that shear‑wave velocity measured by ARFI was significantly higher in the liver cirrhosis group (p<0.001) than in the chronic hepatitis C group, and significantly higher in the chronic hepatitis C group than in the control group (p<0.0023). Mean shear‑wave velocity in each stage of fibrosis was: 1.09±0.22 m/s for F0–1; 1.24±0.52 m/s for F2; 1.61±0.79 m/s for F3; and 2.35±1.11 m/s for F4. ARFI measurements correlated significantly with fibrosis staging (r=0.9772, p=0.002) and all except 1 of the serum marker test results. ARFI showed better diagnostic accuracy for liver cirrhosis than the serum marker tests (AUROC: 0.930, no CI reported). The most appropriate cut‑off value for shear‑wave velocity was judged to be 1.59 (sensitivity 95%, specificity 83%).
Liu et al. (2014) explored the diagnostic accuracy of ARFI (VTq) compared with transient elastography and a biochemical test that determines the aspartate aminotransferase‑to‑platelet ratio index, in 95 people with hepatitis B and 16 healthy volunteers. All 95 people with hepatitis had a liver biopsy to stage fibrosis using METAVIR scoring. The authors developed an optimal linear combination of the 3 intervention methods and evaluated its accuracy. Results were analysed for 108 people; 3 were excluded because of transient elastography failure. ARFI and transient elastography correlated strongly with histological staging (r=0.85, p<0.001 for ARFI; r=0.81, p<0.001 for transient elastography) and APRI correlated moderately (r=0.63, p<0.001). The AUROC curve results reported for ARFI were 0.91 for F2 and 0.96 for F4, and the results for transient elastography were 0.87 for F2 and 0.96 for F4. The authors compared the accuracy of the combined methods against their individual accuracy, and found that accuracy was superior when they were combined, particularly for diagnosis of moderate fibrosis (F2) and cirrhosis (F4).
Nishikawa et al. (2014) investigated the correlation between ARFI and fibrosis stage as well as other factors including BMI, hyaluronic acid blood level, gamma‑glutamyltranspeptidase level and inflammation. ARFI (VTq) was used in 108 people with chronic hepatitis C attending hospital in Japan. All patients had liver biopsy for histological staging of fibrosis using METAVIR scoring, by assessors blinded to the clinical data. The investigators carrying out ARFI and clinical tests were blinded to the histological data. Multiple regression analysis showed that ARFI correlated significantly with fibrosis stage (b=0.1865, p<0.0001) and hyaluronic acid levels (b=0.0008, p<0.0039) independently, in all patients. ARFI correlated significantly with BMI in F≤1 fibrosis, with gamma‑glutamyltranspeptidase level in F2 fibrosis, and with fibrosis stage and hyaluronic acid levels in F3 and F4 fibrosis, indicating that these factors could affect ARFI measurements. ARFI did not correlate with inflammation.
Rizzo et al. (2011) report findings from a study exploring the accuracy of ARFI (VTq) compared with transient elastography in people with chronic hepatitis C, using liver biopsy as a reference standard. In the study, 139 people were recruited consecutively from 2 hospitals in Italy and each had both ARFI and transient elastography as well as liver biopsy for histological staging. Fibrosis staging was done using METAVIR scoring by an assessor blinded to clinical data. No invalid measurements were reported for ARFI, but transient elastography measurements were invalid in 9 people (6.5%). Using pairwise AUROC analysis, ARFI was significantly more accurate than transient elastography for diagnosing moderate (or higher) and severe (or higher) fibrosis (F2: 86 compared with 0.78, p=0.024; F3: 0.94 compared with 0.83, p=0.002) but not for cirrhosis (F4; 0.89 compared with 0.80, p=0.09). Partial AUROC analysis showed that ARFI was statistically significantly more accurate than transient elastography for all stages of fibrosis.
An international multicentre study was carried out by Sporea et al. (2012a) in 10 centres across 5 countries in Europe and Asia. Liver biopsy (using METAVIR scoring) and ARFI (VTq) measurements of fibrosis were compared for 911 people with chronic hepatitis C. A subset of 400 people also had transient elastography and their results were compared with ARFI and biopsy. Diagnostic accuracy was assessed using AUROC curves. ARFI correlated significantly with liver biopsy staging (Spearman correlation coefficient r=0.654, p<0.0001). In the subgroup having transient elastography and ARFI, the overall correlation with liver biopsy staging was reported as being similar for both ARFI and transient elastography (r=0.689, p<0.001 and 0.728, p<0.001 respectively). The number of people with reliable measurements was significantly higher for ARFI (98.8%) compared with transient elastography (93.7%; p=0.003). The same reliability criteria were used for both ARFI and transient elastography, but different numbers of measurements were used; for ARFI, between 5 and 10 measures were used depending on the centre, and for transient elastography all centres used 10 measurements. The authors reported that ARFI was less effective than transient elastography in predicting liver cirrhosis (F4; AUROC 0.885 compared with 0.932; p=0.01). However, for moderate or severe fibrosis (F2–3), ARFI and transient elastography showed equivalent effectiveness. The authors also noted that the cut‑off levels for ARFI to determine fibrosis at stages F2 and F4 were different for European and Asian people. It is not clear how these subgroups were identified. The authors noted that more people in the Asian group either did not have fibrosis or had mild fibrosis (F1), and that people in the Asian group were older and had a lower mean BMI than those in the European group.
A study done in Japan by Yamada et al. (2014) evaluated the accuracy of ARFI (VTq) in assessing liver fibrosis in people with chronic hepatitis C as well as the association between ARFI and the response to antiviral therapy. Of the 124 people enrolled in the study, 94 had genotype 1 hepatitis C virus, 46 of whom had antiviral pegylated interferon and ribavirin combination therapy. Although not stated, it can be assumed that the remainder had genotype 2 hepatitis C virus, 15 of whom had antiviral therapy. Liver biopsy with histological analysis was used to determine fibrosis stage. Forty (30%) people were judged to have moderate (F2) fibrosis. ARFI was found to have a strong correlation with fibrosis stage (Pearson's r=0.764, p<0.001). people with the genotype 1 hepatitis C virus and less severe fibrosis (indicated by ARFI measurements of less than 1.40 m/s) showed a better response to treatment, indicating that ARFI could have some benefit in predicting response. ARFI could not predict treatment response in people with the genotype 2 hepatitis C virus.
Ye et al. (2012) assessed the performance of ARFI (VTq) to measure liver and spleen stiffness in 204 people with chronic hepatitis B and 60 healthy volunteers. Of those with hepatitis B, 66 had liver biopsy and 138 had been diagnosed previously as having cirrhosis. Histological staging using METAVIR scoring was done by an experienced pathologist for those people having biopsies. ARFI measurements showed good correlation with fibrosis stage using Spearman's correlation coefficient (r= 0.87, p<0.001), and a high diagnostic accuracy for predicting severe fibrosis and cirrhosis using optimal measurement cut‑off values for each stage (AUROC curve F3=0.99; F4=0.97).
## Evidence synthesis
The company included a brief synthesis of the clinical evidence in its submission and concluded that VTq and transient elastography have equivalent accuracy, although transient elastography may be slightly more accurate in diagnosing mild fibrosis (F1). The External Assessment Centre considered that this conclusion was plausible, but noted that the company did not carry out a meta‑analysis which would have provided a more definitive result.
The company provided an overall interpretation of the clinical evidence and concluded that VTq can be a good tool when used in clinical practice to diagnose moderate fibrosis (F2) and an excellent tool to diagnose severe fibrosis (F3) or cirrhosis (F4). The External Assessment Centre considered that this interpretation was reasonable and that the company's assessment of the strengths and weaknesses of the studies was fair.
As a result of its concerns about the studies selected by the company and the subsequent identification of additional clinical evidence, the External Assessment Centre did a meta‑analysis of the 10 studies it selected for inclusion. A random effects approach was used to calculate pooled outcome data for correlation coefficients (between either VTq or transient elastography and liver biopsy METAVIR scores), and for sensitivity, specificity and prevalence for each disease type (hepatitis B, C or a combination) using liver biopsy as the reference standard. Proportions were transformed using the logit function where necessary to overcome skewness, and values of 0 were transformed to 0.5 to allow pooling of the data. Results were back‑transformed to provide estimated pooled proportions and 95% confidence intervals. Nine outcome estimates were made from multiple studies and 6 from single studies. The pooled estimates for sensitivity, specificity and prevalence for each disease type (hepatitis B, C or a combination) are shown in table 1.
## Table 1 Pooled estimates from External Assessment Centre's meta‑analysis with 95% confidence intervals for prevalence and diagnostic accuracy
Hepatitis type
Reference standard ( liver biopsy)
VTq
Transient elastography
Fibrosis stage
F≥1
F≥2
F≥3
F4
F≥1
F≥2
F≥3
F4
B
No. of studies
Prevalence
Sensitivity % (95% CI)
Specificity % (95% CI)
C
No. of studies
Prevalence
Sensitivity % (95% CI)
Specificity % (95% CI)
B and C
No. of studies
Prevalence
Sensitivity % (95% CI)
Specificity % (95% CI)
The results of the meta‑analysis showed that the prevalence of moderate fibrosis (F2) for both hepatitis B and C was lower with VTq (0.55) than transient elastography (0.62). However, the techniques had similar scores for cirrhosis (F4; 0.23 for VTq and 0.23 for transient elastography). Sensitivity and specificity values were similar for hepatitis B and C. VTq had slightly higher values for both sensitivity and specificity in diagnosing moderate fibrosis (F2; 77% and 81% respectively) than transient elastography (76% and 71% respectively) in people with hepatitis B and C. The sensitivity was higher than the specificity for identifying cirrhosis (F4) in the combined study population for VTq (85% and 80% respectively), but the opposite was found for transient elastography (79% and 84% respectively). The correlation coefficients for VTq and transient elastography were similar in the combined study population (0.68 to 0.69).
The External Assessment Centre noted that no adjustment could be made in the meta‑analysis for confounding variables such as patient characteristics, other than disease type, study design and location, because there was insufficient information in the papers.
## Adverse events
In its submission, the company stated that no adverse events have been reported for VTq. None were identified in the literature, or from searches of the MHRA website and US Food and Drug Administration database: Manufacturer and User Device Facility Experience (MAUDE). The External Assessment Centre repeated the literature searches and found no adverse events relating to the use of VTq.
## Committee considerations
The Committee considered that despite some limitations, the clinical evidence was sufficient to demonstrate that VTq has equivalent accuracy to transient elastography for diagnosing liver fibrosis. The Committee recognised that there was no evidence specifically evaluating the use of VTq for monitoring of liver fibrosis, but considered that the technology was likely to be useful for this purpose. It was advised by clinical experts that the use of image‑guided assessment of liver fibrosis in VTq allowed measurements to be taken from the same part of the liver at different times, which would be useful for monitoring changes in fibrosis relating to disease progression.
The Committee heard advice from clinical experts that VTq would be particularly useful in hospitals without access to transient elastography for determining the stage of fibrosis and informing the decision to start antiviral therapy, because those hospitals currently use liver biopsy as their primary method of diagnosis. The Committee considered that using VTq could avoid a considerable number of liver biopsies for both initial assessment and ongoing monitoring (particularly for people with hepatitis B), reducing the risks of morbidity and mortality.
For hospitals with access to transient elastography, the Committee was advised that using VTq could offer advantages by enabling image‑guided assessment of the liver. This assessment offers the opportunity to select areas from which to assess fibrosis and to identify associated pathologies, for example cirrhosis and hepatocellular carcinoma.
The Committee noted that no evidence was available on the use of VTq in children and that the company's instructions for use do not distinguish between adults and children. However, clinical experts advised the Committee that there was no reason to suppose that VTq would be any less effective in children than in adults, although the range of readings considered normal may differ between them. It heard from clinical experts that avoiding liver biopsies would be particularly beneficial for children, who might need a general anaesthetic and an overnight stay in hospital, as well as facing restrictions to their daily activities following each biopsy.
The Committee also noted a lack of evidence for improved quality of life as a consequence of using VTq, but it considered that reducing the need for liver biopsies would have a positive effect on quality of life.
The Committee noted comments made during consultation about the cut‑off values used with VTq. It considered that the interpretation of these values was a matter for clinical judgement by specialists, taking into account results of other tests and the clinical context. It also noted several comments made during consultation that suggested a variety of factors, including obesity and hepatic inflammation, may influence the readings from both VTq and transient elastography. The Committee considered it unclear from the clinical evidence how exactly these factors influence the accuracy of the tests.# NHS considerations
# System impact
The company claimed that use of Virtual Touch Quantification (VTq) had the potential to release resources within the NHS because the VTq procedure does not need to be carried out by a consultant and can be done in an outpatient setting. It also claimed that VTq could reduce the number of liver biopsies needed over several years if used to monitor fibrosis progression. The company was not able to identify any published evidence relating to these claims.
The published evidence provided data on the diagnostic accuracy of VTq compared with transient elastography and with liver biopsy, but none of the studies specifically explored the potential system impact of using VTq. Some authors (Friedrich‑Rust et al. 2013, Yamada et al. 2014 and Rizzo et al. 2011) mentioned in their conclusions that VTq can be used for non‑invasive assessment in people with obesity. Yamada et al. assessed the utility of VTq in predicting response to antiviral therapy and found that this had potential for people with genotype 1 hepatitis C: this could be useful in directing treatment with newer direct‑acting antiviral agents to people who are not likely to respond to existing antiviral therapies.
Four of the studies reported higher failure rates or a greater number of unreliable measurements when using transient elastography compared with VTq (Friedrich‑Rust et al. 2013, Liu et al. 2014, Rizzo et al. 2011, Sporea et al. 2012a). Sporea et al. reported that a significantly higher number of reliable measurements were taken using VTq compared with transient elastography (98.8% compared with 93.7%, p=0.003).
## Committee considerations
The Committee acknowledged that no evidence was available to demonstrate that using VTq reduces the length of hospital stay. However, it considered that using VTq could reduce the need for liver biopsies. This is likely to have an effect on resource use, particularly for children who may need a general anaesthetic and an overnight stay in hospital for liver biopsy.
The Committee considered that using VTq may provide system benefits by allowing assessment of liver fibrosis to be done at the same time as the initial diagnostic ultrasound test included in the current care pathway. The Committee heard expert clinical advice that patients being assessed for liver fibrosis usually have an ultrasound scan, and that adding VTq to the ultrasound may lead to a more streamlined care pathway. It also heard that the Siemens ultrasound machine needed for VTq can be used for other purposes. This was explored in the cost modelling (see section 5).
The Committee noted from the published evidence that VTq appears to have a lower failure rate than transient elastography, and this was confirmed by clinical expert advisers as being the case in clinical practice.
The Committee considered that VTq is likely to be used in an outpatient setting as part of the initial referral from primary care for people who test positive for chronic hepatitis B or C. Clinical experts advised that there is also potential for VTq to be used in primary care settings which offer ultrasound. The Committee was advised by clinical experts that VTq assessments should only be done by staff with specialist training in ultrasound imaging and its interpretation. The Committee also noted that transient elastography can be associated with a range of staff costs, which may be lower than those needed for VTq. The resource impact of these different staff needs was incorporated into the cost modelling done by both the company and the External Assessment Centre.
The Committee considered the issue of the VTq software package being usable only with a Siemens ultrasound machine. It noted that ultrasound machines from a variety of manufacturers are currently in use in the NHS but that individual hospitals are likely to have a number of machines. The Committee considered that the purchase of a compatible Siemens ultrasound machine for VTq can be considered as part of existing device renewal programmes.# Cost considerations
# Cost evidence
The company carried out a literature search for economic studies related to Virtual Touch Quantification (VTq), transient elastography and liver biopsy in hepatitis. After applying inclusion and exclusion criteria, the company did not identify any relevant economic studies for VTq. However, 5 studies were presented relating to the comparators (transient elastography and liver biopsy).
The External Assessment Centre considered that the company's search strategy and inclusion/exclusion criteria were appropriate, but noted that the date range and search terms could have been broader and 2 further databases could have been searched. The External Assessment Centre carried out a revised search addressing these issues and did not find any relevant publications, confirming the company's conclusion that there was no published economic evidence relating to VTq. The External Assessment Centre considered that the 5 papers identified by the company relating to the comparators were useful for modelling purposes, and found 1 additional comparator paper.
## Company's cost model
The company submitted a de novo cost analysis evaluating VTq plus liver biopsy (where needed) compared with transient elastography plus liver biopsy (where needed) and against liver biopsy alone. Costs were modelled from an NHS and personal social services perspective using 2013 prices. The population included in the model was patients with chronic hepatitis B or C needing assessment of liver fibrosis. The model structure was a decision tree based on a cohort of 1000 patients referred by GPs and stratified according to the presence or absence of fibrosis, then sequentially across 3 groups according to stage of fibrosis determined by METAVIR score (F2, F3/F4, or F4). The External Assessment Centre confirmed that the model was internally valid.
The company used the estimated prevalence of fibrosis to stratify the cohort into the 3 stages, and applied the sensitivity and specificity of each diagnostic strategy (VTq plus liver biopsy, transient elastography plus liver biopsy and liver biopsy alone) for each stage, creating estimated numbers of true or false negatives or positives. The External Assessment Centre generally agreed with this approach.
The model was based mainly on fibrosis assessment and did not include any treatment or monitoring costs for patients in the F2 group and the F3/F4 group. For F4 fibrosis (cirrhosis), patients in the true‑positive group had antiviral therapy and those in the false‑negative group had liver biopsy. According to the diagram of the company's model in its submission, false positives had antiviral therapy and true negatives had a biopsy. The External Assessment Centre questioned the rationale for this approach and whether this assumption was actually included in the model calculations.
The company did not state the time horizon for the model, but the External Assessment Centre considered that the outcomes were likely to be realised using a 1‑year horizon, based on the duration of antiviral therapy.
The company's estimates of fibrosis prevalence at each stage were based mainly on clinical expert advice and on 1 study in patients with cirrhosis, because exact figures were difficult to determine. The External Assessment Centre sought additional clinical expert advice to validate these assumptions but the experts consulted were not able to provide any figures.
The diagnostic accuracy figures for VTq and transient elastography were taken from the available literature and liver biopsy was assumed to have 100% sensitivity and specificity. The External Assessment Centre agreed with the approach taken for liver biopsy and transient elastography (figures taken from a meta‑analysis), but considered that the figures used for VTq were not sufficiently robust. The External Assessment Centre addressed this issue in its own meta‑analysis of the clinical evidence.
The company included direct costs for VTq, transient elastography and liver biopsy, calculating the costs of VTq and transient elastography using a bottom‑up approach which included capital, infrastructure, maintenance, staffing, training and consumable costs. The cost for transient elastography was calculated based on a nurse carrying out the test with a throughput of 2,500 patients per year over the device lifespan (7 years), giving a per‑patient cost of £25.33. This was compared with a report published by the Centre for Evidence‑based Purchasing (Stamuli et al. 2009), which gave a per‑patient cost of £18.68 (corrected for inflation by the company to £22.91). The cost for VTq was based on the purchase of the software and a Siemens Acuson S2000 machine, and use by a radiographer. It was assumed that VTq assessments would take up 10% of the ultrasound machine use and so this proportion of the annual capital, staffing and consumables costs was used in the estimation. The cost was calculated based on a throughput of 500 patients per year over the device lifespan (5 years), giving a per‑patient cost of £15.02. The cost for liver biopsy was estimated from the 2013–14 payment by results tariff to be £615, based on a mix of procedures.
The External Assessment Centre agreed with the estimates for these costs but considered that they could be further explored in sensitivity analyses. The capital costs for VTq and transient elastography were not estimated using the annuity method, and the company did not describe the exact mix of procedures used to calculate the biopsy cost. The cost of antiviral therapy was estimated to be £10,000 per patient in the executable model; the External Assessment Centre was unsure about the rationale behind this figure.
The company carried out deterministic 1‑way and multi‑way sensitivity analyses varying the prevalence of liver disease, prevalence for different liver fibrosis stages, the diagnostic accuracy of VTq, technology and treatment costs and whether or not liver biopsy was done. The External Assessment Centre generally agreed with the company's approach but commented that the company did not explain the rationale for the variations in prevalence which it used.
The results of the company's base case indicated that VTq could result in a cost saving of £10.31 per patient when compared with transient elastography and £599.08 per patient when compared with liver biopsy.
Findings from the company's sensitivity analysis showed that if each patient had a biopsy, increasing the overall prevalence of liver fibrosis from 10% to 30% lowered the cost saving per patient from £527 to £447 (assuming the best‑case diagnostic accuracy of VTq) and from £496 to £419 (assuming the worst‑case diagnostic accuracy of VTq). If only 20% of patients had a biopsy, the cost savings for VTq were reduced, and at high fibrosis prevalence levels or lower diagnostic accuracy it became cost‑incurring. The cost of antiviral therapy was also varied from the base case assumption of £10,000 to £6500. Over this range, assuming that 20% of patients had a biopsy, the cost savings for VTq varied from around £60 to £8.
The External Assessment Centre considered that the model addressed the decision problem in the scope, but that its structure did not accurately reflect current clinical pathways for people with liver fibrosis. It also did not include all the relevant costs and outcomes for diagnosing and treating the condition. No monitoring or treatment costs were included for patients in the F2 or F3/F4 fibrosis groups. The External Assessment Centre considered that this was erroneous, because people with less severe fibrosis may benefit from treatment.
The External Assessment Centre also questioned the assumption that patients falsely classified as negative for fibrosis would not incur any treatment costs and would re‑enter the model as new patients. It considered that this was a misleading approach, because misdiagnosis may incur additional costs (from further diagnostic tests, inpatient or emergency episodes and treatment). The External Assessment Centre considered that a mortality arm would have been appropriate to account for the small increased risk associated with liver biopsy, but acknowledged that this was likely to have been incorporated in the chosen tariff cost. The External Assessment Centre also noted that the company had used a cohort approach rather than a per‑patient approach as specified in NICE's methodology.
## Additional work by the External Assessment Centre
The External Assessment Centre revised some parameters and re‑ran the company's model to address these issues. The revised model included true positives, false positives, true negatives and false negatives at each of the F≥2, F≥3 and F4 stages. Revised prevalence and diagnostic accuracy parameters for the model were taken mainly from the External Assessment Centre's meta‑analysis and applied at each sequential stage for VTq, transient elastography and liver biopsy. Liver biopsy was treated as the reference standard with 100% sensitivity and specificity.
Key assumptions made by the External Assessment Centre in its revisions to the company's model were as follows:
Patients categorised as false negative for fibrosis would return and be re‑diagnosed as true positive within 1 year.
Prevalence rates for stages of fibrosis were different for VTq and transient elastography based on the External Assessment Centre's meta‑analysis. The combined hepatitis B and C prevalence rates for VTq were used for transient elastography and liver biopsy in the model to ensure compatibility.
Combined hepatitis B and C prevalence and diagnostic accuracy figures for F3 fibrosis were not available from the meta‑analysis. The External Assessment Centre therefore used figures for hepatitis C across the model for this stage.
Treatment delay resulting from misdiagnosis was unlikely to have a clinical effect and so long‑term modelling of disease progression was not needed. According to published clinical evidence and expert advice gathered by the External Assessment Centre, progression in both hepatitis B and C is relatively slow.
Patients diagnosed as being at stage F2 had fibrosis and those at stage F≤1 did not.
Most misclassified (false positive) patients for VTq and transient elastography would be diagnosed as having F2 fibrosis. A proportion of those with F2 fibrosis would be misclassified as having F3 or F4 fibrosis. These proportions were chosen arbitrarily and subjected to sensitivity analyses.
Patients diagnosed with F3 or F4 fibrosis would have antiviral therapy.
A mortality risk of 0.003 would apply to liver biopsy, based on available literature.
The unit costs for VTq and transient elastography were estimated using an annuity method and discounted at 3%, to give per‑test figures of £15.24 for VTq and £25.90 for transient elastography. The cost for liver biopsy was estimated from tariff costs to be £622. The costs for antiviral therapy were based on duration of treatment, which was estimated to be 12 weeks for patients with F3 fibrosis and 24 weeks for patients with F4 fibrosis, based on NICE technology appraisal guidance on peginterferon alfa and ribavirin for the treatment of chronic hepatitis C. Costs for a compatible Siemens ultrasound machine were modelled in 2 scenarios: 1 including purchase costs and 1 assuming that a machine was already available.
Findings from the base case (incorporating the External Assessment Centre's revised parameters) showed that in a scenario where a compatible Siemens ultrasound machine would be purchased along with the VTq software, using VTq would generate cost savings of £53 per patient compared with transient elastography and £434 compared with liver biopsy. If a compatible ultrasound machine was already available, the cost savings for VTq increased slightly to £57 compared with transient elastography and £438 compared with liver biopsy.
The External Assessment Centre carried out deterministic sensitivity analyses varying prevalence rates, sensitivity and specificity for VTq and transient elastography, distribution of false positives between stages F2 and F3, unit costs of VTq and transient elastography, usage levels of transient elastography and antiviral therapy costs. Findings from the sensitivity analyses showed that VTq remained cost‑saving across all scenarios. The key drivers affecting the cost savings per patient were prevalence of liver fibrosis, the distribution of false positives to other fibrosis stages, the specificity of VTq and transient elastography for stages F2 and F3, unit costs of VTq and transient elastography and antiviral treatment costs.
The External Assessment Centre acknowledged some limitations in its revised parameters. The lack of clear data on prevalence and diagnostic accuracy at each stage of fibrosis meant that figures were extrapolated for the stages in a sequential model, rather than each stage being presented separately. Figures for hepatitis C at stage F3 fibrosis were applied to the whole population because combined data were not available. Several assumptions were made to calculate technology and comparator costs, but the External Assessment Centre varied these parameters in sensitivity analyses to address uncertainty.
## Committee considerations
The Committee recognised the limitations in the cost modelling presented by the company and in the adjustments made by the External Assessment Centre, but considered these revisions sufficiently robust to be plausible. The Committee considered that the External Assessment Centre's sensitivity analyses addressed the uncertainties in the evidence base and it concluded that cost savings for VTq compared with transient elastography and liver biopsy were likely to be realised in practice.
The Committee was satisfied that the cost modelling indicated that use of the VTq software would generate cost savings regardless of whether a compatible Siemens ultrasound machine was purchased.
The Committee noted that the cost modelling included the assumption that the Siemens ultrasound machine would be used for VTq measurements for only 10% of the time and for other scanning procedures for the rest of the time: it was advised by experts that this was reasonable. The External Assessment Centre stated that the findings from the model were robust even when the proportionate use of the machine for VTq (and so VTq's test costs) was raised in sensitivity analyses.
The External Assessment Centre also stated that the findings remained robust if treatment costs (for antiviral therapy) were not included in the model.
For the guidance review, the External Assessment Centre noted that the differences between the updated pooled estimates for the sensitivity and specificity of VTq for hepatitis C compared with the pooled estimates used in the original model (see table 1) are minor, as seen in table 2.
## Table 2 Updated pooled estimates for the sensitivity and specificity of VTq for hepatitis C
Disease
Sensitivity (update)
Sensitivity (original)
Specificity (update)
Specificity (original)
Hepatitis C F≥2
Hepatitis C F=4
%# Conclusions
The Committee concluded that the evidence supports the case for adopting Virtual Touch Quantification (VTq) for diagnosing and monitoring liver fibrosis in people with chronic hepatitis B or C. The Committee considered that the clinical evidence demonstrated that VTq is as accurate as transient elastography for diagnosing and staging liver fibrosis and may offer additional benefits, including image‑guided assessment and a lower failure rate.
The Committee concluded that using VTq may offer particular advantages in hospitals without access to transient elastography, by providing a non‑invasive method of assessment of liver fibrosis in place of liver biopsy. This may have major benefits for people who need monitoring for fibrosis progression for whom liver biopsy may have a substantial effect on quality of life.
Based on the revised cost model and sensitivity analyses, the Committee concluded that using VTq is likely to be cost saving compared with transient elastography and liver biopsy, whether or not the purchase of a compatible Siemens ultrasound machine is needed.
|
{'Recommendations': "NICE medical technologies guidance addresses specific technologies notified\xa0to\xa0NICE by companies. The 'case for adoption' is based on the claimed advantages of introducing the specific technology compared with current management of the condition. This case is reviewed against the evidence submitted and expert advice. If the case for adopting the technology is supported, then the technology has been found\xa0to\xa0offer advantages\xa0to\xa0patients and the NHS. The specific recommendations on individual technologies are not intended\xa0to\xa0limit use of other relevant technologies which may offer similar advantages.\n\nThe case for adopting Virtual Touch Quantification (VTq) software\xa0to\xa0diagnose and monitor liver fibrosis is supported by the evidence. VTq is as accurate as transient elastography in diagnosing and staging liver fibrosis, and may offer other benefits in terms of imaging the liver and sampling selected areas\xa0to\xa0assess fibrosis and identify associated pathologies. By avoiding liver biopsies, it may also benefit\xa0people whose liver fibrosis needs monitoring. Cost savings through adopting VTq will be greater in hospitals in which liver biopsy is the primary method for diagnosing and monitoring liver fibrosis.\n\nVTq should be considered as an option for\xa0people with chronic hepatitis\xa0B or C who need assessment of liver fibrosis.\n\nCost modelling suggests that using VTq is cost saving compared with transient elastography and liver biopsy, whether or not a compatible Siemens ultrasound machine needs\xa0to\xa0be purchased. Compared with transient elastography, the estimated overall cost saving for VTq is around £53 per\xa0person. This saving assumes that 10% of the ultrasound machine capacity would be used for VTq measurements, leaving 90%\xa0to\xa0be applied\xa0to\xa0other uses. Compared with liver biopsy, the corresponding saving is around £434 per\xa0person.", 'The technology': "# Description of the technology\n\nThe Virtual Touch Quantification (VTq; Siemens) software application uses acoustic radiation force impulse (ARFI) imaging technology\xa0to\xa0measure the elasticity of liver tissue. VTq is used in combination with a Siemens Acuson S2000 or S3000 ultrasound platform. Liver tissue can be damaged by inflammation, causing high levels of collagen\xa0to\xa0be deposited in the liver cells (fibrosis), which become stiff. ARFI imaging involves generating a shear wave by applying an acoustic 'push pulse' lateral\xa0to\xa0the area of interest identified during a conventional ultrasound scan. The speed of the shear wave is proportional\xa0to\xa0the stiffness of the tissue.\n\nThe VTq investigation comprises multiple measurements and is both non‑invasive and painless. The software generates a report which includes a statistical summary of the median and mean shear‑wave velocities. The reliability of VTq measurements is usually confirmed by calculating the ratio of the interquartile range\xa0to\xa0median, which should be less than 0.30. VTq is indicated for adults or children needing assessment of liver fibrosis.\n\nThis evaluation focuses on the use of VTq\xa0to\xa0diagnose and monitor liver fibrosis in adults and children with chronic hepatitis\xa0B or C. The use of VTq\xa0to\xa0assess liver fibrosis associated with other conditions was outside the scope and so is not considered here.\n\nThe cost of the VTq software stated in the company's submission is £4,415. A compatible Siemens Acuson S2000 ultrasound system costs from £50,000 with annual maintenance costs, starting in year\xa02, from £2,000. The cost varies with the system configuration; the cost model includes typical values of £59,700 for the ultrasound system and £2,246 for the annual maintenance costs. All costs are excluding VAT.\n\nThe claimed benefits of VTq as presented by the company are as follows:\n\nVTq is painless and may be safer than liver biopsy as the standard of care.\n\nNo hospital stay or post‑procedure monitoring is needed with VTq because it can be done in an outpatient setting.\n\nVTq may avoid the need for serial biopsies over several\xa0years\xa0to\xa0monitor fibrosis progression, improving quality of life and reducing procedure costs (if fibrosis progression is monitored with VTq).\n\nVTq provides a more complete assessment of the liver; during the procedure, a sonogram allows visualization of the liver parenchyma, portal and hepatic veins, portal and hepatic venous and arterial blood flow measurements, and the biliary tree for possible obstructions.\n\nHepatic cellular carcinoma surveillance is included during the sonogram in patients with cirrhosis.\n\nEarly identification of fibrosis in\xa0people with viral hepatitis\xa0may allow earlier intervention with antiviral drugs, which can reverse the course of early disease.\n\nPotential for increased capacity because the VTq procedure does not need\xa0to\xa0be done by a consultant.\n\nReduced resource costs because no hospital admission or stay is needed for VTq measurements in an outpatient setting.\n\n# Current management\n\nThe NICE Pathway for chronic hepatitis\xa0B indicates that initial assessment usually takes place in primary care, through blood tests. All patients who test positive for hepatitis\xa0B surface antigen are then referred\xa0to\xa0a hepatologist, gastroenterologist or infectious diseases specialist with an interest in hepatology (children are referred\xa0to\xa0a similar paediatric specialist in a secondary or tertiary centre).\n\nIn secondary or tertiary care patients are provided with information on disease progress, long‑term prognosis, transmission and antiviral treatment options. Adults are then offered transient elastography as an initial test for chronic liver disease. Transient elastography (using, for example, the FibroScan device) is a non‑invasive method of assessing liver fibrosis by measuring liver stiffness based on a mechanical wave generated by vibration. Children and young\xa0people are offered liver biopsy\xa0to\xa0determine the need for antiviral therapy, with appropriate information provided on biopsy limitations and risks.\n\nNICE's guideline on hepatitis\xa0B recommends:\n\nTransient elastography as the initial test for chronic liver disease, offering antiviral treatment (without a liver biopsy)\xa0to\xa0patients with a transient elastography score of 11\xa0kPa or above.\n\nConsidering liver biopsy in patients with a transient elastography score of 6–10\xa0kPa.\n\nOffering liver biopsy\xa0to\xa0patients with a transient elastography score of less than 6\xa0kPa if they are younger than 30\xa0years of age and have hepatitis\xa0B virus DNA of more than 2000\xa0IU/ml and abnormal alanine aminotransferase (ALT) on 2 consecutive tests conducted months apart.\n\nAnnual reassessment of patients who are not taking antiviral treatment.\n\nThe therapy pathway for people with hepatitis C is described in NICE's clinical knowledge summary on hepatitis C. Presently, patients who test hepatitis\xa0C virus RNA‑positive on a blood test are referred\xa0to\xa0a hepatology clinic. The degree of fibrosis is assessed and treatment options then depend on specific patient characteristics and the severity of their liver disease.\xa0There is a NICE guideline on the management and assessment of cirrhosis.\n\nLiver biopsy is considered\xa0to\xa0be the gold standard for assessing liver fibrosis for both hepatitis\xa0B and C. Histological assessment uses the METAVIR score, based on an assessment of fibrosis and the degree of liver architecture disorganisation, and classifies the severity of liver disease from none (F0), through mild, moderate and severe (F1–F3),\xa0to\xa0cirrhosis (F4).", 'Clinical evidence': "# Summary of clinical evidence\n\nThe key clinical outcomes for Virtual Touch Quantification (VTq) presented in the decision problem were:\n\ncorrelation in assessment of stage of liver disease and stage of fibrosis using METAVIR score\n\nsensitivity and specificity (using area under receiver operating characteristic [AUROC] curve) in assessment of liver fibrosis\n\nuse of antiviral drugs\n\nquality of life measures\n\nhospital bed usage and length of stay\n\nneed for liver biopsy\n\ndevice‑related adverse events.\n\nThe company identified 23 published\xa0papers as suitable for full‑text review. No unpublished\xa0studies were identified. After review, the company excluded 12\xa0papers which were conference abstracts with insufficient information. Of the remaining 11\xa0papers presented as the clinical evidence for VTq, 10 reported case‑control observational\xa0studies and 1 was a meta‑analysis of 8\xa0studies.\n\nThe External Assessment Centre reviewed the literature presented by the company in its submission. It considered that 8 of the 11\xa0papers included by the company should be excluded from further assessment because they reported on\xa0studies with overlapping cohorts. The External Assessment Centre carried out a further literature search using revised search terms and found an additional 7\xa0papers; in total, it considered 10\xa0papers\xa0to\xa0be relevant\xa0to\xa0this evaluation.\n\nSeven of the\xa0papers evaluated VTq in\xa0people with hepatitis\xa0C and 3 evaluated VTq in\xa0people with hepatitis\xa0B. Five\xa0studies compared VTq with transient elastography and liver biopsy and 5 compared it with liver biopsy only. Optimal cut‑off values for VTq measurements were calculated\xa0to\xa0classify fibrosis stages by METAVIR score. Most\xa0studies describe VTq as acoustic radiation force impulse (ARFI) imaging carried out on a Siemens Acuson S2000 ultrasound machine.\n\nChen et al. (2012) carried out a prospective observational study evaluating ARFI (VTq)\xa0to\xa0measure fibrosis in 127\xa0people with chronic hepatitis\xa0C attending a liver centre in Taiwan. ARFI measurements were compared with liver biopsy and blood tests (FibroTest) for staging of fibrosis. Necro‑inflammatory activity was also measured. Histological fibrosis staging was done using METAVIR scoring by a pathologist blinded\xa0to\xa0the ARFI and FibroTest results. The Spearman correlation coefficient between ARFI and liver biopsy was 0.696 (p<0.001). The AUROC curve measures for ARFI were: 0.847 for F1 compared with F2–4 (95% confidence interval [CI] 0.779\xa0to\xa00.914); 0.902 for F1–2 compared with F3–4 (95% CI\xa00.835\xa0to\xa00.97); and 0.831 for F1–3 compared with F4 (95% CI\xa00.723\xa0to\xa00.939). The authors reported that the degree of necro‑inflammatory activity artificially raised the severity of fibrosis detected by ARFI, but concluded that ARFI was a promising alternative technology\xa0to\xa0measure liver stiffness.\n\nThe paper\xa0by Friedrich‑Rust et al. (2014) is a published abstract from a conference poster presentation reporting findings from a prospective international multicentre study. The study examined the use of ARFI (VTq) compared with transient elastography for fibrosis staging in 253\xa0people with chronic hepatitis\xa0C, using liver biopsy as a reference method. Each person had ARFI, transient elastography and blood tests. The extent of fibrosis was staged from liver histology using METAVIR scoring by a single pathologist. The authors did an intention‑to‑diagnose analysis including 247\xa0people and a per‑protocol analysis including 182\xa0people. They reported that both ARFI and transient elastography correlated significantly with the histological fibrosis staging and that no statistically significant differences were found between ARFI and transient elastography for identifying fibrosis at stage F2 or higher in the per‑protocol analysis. The authors concluded that ARFI and transient elastography are comparable methods for non‑invasive fibrosis staging.\n\nFriedrich‑Rust et al. (2013) report findings from a prospective, international multicentre study examining ARFI (VTq) used\xa0to\xa0assess liver fibrosis in\xa0people with chronic hepatitis\xa0B. In the study, 131\xa0people attending hospitals in 3 European centres were recruited consecutively and tested with ARFI\xa0to\xa0assess the extent of fibrosis. Of the 131\xa0people, 105 also had transient elastography (FibroScan). Liver biopsy was used as a reference method for histological assessment using METAVIR scoring, and blood tests were taken\xa0to\xa0confirm the diagnosis of chronic hepatitis\xa0B. Following exclusions because of invalid biopsy or ARFI measurements, data from 114\xa0people were included in the final analysis. Of those, 92 also had transient elastography and were included in an intention‑to‑diagnose analysis. A per‑protocol analysis was done using data for 88\xa0people who had valid ARFI and transient elastography measurements. Diagnostic accuracy was determined by AUROC curves. Both ARFI and transient elastography correlated significantly with liver biopsy results; the Spearman correlation coefficient was 0.415 (p<0.001) for ARFI and 0.556 (p<0.001) for transient elastography. The diagnostic accuracy of ARFI was 0.66 for mild fibrosis (F1), 0.73 for moderate fibrosis (F2), 0.94 for severe fibrosis (F3) and 0.97 for liver cirrhosis (F4). No statistically significant differences were found between ARFI and transient elastography in either the intention‑to‑diagnose or per‑protocol analyses.\n\nKuroda et al. (2010) carried out a prospective diagnostic accuracy study for ARFI (VTq) used in 70\xa0people in Japan; 30 with chronic hepatitis\xa0C, 30 with liver cirrhosis and hepatitis\xa0C, and 10 healthy controls. The assessment of fibrosis by ARFI was compared with blood tests for serum markers of liver function. Liver biopsy for METAVIR staging was done for 19 patients. Mean shear‑wave velocity was 2.67±1.18\xa0m/s in the liver cirrhosis group, 1.33±0.54\xa0m/s in the chronic hepatitis\xa0C group and 0.99±0.21\xa0m/s in the control group. The authors reported that shear‑wave velocity measured by ARFI was significantly higher in the liver cirrhosis group (p<0.001) than in the chronic hepatitis\xa0C group, and significantly higher in the chronic hepatitis\xa0C group than in the control group (p<0.0023). Mean shear‑wave velocity in each stage of fibrosis was: 1.09±0.22\xa0m/s for F0–1; 1.24±0.52\xa0m/s for F2; 1.61±0.79\xa0m/s for F3; and 2.35±1.11\xa0m/s for F4. ARFI measurements correlated significantly with fibrosis staging (r=0.9772, p=0.002) and all except 1 of the serum marker test results. ARFI showed better diagnostic accuracy for liver cirrhosis than the serum marker tests (AUROC: 0.930, no CI\xa0reported). The most appropriate cut‑off value for shear‑wave velocity was judged\xa0to\xa0be 1.59 (sensitivity 95%, specificity 83%).\n\nLiu et al. (2014) explored the diagnostic accuracy of ARFI (VTq) compared with transient elastography and a biochemical test that determines the aspartate aminotransferase‑to‑platelet ratio index, in 95\xa0people with hepatitis\xa0B and 16 healthy volunteers. All 95\xa0people with hepatitis\xa0had a liver biopsy\xa0to\xa0stage fibrosis using METAVIR scoring. The authors developed an optimal linear combination of the 3 intervention methods and evaluated its accuracy. Results were analysed for 108\xa0people; 3 were excluded because of transient elastography failure. ARFI and transient elastography correlated strongly with histological staging (r=0.85, p<0.001 for ARFI; r=0.81, p<0.001 for transient elastography) and APRI correlated moderately (r=0.63, p<0.001). The AUROC curve results reported for ARFI were 0.91 for F2 and 0.96 for F4, and the results for transient elastography were 0.87 for F2 and 0.96 for F4. The authors compared the accuracy of the combined methods against their individual accuracy, and found that accuracy was superior when they were combined, particularly for diagnosis of moderate fibrosis (F2) and cirrhosis (F4).\n\nNishikawa et al. (2014) investigated the correlation between ARFI and fibrosis stage as well as other factors including BMI, hyaluronic acid blood level, gamma‑glutamyltranspeptidase level and inflammation. ARFI (VTq) was used in 108\xa0people with chronic hepatitis\xa0C attending hospital in Japan. All patients had liver biopsy for histological staging of fibrosis using METAVIR scoring, by assessors blinded\xa0to\xa0the clinical data. The investigators carrying out ARFI and clinical tests were blinded\xa0to\xa0the histological data. Multiple regression analysis showed that ARFI correlated significantly with fibrosis stage (b=0.1865, p<0.0001) and hyaluronic acid levels (b=0.0008, p<0.0039) independently, in all patients. ARFI correlated significantly with BMI in F≤1 fibrosis, with gamma‑glutamyltranspeptidase level in F2 fibrosis, and with fibrosis stage and hyaluronic acid levels in F3 and F4 fibrosis, indicating that these factors could affect ARFI measurements. ARFI did not correlate with inflammation.\n\nRizzo et al. (2011) report findings from a study exploring the accuracy of ARFI (VTq) compared with transient elastography in\xa0people with chronic hepatitis\xa0C, using liver biopsy as a reference standard. In the study, 139\xa0people were recruited consecutively from 2 hospitals in Italy and each had both ARFI and transient elastography as well as liver biopsy for histological staging. Fibrosis staging was done using METAVIR scoring by an assessor blinded\xa0to\xa0clinical data. No invalid measurements were reported for ARFI, but transient elastography measurements were invalid in 9\xa0people (6.5%). Using pairwise AUROC analysis, ARFI was significantly more accurate than transient elastography for diagnosing moderate (or higher) and severe (or higher) fibrosis (F2: 86 compared with 0.78, p=0.024; F3: 0.94 compared with 0.83, p=0.002) but not for cirrhosis (F4; 0.89 compared with 0.80, p=0.09). Partial AUROC analysis showed that ARFI was statistically significantly more accurate than transient elastography for all stages of fibrosis.\n\nAn international multicentre study was carried out by Sporea et al. (2012a) in 10 centres across 5 countries in Europe and Asia. Liver biopsy (using METAVIR scoring) and ARFI (VTq) measurements of fibrosis were compared for 911\xa0people with chronic hepatitis\xa0C. A subset of 400\xa0people also had transient elastography and their results were compared with ARFI and biopsy. Diagnostic accuracy was assessed using AUROC curves. ARFI correlated significantly with liver biopsy staging (Spearman correlation coefficient r=0.654, p<0.0001). In the subgroup having transient elastography and ARFI, the overall correlation with liver biopsy staging was reported as being similar for both ARFI and transient elastography (r=0.689, p<0.001 and 0.728, p<0.001 respectively). The number of\xa0people with reliable measurements was significantly higher for ARFI (98.8%) compared with transient elastography (93.7%; p=0.003). The same reliability criteria were used for both ARFI and transient elastography, but different numbers of measurements were used; for ARFI, between 5 and 10 measures were used depending on the centre, and for transient elastography all centres used 10 measurements. The authors reported that ARFI was less effective than transient elastography in predicting liver cirrhosis (F4; AUROC 0.885 compared with 0.932; p=0.01). However, for moderate or severe fibrosis (F2–3), ARFI and transient elastography showed equivalent effectiveness. The authors also noted that the cut‑off levels for ARFI\xa0to\xa0determine fibrosis at stages F2 and F4 were different for European and Asian\xa0people. It is not clear how these subgroups were identified. The authors noted that more\xa0people in the Asian group either did not have fibrosis or had mild fibrosis (F1), and that\xa0people in the Asian group were older and had a lower mean BMI than those in the European group.\n\nA study done in Japan by Yamada et al. (2014) evaluated the accuracy of ARFI (VTq) in assessing liver fibrosis in\xa0people with chronic hepatitis\xa0C as well as the association between ARFI and the response\xa0to\xa0antiviral therapy. Of the 124\xa0people enrolled in the study, 94 had genotype 1 hepatitis\xa0C virus, 46 of whom had antiviral pegylated interferon and ribavirin combination therapy. Although not stated, it can be assumed that the remainder had genotype 2 hepatitis\xa0C virus, 15 of whom had antiviral therapy. Liver biopsy with histological analysis was used\xa0to\xa0determine fibrosis stage. Forty (30%)\xa0people were judged\xa0to\xa0have moderate (F2) fibrosis. ARFI was found\xa0to\xa0have a strong correlation with fibrosis stage (Pearson's r=0.764, p<0.001).\xa0people with the genotype 1 hepatitis\xa0C virus and less severe fibrosis (indicated by ARFI measurements of less than 1.40\xa0m/s) showed a better response\xa0to\xa0treatment, indicating that ARFI could have some benefit in predicting response. ARFI could not predict treatment response in\xa0people with the genotype 2 hepatitis\xa0C virus.\n\nYe et al. (2012) assessed the performance of ARFI (VTq)\xa0to\xa0measure liver and spleen stiffness in 204\xa0people with chronic hepatitis\xa0B and 60 healthy volunteers. Of those with hepatitis\xa0B, 66 had liver biopsy and 138 had been diagnosed previously as having cirrhosis. Histological staging using METAVIR scoring was done by an experienced pathologist for those\xa0people having biopsies. ARFI measurements showed good correlation with fibrosis stage using Spearman's correlation coefficient (r= 0.87, p<0.001), and a high diagnostic accuracy for predicting severe fibrosis and cirrhosis using optimal measurement cut‑off values for each stage (AUROC curve F3=0.99; F4=0.97).\n\n## Evidence synthesis\n\nThe company included a brief synthesis of the clinical evidence in its submission and concluded that VTq and transient elastography have equivalent accuracy, although transient elastography may be slightly more accurate in diagnosing mild fibrosis (F1). The External Assessment Centre considered that this conclusion was plausible, but noted that the company did not carry out a meta‑analysis which would have provided a more definitive result.\n\nThe company provided an overall interpretation of the clinical evidence and concluded that VTq can be a good tool when used in clinical practice\xa0to\xa0diagnose moderate fibrosis (F2) and an excellent tool\xa0to\xa0diagnose severe fibrosis (F3) or cirrhosis (F4). The External Assessment Centre considered that this interpretation was reasonable and that the company's assessment of the strengths and weaknesses of the\xa0studies was fair.\n\nAs a result of its concerns about the\xa0studies selected by the company and the subsequent identification of additional clinical evidence, the External Assessment Centre did a meta‑analysis of the 10\xa0studies it selected for inclusion. A random effects approach was used\xa0to\xa0calculate pooled outcome data for correlation coefficients (between either VTq or transient elastography and liver biopsy METAVIR scores), and for sensitivity, specificity and prevalence for each disease type (hepatitis\xa0B, C or a combination) using liver biopsy as the reference standard. Proportions were transformed using the logit function where necessary\xa0to\xa0overcome skewness, and values of 0 were transformed\xa0to\xa00.5\xa0to\xa0allow pooling of the data. Results were back‑transformed\xa0to\xa0provide estimated pooled proportions and 95% confidence intervals. Nine outcome estimates were made from multiple\xa0studies and 6 from single\xa0studies. The pooled estimates for sensitivity, specificity and prevalence for each disease type (hepatitis\xa0B, C or a combination) are shown in table\xa01.\n\n## Table 1 Pooled estimates from External Assessment Centre's meta‑analysis with 95% confidence intervals for prevalence and diagnostic accuracy\n\nHepatitis\xa0type\n\n\n\nReference standard ( liver biopsy)\n\nVTq\n\nTransient elastography\n\nFibrosis stage\n\nF≥1\n\nF≥2\n\nF≥3\n\nF4\n\nF≥1\n\nF≥2\n\nF≥3\n\nF4\n\nB\n\nNo. of\xa0studies\n\n–\n\n\n\n–\n\n\n\n–\n\n\n\n–\n\n\n\nPrevalence\n\n–\n\n(0.06–0.79)\n\n–\n\n(0.19–0.36)\n\n–\n\n(0.51–0.70)\n\n–\n\n(0.19–0.36)\n\nSensitivity % (95% CI)\n\n–\n\n(31.59–92.19)\n\n–\n\n(77.23–99.15)\n\n–\n\n(70.39–90.24)\n\n–\n\n(72.65–97.81)\n\nSpecificity % (95% CI)\n\n–\n\n(78.69–92.40)\n\n–\n\n(66.40–85.90)\n\n–\n\n(55.42–84.28)\n\n–\n\n(77.95–93.76)\n\nC\n\nNo. of\xa0studies\n\n\n\n\n\n\n\n\n\n–\n\n\n\n\n\n\n\nPrevalence\n\n(0.83–0.95)\n\n(0.48–0.71)\n\n(0.32–0.484\n\n(0.18–0.29)\n\n–\n\n(0.54–0.71)\n\n(0.31–0.47)\n\n(0.15–0.29)\n\nSensitivity % (95% CI)\n\n(66.82–72.66)\n\n(70.04–85.03)\n\n(75.94–91.99)\n\n(79.78–88.24)\n\n–\n\n(60.57–80.46)\n\n(64.40–80.46)\n\n(50.60–85.27)\n\nSpecificity % (95% CI)\n\n(70.44–88.34)\n\n(73.49–83.55)\n\n(80.69–87.45)\n\n(75.43–86.27)\n\n–\n\n(56.92–82.87)\n\n(75.27–91.60)\n\n(73.09–88.42)\n\nB and C\n\nNo. of\xa0studies\n\n–\n\n\n\n–\n\n\n\n–\n\n\n\n–\n\n\n\nPrevalence\n\n–\n\n(0.42–0.67)\n\n–\n\n(0.18–0.29)\n\n–\n\n(0.53–0.70)\n\n–\n\n(00.14–0.36)\n\nSensitivity % (95% CI)\n\n–\n\n(68.88–83.52)\n\n–\n\n(80.59–88.60)\n\n–\n\n(63.89–85.22)\n\n–\n\n(55.69–92.22)\n\nSpecificity % (95% CI)\n\n–\n\n(75.83–85.39)\n\n–\n\n(75.57–84.54)\n\n–\n\n(61.17–79.36)\n\n–\n\n(77.81–88.45)\n\nThe results of the meta‑analysis showed that the prevalence of moderate fibrosis (F2) for both hepatitis\xa0B and C was lower with VTq (0.55) than transient elastography (0.62). However, the techniques had similar scores for cirrhosis (F4; 0.23 for VTq and 0.23 for transient elastography). Sensitivity and specificity values were similar for hepatitis\xa0B and C. VTq had slightly higher values for both sensitivity and specificity in diagnosing moderate fibrosis (F2; 77% and 81% respectively) than transient elastography (76% and 71% respectively) in\xa0people with hepatitis\xa0B and C. The sensitivity was higher than the specificity for identifying cirrhosis (F4) in the combined study population for VTq (85% and 80% respectively), but the opposite was found for transient elastography (79% and 84% respectively). The correlation coefficients for VTq and transient elastography were similar in the combined study population (0.68\xa0to\xa00.69).\n\nThe External Assessment Centre noted that no adjustment could be made in the meta‑analysis for confounding variables such as patient characteristics, other than disease type, study design and location, because there was insufficient information in the\xa0papers.\n\n## Adverse events\n\nIn its submission, the company stated that no adverse events have been reported for VTq. None were identified in the literature, or from searches of the MHRA website and US Food and Drug Administration database: Manufacturer and User Device Facility Experience (MAUDE). The External Assessment Centre repeated the literature searches and found no adverse events relating\xa0to\xa0the use of VTq.\n\n## Committee considerations\n\nThe Committee considered that despite some limitations, the clinical evidence was sufficient\xa0to\xa0demonstrate that VTq has equivalent accuracy\xa0to\xa0transient elastography for diagnosing liver fibrosis. The Committee recognised that there was no evidence specifically evaluating the use of VTq for monitoring of liver fibrosis, but considered that the technology was likely\xa0to\xa0be useful for this purpose. It was advised by clinical experts that the use of image‑guided assessment of liver fibrosis in VTq allowed measurements\xa0to\xa0be taken from the same part of the liver at different times, which would be useful for monitoring changes in fibrosis relating\xa0to\xa0disease progression.\n\nThe Committee heard advice from clinical experts that VTq would be particularly useful in hospitals without access\xa0to\xa0transient elastography for determining the stage of fibrosis and informing the decision\xa0to\xa0start antiviral therapy, because those hospitals currently use liver biopsy as their primary method of diagnosis. The Committee considered that using VTq could avoid a considerable number of liver biopsies for both initial assessment and ongoing monitoring (particularly for\xa0people with hepatitis\xa0B), reducing the risks of morbidity and mortality.\n\nFor hospitals with access\xa0to\xa0transient elastography, the Committee was advised that using VTq could offer advantages by enabling image‑guided assessment of the liver. This assessment offers the opportunity\xa0to\xa0select areas from which\xa0to\xa0assess fibrosis and\xa0to\xa0identify associated pathologies, for example cirrhosis and hepatocellular carcinoma.\n\nThe Committee noted that no evidence was available on the use of VTq in children and that the company's instructions for use do not distinguish between adults and children. However, clinical experts advised the Committee that there was no reason\xa0to\xa0suppose that VTq would be any less effective in children than in adults, although the range of readings considered normal may differ between them. It heard from clinical experts that avoiding liver biopsies would be particularly beneficial for children, who might need a general anaesthetic and an overnight stay in hospital, as well as facing restrictions\xa0to\xa0their daily activities following each biopsy.\n\nThe Committee also noted a lack of evidence for improved quality of life as a consequence of using VTq, but it considered that reducing the need for liver biopsies would have a positive effect on quality of life.\n\nThe Committee noted comments made during consultation about the cut‑off values used with VTq. It considered that the interpretation of these values was a matter for clinical judgement by specialists, taking into account results of other tests and the clinical context. It also noted several comments made during consultation that suggested a variety of factors, including obesity and hepatic inflammation, may influence the readings from both VTq and transient elastography. The Committee considered it unclear from the clinical evidence how exactly these factors influence the accuracy of the tests.", 'NHS considerations': '# System impact\n\nThe company claimed that use of Virtual Touch Quantification (VTq) had the potential\xa0to\xa0release resources within the NHS because the VTq procedure does not need\xa0to\xa0be carried out by a consultant and can be done in an outpatient setting. It also claimed that VTq could reduce the number of liver biopsies needed over several\xa0years if used\xa0to\xa0monitor fibrosis progression. The company was not able\xa0to\xa0identify any published evidence relating\xa0to\xa0these claims.\n\nThe published evidence provided data on the diagnostic accuracy of VTq compared with transient elastography and with liver biopsy, but none of the\xa0studies specifically explored the potential system impact of using VTq. Some authors (Friedrich‑Rust et al. 2013, Yamada et al. 2014 and Rizzo et al. 2011) mentioned in their conclusions that VTq can be used for non‑invasive assessment in\xa0people with obesity. Yamada et al. assessed the utility of VTq in predicting response\xa0to\xa0antiviral therapy and found that this had potential for\xa0people with genotype 1 hepatitis\xa0C: this could be useful in directing treatment with newer direct‑acting antiviral agents\xa0to\xa0people who are not likely\xa0to\xa0respond\xa0to\xa0existing antiviral therapies.\n\nFour of the\xa0studies reported higher failure rates or a greater number of unreliable measurements when using transient elastography compared with VTq (Friedrich‑Rust et al. 2013, Liu et al. 2014, Rizzo et al. 2011, Sporea et al. 2012a). Sporea et al. reported that a significantly higher number of reliable measurements were taken using VTq compared with transient elastography (98.8% compared with 93.7%, p=0.003).\n\n## Committee considerations\n\nThe Committee acknowledged that no evidence was available\xa0to\xa0demonstrate that using VTq reduces the length of hospital stay. However, it considered that using VTq could reduce the need for liver biopsies. This is likely\xa0to\xa0have an effect on resource use, particularly for children who may need a general anaesthetic and an overnight stay in hospital for liver biopsy.\n\nThe Committee considered that using VTq may provide system benefits by allowing assessment of liver fibrosis\xa0to\xa0be done at the same time as the initial diagnostic ultrasound test included in the current care pathway. The Committee heard expert clinical advice that patients being assessed for liver fibrosis usually have an ultrasound scan, and that adding VTq\xa0to\xa0the ultrasound may lead\xa0to\xa0a more streamlined care pathway. It also heard that the Siemens ultrasound machine needed for VTq can be used for other purposes. This was explored in the cost modelling (see section\xa05).\n\nThe Committee noted from the published evidence that VTq appears\xa0to\xa0have a lower failure rate than transient elastography, and this was confirmed by clinical expert advisers as being the case in clinical practice.\n\nThe Committee considered that VTq is likely\xa0to\xa0be used in an outpatient setting as part of the initial referral from primary care for\xa0people who test positive for chronic hepatitis\xa0B or C. Clinical experts advised that there is also potential for VTq\xa0to\xa0be used in primary care settings which offer ultrasound. The Committee was advised by clinical experts that VTq assessments should only be done by staff with specialist training in ultrasound imaging and its interpretation. The Committee also noted that transient elastography can be associated with a range of staff costs, which may be lower than those needed for VTq. The resource impact of these different staff needs was incorporated into the cost modelling done by both the company and the External Assessment Centre.\n\nThe Committee considered the issue of the VTq software package being usable only with a Siemens ultrasound machine. It noted that ultrasound machines from a variety of manufacturers are currently in use in the NHS but that individual hospitals are likely\xa0to\xa0have a number of machines. The Committee considered that the purchase of a compatible Siemens ultrasound machine for VTq can be considered as part of existing device renewal programmes.', 'Cost considerations': "# Cost evidence\n\nThe company carried out a literature search for economic\xa0studies related\xa0to\xa0Virtual Touch Quantification (VTq), transient elastography and liver biopsy in hepatitis. After applying inclusion and exclusion criteria, the company did not identify any relevant economic\xa0studies for VTq. However, 5\xa0studies were presented relating\xa0to\xa0the comparators (transient elastography and liver biopsy).\n\nThe External Assessment Centre considered that the company's search strategy and inclusion/exclusion criteria were appropriate, but noted that the date range and search terms could have been broader and 2 further databases could have been searched. The External Assessment Centre carried out a revised search addressing these issues and did not find any relevant publications, confirming the company's conclusion that there was no published economic evidence relating\xa0to\xa0VTq. The External Assessment Centre considered that the 5\xa0papers identified by the company relating\xa0to\xa0the comparators were useful for modelling purposes, and found 1 additional comparator paper.\n\n## Company's cost model\n\nThe company submitted a de novo cost analysis evaluating VTq plus liver biopsy (where needed) compared with transient elastography plus liver biopsy (where needed) and against liver biopsy alone. Costs were modelled from an NHS and personal social services perspective using 2013 prices. The population included in the model was patients with chronic hepatitis\xa0B or C needing assessment of liver fibrosis. The model structure was a decision tree based on a cohort of 1000 patients referred by GPs and stratified according\xa0to\xa0the presence or absence of fibrosis, then sequentially across 3 groups according\xa0to\xa0stage of fibrosis determined by METAVIR score (F2, F3/F4, or F4). The External Assessment Centre confirmed that the model was internally valid.\n\nThe company used the estimated prevalence of fibrosis\xa0to\xa0stratify the cohort into the 3 stages, and applied the sensitivity and specificity of each diagnostic strategy (VTq plus liver biopsy, transient elastography plus liver biopsy and liver biopsy alone) for each stage, creating estimated numbers of true or false negatives or positives. The External Assessment Centre generally agreed with this approach.\n\nThe model was based mainly on fibrosis assessment and did not include any treatment or monitoring costs for patients in the F2 group and the F3/F4 group. For F4 fibrosis (cirrhosis), patients in the true‑positive group had antiviral therapy and those in the false‑negative group had liver biopsy. According\xa0to\xa0the diagram of the company's model in its submission, false positives had antiviral therapy and true negatives had a biopsy. The External Assessment Centre questioned the rationale for this approach and whether this assumption was actually included in the model calculations.\n\nThe company did not state the time horizon for the model, but the External Assessment Centre considered that the outcomes were likely\xa0to\xa0be realised using a 1‑year horizon, based on the duration of antiviral therapy.\n\nThe company's estimates of fibrosis prevalence at each stage were based mainly on clinical expert advice and on 1 study in patients with cirrhosis, because exact figures were difficult\xa0to\xa0determine. The External Assessment Centre sought additional clinical expert advice\xa0to\xa0validate these assumptions but the experts consulted were not able\xa0to\xa0provide any figures.\n\nThe diagnostic accuracy figures for VTq and transient elastography were taken from the available literature and liver biopsy was assumed\xa0to\xa0have 100% sensitivity and specificity. The External Assessment Centre agreed with the approach taken for liver biopsy and transient elastography (figures taken from a meta‑analysis), but considered that the figures used for VTq were not sufficiently robust. The External Assessment Centre addressed this issue in its own meta‑analysis of the clinical evidence.\n\nThe company included direct costs for VTq, transient elastography and liver biopsy, calculating the costs of VTq and transient elastography using a bottom‑up approach which included capital, infrastructure, maintenance, staffing, training and consumable costs. The cost for transient elastography was calculated based on a nurse carrying out the test with a throughput of 2,500 patients per\xa0year over the device lifespan (7\xa0years), giving a per‑patient cost of £25.33. This was compared with a report published by the Centre for Evidence‑based Purchasing (Stamuli et al. 2009), which gave a per‑patient cost of £18.68 (corrected for inflation by the company\xa0to\xa0£22.91). The cost for VTq was based on the purchase of the software and a Siemens Acuson S2000 machine, and use by a radiographer. It was assumed that VTq assessments would take up 10% of the ultrasound machine use and so this proportion of the annual capital, staffing and consumables costs was used in the estimation. The cost was calculated based on a throughput of 500 patients per\xa0year over the device lifespan (5\xa0years), giving a per‑patient cost of £15.02. The cost for liver biopsy was estimated from the 2013–14 payment by results tariff\xa0to\xa0be £615, based on a mix of procedures.\n\nThe External Assessment Centre agreed with the estimates for these costs but considered that they could be further explored in sensitivity analyses. The capital costs for VTq and transient elastography were not estimated using the annuity method, and the company did not describe the exact mix of procedures used\xa0to\xa0calculate the biopsy cost. The cost of antiviral therapy was estimated\xa0to\xa0be £10,000 per\xa0patient in the executable model; the External Assessment Centre was unsure about the rationale behind this figure.\n\nThe company carried out deterministic 1‑way and multi‑way sensitivity analyses varying the prevalence of liver disease, prevalence for different liver fibrosis stages, the diagnostic accuracy of VTq, technology and treatment costs and whether or not liver biopsy was done. The External Assessment Centre generally agreed with the company's approach but commented that the company did not explain the rationale for the variations in prevalence which it used.\n\nThe results of the company's base case indicated that VTq could result in a cost saving of £10.31 per\xa0patient when compared with transient elastography and £599.08 per\xa0patient when compared with liver biopsy.\n\nFindings from the company's sensitivity analysis showed that if each patient had a biopsy, increasing the overall prevalence of liver fibrosis from 10%\xa0to\xa030% lowered the cost saving per\xa0patient from £527\xa0to\xa0£447 (assuming the best‑case diagnostic accuracy of VTq) and from £496\xa0to\xa0£419 (assuming the worst‑case diagnostic accuracy of VTq). If only 20% of patients had a biopsy, the cost savings for VTq were reduced, and at high fibrosis prevalence levels or lower diagnostic accuracy it became cost‑incurring. The cost of antiviral therapy was also varied from the base case assumption of £10,000\xa0to\xa0£6500. Over this range, assuming that 20% of patients had a biopsy, the cost savings for VTq varied from around £60\xa0to\xa0£8.\n\nThe External Assessment Centre considered that the model addressed the decision problem in the scope, but that its structure did not accurately reflect current clinical pathways for\xa0people with liver fibrosis. It also did not include all the relevant costs and outcomes for diagnosing and treating the condition. No monitoring or treatment costs were included for patients in the F2 or F3/F4 fibrosis groups. The External Assessment Centre considered that this was erroneous, because\xa0people with less severe fibrosis may benefit from treatment.\n\nThe External Assessment Centre also questioned the assumption that patients falsely classified as negative for fibrosis would not incur any treatment costs and would re‑enter the model as new patients. It considered that this was a misleading approach, because misdiagnosis may incur additional costs (from further diagnostic tests, inpatient or emergency episodes and treatment). The External Assessment Centre considered that a mortality arm would have been appropriate\xa0to\xa0account for the small increased risk associated with liver biopsy, but acknowledged that this was likely\xa0to\xa0have been incorporated in the chosen tariff cost. The External Assessment Centre also noted that the company had used a cohort approach rather than a per‑patient approach as specified in NICE's methodology.\n\n## Additional work by the External Assessment Centre\n\nThe External Assessment Centre revised some parameters and re‑ran the company's model\xa0to\xa0address these issues. The revised model included true positives, false positives, true negatives and false negatives at each of the F≥2, F≥3 and F4 stages. Revised prevalence and diagnostic accuracy parameters for the model were taken mainly from the External Assessment Centre's meta‑analysis and applied at each sequential stage for VTq, transient elastography and liver biopsy. Liver biopsy was treated as the reference standard with 100% sensitivity and specificity.\n\nKey assumptions made by the External Assessment Centre in its revisions\xa0to\xa0the company's model were as follows:\n\nPatients categorised as false negative for fibrosis would return and be re‑diagnosed as true positive within 1\xa0year.\n\nPrevalence rates for stages of fibrosis were different for VTq and transient elastography based on the External Assessment Centre's meta‑analysis. The combined hepatitis\xa0B and C prevalence rates for VTq were used for transient elastography and liver biopsy in the model\xa0to\xa0ensure compatibility.\n\nCombined hepatitis\xa0B and C prevalence and diagnostic accuracy figures for F3 fibrosis were not available from the meta‑analysis. The External Assessment Centre therefore used figures for hepatitis\xa0C across the model for this stage.\n\nTreatment delay resulting from misdiagnosis was unlikely\xa0to\xa0have a clinical effect and so long‑term modelling of disease progression was not needed. According\xa0to\xa0published clinical evidence and expert advice gathered by the External Assessment Centre, progression in both hepatitis\xa0B and C is relatively slow.\n\nPatients diagnosed as being at stage F2 had fibrosis and those at stage F≤1 did not.\n\nMost misclassified (false positive) patients for VTq and transient elastography would be diagnosed as having F2 fibrosis. A proportion of those with F2 fibrosis would be misclassified as having F3 or F4 fibrosis. These proportions were chosen arbitrarily and subjected\xa0to\xa0sensitivity analyses.\n\nPatients diagnosed with F3 or F4 fibrosis would have antiviral therapy.\n\nA mortality risk of 0.003 would apply\xa0to\xa0liver biopsy, based on available literature.\n\nThe unit costs for VTq and transient elastography were estimated using an annuity method and discounted at 3%,\xa0to\xa0give per‑test figures of £15.24 for VTq and £25.90 for transient elastography. The cost for liver biopsy was estimated from tariff costs\xa0to\xa0be £622. The costs for antiviral therapy were based on duration of treatment, which was estimated\xa0to\xa0be 12\xa0weeks for patients with F3 fibrosis and 24 weeks for patients with F4 fibrosis, based on NICE technology appraisal guidance on peginterferon alfa and ribavirin for the treatment of chronic hepatitis\xa0C. Costs for a compatible Siemens ultrasound machine were modelled in 2 scenarios: 1 including purchase costs and 1 assuming that a machine was already available.\n\nFindings from the base case (incorporating the External Assessment Centre's revised parameters) showed that in a scenario where a compatible Siemens ultrasound machine would be purchased along with the VTq software, using VTq would generate cost savings of £53 per\xa0patient compared with transient elastography and £434 compared with liver biopsy. If a compatible ultrasound machine was already available, the cost savings for VTq increased slightly\xa0to\xa0£57 compared with transient elastography and £438 compared with liver biopsy.\n\nThe External Assessment Centre carried out deterministic sensitivity analyses varying prevalence rates, sensitivity and specificity for VTq and transient elastography, distribution of false positives between stages F2 and F3, unit costs of VTq and transient elastography, usage levels of transient elastography and antiviral therapy costs. Findings from the sensitivity analyses showed that VTq remained cost‑saving across all scenarios. The key drivers affecting the cost savings per\xa0patient were prevalence of liver fibrosis, the distribution of false positives\xa0to\xa0other fibrosis stages, the specificity of VTq and transient elastography for stages F2 and F3, unit costs of VTq and transient elastography and antiviral treatment costs.\n\nThe External Assessment Centre acknowledged some limitations in its revised parameters. The lack of clear data on prevalence and diagnostic accuracy at each stage of fibrosis meant that figures were extrapolated for the stages in a sequential model, rather than each stage being presented separately. Figures for hepatitis\xa0C at stage F3 fibrosis were applied\xa0to\xa0the whole population because combined data were not available. Several assumptions were made\xa0to\xa0calculate technology and comparator costs, but the External Assessment Centre varied these parameters in sensitivity analyses\xa0to\xa0address uncertainty.\n\n## Committee considerations\n\nThe Committee recognised the limitations in the cost modelling presented by the company and in the adjustments made by the External Assessment Centre, but considered these revisions sufficiently robust\xa0to\xa0be plausible. The Committee considered that the External Assessment Centre's sensitivity analyses addressed the uncertainties in the evidence base and it concluded that cost savings for VTq compared with transient elastography and liver biopsy were likely\xa0to\xa0be realised in practice.\n\nThe Committee was satisfied that the cost modelling indicated that use of the VTq software would generate cost savings regardless of whether a compatible Siemens ultrasound machine was purchased.\n\nThe Committee noted that the cost modelling included the assumption that the Siemens ultrasound machine would be used for VTq measurements for only 10% of the time and for other scanning procedures for the rest of the time: it was advised by experts that this was reasonable. The External Assessment Centre stated that the findings from the model were robust even when the proportionate use of the machine for VTq (and so VTq's test costs) was raised in sensitivity analyses.\n\nThe External Assessment Centre also stated that the findings remained robust if treatment costs (for antiviral therapy) were not included in the model.\n\nFor the guidance review, the External Assessment Centre noted that the differences between the updated pooled estimates for the sensitivity and specificity of VTq for hepatitis C compared with the pooled estimates used in the original model (see table 1) are minor, as seen in table 2. \n\n## Table 2 Updated pooled estimates for the sensitivity and specificity of VTq for hepatitis C\n\nDisease\n\nSensitivity (update)\n\nSensitivity (original)\n\nSpecificity (update)\n\nSpecificity (original)\n\nHepatitis C F≥2\n\n%\n\n%\n\n%\n\n%\n\nHepatitis C F=4\n\n%\n\n%\n\n%\n\n%", 'Conclusions': 'The Committee concluded that the evidence supports the case for adopting Virtual Touch Quantification (VTq) for diagnosing and monitoring liver fibrosis in\xa0people with chronic hepatitis\xa0B or C. The Committee considered that the clinical evidence demonstrated that VTq is as accurate as transient elastography for diagnosing and staging liver fibrosis and may offer additional benefits, including image‑guided assessment and a lower failure rate.\n\nThe Committee concluded that using VTq may offer particular advantages in hospitals without access\xa0to\xa0transient elastography, by providing a non‑invasive method of assessment of liver fibrosis in place of liver biopsy. This may have major benefits for\xa0people who need monitoring for fibrosis progression for whom liver biopsy may have a substantial effect on quality of life.\n\nBased on the revised cost model and sensitivity analyses, the Committee concluded that using VTq is likely\xa0to\xa0be cost saving compared with transient elastography and liver biopsy, whether or not the purchase of a compatible Siemens ultrasound machine is needed.'}
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https://www.nice.org.uk/guidance/mtg27
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Evidence-based recommendations on Virtual Touch Quantification to diagnose and monitor liver fibrosis in chronic hepatitis B and C.
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8e0c147a1dfabad52d18686d9ba43b10446ed3fe
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nice
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Indoor air quality at home
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Indoor air quality at home
This guideline covers indoor air quality in residential buildings. It aims to raise awareness of the importance of good air quality in people's homes and how to achieve this.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
People who may be vulnerable
People who may be particularly vulnerable to ill health as a result of exposure to poor indoor air quality include:
people with a pre‑existing health condition such as asthma, allergies, chronic obstructive pulmonary disease (COPD) and cardiovascular disease
pregnant women and their unborn babies
pre-school children
-lder people
people who live in poor-quality housing
people exposed to tobacco smoke in their homes
people who live in poverty.
Housing conditions
Housing conditions that put people at increased risk of exposure to poor indoor air quality include:
location (external factors such as high levels of outdoor air pollution, or where noise or security risks mean residents do not open windows)
physical infrastructure (such as small room size, inadequate ventilation and the building's layout and orientation)
standard of housing (for example, with damp and mould or physical disrepair including flood damage or with unflued or poorly maintained fuel-burning appliances)
-vercrowding.
There are a number of activities that might contribute to poor indoor air quality (see the section on advice and information for the general population).
For the purposes of this guideline, the term 'local authorities' covers all types of local authority in England; these are county councils, district councils, unitary authorities, metropolitan districts and London boroughs. Each local authority should decide which of the following recommendations are relevant to their local responsibilities.
# Prioritising indoor air quality in local strategy or plans
These recommendations are for local authorities.
Embed a plan for improving indoor air quality in an existing strategy or plan to improve people's health. This could be a general air quality strategy if one exists. Otherwise, for example, include it in a strategy on housing, health and wellbeing, or inequalities.
Ensure the strategy or plan takes account of the housing conditions that put people at increased risk of exposure to poor indoor air quality and especially people who are particularly vulnerable to ill health as a result of such exposure (see box 1).
Emphasise the need for a balanced approach to ventilation, insulation and heating for good indoor air quality. (See the sections on raising awareness of poor indoor air quality in the home and advice and information for the general population, and NICE's guideline on winter deaths and illness and cold homes.)
Encourage joint working between local authority departments, across different local authorities, with local health and social care providers, and with voluntary, community and social enterprise organisations and other organisations with interest in indoor air quality, to improve air quality in people's homes (see the sections on raising awareness of poor indoor air quality in the home and advice and information for the general population).
Encourage the use of existing home visits to identify poor indoor air quality. For example, visits to people's homes by housing officers, environmental health practitioners, community health services, social workers, care workers, and fire and rescue services.
Encourage the use of local inspection protocols to identify poor indoor air quality during home visits. This may include visual inspections, checklists and the monitoring of pollutant levels. Use this information to identify other homes that may be at increased risk of poor indoor air quality.
Encourage joint working with external organisations to inform home improvement programmes and identify grants to combat poor indoor air quality.
Monitor progress against the goals of the strategy. Use audit data (see the recommendation on encouraging the use of existing home visits in this section) plus the lists in box 1 to identify people who may be vulnerable and properties that are at risk.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on prioritising indoor air quality in local strategy or plans .
Full details of the evidence and the committee's discussion are in:
evidence review 1: associations between individual or building characteristics and exposure levels
evidence review 2: exposure to pollutants and health outcomes
evidence review 4: effective strategies for raising awareness.
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# Referrals for a housing assessment
These recommendations are for local authorities.
Develop a structured process so that health and social care professionals and housing and local authority staff can use existing referral pathways to help people request a housing assessment if poor indoor air quality has been identified or is suspected, for example, by using the housing condition factors in box 1.
Advise health and social care professionals and housing and local authority staff on how to help people request a housing assessment if poor indoor air quality is identified or suspected, for example, by using the housing condition factors in box 1.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on referrals for a housing assessment .
Full details of the evidence and the committee's discussion are in:
evidence review 1: associations between individual or building characteristics and exposure levels
evidence review 2: exposure to pollutants and health outcomes.
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# Raising awareness of poor indoor air quality in the home
These recommendations are for local authorities.
Use existing communication strategies to ensure members of the public and relevant professionals (those involved in planning, designing, building, renovating and maintaining homes) are aware of:
the causes of poor indoor air quality
how residents' activities can affect indoor air quality
how health is affected by poor indoor air quality
who is particularly vulnerable (see box 1)
how to prevent or reduce poor indoor air quality.
Use existing professional development opportunities to ensure local authority staff who visit people in their homes (such as housing, healthcare and social care professionals):
know about the sources of indoor air pollutants and how they can affect health
can give general advice on how to avoid activities that increase the level of indoor air pollutants (see the sections on advice and information for the general population and healthcare professionals)
can give general advice on how to improve ventilation if the source of the pollutant cannot be controlled (see the sections on advice and information for the general population and healthcare professionals)
are aware that affordability may be a barrier to effective and efficient heating and ventilation
know that tenants may not be allowed to repair or alter building fabric, fixtures or fittings
know who can provide help with repairs and necessary improvements (for example, the local authority or a home improvement agency)
can advise people on how to request a housing assessment (see the section on referrals for a housing assessment).
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on raising awareness of poor indoor air quality in the home .
Full details of the evidence and the committee's discussion are in evidence review 4: effective strategies for raising awareness.
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# Advice and information for the general population
These recommendations are for local authorities.
Advise people on how to reduce damp and condensation and prevent mould. For example, by:
using background ventilation (such as trickle vents, or whole-house mechanical ventilation systems)
using mechanical ventilation (such as extractor fans), and opening windows where possible and safe to provide temporary increased ventilation
avoiding moisture-producing activities (such as air-drying clothes) indoors if possible, or improving ventilation if these cannot be avoided
repairing sources of water damage and ensuring that residual moisture is removed.
Advise people on how to use trickle vents correctly.
Tell people that the following activities may lead to poor indoor air quality and that they should think about increasing ventilation (by using extractor fans in the bathroom or kitchen, or opening windows if possible and safe):
using cookers, especially gas cookers
using open solid-fuel fires
using candles
using free-standing gas heaters
using cleaning products, household sprays or aerosols and paints
having a bath or shower
air-drying clothes in the home.
Advise private and social tenants to contact their landlord if:
ventilation is not adequate (for example, if the ventilation system is not working, trickle vents are blocked or damaged, extractor fans in the kitchen or bathroom are not working, or if excessive noise from the fans discourages their use)
repairs are needed to prevent water from entering their building
improvements to heating or insulation are needed to prevent condensation.
Advise private and social tenants to contact their local authority if no action is taken to improve ventilation or carry out repairs (see the government guides on private renting and council housing, and the Guide for tenants: Homes Act 2018).
Advise people not to use unflued paraffin heaters in the home.
Advise people to follow the product instructions when using, for example, candles, paints, glues and solvents, to minimise exposure to pollutants.
Advise people to choose low-emission materials (for example, products with a low volatile organic compound or formaldehyde content and emissions) if furniture or flooring needs replacing.
Advise people installing a new cooker about the need for ventilation, especially for gas cookers.
Advise people not to use gas cookers to heat a room.
Encourage people not to smoke in the home (see NICE's guidelines on stop smoking interventions and services and smoking: stopping in pregnancy and after childbirth).
Also see the section on healthcare professionals' advice for women who are pregnant or who have given birth in the past 12 months (see the section on healthcare professionals) and the section on advice for property managers and landlords (see the section on rental properties).
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on advice and information for the general population .
Full details of the evidence and the committee's discussion are in:
evidence review 1: associations between individual or building characteristics and exposure levels
evidence review 2: exposure to pollutants and health outcomes
evidence review 3.1: material and structural interventions.
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# Healthcare professionals
## People with asthma, other respiratory conditions or cardiovascular conditions
Explain that indoor air pollutants (including nitrogen dioxide, damp, mould, particulate matter and VOCs) can trigger or exacerbate asthma, other respiratory conditions or cardiovascular conditions.
If a person has repeated or worsening respiratory symptoms such as a cough or wheezing, ask about their housing conditions. If these are a concern, help them request a housing assessment from the local authority (see the section on referrals for a housing assessment).
Advise people whose asthma is triggered by household sprays, air fresheners or aerosols to:
avoid using them
use non-spray alternatives.
Also see the section on advice and information for recommendations about ventilation and controlling sources of pollution (see the section on advice and information for the general population) and NICE's guideline on asthma.
## People who are allergic to house dust mites
Advise people who are allergic to house dust mites how to reduce their exposure to them. This includes:
avoiding second-hand mattresses if possible
using allergen barriers such as mattress and pillow covers
washing bedding regularly.
Also see the section on advice and information for recommendations about ventilation and controlling sources of pollution (see the section on advice and information for the general population) and NHS advice on allergen avoidance.
## Women who are pregnant or who have given birth in the past 12 months and partners and people who live with them
Ask about the person's housing conditions. If housing factors are a health concern, for example, because of damp or lack of ventilation, help them request a housing assessment from the local authority (see the section on referrals for a housing assessment).
Advise women who are pregnant that they are at increased risk of ill health from exposure to poor indoor air quality. Advise people who care for babies under 12 months old that the baby is at increased risk. Both groups should:
reduce their use of household sprays, air fresheners and other aerosols, and always follow product instructions
if possible, avoid or reduce activities that produce particulate matter such as using open solid-fuel fires or candles
always keep the room well ventilated during these activities.See also recommendations 1.4.3, 1.4.4, 1.4.6 and 1.4.8.
Explain that other people's tobacco smoke is a risk to a woman who is pregnant and her baby, before and after birth. Advise not smoking in the home or around the woman and her baby. (Also see NICE's guideline on smoking: stopping in pregnancy and after childbirth.)
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on healthcare professionals .
Full details of the evidence and the committee's discussion are in:
evidence review 1: associations between individual or building characteristics and exposure levels
evidence review 2: exposure to pollutants and health outcomes
evidence review 3.2: occupant behaviour interventions.
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# Regulators and building control teams
Update existing standards, for example building regulations, or develop new ones for indoor air quality. Base them on current safe limits set for pollutants in residential developments. See, for example, World Health Organization guidelines on selected pollutants (2010) and dampness and mould (2009), and the Public Health England indoor air quality guidelines for selected VOCs (2019).
Use existing building regulation enforcement activities to improve indoor air quality. Ensure enforcement takes place within the specified timelines. (See the government's Building Regulations 2010 and Housing health and safety rating system operating guidance, and the Planning Portal's failure to comply with the building regulations.)
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on regulators and building control teams .
Full details of the evidence and the committee's discussion are in:
evidence review 1: associations between individual or building characteristics and exposure levels
evidence review 2: exposure to pollutants and health outcomes.
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# Architects and designers
## Avoiding sources of pollutants
Consider specifying building materials and products that only emit a low level of formaldehyde and VOCs. Use existing labelling schemes or other available information on product emissions (for example, on product labels) to make these specifications.
Design or specify heating systems that minimise indoor exposure to particulate matter.
## Heating and ventilation
Adopt a whole-building approach to heating and ventilation to ensure indoor air quality is maintained while achieving standards for energy use. (Also see NICE's guideline on winter deaths and illness and cold homes.)
Ensure design strategies include provision for removing indoor air pollutants, for example by:
specifying kitchen extractor fans or cooker hoods that extract to the outside, and are easily accessible for cleaning or maintenance, with simple instructions for residents
when safe and appropriate to do so, specifying that all habitable rooms are provided with windows that are openable and that windows or openings meet the purge ventilation requirements (see the Ministry of Housing, Communities and Local Government's advice on ventilation).
Design ventilation systems to reduce or avoid exposure to outdoor air pollution. For example:
ensure windows that open face away from sources of outdoor air pollution, such as busy roads
fit mechanical systems with filtration to protect against outdoor pollutants. (Also see the government clean air strategy 2019.)
When building dwellings or refurbishing them to improve thermal performance, ensure there is permanent, effective ventilation.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on architects and designers .
Full details of the evidence and the committee's discussion are in:
evidence review 1: associations between individual or building characteristics and exposure levels
evidence review 2: exposure to pollutants and health outcomes
evidence review 3.1: material and structural interventions
evidence review 3.3: ventilation design and use.
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# Builders, contractors and developers
These recommendations apply both to building new homes and renovating or refurbishing existing homes.
Ensure products and materials comply with building regulations, design specifications and the manufacturer's guidance on installation and commissioning.
Use materials that emit a low level of formaldehyde and VOCs as specified. If materials need to be substituted, only use products with the same or lower emission levels.
Ensure all heating and ventilation is installed and commissioned in accordance with the manufacturer's instructions and meets building regulation requirements.
Ensure all installed heating and ventilation systems are easily accessible for regular maintenance.
Ensure any variations to the heating and ventilation specification comply with design specifications and building regulations (see the Ministry of Housing, Communities and Local Government's advice on ventilation).
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on builders, contractors and developers .
Full details of the evidence and the committee's discussion are in evidence review 3.1: material and structural interventions.
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# Rental properties
These recommendations are for local authorities and cover both private and public rented housing.
## Regulations
Use existing regulatory powers to:
reduce people's exposure to pollutants in their homes by ensuring identified problems such as damp and mould are fixed promptly
ensure homes have suitable and efficient heating and ventilation (see the Ministry of Housing, Communities and Local Government's advice on ventilation and housing health and safety rating system operating guidance, and NICE's guideline on winter deaths and illness and cold homes).
Where a housing assessment has identified problems in private or public rented housing that may contribute to poor indoor air quality, ensure the property has:
heating appliances and ventilation systems that:
comply with design and performance requirements
are correctly installed and tested
keep properties warm and ventilated without excessive heat loss or draughts
ventilation that prevents the build‑up of pollutants, including:
trickle vents
working mechanical ventilation systems, such as extractor fans, in bathrooms and kitchens
windows that open (but not onto busy roads or other major sources of outdoor air pollution)
cooking appliances that:
comply with design and performance requirements
are correctly installed and tested.
Where a housing assessment has identified water damage in private or public rented housing, ensure that any water damage is repaired as soon as possible and the property has properly dried out.
## Property management
Advise property managers and landlords to:
develop and undertake maintenance programmes for heating and ventilation systems
provide clear, easy-to-understand instructions telling residents how to use the heating and ventilation systems effectively.
Advise property managers and landlords about:
the health risks associated with poor indoor air quality
methods to control and minimise identified sources of indoor air pollution (see the section for architects and designers)
their responsibilities for maintaining the property.
Advise property managers and landlords to:
use low-pollutant-emission items when replacing furniture or flooring (for example, furniture or flooring with a low formaldehyde content and emission)
ensure rooms are well ventilated and that the manufacturer's guidelines for use of materials are followed
ensure there is adequate ventilation provision before installing a new cooker (especially a gas cooker).
For a short explanation of why the committee made these recommendations and how they might affect practice,see the rationale and impact section on rental properties .
Full details of the evidence and the committee's discussion are in:
evidence review 1: associations between individual or building characteristics and exposure levels
evidence review 2: exposure to pollutants and health outcomes
evidence review 3.1: material and structural interventions
evidence review 3.2: occupant behaviour interventions
evidence review 4: effective strategies for raising awareness.
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# Terms used in this guideline
This section defines terms that have been used in a particular way for this guideline. For other definitions, see the NICE glossary or, for public health and social care terms, the Think Local, Act Personal Care and Support Jargon Buster.
## Particulate matter
Particulate matter (also referred to as PM or particle pollution) is a complex mixture of solid or liquid particles suspended in air. These particles can vary in size, shape and composition. Indoor particulate matter can be generated through cooking, combustion (including candles, open solid-fuel fires, unvented space heaters or paraffin heaters) and smoking.
## Purge ventilation
Manually controlled ventilation of rooms or spaces at a relatively high rate to rapidly dilute pollutants or water vapour, for example by opening a window or using a fan.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Key recommendations for research
## Health impact of air pollutants at home
What is the health impact of exposure to individual air pollutants alone or combined with each other in the home?
For a short explanation of why the committee made the recommendation for research, see the rationale on raising awareness of poor indoor air quality in the home and advice and information for the general population .
Full details of the evidence and the committee's discussion are in:
evidence review 1: associations between individual or building characteristics and exposure levels
evidence review 2: exposure to pollutants and health outcomes
evidence review 3.1: material and structural interventions.
evidence review 4: effective strategies for raising awareness.
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## Effective interventions to improve indoor air quality for people without pre‑existing health conditions
What is the effectiveness and cost effectiveness of interventions to improve indoor air quality at home for people without pre‑existing health conditions?
For a short explanation of why the committee made the recommendation for research, see the rationale on advice and information for the general population and healthcare professionals .
Full details of the evidence and the committee's discussion are in:
evidence review 1: associations between individual or building characteristics and exposure levels
evidence review 2: exposure to pollutants and health outcomes
evidence review 3.1: material and structural interventions
evidence review 3.2: occupant behaviour interventions.
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## Air exchange rate and the quality of indoor air at home
What is the minimum air exchange rate to minimise the health effects of poor indoor air quality in the home?
For a short explanation of why the committee made the recommendation for research, see the rationale on architects and designers .
Full details of the evidence and the committee's discussion are in:
evidence review 1: associations between individual or building characteristics and exposure levels
evidence review 2: exposure to pollutants and health outcomes
evidence review 3.1: material and structural interventions
evidence review 3.3: ventilation design and use.
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## Impact of building materials on indoor air quality
What are the emission profiles of indoor air pollutants released from building materials in a lived‑in home environment?
For a short explanation of why the committee made the recommendation for research, see the rationale on architects and designers .
Full details of the evidence and the committee's discussion are in:
evidence review 1: associations between individual or building characteristics and exposure levels
evidence review 2: exposure to pollutants and health outcomes
evidence review 3.1: material and structural interventions
evidence review 3.3: ventilation design and use.
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## Raising awareness of the health risks of damp and mould at home
What interventions are effective and cost effective at raising awareness of the health risks of damp and mould in the home?
For a short explanation of why the committee made the recommendation for research, see the rationale on raising awareness of poor indoor air quality in the home .
Full details of the evidence and the committee's discussion are in evidence review 4: effective strategies for raising awareness.
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# Other recommendations for research
## Damp and mould in the home
How can damp and mould in the home be prevented?
How is damp and mould in the home best identified?
How is damp and mould in the home best fixed?
How can tenants be best made aware of whose responsibility it is to make any changes needed as a result of damp and mould in the home?
To find out why the committee made the research recommendations about damp and mould, see evidence review 4: effective strategies for raising awareness.# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.
# Prioritising indoor air quality in local strategy or plans
Recommendations 1.1.1 to 1.1.8
## Why the committee made the recommendations
The committee noted that local authorities have a duty of care to ensure both public sector and private homes are maintained to a 'decent' standard. The committee also noted that local authorities are responsible for ensuring people's health and wellbeing.
Limited evidence showed that exposure to poor indoor air quality is linked to a range of health problems. These include respiratory conditions such as a cough, wheezing or asthma, and allergic symptoms such as a runny nose or eye irritation.
Local authorities that have been declared an 'air quality management area' must have an air quality action plan (government clean air strategy 2019). The committee agreed that indoor air quality would fit within this plan, where it exists. Otherwise, they agreed it could be embedded within one of several existing, health-related local authority strategies.
Poor indoor air quality is a risk to everyone's health. But evidence showed that some groups are more at risk than others (see box 1).
For example, people living in poor-quality housing – including housing with damp or with inadequate heating due to fuel poverty or housing that may need remedial work – are at increased risk. They may not have the resources to carry out the necessary work or may have to wait a while for landlords or property managers to carry it out. This could leave them exposed to pollutants for longer.
Good evidence showed that homes with damp and those in need of repair are both linked to an increased risk of health problems. (Homes with serious damp and mould are likely to be classified as having a category 1 hazard by the Ministry of Housing, Communities and Local Government's housing health and safety rating system.)
There was no evidence on the effect of poor indoor air quality on older people. But the committee agreed, based on their experience, that older people may spend longer than average at home and so may be at increased risk of exposure. People with existing health problems such as asthma or chronic obstructive pulmonary disease (COPD) are also more likely to be affected by poor indoor air quality.
Pregnant women, those who have recently given birth, and pre‑school children are also at increased risk from damp and other indoor pollutants. This is partly because pregnant women and those who have recently given birth may have compromised immune systems, and pre‑school children are likely to spend more time at home.
The committee agreed that location is a risk factor because if the property is near a busy road, for example, then opening windows to improve ventilation may be counterproductive. It is also important to consider other pollutant sources associated with building location, such as nearby open fires, bonfire and firework events, agricultural sources, industrial sources or railway lines, as outlined in the government clean air strategy 2019.
Evidence also showed that overcrowding increases moisture in the air from everyday activities such as cooking and washing. This creates damp conditions. In addition, in properties where rooms are used for both living and sleeping (for example, in bedsits or studio flats), poor indoor air quality can have a greater impact. That is because residents are exposed to it for a greater proportion of time and smaller dwellings have less space in which to dilute pollutants. Local authorities should assess crowding and space using the housing health and safety rating system of the Housing Act 2004.
Heating and ventilation can help to maintain good air quality. The committee agreed to stress that the balance has to be right, and remedial or maintenance works for any property should be assessed individually. For example, insulating the home to prevent cold without thinking of ventilation might lead to increased humidity and condensation, which in turn results in damp. But the committee concluded that because buildings vary so much (for example, in terms of age, type, location and state of repair), it wouldn't be practical to make any specific recommendations in this area.
There was evidence on the benefits of home visits by healthcare professionals to prevent or reduce indoor air pollution. The committee were also aware of examples of shared decision making on health and funding in England.
There was a lack of evidence on the benefits of joint working and local inspection protocols to prevent or reduce indoor air pollution. But the committee agreed to recommend these actions because:
Staff who visit vulnerable people in their homes are ideally placed to report on poor housing conditions, particularly if there are inspection protocols in place.
Sharing this information, subject to local data-sharing arrangements, would speed up the process of assessment and remedying the poor housing conditions.
Based on their knowledge of current practice in England, the committee agreed that local authorities would benefit from working with local home improvement agencies who provide home improvement grants to vulnerable groups. The committee also considered the benefits of working with professional organisations such as the Chartered Institution of Building Services Engineers, the Chartered Institute of Environmental Health, the Royal Institute of British Architects, the Chartered Institute of Architectural Technologists and the Royal Town Planning Institute. These organisations would be able to provide practical information to support home improvements, which may include information on grants available. Not only would it free up resources, but it would also allow them to work with local partners to emphasise the importance of maintaining good air quality in the home.
Based on their experience, the committee agreed that it would be helpful if local authorities regularly checked existing and new strategies to ensure air quality in the home is being given priority.
This could include monitoring buildings for signs of poor indoor air quality and checking whether data collected during home visits and local inspections identify vulnerable people and other neighbouring or similar types of properties that may be at risk.
## How the recommendations might affect practice
Local authorities regularly update their strategies. But additional resources (in terms of staff time and meetings) may be needed to include indoor air quality in an existing strategy and ensure it is implemented.
Because making indoor air quality a public health priority will improve people's health, this will lead to resource savings elsewhere. For example, by reducing the need for enforcement teams to intervene. There may also be additional economic benefits to the local economy and wider social benefits including improved educational outcomes and contributing to the achievement of government policies supporting policies such as Best Start in Life.
Local health and wellbeing boards are already in place to review current and future health and social care needs. So the costs of staff time and meetings associated with multi-agency working are expected to be minimal. Also, increased collaboration with home improvement agencies could mean that local authority resources set aside for issues related to indoor air quality could be reallocated.
Staff who visit people in their homes may need training to identify problems with indoor air quality and give advice on how to prevent or resolve such problems. Incorporating this training into existing continuous professional development could help minimise costs. But the visits may take longer if staff give advice and they may also result in additional enforcement activities.
Using building control or enforcement teams to collect and use performance data may have resource implications. For example, staff time, communication, and meetings for cross-team working. But improved health outcomes and resource savings elsewhere in the system (for example, by reducing the need for enforcement teams to intervene) might offset costs. The committee also considered the impact of not taking action. This may increase the risk of any future litigation arising from 'unhealthy' homes.
There were limited data on the link between someone who was at high risk and their level of exposure, so the committee had to estimate this.
Some benefits that were identified could not be quantified. So the overall benefits are likely to have been underestimated. The committee concluded that interventions could offer good value for money, but that this will depend on local factors.
Return to recommendations
# Referrals for a housing assessment
Recommendations 1.2.1 and 1.2.2
## Why the committee made the recommendations
There are several ways tenants can request a housing assessment:
Tenants in local authority housing can follow their complaints procedure, take action themselves or go to the Housing Ombudsman.
Tenants in housing association housing can follow their complaints procedure and can contact the Housing Ombudsman or Environmental Health.
Tenants in private rented properties can contact Environmental Health or take action themselves.
Private homeowners can also contact the local authority for advice if they are worried about the condition of their home. In the committee's experience, many people – including professionals working in housing services – don't know about these processes.
The committee also agreed that health and social care staff who visit people in their homes, and healthcare professionals who have concerns, need to be able to help people request a housing assessment. This is especially important for people who may be particularly vulnerable to ill health as a result of exposure to poor indoor air quality due to their housing conditions (see box 1). There was no evidence on how effective this would be. But the committee agreed it would ensure staff can make every contact count and could improve people's health.
Based on their experience, the committee agreed that there might be barriers preventing tenants from requesting a housing assessment. For example, they might be concerned about eviction, or about a possible increase in rent due to maintenance and repairs of heating and ventilation systems.
## How the recommendations might affect practice
Housing assessment pathways already cover some of the causes of poor indoor air quality. For example, professionals such as heating engineers are given instructions on how to identify signs of poor ventilation (see NICE's guideline on winter deaths and illness and cold homes).
Minimal additional resources would be needed to extend this to health and social care professionals and public service staff (for example, fire and rescue service professionals, ambulance service staff) who visit people in their homes. Healthcare professionals may need training on how poor air quality affects health, how to identify poor indoor air quality and how to take steps to mitigate its effects. This could be incorporated within existing training pathways, including professional training and accreditation examinations.
If more professionals are made aware of how to make referrals, this could lead to more housing assessments and more remedial work or legal actions. But local authorities have budgets for regular maintenance and upkeep of their properties. In addition, if legal action is taken to enforce standards in private properties, these costs will be recovered if the action is successful.
Return to recommendations
# Raising awareness of poor indoor air quality in the home
Recommendations 1.3.1 and 1.3.2
## Why the committee made the recommendations
Good evidence showed that exposure to poor indoor air quality is linked to a range of health problems. This includes respiratory conditions such as a cough, wheezing or asthma, and allergic symptoms such as a runny nose or eye irritation. Certain groups are more vulnerable, either because of their personal circumstances or because of where they live. Because poor indoor air quality is a hidden health threat, raising awareness is a first step in reducing the risk of long-term health issues, especially for vulnerable groups.
In the committee's experience, professionals such as care workers and health visitors, and the public, are generally unaware of the factors affecting indoor air quality. The same applies to private and social landlords, and those who regulate them.
Similarly, the committee agreed that not all professionals who see people in their home know who is likely to be most vulnerable to poor indoor air quality. And they will not necessarily know how to get help for those who cannot afford repairs or modifications.
Evidence showed that advice given on sources of poor indoor air quality could reduce people's risk of exposure. This includes general advice on using ventilation systems, barriers to heating and ventilation, and more specific advice about particular situations and activities, including how to get a housing assessment.
The committee noted that people on a low income, particularly in poorly insulated homes, may not be able to afford effective heating and may try to make their homes airtight to keep heat in. This, in turn, can mean the ventilation is less effective. They also may not be able to afford to heat all rooms to a constant temperature, or may only use heating occasionally (for example, when expecting a home visit). Both approaches can cause damp and condensation.
The committee were also aware of the increased risk for those who cannot afford remedial work or have to rely on landlords or property managers to do the work. In both cases, this could leave them exposed to pollutants while they wait for it to be done. The committee pointed out that there are enforcement powers that local authorities can use to ensure compliance with regulations. (See the recommendation on using existing building regulation enforcement activities in the section on regulators and building control teams and also the Ministry of Housing, Communities and Local Government's Housing health and safety rating system operating guidance.)
Most of the evidence focused on homes where a problem had already been identified. The committee agreed that research is needed on how to give people information on identifying the sources of the problem in the first place. Also, the committee considered that further research on the health impact of pollutants, alone or in combination with each other, would help identify the pollutant or combination of pollutants that have the largest impact on people's health. This research would also provide useful information to help raise awareness around indoor air pollutants. (See the research recommendations on the health impact of air pollutants at home, effective interventions to improve indoor air quality in the healthy population, air exchange rate and good air quality, health impact of building materials, and effective strategies for raising awareness.)
## How the recommendations might affect practice
The government clean air strategy 2019 already outlines how the government and local authorities need to raise awareness of poor indoor air quality. These recommendations support the strategy and should have minimal additional impact.
Resident satisfaction from improved health outcomes should result in resource savings elsewhere in the system and will offset costs. For social landlords, improved tenant satisfaction reduces both the time properties are left vacant and the likelihood of compensation claims.
It is not expected that any extra resources would be needed. Staff may need training on raising awareness of poor indoor air quality and in giving advice in a language the tenant understands. But incorporating this into existing general training and continuous professional development could minimise costs. Improved health outcomes leading to potentially fewer hospital visits, GP visits, or visits from community nurses should result in resource savings elsewhere in the system and will offset costs.
Return to recommendations
# Advice and information for the general population
Recommendations 1.4.1 to 1.4.12
## Why the committee made the recommendations
The committee looked at evidence for specific interventions such as air filtering systems or air purifiers. But they agreed that buildings vary so much that it wouldn't be practical to make any specific recommendations in this area.
Evidence showed that giving people advice on specific pollutants and their sources can help them reduce the pollution levels in their homes and improve their health. Evidence also showed that giving people advice on how to reduce or prevent indoor air pollution is cost effective for people who are already ill, because it can prevent their condition worsening. So this can lead to savings for the NHS.
The committee agreed that local authority staff are in a good position to give this advice because they are in contact with members of the public who use their services, including social housing. (They also have a regulatory responsibility for privately rented properties.)
There is clear evidence of a link between gas cookers and increased levels of nitrogen dioxide, and between open solid-fuel fires and increased levels of particulate matter. Exposure to these is linked to poor health, especially if there isn't sufficient ventilation to prevent the build‑up of pollutants.
Based on their experience, the committee agreed that rooms should be well ventilated when cooking to prevent moisture and condensation. The committee also agreed that gas cookers should not be used for heating rooms because this can result in the build‑up of moisture and indoor air pollutants (for example, nitrogen dioxides).
Although there was no evidence on candles, the committee, based on their experience, extrapolated from the evidence on particulate matter from other combustion sources and from the Chief Medical Officer annual report 2017: health impacts of all pollution. This stated that candles were one of a number of large combustion sources of pollutants alongside heating, cooking and open solid fuel fires. The committee therefore agreed that candles should not be used unless the room is well ventilated.
There was insufficient evidence on the health effects of indoor air pollutants in the home. The committee agreed that research on the relative health impact of individual pollutants alone or combined with each other, would help give people better information to understand and avoid harms associated with indoor air pollution (see the research recommendation on the health impact of air pollutants at home).
Evidence showed that poor housing in need of repair (for example, houses with damp) puts people's health at risk. Again, the committee agreed it was important to emphasise the significance of ventilation not only when washing or cooking, but also during other moisture-producing activities, for example, air-drying clothes indoors. The committee agreed that it is important for the local authority to take action if landlords do not carry out repairs or improve ventilation.
Evidence shows that paraffin heaters are linked with respiratory symptoms such as wheezing. These appliances are not in widespread use in England. But the committee agreed, based on their experience, that it was important to avoid using them at all indoors. They also agreed that paraffin heaters are more harmful than open solid-fuel fires, for example, because the latter are flued so that any harmful fumes should, in theory, be extracted outdoors.
Based on their experience, the committee were aware that many people do not know how and when to use ventilation systems. Ensuring a room is adequately ventilated is usually a key part of reducing exposure to volatile organic compounds (VOCs) especially while painting, renovating or decorating and using household products such as cleaning sprays and aerosols. The committee noted that there is a labelling scheme for paints in the UK. Although newer paints have a lower VOC content than older paints, the product advice is still to ensure good ventilation when using these products. The committee also agreed that people should be reminded to read the manufacturer's instructions and increase ventilation during these activities.
The evidence showed that flooring and furniture are often sources of VOCs or formaldehyde. Based on the evidence, the committee agreed it was important to highlight these dangers, because both can damage people's health.
Smoking and environmental tobacco smoke are always a health risk. The committee agreed it was important to encourage people not to smoke in their homes, and so they referred to NICE's guidance on smoking.
The committee agreed that research is needed on ways to improve indoor air quality for people who do not have pre‑existing health conditions that put them at risk from poor indoor air quality (see the research recommendation on effective interventions to improve indoor air quality in the healthy population).
## How the recommendations might affect practice
Local authorities will need to develop or update existing practice to provide people with information on how to improve indoor air quality and where to go for help. Staff might need training but incorporating this into existing continuous professional development could help minimise costs.
Improved health outcomes leading to higher resident satisfaction should result in resource savings elsewhere in the system and will offset costs. For example, by reducing the need for enforcement teams to intervene if a problem develops.
Return to recommendations
# Healthcare professionals
Recommendations 1.5.1 to 1.5.7
## Why the committee made the recommendations
Healthcare professionals frequently see people with pre‑existing health conditions and women who are pregnant or have young children. The committee agreed that this puts them in an ideal position to give advice on how indoor air pollutants, as well as damp and mould, can affect their health.
Evidence showed that people with respiratory or cardiovascular conditions or allergies are particularly affected by poor indoor air quality, including pollutants from damp and from open solid-fuel fires.
Good evidence showed that exposure to poor indoor air quality is linked to a range of health problems. These include respiratory symptoms and conditions such as a cough, wheezing or asthma, and allergic symptoms such as a runny nose or eye irritation.
Based on the evidence, the committee agreed that if people keep getting these types of symptoms – or they are getting worse – then they might be linked to the home environment.
Evidence showed that allergen barriers like mattress and pillow covers can reduce exposure to house dust mite allergens. Evidence also showed that second-hand mattresses were associated with increased levels of house dust mites.
Good evidence showed that damp homes and those in need of repair are both linked to an increased risk of health problems. (Homes with serious damp and mould are likely to be classified as having a category 1 hazard by the Ministry of Housing, Communities and Local Government's housing health and safety rating system.)
Pregnant women, those who have recently given birth, and young children are at increased risk from damp and other indoor pollutants. This is partly because these groups may have compromised or undeveloped immune systems, and also because young children are likely to spend longer than average at home. So the committee agreed that it was important to make sure they are living in a 'healthy' home that is well ventilated.
Women who are pregnant and babies under 12 months may be particularly vulnerable to pollutants such as VOCs. In addition, evidence suggested that exposure to VOCs during pregnancy was linked with coughing, wheezing and other health issues in the first years of the child's life. VOCs are found in products like aerosol sprays and glue.
Women who are pregnant and babies under 12 months may also be particularly susceptible to the effects of particulate matter – released from, for example, open solid-fuel fires. Based on this evidence, the committee agreed that using proper ventilation to disperse these pollutants is very important – as is reducing use of such appliances when this is feasible.
The committee did not look at evidence on environmental tobacco smoke because any level is considered unsafe. Instead they agreed to adapt recommendations from and cross-refer to NICE's guidance on smoking during pregnancy.
There was a lack of evidence on how indoor air pollutants affect people without pre‑existing health conditions and how to improve air quality in their homes. So the committee made a research recommendation on this group (see the research recommendation on effective interventions to improve indoor air quality in the healthy population ).
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## How the recommendations might affect practice
Most healthcare professionals might need training on how poor indoor air quality affects health and how to mitigate it. Incorporating this training into existing general training and continuous professional development could help minimise costs.
Asking about housing conditions and helping people request a housing assessment may increase consultation times. But this will be offset by future healthcare savings.
Return to recommendations
# Regulators and building control teams
Recommendations 1.6.1 and 1.6.2
## Why the committee made the recommendations
There are no national regulations or guidelines to determine 'safe' levels of indoor air pollutants. But based on their experience, the committee agreed that standards such as the World Health Organization or Public Health England guidelines could be used.
Building regulations are generally used to enforce standards in new housing. Other local standards may be used for existing homes, for example, standards on repairs and property condition or room size. Using these regulations will ensure existing and new buildings meet air quality standards.
The committee noted that enforcement and prosecution practice may vary across local authorities. Reasons for this variation include capacity for follow‑up visits and time taken to confirm non-compliance. They agreed to highlight the importance of meeting the government Building Regulations 2010 legislation and housing health and safety rating system operating guidance because this can improve people's health.
## How the recommendations might affect practice
Increased use of building control or enforcement teams may have resource implications. For example, staff time for inspection, communication, follow‑up and meetings. But improved health outcomes and resource savings elsewhere in the system (for example, by reducing the need for enforcement teams to intervene) might offset costs.
Using existing international guidelines will minimise the resource impact of developing new standards or updating existing ones.
Return to recommendations
# Architects and designers
Recommendations 1.7.1 to 1.7.6
## Why the committee made the recommendations
Evidence showed that some building materials can emit high levels of pollutants. There was no evidence on building materials and products that emit a low level of VOCs and formaldehyde. The committee agreed that specifying low-emission materials could help protect people's health. But because of the lack of evidence, they could only suggest professionals consider their use on a case-by-case basis when drawing up specifications.
The committee also noted that there are no national labelling schemes for building materials or consumer products in England (apart from a scheme for paints). They also noted government plans to set up a voluntary labelling scheme in England, as outlined in the government's clean air strategy 2019.
The committee noted the Department for Education's Building bulletin BB101: ventilation, thermal comfort and indoor air quality 2018 and considered that its recommended performance levels could also be applied to homes.
Evidence showed that open solid-fuel fires emit particulate matter and are a major cause of poor indoor air quality. This evidence was limited, but the committee agreed that designing heating options that avoid them will help protect people's health.
Ventilation affects indoor air quality, and its role in removing potential pollutants is critical.
Evidence showed a clear link between cooking with gas and pollutant levels – these are higher in the kitchen when cooking using gas than outdoor pollutant levels unless there is an air quality alert.
Evidence also showed that some causes of poor indoor air quality, such as condensation, are the result of poor thermal performance, high moisture levels combined with poor ventilation. The current focus on draught proofing and energy efficiency can add to the problem.
Because buildings vary so much, the committee were unable to recommend specific types of ventilation or heating strategies. But they agreed it is important that design strategies achieve the correct balance between ventilation, energy efficiency and heating.
Outdoor pollutants entering through windows can contribute substantially to poor indoor air quality. This is particularly the case in deprived areas where housing is likely to be close to busy roads (see the government's clean air strategy 2019). The committee agreed that if opening windows is not safe or lets in more outdoor pollutants (for example, if the window faces a busy road) then other methods of ventilation or methods of preventing pollutant ingress without resorting to opening windows are needed. This includes mechanical systems with filtration to protect against outdoor pollutants including intelligent ventilation systems.
Building or refurbishing homes to improve heating without taking ventilation into consideration can affect the health of people who live in them. So the committee stressed the importance of balancing the need for heating and ventilation, and taking into account all factors affecting indoor air quality.
They noted that the British Standards Institute standards for domestic retrofits and energy efficiency could be a useful source of information for architects and designers.
The committee agreed that more research is needed about the benefits and harms of different air exchange rates, and the health risks associated with pollutants released from building materials over time in lived‑in home environments. This would improve understanding of the minimum ventilation thresholds and appropriate building materials that designers and builders should use. (See the research recommendations on air exchange rate and good air quality and health impact of building materials.)
## How the recommendations might affect practice
The recommendations will reinforce current best practice. Architects and building designers should already be aware of the potential risks of the products and materials that they specify.
Balancing ventilation, insulation and heating is already best practice to maintain good air quality so there should be no additional resource impact.
Return to recommendations
# Builders, contractors and developers
Recommendations 1.8.1 to 1.8.5
## Why the committee made the recommendations
In the UK, materials specified for use by builders, contractors and developers have to comply with existing building regulations and should be used according to the manufacturer's instructions. The same is true for heating and ventilation systems. Based on their collective experience, the committee felt that compliance with regulations and instructions can be variable, so they agreed it was important to highlight them.
There are regulations on pollutant threshold levels but information on the level of emissions from different materials is limited. Few regulations exist to guide the choice of materials according to their effect on indoor air quality.
In the committee's experience, it is common practice for builders to use substitute materials if the specified ones are not available. Members agreed that emission levels need to be taken into account in such cases, whether working on a new building or a refurbishment.
Evidence showed that people's health is affected if best practice and standards are not complied with during home renovations. This is most likely during works that do not require building regulation approval.
In the committee's experience, building regulation enforcement may vary across local authorities. The committee stressed the particular need for enforcing compliance with heating and ventilation regulations, because any imbalance can have a disproportionate effect on indoor air quality.
The committee also highlighted that heating and ventilation systems in the home should be installed by a recognised competent installer, so as to avoid issues of poor-quality installation, in ways that make them easily accessible for regular checks and maintenance.
## How the recommendations might affect practice
The recommendations reinforce current best practice and will help local authorities meet their obligations to improve people's health and reduce health inequalities. Ensuring compliance will lead to cost savings in healthcare, because it will reduce the number of homes with poor indoor air quality and, in turn, improve residents' health.
Building regulations and standards already exist for enforcement teams. But building control teams may need to monitor their activities more closely, unless building work is under the control of an approved inspector. This may incur costs for local authorities and homeowners, particularly if issues are identified that need to be fixed. (Only local authorities have the power to enforce standards if things go wrong.)
Training on specifications and compliance will involve costs and time away from work. Incorporating this training into existing continuous professional development could help minimise costs. For small contractors and companies that do not run continuous professional development programmes, the cost will be offset by reducing the risk of future litigation that may arise from building 'unhealthy' homes.
Return to recommendations
# Rental properties
Recommendations 1.9.1 to 1.9.6
## Why the committee made the recommendations
Local authorities have a responsibility for public health, improving wellbeing and reducing inequalities, and a duty of care to ensure public sector homes are maintained to a decent standard. This duty extends to private housing with hazards considered to be a serious and immediate risk to a person's health and safety (category 1 hazards). Homes with serious damp and mould, excess cold or excess heat are likely to be classified as having a category 1 hazard by the Ministry of Housing, Communities and Local Government's housing health and safety rating system. Local authorities can also take action for hazards that are less serious or less urgent (category 2 hazards).
Local authorities have a range of enforcement options (see Ministry of Housing, Communities and Local Government's housing health and safety rating system enforcement guidance: housing conditions). The most commonly used enforcement option is an improvement notice, which requires work to be carried out within a defined time period to remove a category 1 or category 2 hazard. If the works are not carried out, the local authority may prosecute for not complying with the notice, and/or carry out the works itself and charge the owner.
The committee were aware that it is best practice to have heating and ventilation systems that meet performance requirements and are regularly maintained, which should include checking the airflow rates of extractor fans. The committee emphasised that some pollutants (such and damp and mould) and some hazards associated with poor indoor air quality (such as excess cold and excess heat) can only be dealt with if a problem has been identified and by ensuring that appropriate heating and ventilation systems are in place. But they agreed that this does not always happen – and so this needs to be stressed to all landlords as part of local authority advice to the public (see the section on advice and information for the general population) and implemented, if a housing assessment has identified a problem that may contribute to poor indoor air quality.
The committee agreed that best practice also involves repairing any water damage and removing its cause as soon as possible, to prevent mould and damp developing. Local standards may be used for existing homes, for example, landlord legislation or standards on repairs and property conditions or room size.
The committee were also aware of the increased risk for tenants who cannot afford remedial work or have to wait for landlords or property managers to do repairs (including to heating and ventilation systems). This could leave them exposed to pollutants while they wait for the work to be done.
Based on their experience, the committee agreed that if properties are properly equipped and maintained, this will control and reduce sources of indoor air pollution.
But they were concerned that property managers and landlords might not be aware of how mould, damp and other indoor air pollutants affect people's health. So they made a recommendation to advise on this and their general responsibilities to safely maintain their properties.
The evidence showed that flooring and furniture that contain flame retardants are often sources of VOCs or formaldehyde. Based on the evidence, the committee agreed it was important that these dangers were highlighted to property managers and landlords, because both can damage people's health.
## How the recommendations might affect practice
The recommendations will reinforce current best practice and the need to use existing regulatory powers to ensure homes are safe (see the government's advice on renting out your property ) and the Ministry of Housing, Communities and Local Government's housing health and safety rating system operating guidance. Because many people on a low income live in rented accommodation, this will help address health inequalities. It will also help improve the health of other vulnerable groups and others who live in rented accommodation.
These recommendations will reinforce current best practice.
Property managers are legally obliged to carry out maintenance checks and the following have to be embedded in tenancy agreements:
checks and maintenance of ventilation systems (including airflow rates of extractor fans)
gas and electricity safety checks.
So, the impact on practice and resources should be minimal, although there may be costs for repair of any problems found during the checks.
Housing has an important effect on health and health inequalities, particularly when properties need repairs. These recommendations will help meet local authorities' obligations to tackle health inequalities.
Return to recommendations# Context
People spend up to 90% of their lives indoors and 60% of that time at home.
Indoor air pollutants come from many sources, including:
building materials (including fittings and flooring)
furniture and furnishings
consumer products, including household and personal care products
activities such as cooking and smoking
biological sources, including mould, house dust mites, bacteria, pests and pet dander.
Exposure to indoor air pollutants including, for example, nitrogen dioxide, carbon monoxide, particulates, biological agents and volatile organic compounds (VOCs), is widespread and can cause respiratory and other conditions, and premature death in some people. Asthma is a common respiratory condition, with over 5 million people receiving treatment for it in the UK. Indoor air pollutants such as dust mite allergens, nitrogen dioxide and particulate matter are small enough to get into the lungs, making the airways inflamed and swollen. This can exacerbate asthma symptoms and trigger asthma attacks.
It is best practice to reduce pollutant sources and reduce emissions as much as possible, especially for those who are more vulnerable to health problems caused by poor indoor air quality. This includes children and people with respiratory and cardiovascular conditions (Committee on the Medical Effects of Air Pollutants guidance on the health effects of air pollutants).
Usually the most effective way to deal with indoor pollutants is to either remove the source or reduce emissions from it. If these are not possible, the pollutant can be diluted by ventilation (for example, opening windows) to reduce exposure. But outdoor pollutants also enter through windows or gaps in the structure and are a significant contributor to indoor air quality, particularly in deprived areas (see the government's clean air strategy 2019). NICE has also produced a guideline on outdoor air pollution.
This guideline covers the whole population. But special consideration has been given to those at increased risk of exposure to or adverse effects from poor indoor air quality.# Finding more information and resources
You can see everything NICE says on this topic in the NICE Pathway on air pollution.
To find NICE guidance on related topics, including guidance in development, see the NICE web page on environment.
For full details of the evidence and the guideline committee's discussions, see the evidence reviews. You can also find information about how the guideline was developed, including details of the committee.
NICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting NICE guidelines into practice, see resources to help you put guidance into practice.
ISBN: 978-1-4731-3625-0
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nPeople who may be vulnerable\n\nPeople who may be particularly vulnerable to ill health as a result of exposure to poor indoor air quality include:\n\npeople with a pre‑existing health condition such as asthma, allergies, chronic obstructive pulmonary disease (COPD) and cardiovascular disease\n\npregnant women and their unborn babies\n\npre-school children\n\nolder people\n\npeople who live in poor-quality housing\n\npeople exposed to tobacco smoke in their homes\n\npeople who live in poverty.\n\nHousing conditions\n\nHousing conditions that put people at increased risk of exposure to poor indoor air quality include:\n\nlocation (external factors such as high levels of outdoor air pollution, or where noise or security risks mean residents do not open windows)\n\nphysical infrastructure (such as small room size, inadequate ventilation and the building's layout and orientation)\n\nstandard of housing (for example, with damp and mould or physical disrepair including flood damage or with unflued or poorly maintained fuel-burning appliances)\n\novercrowding.\n\nThere are a number of activities that might contribute to poor indoor air quality (see the section on advice and information for the general population).\n\nFor the purposes of this guideline, the term 'local authorities' covers all types of local authority in England; these are county councils, district councils, unitary authorities, metropolitan districts and London boroughs. Each local authority should decide which of the following recommendations are relevant to their local responsibilities.\n\n# Prioritising indoor air quality in local strategy or plans\n\nThese recommendations are for local authorities.\n\nEmbed a plan for improving indoor air quality in an existing strategy or plan to improve people's health. This could be a general air quality strategy if one exists. Otherwise, for example, include it in a strategy on housing, health and wellbeing, or inequalities.\n\nEnsure the strategy or plan takes account of the housing conditions that put people at increased risk of exposure to poor indoor air quality and especially people who are particularly vulnerable to ill health as a result of such exposure (see box\xa01).\n\nEmphasise the need for a balanced approach to ventilation, insulation and heating for good indoor air quality. (See the sections on raising awareness of poor indoor air quality in the home and advice and information for the general population, and NICE's guideline on winter deaths and illness and cold homes.)\n\nEncourage joint working between local authority departments, across different local authorities, with local health and social care providers, and with voluntary, community and social enterprise organisations and other organisations with interest in indoor air quality, to improve air quality in people's homes (see the sections on raising awareness of poor indoor air quality in the home and advice and information for the general population).\n\nEncourage the use of existing home visits to identify poor indoor air quality. For example, visits to people's homes by housing officers, environmental health practitioners, community health services, social workers, care workers, and fire and rescue services.\n\nEncourage the use of local inspection protocols to identify poor indoor air quality during home visits. This may include visual inspections, checklists and the monitoring of pollutant levels. Use this information to identify other homes that may be at increased risk of poor indoor air quality.\n\nEncourage joint working with external organisations to inform home improvement programmes and identify grants to combat poor indoor air quality.\n\nMonitor progress against the goals of the strategy. Use audit data (see the recommendation on encouraging the use of existing home visits in this section) plus the lists in box\xa01 to identify people who may be vulnerable and properties that are at risk.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on prioritising indoor air quality in local strategy or plans\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review 1: associations between individual or building characteristics and exposure levels\n\nevidence review 2: exposure to pollutants and health outcomes\n\nevidence review 4: effective strategies for raising awareness.\n\nLoading. Please wait.\n\n# Referrals for a housing assessment\n\nThese recommendations are for local authorities.\n\nDevelop a structured process so that health and social care professionals and housing and local authority staff can use existing referral pathways to help people request a housing assessment if poor indoor air quality has been identified or is suspected, for example, by using the housing condition factors in box\xa01.\n\nAdvise health and social care professionals and housing and local authority staff on how to help people request a housing assessment if poor indoor air quality is identified or suspected, for example, by using the housing condition factors in box\xa01.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on referrals for a housing assessment\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review 1: associations between individual or building characteristics and exposure levels\n\nevidence review 2: exposure to pollutants and health outcomes.\n\nLoading. Please wait.\n\n# Raising awareness of poor indoor air quality in the home\n\nThese recommendations are for local authorities.\n\nUse existing communication strategies to ensure members of the public and relevant professionals (those involved in planning, designing, building, renovating and maintaining homes) are aware of:\n\nthe causes of poor indoor air quality\n\nhow residents' activities can affect indoor air quality\n\nhow health is affected by poor indoor air quality\n\nwho is particularly vulnerable (see box\xa01)\n\nhow to prevent or reduce poor indoor air quality.\n\nUse existing professional development opportunities to ensure local authority staff who visit people in their homes (such as housing, healthcare and social care professionals):\n\nknow about the sources of indoor air pollutants and how they can affect health\n\ncan give general advice on how to avoid activities that increase the level of indoor air pollutants (see the sections on advice and information for the general population and healthcare professionals)\n\ncan give general advice on how to improve ventilation if the source of the pollutant cannot be controlled (see the sections on advice and information for the general population and healthcare professionals)\n\nare aware that affordability may be a barrier to effective and efficient heating and ventilation\n\nknow that tenants may not be allowed to repair or alter building fabric, fixtures or fittings\n\nknow who can provide help with repairs and necessary improvements (for example, the local authority or a home improvement agency)\n\ncan advise people on how to request a housing assessment (see the section on referrals for a housing assessment).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on raising awareness of poor indoor air quality in the home\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa04: effective strategies for raising awareness.\n\nLoading. Please wait.\n\n# Advice and information for the general population\n\nThese recommendations are for local authorities.\n\nAdvise people on how to reduce damp and condensation and prevent mould. For example, by:\n\nusing background ventilation (such as trickle vents, or whole-house mechanical ventilation systems)\n\nusing mechanical ventilation (such as extractor fans), and opening windows where possible and safe to provide temporary increased ventilation\n\navoiding moisture-producing activities (such as air-drying clothes) indoors if possible, or improving ventilation if these cannot be avoided\n\nrepairing sources of water damage and ensuring that residual moisture is removed.\n\nAdvise people on how to use trickle vents correctly.\n\nTell people that the following activities may lead to poor indoor air quality and that they should think about increasing ventilation (by using extractor fans in the bathroom or kitchen, or opening windows if possible and safe):\n\nusing cookers, especially gas cookers\n\nusing open solid-fuel fires\n\nusing candles\n\nusing free-standing gas heaters\n\nusing cleaning products, household sprays or aerosols and paints\n\nhaving a bath or shower\n\nair-drying clothes in the home.\n\nAdvise private and social tenants to contact their landlord if:\n\nventilation is not adequate (for example, if the ventilation system is not working, trickle vents are blocked or damaged, extractor fans in the kitchen or bathroom are not working, or if excessive noise from the fans discourages their use)\n\nrepairs are needed to prevent water from entering their building\n\nimprovements to heating or insulation are needed to prevent condensation.\n\nAdvise private and social tenants to contact their local authority if no action is taken to improve ventilation or carry out repairs (see the government guides on private renting and council housing, and the Guide for tenants: Homes [Fitness for Human Habitation] Act\xa02018).\n\nAdvise people not to use unflued paraffin heaters in the home.\n\nAdvise people to follow the product instructions when using, for example, candles, paints, glues and solvents, to minimise exposure to pollutants.\n\nAdvise people to choose low-emission materials (for example, products with a low volatile organic compound [VOC] or formaldehyde content and emissions) if furniture or flooring needs replacing.\n\nAdvise people installing a new cooker about the need for ventilation, especially for gas cookers.\n\nAdvise people not to use gas cookers to heat a room.\n\nEncourage people not to smoke in the home (see NICE's guidelines on stop smoking interventions and services and smoking: stopping in pregnancy and after childbirth).\n\nAlso see the section on healthcare professionals' advice for women who are pregnant or who have given birth in the past 12\xa0months (see the section on healthcare professionals) and the section on advice for property managers and landlords (see the section on rental properties).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on advice and information for the general population\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review 1: associations between individual or building characteristics and exposure levels\n\nevidence review 2: exposure to pollutants and health outcomes\n\nevidence review 3.1: material and structural interventions.\n\nLoading. Please wait.\n\n# Healthcare professionals\n\n## People with asthma, other respiratory conditions or cardiovascular conditions\n\nExplain that indoor air pollutants (including nitrogen dioxide, damp, mould, particulate matter and VOCs) can trigger or exacerbate asthma, other respiratory conditions or cardiovascular conditions.\n\nIf a person has repeated or worsening respiratory symptoms such as a cough or wheezing, ask about their housing conditions. If these are a concern, help them request a housing assessment from the local authority (see the section on referrals for a housing assessment).\n\nAdvise people whose asthma is triggered by household sprays, air fresheners or aerosols to:\n\navoid using them\n\nuse non-spray alternatives.\n\nAlso see the section on advice and information for recommendations about ventilation and controlling sources of pollution (see the section on advice and information for the general population) and NICE's guideline on asthma.\n\n## People who are allergic to house dust mites\n\nAdvise people who are allergic to house dust mites how to reduce their exposure to them. This includes:\n\navoiding second-hand mattresses if possible\n\nusing allergen barriers such as mattress and pillow covers\n\nwashing bedding regularly.\n\nAlso see the section on advice and information for recommendations about ventilation and controlling sources of pollution (see the section on advice and information for the general population) and NHS advice on allergen avoidance.\n\n## Women who are pregnant or who have given birth in the past 12\xa0months and partners and people who live with them\n\nAsk about the person's housing conditions. If housing factors are a health concern, for example, because of damp or lack of ventilation, help them request a housing assessment from the local authority (see the section on referrals for a housing assessment).\n\nAdvise women who are pregnant that they are at increased risk of ill health from exposure to poor indoor air quality. Advise people who care for babies under 12\xa0months old that the baby is at increased risk. Both groups should:\n\nreduce their use of household sprays, air fresheners and other aerosols, and always follow product instructions\n\nif possible, avoid or reduce activities that produce particulate matter such as using open solid-fuel fires or candles\n\nalways keep the room well ventilated during these activities.See also recommendations 1.4.3, 1.4.4, 1.4.6 and\xa01.4.8.\n\nExplain that other people's tobacco smoke is a risk to a woman who is pregnant and her baby, before and after birth. Advise not smoking in the home or around the woman and her baby. (Also see NICE's guideline on smoking: stopping in pregnancy and after childbirth.)\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on healthcare professionals\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review 1: associations between individual or building characteristics and exposure levels\n\nevidence review 2: exposure to pollutants and health outcomes\n\nevidence review 3.2: occupant behaviour interventions.\n\nLoading. Please wait.\n\n# Regulators and building control teams\n\nUpdate existing standards, for example building regulations, or develop new ones for indoor air quality. Base them on current safe limits set for pollutants in residential developments. See, for example, World Health Organization guidelines on selected pollutants (2010) and dampness and mould (2009), and the Public Health England indoor air quality guidelines for selected VOCs (2019).\n\nUse existing building regulation enforcement activities to improve indoor air quality. Ensure enforcement takes place within the specified timelines. (See the government's Building Regulations\xa02010 and Housing health and safety rating system operating guidance, and the Planning Portal's failure to comply with the building regulations.)\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on regulators and building control teams\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review 1: associations between individual or building characteristics and exposure levels\n\nevidence review 2: exposure to pollutants and health outcomes.\n\nLoading. Please wait.\n\n# Architects and designers\n\n## Avoiding sources of pollutants\n\nConsider specifying building materials and products that only emit a low level of formaldehyde and VOCs. Use existing labelling schemes or other available information on product emissions (for example, on product labels) to make these specifications.\n\nDesign or specify heating systems that minimise indoor exposure to particulate matter.\n\n## Heating and ventilation\n\nAdopt a whole-building approach to heating and ventilation to ensure indoor air quality is maintained while achieving standards for energy use. (Also see NICE's guideline on winter deaths and illness and cold homes.)\n\nEnsure design strategies include provision for removing indoor air pollutants, for example by:\n\nspecifying kitchen extractor fans or cooker hoods that extract to the outside, and are easily accessible for cleaning or maintenance, with simple instructions for residents\n\nwhen safe and appropriate to do so, specifying that all habitable rooms are provided with windows that are openable and that windows or openings meet the purge ventilation requirements (see the Ministry of Housing, Communities and Local Government's advice on ventilation).\n\nDesign ventilation systems to reduce or avoid exposure to outdoor air pollution. For example:\n\nensure windows that open face away from sources of outdoor air pollution, such as busy roads\n\nfit mechanical systems with filtration to protect against outdoor pollutants. (Also see the government clean air strategy\xa02019.)\n\nWhen building dwellings or refurbishing them to improve thermal performance, ensure there is permanent, effective ventilation.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on architects and designers\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review 1: associations between individual or building characteristics and exposure levels\n\nevidence review 2: exposure to pollutants and health outcomes\n\nevidence review 3.1: material and structural interventions\n\nevidence review 3.3: ventilation design and use.\n\nLoading. Please wait.\n\n# Builders, contractors and developers\n\nThese recommendations apply both to building new homes and renovating or refurbishing existing homes.\n\nEnsure products and materials comply with building regulations, design specifications and the manufacturer's guidance on installation and commissioning.\n\nUse materials that emit a low level of formaldehyde and VOCs as specified. If materials need to be substituted, only use products with the same or lower emission levels.\n\nEnsure all heating and ventilation is installed and commissioned in accordance with the manufacturer's instructions and meets building regulation requirements.\n\nEnsure all installed heating and ventilation systems are easily accessible for regular maintenance.\n\nEnsure any variations to the heating and ventilation specification comply with design specifications and building regulations (see the Ministry of Housing, Communities and Local Government's advice on ventilation).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on builders, contractors and developers\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa03.1: material and structural interventions.\n\nLoading. Please wait.\n\n# Rental properties\n\nThese recommendations are for local authorities and cover both private and public rented housing.\n\n## Regulations\n\nUse existing regulatory powers to:\n\nreduce people's exposure to pollutants in their homes by ensuring identified problems such as damp and mould are fixed promptly\n\nensure homes have suitable and efficient heating and ventilation (see the Ministry of Housing, Communities and Local Government's advice on ventilation and housing health and safety rating system operating guidance, and NICE's guideline on winter deaths and illness and cold homes).\n\nWhere a housing assessment has identified problems in private or public rented housing that may contribute to poor indoor air quality, ensure the property has:\n\nheating appliances and ventilation systems that:\n\n\n\ncomply with design and performance requirements\n\nare correctly installed and tested\n\nkeep properties warm and ventilated without excessive heat loss or draughts\n\n\n\nventilation that prevents the build‑up of pollutants, including:\n\n\n\ntrickle vents\n\nworking mechanical ventilation systems, such as extractor fans, in bathrooms and kitchens\n\nwindows that open (but not onto busy roads or other major sources of outdoor air pollution)\n\n\n\ncooking appliances that:\n\n\n\ncomply with design and performance requirements\n\nare correctly installed and tested.\n\n\n\nWhere a housing assessment has identified water damage in private or public rented housing, ensure that any water damage is repaired as soon as possible and the property has properly dried out.\n\n## Property management\n\nAdvise property managers and landlords to:\n\ndevelop and undertake maintenance programmes for heating and ventilation systems\n\nprovide clear, easy-to-understand instructions telling residents how to use the heating and ventilation systems effectively.\n\nAdvise property managers and landlords about:\n\nthe health risks associated with poor indoor air quality\n\nmethods to control and minimise identified sources of indoor air pollution (see the section for architects and designers)\n\ntheir responsibilities for maintaining the property.\n\nAdvise property managers and landlords to:\n\nuse low-pollutant-emission items when replacing furniture or flooring (for example, furniture or flooring with a low formaldehyde content and emission)\n\nensure rooms are well ventilated and that the manufacturer's guidelines for use of materials are followed\n\nensure there is adequate ventilation provision before installing a new cooker (especially a gas cooker).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice,see the rationale and impact section on rental properties\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review 1: associations between individual or building characteristics and exposure levels\n\nevidence review 2: exposure to pollutants and health outcomes\n\nevidence review 3.1: material and structural interventions\n\nevidence review 3.2: occupant behaviour interventions\n\nevidence review 4: effective strategies for raising awareness.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a particular way for this guideline. For other definitions, see the NICE glossary or, for public health and social care terms, the Think Local, Act Personal Care and Support Jargon Buster.\n\n## Particulate matter\n\nParticulate matter (also referred to as PM or particle pollution) is a complex mixture of solid or liquid particles suspended in air. These particles can vary in size, shape and composition. Indoor particulate matter can be generated through cooking, combustion (including candles, open solid-fuel fires, unvented space heaters or paraffin heaters) and smoking.\n\n## Purge ventilation\n\nManually controlled ventilation of rooms or spaces at a relatively high rate to rapidly dilute pollutants or water vapour, for example by opening a window or using a fan.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Health impact of air pollutants at home\n\nWhat is the health impact of exposure to individual air pollutants alone or combined with each other in the home?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on raising awareness of poor indoor air quality in the home\xa0 and advice and information for the general population\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review 1: associations between individual or building characteristics and exposure levels\n\nevidence review 2: exposure to pollutants and health outcomes\n\nevidence review 3.1: material and structural interventions.\n\nevidence review\xa04: effective strategies for raising awareness.\n\nLoading. Please wait.\n\nLoading. Please wait.\n\n## Effective interventions to improve indoor air quality for people without pre‑existing health conditions\n\nWhat is the effectiveness and cost effectiveness of interventions to improve indoor air quality at home for people without pre‑existing health conditions?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on advice and information for the general population\xa0 and healthcare professionals\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review 1: associations between individual or building characteristics and exposure levels\n\nevidence review 2: exposure to pollutants and health outcomes\n\nevidence review 3.1: material and structural interventions\n\nevidence review 3.2: occupant behaviour interventions.\n\nLoading. Please wait.\n\nLoading. Please wait.\n\n## Air exchange rate and the quality of indoor air at home\n\nWhat is the minimum air exchange rate to minimise the health effects of poor indoor air quality in the home?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on architects and designers\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review 1: associations between individual or building characteristics and exposure levels\n\nevidence review 2: exposure to pollutants and health outcomes\n\nevidence review 3.1: material and structural interventions\n\nevidence review 3.3: ventilation design and use.\n\nLoading. Please wait.\n\n## Impact of building materials on indoor air quality\n\nWhat are the emission profiles of indoor air pollutants released from building materials in a lived‑in home environment?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on architects and designers\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review 1: associations between individual or building characteristics and exposure levels\n\nevidence review 2: exposure to pollutants and health outcomes\n\nevidence review 3.1: material and structural interventions\n\nevidence review 3.3: ventilation design and use.\n\nLoading. Please wait.\n\n## Raising awareness of the health risks of damp and mould at home\n\nWhat interventions are effective and cost effective at raising awareness of the health risks of damp and mould in the home?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on raising awareness of poor indoor air quality in the home\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa04: effective strategies for raising awareness.\n\nLoading. Please wait.\n\n# Other recommendations for research\n\n## Damp and mould in the home\n\nHow can damp and mould in the home be prevented?\n\nHow is damp and mould in the home best identified?\n\nHow is damp and mould in the home best fixed?\n\nHow can tenants be best made aware of whose responsibility it is to make any changes needed as a result of damp and mould in the home?\n\nTo find out why the committee made the research recommendations about damp and mould, see evidence review\xa04: effective strategies for raising awareness.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.\n\n# Prioritising indoor air quality in local strategy or plans\n\nRecommendations 1.1.1 to 1.1.8\n\n## Why the committee made the recommendations\n\nThe committee noted that local authorities have a duty of care to ensure both public sector and private homes are maintained to a 'decent' standard. The committee also noted that local authorities are responsible for ensuring people's health and wellbeing.\n\nLimited evidence showed that exposure to poor indoor air quality is linked to a range of health problems. These include respiratory conditions such as a cough, wheezing or asthma, and allergic symptoms such as a runny nose or eye irritation.\n\nLocal authorities that have been declared an 'air quality management area' must have an air quality action plan (government clean air strategy\xa02019). The committee agreed that indoor air quality would fit within this plan, where it exists. Otherwise, they agreed it could be embedded within one of several existing, health-related local authority strategies.\n\nPoor indoor air quality is a risk to everyone's health. But evidence showed that some groups are more at risk than others (see box\xa01).\n\nFor example, people living in poor-quality housing – including housing with damp or with inadequate heating due to fuel poverty or housing that may need remedial work – are at increased risk. They may not have the resources to carry out the necessary work or may have to wait a while for landlords or property managers to carry it out. This could leave them exposed to pollutants for longer.\n\nGood evidence showed that homes with damp and those in need of repair are both linked to an increased risk of health problems. (Homes with serious damp and mould are likely to be classified as having a category\xa01 hazard by the Ministry of Housing, Communities and Local Government's housing health and safety rating system.)\n\nThere was no evidence on the effect of poor indoor air quality on older people. But the committee agreed, based on their experience, that older people may spend longer than average at home and so may be at increased risk of exposure. People with existing health problems such as asthma or chronic obstructive pulmonary disease (COPD) are also more likely to be affected by poor indoor air quality.\n\nPregnant women, those who have recently given birth, and pre‑school children are also at increased risk from damp and other indoor pollutants. This is partly because pregnant women and those who have recently given birth may have compromised immune systems, and pre‑school children are likely to spend more time at home.\n\nThe committee agreed that location is a risk factor because if the property is near a busy road, for example, then opening windows to improve ventilation may be counterproductive. It is also important to consider other pollutant sources associated with building location, such as nearby open fires, bonfire and firework events, agricultural sources, industrial sources or railway lines, as outlined in the government clean air strategy\xa02019.\n\nEvidence also showed that overcrowding increases moisture in the air from everyday activities such as cooking and washing. This creates damp conditions. In addition, in properties where rooms are used for both living and sleeping (for example, in bedsits or studio flats), poor indoor air quality can have a greater impact. That is because residents are exposed to it for a greater proportion of time and smaller dwellings have less space in which to dilute pollutants. Local authorities should assess crowding and space using the housing health and safety rating system of the Housing Act\xa02004.\n\nHeating and ventilation can help to maintain good air quality. The committee agreed to stress that the balance has to be right, and remedial or maintenance works for any property should be assessed individually. For example, insulating the home to prevent cold without thinking of ventilation might lead to increased humidity and condensation, which in turn results in damp. But the committee concluded that because buildings vary so much (for example, in terms of age, type, location and state of repair), it wouldn't be practical to make any specific recommendations in this area.\n\nThere was evidence on the benefits of home visits by healthcare professionals to prevent or reduce indoor air pollution. The committee were also aware of examples of shared decision making on health and funding in England.\n\nThere was a lack of evidence on the benefits of joint working and local inspection protocols to prevent or reduce indoor air pollution. But the committee agreed to recommend these actions because:\n\nStaff who visit vulnerable people in their homes are ideally placed to report on poor housing conditions, particularly if there are inspection protocols in place.\n\nSharing this information, subject to local data-sharing arrangements, would speed up the process of assessment and remedying the poor housing conditions.\n\nBased on their knowledge of current practice in England, the committee agreed that local authorities would benefit from working with local home improvement agencies who provide home improvement grants to vulnerable groups. The committee also considered the benefits of working with professional organisations such as the Chartered Institution of Building Services Engineers, the Chartered Institute of Environmental Health, the Royal Institute of British Architects, the Chartered Institute of Architectural Technologists and the Royal Town Planning Institute. These organisations would be able to provide practical information to support home improvements, which may include information on grants available. Not only would it free up resources, but it would also allow them to work with local partners to emphasise the importance of maintaining good air quality in the home.\n\nBased on their experience, the committee agreed that it would be helpful if local authorities regularly checked existing and new strategies to ensure air quality in the home is being given priority.\n\nThis could include monitoring buildings for signs of poor indoor air quality and checking whether data collected during home visits and local inspections identify vulnerable people and other neighbouring or similar types of properties that may be at risk.\n\n## How the recommendations might affect practice\n\nLocal authorities regularly update their strategies. But additional resources (in terms of staff time and meetings) may be needed to include indoor air quality in an existing strategy and ensure it is implemented.\n\nBecause making indoor air quality a public health priority will improve people's health, this will lead to resource savings elsewhere. For example, by reducing the need for enforcement teams to intervene. There may also be additional economic benefits to the local economy and wider social benefits including improved educational outcomes and contributing to the achievement of government policies supporting policies such as Best Start in Life.\n\nLocal health and wellbeing boards are already in place to review current and future health and social care needs. So the costs of staff time and meetings associated with multi-agency working are expected to be minimal. Also, increased collaboration with home improvement agencies could mean that local authority resources set aside for issues related to indoor air quality could be reallocated.\n\nStaff who visit people in their homes may need training to identify problems with indoor air quality and give advice on how to prevent or resolve such problems. Incorporating this training into existing continuous professional development could help minimise costs. But the visits may take longer if staff give advice and they may also result in additional enforcement activities.\n\nUsing building control or enforcement teams to collect and use performance data may have resource implications. For example, staff time, communication, and meetings for cross-team working. But improved health outcomes and resource savings elsewhere in the system (for example, by reducing the need for enforcement teams to intervene) might offset costs. The committee also considered the impact of not taking action. This may increase the risk of any future litigation arising from 'unhealthy' homes.\n\nThere were limited data on the link between someone who was at high risk and their level of exposure, so the committee had to estimate this.\n\nSome benefits that were identified could not be quantified. So the overall benefits are likely to have been underestimated. The committee concluded that interventions could offer good value for money, but that this will depend on local factors.\n\nReturn to recommendations\n\n# Referrals for a housing assessment\n\nRecommendations 1.2.1 and 1.2.2\n\n## Why the committee made the recommendations\n\nThere are several ways tenants can request a housing assessment:\n\nTenants in local authority housing can follow their complaints procedure, take action themselves or go to the Housing Ombudsman.\n\nTenants in housing association housing can follow their complaints procedure and can contact the Housing Ombudsman or Environmental Health.\n\nTenants in private rented properties can contact Environmental Health or take action themselves.\n\nPrivate homeowners can also contact the local authority for advice if they are worried about the condition of their home. In the committee's experience, many people – including professionals working in housing services – don't know about these processes.\n\nThe committee also agreed that health and social care staff who visit people in their homes, and healthcare professionals who have concerns, need to be able to help people request a housing assessment. This is especially important for people who may be particularly vulnerable to ill health as a result of exposure to poor indoor air quality due to their housing conditions (see box\xa01). There was no evidence on how effective this would be. But the committee agreed it would ensure staff can make every contact count and could improve people's health.\n\nBased on their experience, the committee agreed that there might be barriers preventing tenants from requesting a housing assessment. For example, they might be concerned about eviction, or about a possible increase in rent due to maintenance and repairs of heating and ventilation systems.\n\n## How the recommendations might affect practice\n\nHousing assessment pathways already cover some of the causes of poor indoor air quality. For example, professionals such as heating engineers are given instructions on how to identify signs of poor ventilation (see NICE's guideline on winter deaths and illness and cold homes).\n\nMinimal additional resources would be needed to extend this to health and social care professionals and public service staff (for example, fire and rescue service professionals, ambulance service staff) who visit people in their homes. Healthcare professionals may need training on how poor air quality affects health, how to identify poor indoor air quality and how to take steps to mitigate its effects. This could be incorporated within existing training pathways, including professional training and accreditation examinations.\n\nIf more professionals are made aware of how to make referrals, this could lead to more housing assessments and more remedial work or legal actions. But local authorities have budgets for regular maintenance and upkeep of their properties. In addition, if legal action is taken to enforce standards in private properties, these costs will be recovered if the action is successful.\n\nReturn to recommendations\n\n# Raising awareness of poor indoor air quality in the home\n\nRecommendations 1.3.1 and 1.3.2\n\n## Why the committee made the recommendations\n\nGood evidence showed that exposure to poor indoor air quality is linked to a range of health problems. This includes respiratory conditions such as a cough, wheezing or asthma, and allergic symptoms such as a runny nose or eye irritation. Certain groups are more vulnerable, either because of their personal circumstances or because of where they live. Because poor indoor air quality is a hidden health threat, raising awareness is a first step in reducing the risk of long-term health issues, especially for vulnerable groups.\n\nIn the committee's experience, professionals such as care workers and health visitors, and the public, are generally unaware of the factors affecting indoor air quality. The same applies to private and social landlords, and those who regulate them.\n\nSimilarly, the committee agreed that not all professionals who see people in their home know who is likely to be most vulnerable to poor indoor air quality. And they will not necessarily know how to get help for those who cannot afford repairs or modifications.\n\nEvidence showed that advice given on sources of poor indoor air quality could reduce people's risk of exposure. This includes general advice on using ventilation systems, barriers to heating and ventilation, and more specific advice about particular situations and activities, including how to get a housing assessment.\n\nThe committee noted that people on a low income, particularly in poorly insulated homes, may not be able to afford effective heating and may try to make their homes airtight to keep heat in. This, in turn, can mean the ventilation is less effective. They also may not be able to afford to heat all rooms to a constant temperature, or may only use heating occasionally (for example, when expecting a home visit). Both approaches can cause damp and condensation.\n\nThe committee were also aware of the increased risk for those who cannot afford remedial work or have to rely on landlords or property managers to do the work. In both cases, this could leave them exposed to pollutants while they wait for it to be done. The committee pointed out that there are enforcement powers that local authorities can use to ensure compliance with regulations. (See the recommendation on using existing building regulation enforcement activities in the section on regulators and building control teams and also the Ministry of Housing, Communities and Local Government's Housing health and safety rating system operating guidance.)\n\nMost of the evidence focused on homes where a problem had already been identified. The committee agreed that research is needed on how to give people information on identifying the sources of the problem in the first place. Also, the committee considered that further research on the health impact of pollutants, alone or in combination with each other, would help identify the pollutant or combination of pollutants that have the largest impact on people's health. This research would also provide useful information to help raise awareness around indoor air pollutants. (See the research recommendations on the health impact of air pollutants at home, effective interventions to improve indoor air quality in the healthy population, air exchange rate and good air quality, health impact of building materials, and effective strategies for raising awareness.)\n\n## How the recommendations might affect practice\n\nThe government clean air strategy\xa02019 already outlines how the government and local authorities need to raise awareness of poor indoor air quality. These recommendations support the strategy and should have minimal additional impact.\n\nResident satisfaction from improved health outcomes should result in resource savings elsewhere in the system and will offset costs. For social landlords, improved tenant satisfaction reduces both the time properties are left vacant and the likelihood of compensation claims.\n\nIt is not expected that any extra resources would be needed. Staff may need training on raising awareness of poor indoor air quality and in giving advice in a language the tenant understands. But incorporating this into existing general training and continuous professional development could minimise costs. Improved health outcomes leading to potentially fewer hospital visits, GP visits, or visits from community nurses should result in resource savings elsewhere in the system and will offset costs.\n\nReturn to recommendations\n\n# Advice and information for the general population\n\nRecommendations 1.4.1 to 1.4.12\n\n## Why the committee made the recommendations\n\nThe committee looked at evidence for specific interventions such as air filtering systems or air purifiers. But they agreed that buildings vary so much that it wouldn't be practical to make any specific recommendations in this area.\n\nEvidence showed that giving people advice on specific pollutants and their sources can help them reduce the pollution levels in their homes and improve their health. Evidence also showed that giving people advice on how to reduce or prevent indoor air pollution is cost effective for people who are already ill, because it can prevent their condition worsening. So this can lead to savings for the NHS.\n\nThe committee agreed that local authority staff are in a good position to give this advice because they are in contact with members of the public who use their services, including social housing. (They also have a regulatory responsibility for privately rented properties.)\n\nThere is clear evidence of a link between gas cookers and increased levels of nitrogen dioxide, and between open solid-fuel fires and increased levels of particulate matter. Exposure to these is linked to poor health, especially if there isn't sufficient ventilation to prevent the build‑up of pollutants.\n\nBased on their experience, the committee agreed that rooms should be well ventilated when cooking to prevent moisture and condensation. The committee also agreed that gas cookers should not be used for heating rooms because this can result in the build‑up of moisture and indoor air pollutants (for example, nitrogen dioxides).\n\nAlthough there was no evidence on candles, the committee, based on their experience, extrapolated from the evidence on particulate matter from other combustion sources and from the Chief Medical Officer annual report\xa02017: health impacts of all pollution. This stated that candles were one of a number of large combustion sources of pollutants alongside heating, cooking and open solid fuel fires. The committee therefore agreed that candles should not be used unless the room is well ventilated.\n\nThere was insufficient evidence on the health effects of indoor air pollutants in the home. The committee agreed that research on the relative health impact of individual pollutants alone or combined with each other, would help give people better information to understand and avoid harms associated with indoor air pollution (see the research recommendation on the health impact of air pollutants at home).\n\nEvidence showed that poor housing in need of repair (for example, houses with damp) puts people's health at risk. Again, the committee agreed it was important to emphasise the significance of ventilation not only when washing or cooking, but also during other moisture-producing activities, for example, air-drying clothes indoors. The committee agreed that it is important for the local authority to take action if landlords do not carry out repairs or improve ventilation.\n\nEvidence shows that paraffin heaters are linked with respiratory symptoms such as wheezing. These appliances are not in widespread use in England. But the committee agreed, based on their experience, that it was important to avoid using them at all indoors. They also agreed that paraffin heaters are more harmful than open solid-fuel fires, for example, because the latter are flued so that any harmful fumes should, in theory, be extracted outdoors.\n\nBased on their experience, the committee were aware that many people do not know how and when to use ventilation systems. Ensuring a room is adequately ventilated is usually a key part of reducing exposure to volatile organic compounds (VOCs) especially while painting, renovating or decorating and using household products such as cleaning sprays and aerosols. The committee noted that there is a labelling scheme for paints in the UK. Although newer paints have a lower VOC content than older paints, the product advice is still to ensure good ventilation when using these products. The committee also agreed that people should be reminded to read the manufacturer's instructions and increase ventilation during these activities.\n\nThe evidence showed that flooring and furniture are often sources of VOCs or formaldehyde. Based on the evidence, the committee agreed it was important to highlight these dangers, because both can damage people's health.\n\nSmoking and environmental tobacco smoke are always a health risk. The committee agreed it was important to encourage people not to smoke in their homes, and so they referred to NICE's guidance on smoking.\n\nThe committee agreed that research is needed on ways to improve indoor air quality for people who do not have pre‑existing health conditions that put them at risk from poor indoor air quality (see the research recommendation on effective interventions to improve indoor air quality in the healthy population).\n\n## How the recommendations might affect practice\n\nLocal authorities will need to develop or update existing practice to provide people with information on how to improve indoor air quality and where to go for help. Staff might need training but incorporating this into existing continuous professional development could help minimise costs.\n\nImproved health outcomes leading to higher resident satisfaction should result in resource savings elsewhere in the system and will offset costs. For example, by reducing the need for enforcement teams to intervene if a problem develops.\n\nReturn to recommendations\n\n# Healthcare professionals\n\nRecommendations 1.5.1 to 1.5.7\n\n## Why the committee made the recommendations\n\nHealthcare professionals frequently see people with pre‑existing health conditions and women who are pregnant or have young children. The committee agreed that this puts them in an ideal position to give advice on how indoor air pollutants, as well as damp and mould, can affect their health.\n\nEvidence showed that people with respiratory or cardiovascular conditions or allergies are particularly affected by poor indoor air quality, including pollutants from damp and from open solid-fuel fires.\n\nGood evidence showed that exposure to poor indoor air quality is linked to a range of health problems. These include respiratory symptoms and conditions such as a cough, wheezing or asthma, and allergic symptoms such as a runny nose or eye irritation.\n\nBased on the evidence, the committee agreed that if people keep getting these types of symptoms – or they are getting worse – then they might be linked to the home environment.\n\nEvidence showed that allergen barriers like mattress and pillow covers can reduce exposure to house dust mite allergens. Evidence also showed that second-hand mattresses were associated with increased levels of house dust mites.\n\nGood evidence showed that damp homes and those in need of repair are both linked to an increased risk of health problems. (Homes with serious damp and mould are likely to be classified as having a category\xa01 hazard by the Ministry of Housing, Communities and Local Government's housing health and safety rating system.)\n\nPregnant women, those who have recently given birth, and young children are at increased risk from damp and other indoor pollutants. This is partly because these groups may have compromised or undeveloped immune systems, and also because young children are likely to spend longer than average at home. So the committee agreed that it was important to make sure they are living in a 'healthy' home that is well ventilated.\n\nWomen who are pregnant and babies under 12\xa0months may be particularly vulnerable to pollutants such as VOCs. In addition, evidence suggested that exposure to VOCs during pregnancy was linked with coughing, wheezing and other health issues in the first years of the child's life. VOCs are found in products like aerosol sprays and glue.\n\nWomen who are pregnant and babies under 12\xa0months may also be particularly susceptible to the effects of particulate matter – released from, for example, open solid-fuel fires. Based on this evidence, the committee agreed that using proper ventilation to disperse these pollutants is very important – as is reducing use of such appliances when this is feasible.\n\nThe committee did not look at evidence on environmental tobacco smoke because any level is considered unsafe. Instead they agreed to adapt recommendations from and cross-refer to NICE's guidance on smoking during pregnancy.\n\nThere was a lack of evidence on how indoor air pollutants affect people without pre‑existing health conditions and how to improve air quality in their homes. So the committee made a research recommendation on this group (see the research recommendation on effective interventions to improve indoor air quality in the healthy population\xa0).\n\nLoading. Please wait.\n\n## How the recommendations might affect practice\n\nMost healthcare professionals might need training on how poor indoor air quality affects health and how to mitigate it. Incorporating this training into existing general training and continuous professional development could help minimise costs.\n\nAsking about housing conditions and helping people request a housing assessment may increase consultation times. But this will be offset by future healthcare savings.\n\nReturn to recommendations\n\n# Regulators and building control teams\n\nRecommendations 1.6.1 and 1.6.2\n\n## Why the committee made the recommendations\n\nThere are no national regulations or guidelines to determine 'safe' levels of indoor air pollutants. But based on their experience, the committee agreed that standards such as the World Health Organization or Public Health England guidelines could be used.\n\nBuilding regulations are generally used to enforce standards in new housing. Other local standards may be used for existing homes, for example, standards on repairs and property condition or room size. Using these regulations will ensure existing and new buildings meet air quality standards.\n\nThe committee noted that enforcement and prosecution practice may vary across local authorities. Reasons for this variation include capacity for follow‑up visits and time taken to confirm non-compliance. They agreed to highlight the importance of meeting the government Building Regulations\xa02010 legislation and housing health and safety rating system operating guidance because this can improve people's health.\n\n## How the recommendations might affect practice\n\nIncreased use of building control or enforcement teams may have resource implications. For example, staff time for inspection, communication, follow‑up and meetings. But improved health outcomes and resource savings elsewhere in the system (for example, by reducing the need for enforcement teams to intervene) might offset costs.\n\nUsing existing international guidelines will minimise the resource impact of developing new standards or updating existing ones.\n\nReturn to recommendations\n\n# Architects and designers\n\nRecommendations 1.7.1 to 1.7.6\n\n## Why the committee made the recommendations\n\nEvidence showed that some building materials can emit high levels of pollutants. There was no evidence on building materials and products that emit a low level of VOCs and formaldehyde. The committee agreed that specifying low-emission materials could help protect people's health. But because of the lack of evidence, they could only suggest professionals consider their use on a case-by-case basis when drawing up specifications.\n\nThe committee also noted that there are no national labelling schemes for building materials or consumer products in England (apart from a scheme for paints). They also noted government plans to set up a voluntary labelling scheme in England, as outlined in the government's clean air strategy\xa02019.\n\nThe committee noted the Department for Education's Building bulletin BB101: ventilation, thermal comfort and indoor air quality\xa02018 and considered that its recommended performance levels could also be applied to homes.\n\nEvidence showed that open solid-fuel fires emit particulate matter and are a major cause of poor indoor air quality. This evidence was limited, but the committee agreed that designing heating options that avoid them will help protect people's health.\n\nVentilation affects indoor air quality, and its role in removing potential pollutants is critical.\n\nEvidence showed a clear link between cooking with gas and pollutant levels – these are higher in the kitchen when cooking using gas than outdoor pollutant levels unless there is an air quality alert.\n\nEvidence also showed that some causes of poor indoor air quality, such as condensation, are the result of poor thermal performance, high moisture levels combined with poor ventilation. The current focus on draught proofing and energy efficiency can add to the problem.\n\nBecause buildings vary so much, the committee were unable to recommend specific types of ventilation or heating strategies. But they agreed it is important that design strategies achieve the correct balance between ventilation, energy efficiency and heating.\n\nOutdoor pollutants entering through windows can contribute substantially to poor indoor air quality. This is particularly the case in deprived areas where housing is likely to be close to busy roads (see the government's clean air strategy\xa02019). The committee agreed that if opening windows is not safe or lets in more outdoor pollutants (for example, if the window faces a busy road) then other methods of ventilation or methods of preventing pollutant ingress without resorting to opening windows are needed. This includes mechanical systems with filtration to protect against outdoor pollutants including intelligent ventilation systems.\n\nBuilding or refurbishing homes to improve heating without taking ventilation into consideration can affect the health of people who live in them. So the committee stressed the importance of balancing the need for heating and ventilation, and taking into account all factors affecting indoor air quality.\n\nThey noted that the British Standards Institute standards for domestic retrofits and energy efficiency could be a useful source of information for architects and designers.\n\nThe committee agreed that more research is needed about the benefits and harms of different air exchange rates, and the health risks associated with pollutants released from building materials over time in lived‑in home environments. This would improve understanding of the minimum ventilation thresholds and appropriate building materials that designers and builders should use. (See the research recommendations on air exchange rate and good air quality and health impact of building materials.)\n\n## How the recommendations might affect practice\n\nThe recommendations will reinforce current best practice. Architects and building designers should already be aware of the potential risks of the products and materials that they specify.\n\nBalancing ventilation, insulation and heating is already best practice to maintain good air quality so there should be no additional resource impact.\n\nReturn to recommendations\n\n# Builders, contractors and developers\n\nRecommendations 1.8.1 to 1.8.5\n\n## Why the committee made the recommendations\n\nIn the UK, materials specified for use by builders, contractors and developers have to comply with existing building regulations and should be used according to the manufacturer's instructions. The same is true for heating and ventilation systems. Based on their collective experience, the committee felt that compliance with regulations and instructions can be variable, so they agreed it was important to highlight them.\n\nThere are regulations on pollutant threshold levels but information on the level of emissions from different materials is limited. Few regulations exist to guide the choice of materials according to their effect on indoor air quality.\n\nIn the committee's experience, it is common practice for builders to use substitute materials if the specified ones are not available. Members agreed that emission levels need to be taken into account in such cases, whether working on a new building or a refurbishment.\n\nEvidence showed that people's health is affected if best practice and standards are not complied with during home renovations. This is most likely during works that do not require building regulation approval.\n\nIn the committee's experience, building regulation enforcement may vary across local authorities. The committee stressed the particular need for enforcing compliance with heating and ventilation regulations, because any imbalance can have a disproportionate effect on indoor air quality.\n\nThe committee also highlighted that heating and ventilation systems in the home should be installed by a recognised competent installer, so as to avoid issues of poor-quality installation, in ways that make them easily accessible for regular checks and maintenance.\n\n## How the recommendations might affect practice\n\nThe recommendations reinforce current best practice and will help local authorities meet their obligations to improve people's health and reduce health inequalities. Ensuring compliance will lead to cost savings in healthcare, because it will reduce the number of homes with poor indoor air quality and, in turn, improve residents' health.\n\nBuilding regulations and standards already exist for enforcement teams. But building control teams may need to monitor their activities more closely, unless building work is under the control of an approved inspector. This may incur costs for local authorities and homeowners, particularly if issues are identified that need to be fixed. (Only local authorities have the power to enforce standards if things go wrong.)\n\nTraining on specifications and compliance will involve costs and time away from work. Incorporating this training into existing continuous professional development could help minimise costs. For small contractors and companies that do not run continuous professional development programmes, the cost will be offset by reducing the risk of future litigation that may arise from building 'unhealthy' homes.\n\nReturn to recommendations\n\n# Rental properties\n\nRecommendations 1.9.1 to 1.9.6\n\n## Why the committee made the recommendations\n\nLocal authorities have a responsibility for public health, improving wellbeing and reducing inequalities, and a duty of care to ensure public sector homes are maintained to a decent standard. This duty extends to private housing with hazards considered to be a serious and immediate risk to a person's health and safety (category\xa01 hazards). Homes with serious damp and mould, excess cold or excess heat are likely to be classified as having a category\xa01 hazard by the Ministry of Housing, Communities and Local Government's housing health and safety rating system. Local authorities can also take action for hazards that are less serious or less urgent (category\xa02 hazards).\n\nLocal authorities have a range of enforcement options (see Ministry of Housing, Communities and Local Government's housing health and safety rating system enforcement guidance: housing conditions). The most commonly used enforcement option is an improvement notice, which requires work to be carried out within a defined time period to remove a category\xa01 or category\xa02 hazard. If the works are not carried out, the local authority may prosecute for not complying with the notice, and/or carry out the works itself and charge the owner.\n\nThe committee were aware that it is best practice to have heating and ventilation systems that meet performance requirements and are regularly maintained, which should include checking the airflow rates of extractor fans. The committee emphasised that some pollutants (such and damp and mould) and some hazards associated with poor indoor air quality (such as excess cold and excess heat) can only be dealt with if a problem has been identified and by ensuring that appropriate heating and ventilation systems are in place. But they agreed that this does not always happen – and so this needs to be stressed to all landlords as part of local authority advice to the public (see the section on advice and information for the general population) and implemented, if a housing assessment has identified a problem that may contribute to poor indoor air quality.\n\nThe committee agreed that best practice also involves repairing any water damage and removing its cause as soon as possible, to prevent mould and damp developing. Local standards may be used for existing homes, for example, landlord legislation or standards on repairs and property conditions or room size.\n\nThe committee were also aware of the increased risk for tenants who cannot afford remedial work or have to wait for landlords or property managers to do repairs (including to heating and ventilation systems). This could leave them exposed to pollutants while they wait for the work to be done.\n\nBased on their experience, the committee agreed that if properties are properly equipped and maintained, this will control and reduce sources of indoor air pollution.\n\nBut they were concerned that property managers and landlords might not be aware of how mould, damp and other indoor air pollutants affect people's health. So they made a recommendation to advise on this and their general responsibilities to safely maintain their properties.\n\nThe evidence showed that flooring and furniture that contain flame retardants are often sources of VOCs or formaldehyde. Based on the evidence, the committee agreed it was important that these dangers were highlighted to property managers and landlords, because both can damage people's health.\n\n## How the recommendations might affect practice\n\nThe recommendations will reinforce current best practice and the need to use existing regulatory powers to ensure homes are safe (see the government's advice on renting out your property [England and Wales]) and the Ministry of Housing, Communities and Local Government's housing health and safety rating system operating guidance. Because many people on a low income live in rented accommodation, this will help address health inequalities. It will also help improve the health of other vulnerable groups and others who live in rented accommodation.\n\nThese recommendations will reinforce current best practice.\n\nProperty managers are legally obliged to carry out maintenance checks and the following have to be embedded in tenancy agreements:\n\nchecks and maintenance of ventilation systems (including airflow rates of extractor fans)\n\ngas and electricity safety checks.\n\nSo, the impact on practice and resources should be minimal, although there may be costs for repair of any problems found during the checks.\n\nHousing has an important effect on health and health inequalities, particularly when properties need repairs. These recommendations will help meet local authorities' obligations to tackle health inequalities.\n\nReturn to recommendations", 'Context': "People spend up to 90% of their lives indoors and 60% of that time at home.\n\nIndoor air pollutants come from many sources, including:\n\nbuilding materials (including fittings and flooring)\n\nfurniture and furnishings\n\nconsumer products, including household and personal care products\n\nactivities such as cooking and smoking\n\nbiological sources, including mould, house dust mites, bacteria, pests and pet dander.\n\nExposure to indoor air pollutants including, for example, nitrogen dioxide, carbon monoxide, particulates, biological agents and volatile organic compounds (VOCs), is widespread and can cause respiratory and other conditions, and premature death in some people. Asthma is a common respiratory condition, with over 5\xa0million people receiving treatment for it in the UK. Indoor air pollutants such as dust mite allergens, nitrogen dioxide and particulate matter are small enough to get into the lungs, making the airways inflamed and swollen. This can exacerbate asthma symptoms and trigger asthma attacks.\n\nIt is best practice to reduce pollutant sources and reduce emissions as much as possible, especially for those who are more vulnerable to health problems caused by poor indoor air quality. This includes children and people with respiratory and cardiovascular conditions (Committee on the Medical Effects of Air Pollutants guidance on the health effects of air pollutants).\n\nUsually the most effective way to deal with indoor pollutants is to either remove the source or reduce emissions from it. If these are not possible, the pollutant can be diluted by ventilation (for example, opening windows) to reduce exposure. But outdoor pollutants also enter through windows or gaps in the structure and are a significant contributor to indoor air quality, particularly in deprived areas (see the government's clean air strategy\xa02019). NICE has also produced a guideline on outdoor air pollution.\n\nThis guideline covers the whole population. But special consideration has been given to those at increased risk of exposure to or adverse effects from poor indoor air quality.", 'Finding more information and resources': "You can see everything NICE says on this topic in the NICE Pathway on air pollution.\n\nTo find NICE guidance on related topics, including guidance in development, see the NICE web page on environment.\n\nFor full details of the evidence and the guideline committee's discussions, see the evidence reviews. You can also find information about how the guideline was developed, including details of the committee.\n\nNICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting NICE guidelines into practice, see resources to help you put guidance into practice.\n\nISBN: 978-1-4731-3625-0"}
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https://www.nice.org.uk/guidance/ng149
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This guideline covers indoor air quality in residential buildings. It aims to raise awareness of the importance of good air quality in people's homes and how to achieve this.
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21ebc40b0e6ce0313f8186f5721211853280cd5e
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nice
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Lusutrombopag for treating thrombocytopenia in people with chronic liver disease needing a planned invasive procedure
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Lusutrombopag for treating thrombocytopenia in people with chronic liver disease needing a planned invasive procedure
Evidence-based recommendations on lusutrombopag (Mulpleo) for treating severe thrombocytopenia in adults with chronic liver disease needing a planned invasive procedure.
# Recommendations
Lusutrombopag is recommended, within its marketing authorisation, as an option for treating severe thrombocytopenia (that is, a platelet count of below 50,000 platelets per microlitre of blood) in adults with chronic liver disease having planned invasive procedures.
Why the committee made these recommendations
People with chronic liver disease often have low blood platelet levels. This means that they are more likely to bleed during invasive medical procedures, including surgery. Currently, they have a platelet transfusion before invasive procedures to help reduce their chances of bleeding.
Avatrombopag and lusutrombopag are oral therapies that raise platelet levels, the aim being to reduce (but not eliminate) the chances of a patient needing a platelet transfusion. Platelet transfusions rely on donors and are given intravenously, so the possibility of replacing them with an oral treatment is an improvement. The drugs have several other benefits, including:
the convenience of fewer transfusions
fewer hospital stays
a decreased chance of having transfusion-related complications.
In addition, platelets are a limited resource and can only be stored for a short time. This means that there can be problems getting them to people in time for their procedure, which can delay surgery. On the other hand, avatrombopag and lusutrombopag need to be taken more than a week before a procedure, so can be used only for planned procedures.
Clinical trial evidence shows that fewer people need a platelet transfusion if they have avatrombopag or lusutrombopag rather than a placebo treatment. But whether the drugs improve survival compared with platelet transfusions has not been measured. There is also no clinical evidence that either drug is better than the other.
The economic modelling does not fully account for the benefits for patients and service delivery when using avatrombopag and lusutrombopag. If these are considered, using lusutrombopag would likely save the NHS money. So, lusutrombopag can be recommended for treating thrombocytopenia in people with chronic liver disease who need planned invasive procedures. It is not possible for NICE to make a recommendation for avatrombopag because the drug does not have a UK price.# Information about avatrombopag and lusutrombopag
# Marketing authorisations
Avatrombopag (Doptelet, Sobi) is recommended 'for the treatment of severe thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo an invasive procedure'.
Lusutrombopag (Mulpleo, Shionogi BV) is recommended 'for the treatment of severe thrombocytopenia in adult patients with chronic liver disease undergoing invasive procedures'.
# Dosages in the marketing authorisations
The recommended dosage of avatrombopag is based on the patient's platelet count:
below 40,000 platelets per microlitre of blood – 60 mg once daily
,000 to below 50,000 platelets per microlitre of blood – 40 mg once daily.Dosing should begin 10 to 13 days before the planned procedure. Patients should have their procedure 5 to 8 days after the last dose of avatrombopag. Avatrombopag is taken orally.
The recommended dosage of lusutrombopag is 3 mg once daily for 7 days. The procedure should be done from day 9 after the start of lusutrombopag treatment. Platelet count should be measured before the procedure. Lusutrombopag is taken orally.
# Price
The company has stated that the price of avatrombopag is £640.00 or £960.00 per 5‑day treatment course for the 40,000 to below 50,000 and below 40,000 platelets per microlitre of blood groups respectively.
The company has stated that the cost of lusutrombopag is £800 per 7‑day treatment course. Costs may vary in different settings because of negotiated procurement discounts.# Committee discussion
The appraisal committee (section 5) considered evidence from a number of sources. See the committee papers for full details of the evidence.
# Treatment pathway
## People with chronic liver disease and a count of below 50,000 platelets per microlitre of blood would be eligible for avatrombopag or lusutrombopag
The clinical experts explained that people with chronic liver disease and thrombocytopenia (traditionally defined as a platelet count below 150,000 platelets per microlitre of blood) have an increased risk of bleeding when having invasive procedures, including surgery. This is irrespective of whether the procedure is planned or an emergency. These procedures may include investigative or therapeutic procedures such as dental, multiple and repeated procedures. Because of this bleeding risk, people may have a platelet transfusion before the invasive procedure to aid blood clotting. The clinical experts acknowledged that they were unaware of trials testing whether platelets lowered the risk of bleeding. However, they agreed that transfusing platelets prophylactically was the standard of care. The clinical experts also stated that the risk of bleeding during a procedure depends on the platelet count, the specific procedure, other manifestations of liver disease, history of bleeding and age. NICE's guideline on blood transfusion recommends that prophylactic platelet transfusions should be considered for people having invasive procedures or surgery to raise the platelet count above 50,000 platelets per microlitre of blood. The committee heard that higher platelet counts might be needed for invasive procedures on some sites (such as the eyes). It noted that avatrombopag is licensed for treating thrombocytopenia when the platelet count is below 50,000 platelets per microlitre of blood. It also noted that, although the marketing authorisation for lusutrombopag does not define severe thrombocytopenia, the company and the assessment group only presented evidence (that is, clinical trial data, indirect clinical data and cost-effectiveness analyses) for people with a platelet count below 50,000 platelets per microlitre of blood. If people bleed during or after a procedure, they may need a 'rescue therapy', including further platelet transfusions, fresh frozen plasma or tranexamic acid. The committee concluded that people with chronic liver disease having a planned invasive procedure would be eligible for treatment with avatrombopag and lusutrombopag if they had a platelet count of below 50,000 platelets per microlitre of blood. It agreed to make recommendations for this group.
## The appraisal applies to people needing planned procedures scheduled for 9 or 10 days in the future
The marketing authorisations stipulate that avatrombopag and lusutrombopag oral treatments need to be taken at least 10 days or 9 days respectively before a procedure. The clinical experts stated that it would be relatively straightforward to co-ordinate testing platelet levels and prescribing these treatments with a GP. Because of the time needed to increase the platelet count, the committee heard that avatrombopag and lusutrombopag would be appropriate only for planned elective procedures. However, these drugs would not have a role in planned procedures that need to be done within 9 or 10 days. The committee concluded that the appraisal applies to people with chronic liver disease and a platelet count below 50,000 platelets per microlitre of blood needing planned ('elective') invasive procedures rather than emergency procedures.
## Avatrombopag and lusutrombopag raise platelet levels for longer than a transfusion, and are taken at home so reduce wastage and hospital stays
The clinical experts explained that a platelet transfusion increases platelet levels for only a short time. This means that patients need to have their procedures soon after having a transfusion. According to the clinical experts, about 50% of patients go into hospital to have a transfusion the evening before their planned procedure and, when possible, the transfusion is given on the day of the procedure. If the 'treatment window' (that is, the time when platelet levels are raised) is missed, a patient would have another platelet transfusion before having the procedure. Avatrombopag and lusutrombopag have longer treatment windows in which to do planned invasive procedures than do platelet transfusions. Specifically, these windows are 10 to 13 days (stated in the marketing authorisation for avatrombopag) after starting avatrombopag and from day 9 (stated in the marketing authorisation for lusutrombopag) after starting lusutrombopag. The committee considered that this would ease procedure scheduling compared with platelet transfusion and may make it possible to carry out multiple procedures within a treatment window. It concluded that avatrombopag and lusutrombopag have some potential advantages over transfusing platelets. These include reducing wastage if an invasive procedure is delayed, increasing the time in which procedures can occur and reducing hospital stays.
## People would welcome an oral treatment alternative to platelet transfusions
The patient expert stated that, typically, people with chronic liver disease and thrombocytopenia are sick and have many hospital appointments; this, and the associated travel, disrupts their lives. They would value any treatment that could reduce this burden. Avatrombopag and lusutrombopag are oral treatments, and would reduce the need for a trip to hospital for a transfusion. The clinical experts acknowledged that some people who develop chronic liver disease from intravenous drug use have poor venous access. For them, transfusing platelets is difficult without central venous access, for which a procedure is also needed. The patient expert stated that the risks of adverse effects associated with platelet transfusions are low. However, people perceive oral treatments to be safer, and even just the perceived risk of platelet transfusions can cause anxiety. The committee concluded that there are benefits related to an oral treatment compared with platelet transfusions, and that people would welcome an oral treatment option.
## Reducing dependence on platelets would minimise problems associated with obtaining and transfusing platelets
Platelet transfusions, like all blood products, are a scarce resource limited by the number of donations received. The clinical experts explained that platelets also have a short shelf life (of 5 to 7 days) and need to be stored at room temperature. This means that larger hospitals store only limited amounts to avoid wastage, and that smaller hospitals do not store platelets on site. The clinical experts explained that patients can become refractory to repeated platelet transfusions. Repeated transfusions can also increase the risk of infection. Some people can react to the plasma contained in the platelets or develop antibodies against donor platelets after repeated transfusions. People who have an immune reaction to donated platelets may reduce their chance of having a successful liver transplant. The clinical experts also stated that, although donor platelets are not usually matched to the recipient, sometimes they have to be. This then makes it more difficult to find platelets, and means that no one else can use these matched platelets (for example, human leucocyte antigen matched). The committee agreed that obtaining, storing and administering platelets carries a number of practical implications for patients and for service delivery. It concluded that reducing dependence on platelets would minimise problems associated with obtaining and transfusing platelets.
# Clinical evidence
## Avatrombopag and lusutrombopag reduce the number of platelet transfusions
The avatrombopag randomised placebo-controlled trials (ADAPT 1 and ADAPT 2) assessed 2 doses of avatrombopag: 40 mg for people with a platelet count of between 40,000 and below 50,000 platelets per microlitre of blood and 60 mg for people with a platelet count below 40,000 platelets per microlitre of blood. The lusutrombopag trials (L‑PLUS 1, L‑PLUS 2 and JapicCTI 121944) assessed 3 mg lusutrombopag in people with a platelet count below 50,000 platelets per microlitre of blood. To compare the lusutrombopag results with the avatrombopag results, the assessment group chose to separate lusutrombopag results into the same subgroups as avatrombopag. That is, it considered the lusutrombopag trial results for 2 subgroups: people with a platelet count of between 40,000 and below 50,000 platelets per microlitre of blood; and people with a platelet count below 40,000 platelets per microlitre of blood separately. However, the assessment group also presented analyses for lusutrombopag for the full population. The avatrombopag and lusutrombopag trials measured the proportion of people needing a platelet transfusion before an invasive procedure. Across all subgroups, at least 40% fewer people needed a platelet transfusion if they were randomised to avatrombopag or lusutrombopag compared with placebo. The committee concluded that the trial evidence presented was appropriate for decision making. It further concluded that the evidence showed that avatrombopag and lusutrombopag reduce the number of platelet transfusions before invasive procedures in people with chronic liver disease and thrombocytopenia when compared with placebo.
## Although both drugs' trials include people fitter than those having platelet transfusions in UK clinical practice, the results are generalisable
One way to categorise the severity of chronic liver disease is by Child-Pugh score. People in the Child-Pugh A category have less severe disease and the best prognosis; people in the Child-Pugh C category have the most severe disease and the poorest prognosis. The regulatory trials of avatrombopag included between 8.6% (40,000 to below 50,000 platelets per microlitre of blood subgroup in the avatrombopag arm of ADAPT-1) and 15.2% (in the same subgroup of the avatrombopag arm of ADAPT-2) of people in the Child-Pugh C category. The trials of lusutrombopag excluded people with disease scored as Child-Pugh C (although 3.6% of the pooled-trials population were in the Child-Pugh C category). The summary of product characteristics for both drugs state that they should only be used in people with Child-Pugh C liver disease if the expected benefits outweigh the expected risks. The clinical experts explained that patients with thrombocytopenia tend to have Child-Pugh B or C liver disease, and that people with Child-Pugh A liver disease rarely have thrombocytopenia. The committee agreed that this meant that the avatrombopag and lusutrombopag trials were carried out in people who were fitter than people who would have the drugs in UK clinical practice. The clinical experts explained that outcomes might be better in clinical practice than in the trials. This was because using a thrombopoietin receptor agonist such as avatrombopag or lusutrombopag in people with more severe disease and less ability to make thrombopoietin has a larger effect than in people with less severe disease. The committee agreed that this seemed a reasonable expectation, but that there was no evidence to support it. Overall, however, the committee concluded that the trial results were generalisable to NHS practice.
## There is no trial evidence to determine whether avatrombopag or lusutrombopag increase life expectancy compared with platelet transfusions
The trials of avatrombopag and lusutrombopag had a follow up of 5 weeks and did not measure survival as a clinical outcome. The committee considered that survival on avatrombopag or lusutrombopag compared with standard care may depend on:
Death rate associated with platelet transfusion: People having avatrombopag or lusutrombopag would, on average, have fewer platelet transfusions (see section 3.6). The clinical experts explained that the risk of death with a platelet transfusion was very small (see section 3.11).
Fatal bleeds: The company for lusutrombopag (Shionogi) showed data suggesting that lusutrombopag was associated with fewer severe bleeds than placebo. The committee considered it plausible that there would be fewer bleeds with a thrombopoietin receptor agonist because these drugs raise platelet levels for a longer time than a platelet transfusion. It also considered that it was difficult to use the rates of rescue therapy for bleeding (which had been measured in the avatrombopag and lusutrombopag trials) as a proxy measure for bleeding rates. This was because the definition of rescue therapy differed between the trials.
Adverse events associated with avatrombopag or lusutrombopag: The committee acknowledged that thrombopoietin receptor agonists increase the risk of thromboembolic events, but that the short-term trial results did not show a difference in thromboembolic events between placebo and avatrombopag or lusutrombopag.The committee concluded that there were no data to determine whether avatrombopag or lusutrombopag increase or decrease life expectancy compared with platelet transfusions, but that they were unlikely to. It further concluded that it was appropriate to assume no difference in death rates between people treated with or without thrombopoietin receptor agonists.
## Avatrombopag and lusutrombopag are expected to be of similar clinical effectiveness to each other
There were no head-to-head trials comparing avatrombopag with lusutrombopag, and the assessment group carried out a network meta-analysis. The committee agreed with the assessment group's concerns about comparing the clinical trials for avatrombopag and lusutrombopag. It noted that the trials defined rescue therapy differently, and had different criteria defining when platelet transfusions were indicated. The clinical experts and the company explained that they did not expect the effectiveness to differ between avatrombopag and lusutrombopag, which share the same mechanism of action. The committee agreed that this seemed plausible, and also noted that the indirect analyses mostly showed that there were no differences between drugs. The committee concluded that there was no evidence that either avatrombopag or lusutrombopag was more effective than the other.
# Cost-effectiveness evidence
## It is not possible to consider the cost effectiveness of avatrombopag because it does not have a UK price
Shionogi (who manufacturers lusutrombopag) and the assessment group provided estimates of cost effectiveness. The assessment group presented the results comparing lusutrombopag with established care (without a thrombopoietin receptor agonist), which it split by baseline platelet level (see section 3.6). It also provided a pairwise comparison not split by baseline platelet level. The company for avatrombopag stated that it did not have a UK list price for its drug, at this time. The committee noted its earlier conclusion that there was no evidence that avatrombopag or lusutrombopag differed in clinical effectiveness. However, without a known price, the committee could not judge whether avatrombopag represented a cost-effective use of NHS resources. The committee agreed that it could make recommendations only for lusutrombopag.
## The assessment group's and Shionogi's models are structured similarly but model bleeds differently
The models from Shionogi and the assessment group shared a similar structure because the assessment group adapted Shionogi's model. The company's model included a short-term decision tree to model the clinical trial period (35 days). It also included a Markov model to model the life expectancy of a person with chronic liver disease over the long term (50 years). However, the models differed in how they modelled quality of life and survival related to bleeding and death associated with platelet transfusion. Shionogi modelled a risk of death associated with platelet transfusion of 0.3315%, and assumed that death happens before surgery. The assessment group's model estimated a lower (0.0005%) risk of death associated with platelet transfusion, which could occur before, during or after the procedure. The clinical experts explained that the assessment group's model was more plausible. Shionogi modelled risk of bleeding separately to risk of having rescue therapy, and assumed a lower rate of bleeds with lusutrombopag compared with established care. The assessment group did not model bleeding separately from rescue therapy. The clinical experts explained that people who bleed have rescue therapy, even after being discharged from hospital. Both Shionogi and the assessment group assumed that bleeding lowered quality of life and increased the risk of dying. The assessment group's approach resulted in about a 90‑minute difference in quality-adjusted life years (QALYs; 0.00018 in its base case) between lusutrombopag and established care without a thrombopoietin receptor antagonist. The Shionogi approach resulted in a larger (but still small) difference in QALYs (0.015 in its base case). The committee concluded that it was plausible that lusutrombopag plus a platelet transfusion and rescue therapy would be associated with similar long-term quality of life and risk of death as a platelet transfusion and rescue therapy.
## Baseline utility values are low but appropriate for decision making
The baseline utility value, applied by both Shionogi and the assessment group to people who did or did not have a thrombopoietin receptor agonist, was 0.544. The committee considered that this seemed low. The patient expert explained that the estimate seemed reasonable because this population is very unwell. The committee was aware that the assessment group conducted a scenario analysis using a higher baseline utility of 0.801, which minimally affected the cost-effectiveness results. The committee agreed that the baseline utility values used in the assessment group's and company's base cases were appropriate for decision making.
## Costs of platelet transfusions and delayed surgery could offset lusutrombopag drug costs, but the models do not include all relevant costs
Shionogi modelled a higher cost for platelet transfusions than did the assessment group. It assumed a person would have an average of 3 units of platelets. The assessment group assumed an average of around 1 unit. The assessment group based its calculations on the volume of platelets transfused in the lusutrombopag trials divided by the number of platelets estimated to be in a unit of platelets obtained by apheresis. The clinical experts stated that the costs of a platelet transfusion likely fell between Shionogi's and the assessment group's estimates. The committee considered that the incremental costs for lusutrombopag compared with established care modelled in the assessment group's base case (£603) may have overestimated the true costs. This was because the assessment group did not include all relevant costs. In particular, neither models included the costs of admitting patients to hospital the night before a procedure for transfusion or took into account that transfusion costs increase for patients who develop immunity. In addition, using NHS reference costs, Shionogi modelled wasted surgery time for delayed or cancelled procedures, but the assessment group did not. The committee did not see evidence that avatrombopag or lusutrombopag resulted in fewer cancelled or delayed procedures. However, it accepted that there would likely be fewer delays and cancellations with the drugs because of the longer treatment window in which platelet counts are expected to remain high (see section 3.3). The clinical experts explained that, when procedures are cancelled, some resources are redirected elsewhere, but the NHS likely accrues unrecoverable costs. The committee agreed that the models did not take into account all the costs that might be averted.
## Avatrombopag and lusutrombopag are innovative treatments
The patient and clinical experts explained that they considered avatrombopag and lusutrombopag to be a step change in terms of preparing people with chronic liver disease and thrombocytopenia for planned invasive procedures. This is because they are oral treatments that, on average, reduce the need for intravenous platelet transfusion. The committee agreed that benefits not captured in the QALY calculation included:
the lower risk of developing antiplatelet antibodies
increasing the availability of platelets for emergency procedures
that it is an oral treatment rather than a transfusion.The committee agreed that lusutrombopag and avatrombopag are innovative, and took this into account in its decision making for lusutrombopag.
## Because of costs and benefits not captured in the economic modelling, lusutrombopag is highly likely to be value for money
The base case from the assessment group showed that, compared with established care without a thrombopoietin receptor agonist, lusutrombopag cost £603 more and was associated with 0.00018 more QALYs. This resulted in an incremental cost-effectiveness ratio (ICER) of £3.4 million per QALY gained. The committee noted that the ICER was very large, and that the QALY difference was extremely small. The Shionogi base case (updated after consultation on the assessment group report) was £9,599 per QALY gained (incremental costs £38, incremental QALYs 0.0040). The committee agreed that neither Shionogi nor the assessment group modelled the following benefits:
avoiding the costs of admitting patients to hospital the night before a procedure to have a platelet transfusion
lowering the risk of developing antiplatelet antibodies and the need for matched platelets
making donated platelets more readily available for emergency procedures
increasing the 'treatment window' and available scheduling when using lusutrombopag
-ffering an oral treatment for people with poor venous access.The committee agreed that although it could not quantify the effect on the ICER of these benefits, the factors would lower the incremental costs and increase the incremental QALYs. It was aware that, because these drugs generated very small incremental QALYs, small changes to the incremental costs or QALYs would have large effects on the estimate of cost effectiveness. The committee noted its conclusion that avatrombopag and lusutrombopag represent an innovative treatment (see section 3.14). It concluded that the benefits not captured in the model made it highly likely that lusutrombopag would reflect a good use of scarce NHS resources.
## Using blood products or platelets from someone of a different ethnic origin is not an equalities issue
For some people, using blood products including platelets is against their religious beliefs. The clinical experts explained that the chance of developing antiplatelet antibodies is higher if a person having platelets is of a different ethnic origin to the person donating the platelets. The committee considered that it was possible that the donating population would represent a different ethnic mix than the population with chronic liver disease and thrombocytopenia. It agreed that these were not equalities issues because they did not make it any harder for these groups to access thrombopoietin receptor agonists.
# Conclusion
## Lusutrombopag would be a good use of scarce NHS resources
The committee concluded that:
lusutrombopag did not improve survival compared with established care
the economic modelling had not included all the potential benefits of lusutrombopag in terms of quality of life and costs
lusutrombopag is innovative
including the benefits not captured in the model would make it highly likely that lusutrombopag would reflect a good use of scarce NHS resources.Therefore, the committee concluded that lusutrombopag could be recommended for treating thrombocytopenia in people with chronic liver disease needing planned invasive procedures.
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{'Recommendations': 'Lusutrombopag is recommended, within its marketing authorisation, as an option for treating severe thrombocytopenia (that is, a platelet count of below 50,000\xa0platelets per microlitre of blood) in adults with chronic liver disease having planned invasive procedures.\n\nWhy the committee made these recommendations\n\nPeople with chronic liver disease often have low blood platelet levels. This means that they are more likely to bleed during invasive medical procedures, including surgery. Currently, they have a platelet transfusion before invasive procedures to help reduce their chances of bleeding.\n\nAvatrombopag and lusutrombopag are oral therapies that raise platelet levels, the aim being to reduce (but not eliminate) the chances of a patient needing a platelet transfusion. Platelet transfusions rely on donors and are given intravenously, so the possibility of replacing them with an oral treatment is an improvement. The drugs have several other benefits, including:\n\nthe convenience of fewer transfusions\n\nfewer hospital stays\n\na decreased chance of having transfusion-related complications.\n\nIn addition, platelets are a limited resource and can only be stored for a short time. This means that there can be problems getting them to people in time for their procedure, which can delay surgery. On the other hand, avatrombopag and lusutrombopag need to be taken more than a week before a procedure, so can be used only for planned procedures.\n\nClinical trial evidence shows that fewer people need a platelet transfusion if they have avatrombopag or lusutrombopag rather than a placebo treatment. But whether the drugs improve survival compared with platelet transfusions has not been measured. There is also no clinical evidence that either drug is better than the other.\n\nThe economic modelling does not fully account for the benefits for patients and service delivery when using avatrombopag and lusutrombopag. If these are considered, using lusutrombopag would likely save the NHS money. So, lusutrombopag can be recommended for treating thrombocytopenia in people with chronic liver disease who need planned invasive procedures. It is not possible for NICE to make a recommendation for avatrombopag because the drug does not have a UK price.', 'Information about avatrombopag and lusutrombopag': "# Marketing authorisations\n\nAvatrombopag (Doptelet, Sobi) is recommended 'for the treatment of severe thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo an invasive procedure'.\n\nLusutrombopag (Mulpleo, Shionogi BV) is recommended 'for the treatment of severe thrombocytopenia in adult patients with chronic liver disease undergoing invasive procedures'.\n\n# Dosages in the marketing authorisations\n\nThe recommended dosage of avatrombopag is based on the patient's platelet count:\n\nbelow 40,000\xa0platelets per microlitre of blood – 60\xa0mg once daily\n\n,000\xa0to below 50,000\xa0platelets per microlitre of blood – 40\xa0mg once daily.Dosing should begin 10\xa0to 13\xa0days before the planned procedure. Patients should have their procedure 5\xa0to 8\xa0days after the last dose of avatrombopag. Avatrombopag is taken orally.\n\nThe recommended dosage of lusutrombopag is 3\xa0mg once daily for 7\xa0days. The procedure should be done from day\xa09 after the start of lusutrombopag treatment. Platelet count should be measured before the procedure. Lusutrombopag is taken orally.\n\n# Price\n\nThe company has stated that the price of avatrombopag is £640.00 or £960.00 per 5‑day treatment course for the 40,000 to below 50,000 and below 40,000 platelets per microlitre of blood groups respectively.\n\nThe company has stated that the cost of lusutrombopag is £800 per 7‑day treatment course. Costs may vary in different settings because of negotiated procurement discounts.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence from a number of sources. See the committee papers for full details of the evidence.\n\n# Treatment pathway\n\n## People with chronic liver disease and a count of below 50,000\xa0platelets per microlitre of blood would be eligible for avatrombopag or lusutrombopag\n\nThe clinical experts explained that people with chronic liver disease and thrombocytopenia (traditionally defined as a platelet count below 150,000\xa0platelets per microlitre of blood) have an increased risk of bleeding when having invasive procedures, including surgery. This is irrespective of whether the procedure is planned or an emergency. These procedures may include investigative or therapeutic procedures such as dental, multiple and repeated procedures. Because of this bleeding risk, people may have a platelet transfusion before the invasive procedure to aid blood clotting. The clinical experts acknowledged that they were unaware of trials testing whether platelets lowered the risk of bleeding. However, they agreed that transfusing platelets prophylactically was the standard of care. The clinical experts also stated that the risk of bleeding during a procedure depends on the platelet count, the specific procedure, other manifestations of liver disease, history of bleeding and age. NICE's guideline on blood transfusion recommends that prophylactic platelet transfusions should be considered for people having invasive procedures or surgery to raise the platelet count above 50,000\xa0platelets per microlitre of blood. The committee heard that higher platelet counts might be needed for invasive procedures on some sites (such as the eyes). It noted that avatrombopag is licensed for treating thrombocytopenia when the platelet count is below 50,000\xa0platelets per microlitre of blood. It also noted that, although the marketing authorisation for lusutrombopag does not define severe thrombocytopenia, the company and the assessment group only presented evidence (that is, clinical trial data, indirect clinical data and cost-effectiveness analyses) for people with a platelet count below 50,000\xa0platelets per microlitre of blood. If people bleed during or after a procedure, they may need a 'rescue therapy', including further platelet transfusions, fresh frozen plasma or tranexamic acid. The committee concluded that people with chronic liver disease having a planned invasive procedure would be eligible for treatment with avatrombopag and lusutrombopag if they had a platelet count of below 50,000\xa0platelets per microlitre of blood. It agreed to make recommendations for this group.\n\n## The appraisal applies to people needing planned procedures scheduled for 9\xa0or 10\xa0days in the future\n\nThe marketing authorisations stipulate that avatrombopag and lusutrombopag oral treatments need to be taken at least 10\xa0days or 9\xa0days respectively before a procedure. The clinical experts stated that it would be relatively straightforward to co-ordinate testing platelet levels and prescribing these treatments with a GP. Because of the time needed to increase the platelet count, the committee heard that avatrombopag and lusutrombopag would be appropriate only for planned elective procedures. However, these drugs would not have a role in planned procedures that need to be done within 9\xa0or 10\xa0days. The committee concluded that the appraisal applies to people with chronic liver disease and a platelet count below 50,000\xa0platelets per microlitre of blood needing planned ('elective') invasive procedures rather than emergency procedures.\n\n## Avatrombopag and lusutrombopag raise platelet levels for longer than a transfusion, and are taken at home so reduce wastage and hospital stays\n\nThe clinical experts explained that a platelet transfusion increases platelet levels for only a short time. This means that patients need to have their procedures soon after having a transfusion. According to the clinical experts, about 50% of patients go into hospital to have a transfusion the evening before their planned procedure and, when possible, the transfusion is given on the day of the procedure. If the 'treatment window' (that is, the time when platelet levels are raised) is missed, a patient would have another platelet transfusion before having the procedure. Avatrombopag and lusutrombopag have longer treatment windows in which to do planned invasive procedures than do platelet transfusions. Specifically, these windows are 10\xa0to 13\xa0days (stated in the marketing authorisation for avatrombopag) after starting avatrombopag and from day\xa09 (stated in the marketing authorisation for lusutrombopag) after starting lusutrombopag. The committee considered that this would ease procedure scheduling compared with platelet transfusion and may make it possible to carry out multiple procedures within a treatment window. It concluded that avatrombopag and lusutrombopag have some potential advantages over transfusing platelets. These include reducing wastage if an invasive procedure is delayed, increasing the time in which procedures can occur and reducing hospital stays.\n\n## People would welcome an oral treatment alternative to platelet transfusions\n\nThe patient expert stated that, typically, people with chronic liver disease and thrombocytopenia are sick and have many hospital appointments; this, and the associated travel, disrupts their lives. They would value any treatment that could reduce this burden. Avatrombopag and lusutrombopag are oral treatments, and would reduce the need for a trip to hospital for a transfusion. The clinical experts acknowledged that some people who develop chronic liver disease from intravenous drug use have poor venous access. For them, transfusing platelets is difficult without central venous access, for which a procedure is also needed. The patient expert stated that the risks of adverse effects associated with platelet transfusions are low. However, people perceive oral treatments to be safer, and even just the perceived risk of platelet transfusions can cause anxiety. The committee concluded that there are benefits related to an oral treatment compared with platelet transfusions, and that people would welcome an oral treatment option.\n\n## Reducing dependence on platelets would minimise problems associated with obtaining and transfusing platelets\n\nPlatelet transfusions, like all blood products, are a scarce resource limited by the number of donations received. The clinical experts explained that platelets also have a short shelf life (of 5\xa0to 7\xa0days) and need to be stored at room temperature. This means that larger hospitals store only limited amounts to avoid wastage, and that smaller hospitals do not store platelets on site. The clinical experts explained that patients can become refractory to repeated platelet transfusions. Repeated transfusions can also increase the risk of infection. Some people can react to the plasma contained in the platelets or develop antibodies against donor platelets after repeated transfusions. People who have an immune reaction to donated platelets may reduce their chance of having a successful liver transplant. The clinical experts also stated that, although donor platelets are not usually matched to the recipient, sometimes they have to be. This then makes it more difficult to find platelets, and means that no one else can use these matched platelets (for example, human leucocyte antigen matched). The committee agreed that obtaining, storing and administering platelets carries a number of practical implications for patients and for service delivery. It concluded that reducing dependence on platelets would minimise problems associated with obtaining and transfusing platelets.\n\n# Clinical evidence\n\n## Avatrombopag and lusutrombopag reduce the number of platelet transfusions\n\nThe avatrombopag randomised placebo-controlled trials (ADAPT\xa01 and ADAPT\xa02) assessed 2\xa0doses of avatrombopag: 40\xa0mg for people with a platelet count of between 40,000\xa0and below\xa050,000 platelets per microlitre of blood and 60\xa0mg for people with a platelet count below 40,000\xa0platelets per microlitre of blood. The lusutrombopag trials (L‑PLUS\xa01, L‑PLUS\xa02 and JapicCTI\xa0121944) assessed 3\xa0mg lusutrombopag in people with a platelet count below 50,000\xa0platelets per microlitre of blood. To compare the lusutrombopag results with the avatrombopag results, the assessment group chose to separate lusutrombopag results into the same subgroups as avatrombopag. That is, it considered the lusutrombopag trial results for 2\xa0subgroups: people with a platelet count of between 40,000\xa0and below\xa050,000 platelets per microlitre of blood; and people with a platelet count below 40,000\xa0platelets per microlitre of blood separately. However, the assessment group also presented analyses for lusutrombopag for the full population. The avatrombopag and lusutrombopag trials measured the proportion of people needing a platelet transfusion before an invasive procedure. Across all subgroups, at least 40% fewer people needed a platelet transfusion if they were randomised to avatrombopag or lusutrombopag compared with placebo. The committee concluded that the trial evidence presented was appropriate for decision making. It further concluded that the evidence showed that avatrombopag and lusutrombopag reduce the number of platelet transfusions before invasive procedures in people with chronic liver disease and thrombocytopenia when compared with placebo.\n\n## Although both drugs' trials include people fitter than those having platelet transfusions in UK clinical practice, the results are generalisable\n\nOne way to categorise the severity of chronic liver disease is by Child-Pugh score. People in the Child-Pugh A\xa0category have less severe disease and the best prognosis; people in the Child-Pugh C\xa0category have the most severe disease and the poorest prognosis. The regulatory trials of avatrombopag included between 8.6% (40,000\xa0to below\xa050,000 platelets per microlitre of blood subgroup in the avatrombopag arm of ADAPT-1) and 15.2% (in the same subgroup of the avatrombopag arm of ADAPT-2) of people in the Child-Pugh C\xa0category. The trials of lusutrombopag excluded people with disease scored as Child-Pugh\xa0C (although 3.6% of the pooled-trials population were in the Child-Pugh C\xa0category). The summary of product characteristics for both drugs state that they should only be used in people with Child-Pugh C\xa0liver disease if the expected benefits outweigh the expected risks. The clinical experts explained that patients with thrombocytopenia tend to have Child-Pugh B\xa0or C\xa0liver disease, and that people with Child-Pugh A\xa0liver disease rarely have thrombocytopenia. The committee agreed that this meant that the avatrombopag and lusutrombopag trials were carried out in people who were fitter than people who would have the drugs in UK clinical practice. The clinical experts explained that outcomes might be better in clinical practice than in the trials. This was because using a thrombopoietin receptor agonist such as avatrombopag or lusutrombopag in people with more severe disease and less ability to make thrombopoietin has a larger effect than in people with less severe disease. The committee agreed that this seemed a reasonable expectation, but that there was no evidence to support it. Overall, however, the committee concluded that the trial results were generalisable to NHS practice.\n\n## There is no trial evidence to determine whether avatrombopag or lusutrombopag increase life expectancy compared with platelet transfusions\n\nThe trials of avatrombopag and lusutrombopag had a follow up of 5\xa0weeks and did not measure survival as a clinical outcome. The committee considered that survival on avatrombopag or lusutrombopag compared with standard care may depend on:\n\nDeath rate associated with platelet transfusion: People having avatrombopag or lusutrombopag would, on average, have fewer platelet transfusions (see section\xa03.6). The clinical experts explained that the risk of death with a platelet transfusion was very small (see section\xa03.11).\n\nFatal bleeds: The company for lusutrombopag (Shionogi) showed data suggesting that lusutrombopag was associated with fewer severe bleeds than placebo. The committee considered it plausible that there would be fewer bleeds with a thrombopoietin receptor agonist because these drugs raise platelet levels for a longer time than a platelet transfusion. It also considered that it was difficult to use the rates of rescue therapy for bleeding (which had been measured in the avatrombopag and lusutrombopag trials) as a proxy measure for bleeding rates. This was because the definition of rescue therapy differed between the trials.\n\nAdverse events associated with avatrombopag or lusutrombopag: The committee acknowledged that thrombopoietin receptor agonists increase the risk of thromboembolic events, but that the short-term trial results did not show a difference in thromboembolic events between placebo and avatrombopag or lusutrombopag.The committee concluded that there were no data to determine whether avatrombopag or lusutrombopag increase or decrease life expectancy compared with platelet transfusions, but that they were unlikely to. It further concluded that it was appropriate to assume no difference in death rates between people treated with or without thrombopoietin receptor agonists.\n\n## Avatrombopag and lusutrombopag are expected to be of similar clinical effectiveness to each other\n\nThere were no head-to-head trials comparing avatrombopag with lusutrombopag, and the assessment group carried out a network meta-analysis. The committee agreed with the assessment group's concerns about comparing the clinical trials for avatrombopag and lusutrombopag. It noted that the trials defined rescue therapy differently, and had different criteria defining when platelet transfusions were indicated. The clinical experts and the company explained that they did not expect the effectiveness to differ between avatrombopag and lusutrombopag, which share the same mechanism of action. The committee agreed that this seemed plausible, and also noted that the indirect analyses mostly showed that there were no differences between drugs. The committee concluded that there was no evidence that either avatrombopag or lusutrombopag was more effective than the other.\n\n# Cost-effectiveness evidence\n\n## It is not possible to consider the cost effectiveness of avatrombopag because it does not have a UK price\n\nShionogi (who manufacturers lusutrombopag) and the assessment group provided estimates of cost effectiveness. The assessment group presented the results comparing lusutrombopag with established care (without a thrombopoietin receptor agonist), which it split by baseline platelet level (see section\xa03.6). It also provided a pairwise comparison not split by baseline platelet level. The company for avatrombopag stated that it did not have a UK list price for its drug, at this time. The committee noted its earlier conclusion that there was no evidence that avatrombopag or lusutrombopag differed in clinical effectiveness. However, without a known price, the committee could not judge whether avatrombopag represented a cost-effective use of NHS resources. The committee agreed that it could make recommendations only for lusutrombopag.\n\n## The assessment group's and Shionogi's models are structured similarly but model bleeds differently\n\nThe models from Shionogi and the assessment group shared a similar structure because the assessment group adapted Shionogi's model. The company's model included a short-term decision tree to model the clinical trial period (35\xa0days). It also included a Markov model to model the life expectancy of a person with chronic liver disease over the long term (50\xa0years). However, the models differed in how they modelled quality of life and survival related to bleeding and death associated with platelet transfusion. Shionogi modelled a risk of death associated with platelet transfusion of 0.3315%, and assumed that death happens before surgery. The assessment group's model estimated a lower (0.0005%) risk of death associated with platelet transfusion, which could occur before, during or after the procedure. The clinical experts explained that the assessment group's model was more plausible. Shionogi modelled risk of bleeding separately to risk of having rescue therapy, and assumed a lower rate of bleeds with lusutrombopag compared with established care. The assessment group did not model bleeding separately from rescue therapy. The clinical experts explained that people who bleed have rescue therapy, even after being discharged from hospital. Both Shionogi and the assessment group assumed that bleeding lowered quality of life and increased the risk of dying. The assessment group's approach resulted in about a 90‑minute difference in quality-adjusted life years (QALYs; 0.00018 in its base case) between lusutrombopag and established care without a thrombopoietin receptor antagonist. The Shionogi approach resulted in a larger (but still small) difference in QALYs (0.015 in its base case). The committee concluded that it was plausible that lusutrombopag plus a platelet transfusion and rescue therapy would be associated with similar long-term quality of life and risk of death as a platelet transfusion and rescue therapy.\n\n## Baseline utility values are low but appropriate for decision making\n\nThe baseline utility value, applied by both Shionogi and the assessment group to people who did or did not have a thrombopoietin receptor agonist, was 0.544. The committee considered that this seemed low. The patient expert explained that the estimate seemed reasonable because this population is very unwell. The committee was aware that the assessment group conducted a scenario analysis using a higher baseline utility of 0.801, which minimally affected the cost-effectiveness results. The committee agreed that the baseline utility values used in the assessment group's and company's base cases were appropriate for decision making.\n\n## Costs of platelet transfusions and delayed surgery could offset lusutrombopag drug costs, but the models do not include all relevant costs\n\nShionogi modelled a higher cost for platelet transfusions than did the assessment group. It assumed a person would have an average of 3\xa0units of platelets. The assessment group assumed an average of around 1\xa0unit. The assessment group based its calculations on the volume of platelets transfused in the lusutrombopag trials divided by the number of platelets estimated to be in a unit of platelets obtained by apheresis. The clinical experts stated that the costs of a platelet transfusion likely fell between Shionogi's and the assessment group's estimates. The committee considered that the incremental costs for lusutrombopag compared with established care modelled in the assessment group's base case (£603) may have overestimated the true costs. This was because the assessment group did not include all relevant costs. In particular, neither models included the costs of admitting patients to hospital the night before a procedure for transfusion or took into account that transfusion costs increase for patients who develop immunity. In addition, using NHS reference costs, Shionogi modelled wasted surgery time for delayed or cancelled procedures, but the assessment group did not. The committee did not see evidence that avatrombopag or lusutrombopag resulted in fewer cancelled or delayed procedures. However, it accepted that there would likely be fewer delays and cancellations with the drugs because of the longer treatment window in which platelet counts are expected to remain high (see section\xa03.3). The clinical experts explained that, when procedures are cancelled, some resources are redirected elsewhere, but the NHS likely accrues unrecoverable costs. The committee agreed that the models did not take into account all the costs that might be averted.\n\n## Avatrombopag and lusutrombopag are innovative treatments\n\nThe patient and clinical experts explained that they considered avatrombopag and lusutrombopag to be a step change in terms of preparing people with chronic liver disease and thrombocytopenia for planned invasive procedures. This is because they are oral treatments that, on average, reduce the need for intravenous platelet transfusion. The committee agreed that benefits not captured in the QALY calculation included:\n\nthe lower risk of developing antiplatelet antibodies\n\nincreasing the availability of platelets for emergency procedures\n\nthat it is an oral treatment rather than a transfusion.The committee agreed that lusutrombopag and avatrombopag are innovative, and took this into account in its decision making for lusutrombopag.\n\n## Because of costs and benefits not captured in the economic modelling, lusutrombopag is highly likely to be value for money\n\nThe base case from the assessment group showed that, compared with established care without a thrombopoietin receptor agonist, lusutrombopag cost £603 more and was associated with 0.00018 more QALYs. This resulted in an incremental cost-effectiveness ratio (ICER) of £3.4 million per QALY gained. The committee noted that the ICER was very large, and that the QALY difference was extremely small. The Shionogi base case (updated after consultation on the assessment group report) was £9,599 per QALY gained (incremental costs £38, incremental QALYs 0.0040). The committee agreed that neither Shionogi nor the assessment group modelled the following benefits:\n\navoiding the costs of admitting patients to hospital the night before a procedure to have a platelet transfusion\n\nlowering the risk of developing antiplatelet antibodies and the need for matched platelets\n\nmaking donated platelets more readily available for emergency procedures\n\nincreasing the 'treatment window' and available scheduling when using lusutrombopag\n\noffering an oral treatment for people with poor venous access.The committee agreed that although it could not quantify the effect on the ICER of these benefits, the factors would lower the incremental costs and increase the incremental QALYs. It was aware that, because these drugs generated very small incremental QALYs, small changes to the incremental costs or QALYs would have large effects on the estimate of cost effectiveness. The committee noted its conclusion that avatrombopag and lusutrombopag represent an innovative treatment (see section\xa03.14). It concluded that the benefits not captured in the model made it highly likely that lusutrombopag would reflect a good use of scarce NHS resources.\n\n## Using blood products or platelets from someone of a different ethnic origin is not an equalities issue\n\nFor some people, using blood products including platelets is against their religious beliefs. The clinical experts explained that the chance of developing antiplatelet antibodies is higher if a person having platelets is of a different ethnic origin to the person donating the platelets. The committee considered that it was possible that the donating population would represent a different ethnic mix than the population with chronic liver disease and thrombocytopenia. It agreed that these were not equalities issues because they did not make it any harder for these groups to access thrombopoietin receptor agonists.\n\n# Conclusion\n\n## Lusutrombopag would be a good use of scarce NHS resources\n\nThe committee concluded that:\n\nlusutrombopag did not improve survival compared with established care\n\nthe economic modelling had not included all the potential benefits of lusutrombopag in terms of quality of life and costs\n\nlusutrombopag is innovative\n\nincluding the benefits not captured in the model would make it highly likely that lusutrombopag would reflect a good use of scarce NHS resources.Therefore, the committee concluded that lusutrombopag could be recommended for treating thrombocytopenia in people with chronic liver disease needing planned invasive procedures."}
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https://www.nice.org.uk/guidance/ta617
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Evidence-based recommendations on lusutrombopag (Mulpleo) for treating severe thrombocytopenia in adults with chronic liver disease needing a planned invasive procedure.
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f4011e6053bad7a8956fc042bc9b0f96acdf9006
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nice
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Cladribine for treating relapsing–remitting multiple sclerosis
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Cladribine for treating relapsing–remitting multiple sclerosis
Evidence-based recommendations on cladribine (Mavenclad) for relapsing–remitting multiple sclerosis in adults.
# Recommendations
Cladribine is recommended as an option for treating highly active multiple sclerosis in adults, only if the person has:
rapidly evolving severe relapsing–remitting multiple sclerosis, that is with at least:
relapses in the previous year and
T1 gadolinium-enhancing lesion at baseline MRI or a significant increase in T2‑lesion load compared with a previous MRI, or
relapsing–remitting multiple sclerosis that has responded inadequately to treatment with disease-modifying therapy, defined as 1 relapse in the previous year and MRI evidence of disease activity.
This recommendation is not intended to affect treatment with cladribine that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Highly active relapsing–remitting multiple sclerosis is currently treated with alemtuzumab, fingolimod or natalizumab. This appraisal focuses on 2 subgroups of people with highly active relapsing–remitting multiple sclerosis, that is, those with rapidly evolving severe disease and those with suboptimally treated relapsing–remitting multiple sclerosis (disease that has responded inadequately to disease-modifying therapy).
Clinical trial results show that cladribine tablets (hereafter referred to as cladribine) reduce relapses and slow the progression of disability compared with placebo for people with relapsing–remitting multiple sclerosis. The effectiveness of cladribine for treating rapidly evolving severe or suboptimally treated relapsing–remitting multiple sclerosis is not proven, but it is likely to be more effective than placebo.
Based on indirect analyses, there is not enough evidence to determine whether cladribine is more or less effective than other treatments for people with rapidly evolving severe and suboptimally treated multiple sclerosis. Because of this, cladribine and alternative treatments are considered equally effective for this appraisal.
The MRI criteria used by clinicians to define rapidly evolving severe relapsing–remitting multiple sclerosis have changed over time. In addition to the presence of T1 gadolinium-enhancing lesions at baseline, clinicians may now identify patients with rapidly evolving severe relapsing–remitting multiple sclerosis by a significant increase in T2‑lesion load compared with a previous MRI.
Cladribine is less costly than other treatments and needs less frequent dosing and monitoring. It is cost effective compared with all other treatments, so can be recommended for rapidly evolving severe and suboptimally treated relapsing–remitting multiple sclerosis.# Information about cladribine
# Marketing authorisation indication
Cladribine tablets (Mavenclad, Merck Serono) are 'indicated for the treatment of adult patients with highly active relapsing multiple sclerosis as defined by clinical or imaging features'.
# Dosage in the marketing authorisation
In the summary of product characteristics, the recommended cumulative dose is 3.5 mg/kg body weight over 2 years, taken as 1 treatment course of 1.75 mg/kg per year. Each treatment course consists of 2 treatment weeks, 1 at the beginning of the first month and 1 at the beginning of the second month of the respective treatment year. Each treatment week consists of 4 days or 5 days on which a patient takes 10 mg or 20 mg (1 or 2 tablets) as a single daily dose, depending on body weight. After completing the 2 treatment courses, no further cladribine treatment is needed in years 3 and 4.
# Price
The list price is £2,047.24 per 10 mg tablet (excluding VAT, BNF online, November 2019). Costs may vary in different settings because of negotiated procurement discounts.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Merck Serono and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Clinical need and patient perspective
## Clinicians and patients would value an oral treatment with less frequent dosing and monitoring
Relapsing–remitting multiple sclerosis is a chronic, disabling neurological condition. The patient experts explained that relapses and residual disability between relapses can substantially reduce quality of life. The committee was aware that relapsing–remitting multiple sclerosis can limit people's ability to work, and to engage in social and family life. The patient experts also explained that many of the available treatments need frequent hospital appointments for treatment and monitoring and that this causes significant disruption to patients' lives and careers. The committee heard that an oral treatment taken in 2 short courses over 2 years would be less disruptive.
# Treatment pathway and comparators
## The definitions of multiple sclerosis subgroups are not meaningful in NHS clinical practice
In the NHS, disease-modifying therapy is used to treat relapsing–remitting multiple sclerosis. The choice of therapy partly depends on the number of relapses and MRI evidence of disease activity, as defined in each treatment's marketing authorisation. Previous NICE technology appraisal guidance has usually defined active disease as at least 2 clinically significant relapses in the previous 2 years. The committee understood that some people with relapsing–remitting multiple sclerosis have highly active disease but that there is no universally accepted definition of highly active disease. The company defined a group of people with 'high disease activity' as having either 1 relapse in the previous year while the person was on disease-modifying therapy and at least 1 T1 gadolinium-enhancing lesion on MRI, or at least 2 relapses (with or without lesions) in the previous year regardless of treatment. The clinical experts explained that this definition was not used in clinical practice and considered it to be very broad. The committee noted that, in previous appraisals, 'highly active disease' has been used to describe a population broadly similar to the population the company referred to as having suboptimally treated multiple sclerosis (see section 3.3). It also heard that, in practice, increases in T2‑lesion numbers compared with a previous MRI are an important indicator of disease activity, and may be more important than the absolute number. The committee concluded that the group referred to by the company as having 'high disease activity' may not be meaningful in NHS clinical practice.
## The subgroups in the company submission are appropriate for decision making
People with 'high disease activity' relapsing–remitting multiple sclerosis were divided into 2 subgroups:
Rapidly evolving severe relapsing–remitting multiple sclerosis: 2 or more relapses in the previous year whether the person was on treatment or not, and at least 1 T1 gadolinium-enhancing lesion.
Suboptimally treated relapsing–remitting multiple sclerosis: at least 1 relapse in the previous year while the person was on disease-modifying therapy, and at least 1 T1 gadolinium-enhancing lesion or 9 T2 lesions.In addition to these subgroups, the 'high disease activity' subgroup also included an undefined group of people, who the committee understood to be those with 2 or more relapses in the previous year without a T1 gadolinium-enhancing lesion. The clinical experts explained that this group was clinically identifiable, but that suboptimal treatment was more difficult to define. The committee considered that the suboptimal treatment subgroup represented people who have highly active disease that had responded inadequately to previous treatment. However, it noted that the criteria used for MRI evidence of disease activity in this group may not be relevant for clinical practice, particularly given the concerns of the clinical experts about using the absolute number of T2 lesions as a criterion (see section 3.2). The clinical experts explained that the categorisations in marketing authorisations are difficult to use in clinical practice because there is a spectrum of disease activity rather than rigidly defined stages. However, they explained that the rapidly evolving severe and suboptimal treatment groups were broadly representative of patients at the more active end of the disease spectrum. The committee concluded that the subgroups broadly represent the population who would have cladribine tablets (hereafter referred to as cladribine) in clinical practice, and are appropriate for decision making. However, it also concluded that it would not use the company's definition of suboptimal treatment as the basis of any recommendation.
# Comparators
## The choice of comparator varies by subgroup
The clinical experts explained that many people with multiple sclerosis do not take disease-modifying therapies, but that people with highly active disease would. The committee understood that, for people with more active disease, clinicians follow NICE guidance, which recommends that people with rapidly evolving severe multiple sclerosis have alemtuzumab or natalizumab. Similarly, in line with NICE guidance, people with suboptimally treated multiple sclerosis (as defined in the company submission) could have alemtuzumab or fingolimod. The committee concluded that it was appropriate to consider the following comparators for cladribine:
alemtuzumab and natalizumab for people with rapidly evolving severe disease
alemtuzumab and fingolimod for people with suboptimally treated disease.
# Direct clinical evidence
## The main clinical evidence for cladribine comes from the CLARITY trial
The CLARITY trial was a randomised double-blind study of 1,326 people with active relapsing–remitting multiple sclerosis, which compared 2 different doses of cladribine with placebo. In the study, 433 people had the licensed dose (3.5 mg/kg body weight) of cladribine and 437 people had placebo. The primary outcome was annualised relapse rate. An important post-hoc outcome was time to 6‑month confirmed disability progression.
## The relevant subgroups are defined post hoc in CLARITY
The company provided clinical evidence for the whole (intention-to-treat) population and for a post-hoc high disease activity subgroup from CLARITY. However, it did not provide cost-effectiveness estimates for these groups. The company's main evidence in its cost-effectiveness analysis was based on smaller post-hoc subgroups of the post-hoc high disease activity subgroup. These smaller subgroups were people with rapidly evolving severe and suboptimally treated relapsing–remitting multiple sclerosis. The company explained that it considered the rapidly evolving severe and suboptimal treatment post-hoc groups to broadly reflect the groups in previous NICE appraisals. The committee was concerned that the number of patients who had cladribine in these subgroups was small (50 and 19 patients respectively) meaning that the data based on these subgroups are uncertain. The committee agreed that evidence based on a larger pre-specified subgroup is preferable but appreciated that CLARITY had been planned before the current disease categorisations had emerged.
## Definitions of outcomes in CLARITY differ from other clinical trials and previous appraisals
To determine disability progression above the Expanded Disability Status Scale (EDSS) state 5, a 0.5‑point change in EDSS state was used in CLARITY, whereas other clinical trials used a 1.0‑point change. A clinical expert explained that the difference between EDSS state 5 and EDSS state 5.5 is more subjective, and that it is less clinically significant than a change from EDSS state 5 to EDSS state 6, which requires the use of a walking aid. The committee noted that there were also differences in how a relapse was defined, with relapse-related disability specifically based on EDSS state in CLARITY but not in other trials. On balance, the committee considered that the differences in outcomes were unlikely to have a large effect on the comparative effectiveness, and concluded that the outcomes were broadly comparable across trials.
## Cladribine reduces relapses and delays disability compared with placebo in the whole population and the high disease activity subgroup
In the intention-to-treat analysis and in the high disease activity subgroup, cladribine reduced the annualised relapse rate and delayed disability progression sustained for 6 months compared with placebo (see table 1). The committee concluded that, for the overall population of people with relapsing–remitting multiple sclerosis and for the overall high disease activity subgroup, cladribine was more effective than placebo.
Outcome
Intention to treat (433 people having cladribine)
Overall high disease activity (140 people having cladribine)
Annualised relapse rate
(rate ratio )
(0.33 to 0.53)
(0.24 to 0.50)
Time to confirmed 6‑month disability progression
(hazard ratio )
(0.36 to 0.78)
(0.08 to 0.44)
## Results for the rapidly evolving severe and suboptimal treatment subgroups are uncertain
In the rapidly evolving severe subgroup, cladribine reduced relapses and delayed disability progression compared with placebo. However, the effect on disability progression was not statistically significant. In the suboptimal treatment subgroup, the annualised relapse rate was lower with cladribine than with placebo, but the effect was not statistically significant. The effect on disability progression could not be estimated in this group because of small patient numbers. The exact results for the rapidly evolving severe and suboptimal treatment subgroups are commercial in confidence. The committee considered that the lack of statistical significance was partly because of the small patient numbers. It noted that, in the overall high disease activity group, which included both of the smaller subgroups, cladribine was highly effective and the results were statistically significant (see section 3.8). The committee concluded that, despite some uncertainty over the effect size, cladribine was likely to be more effective than placebo in both the rapidly evolving severe and suboptimal treatment groups.
# Indirect clinical evidence
## The company network meta-analysis is appropriate
The company's network meta-analysis compared cladribine with other treatments (including the comparators for this appraisal and other disease-modifying therapies such as beta interferon), in the overall population, and in the high disease activity, rapidly evolving severe and suboptimal treatment subgroups. The committee discussed the company's assumptions in the network meta-analysis:
The company assumed that the relevant outcomes were comparable between trials, despite the differences in outcome measures in CLARITY compared with clinical trials for other treatments (see section 3.7). The ERG explained that it considered this to be a major limitation, but the company suggested that these subtle differences should not have a major impact. The committee agreed that the outcome measures used were broadly similar across trials.
The company assumed that the subgroups in CLARITY were comparable to those used in other clinical trials. The committee was aware that the definitions of high disease activity, rapidly evolving severe disease and suboptimally treated disease despite previous treatment differed from those used in previous NICE guidance for relapsing–remitting multiple sclerosis (see section 3.2 and section 3.3). However, the committee considered that the subgroups were defined based on similar radiological and clinical criteria. It accepted that the subgroup populations were comparable between this appraisal and previously published appraisals.The committee concluded that the network meta-analysis was appropriate for this appraisal.
## The network meta-analysis does not provide conclusive evidence for the effectiveness of cladribine compared with current NHS treatments
For each subgroup, the company used separate evidence networks to estimate the relative effectiveness of cladribine on annualised relapse rate, disability progression sustained for 3 months, and disability progression sustained for 6 months. Comparisons with cladribine were not possible for some of the comparators in each of the subgroups. Notably, results were not available for disability progression in the suboptimal treatment subgroup. Among the comparisons presented, cladribine did not have a statistically significant effect relative to its comparators (that is, alemtuzumab, fingolimod and natalizumab) on any of the outcomes in any of the subgroups. The committee also noted that the confidence intervals were wide and overlapped between treatments. It concluded that there was insufficient evidence from the network meta-analysis to show that cladribine had substantially different effectiveness to alemtuzumab, fingolimod or natalizumab.
## The meta-regression provides a full set of comparisons but may use invalid methods
The company did a meta-regression for the outcome of disability progression sustained for 6 months for cladribine, alemtuzumab, fingolimod and natalizumab compared with placebo to address the weaknesses of the network meta-analysis, particularly for the suboptimal treatment group. In the absence of data in the network meta-analysis (see section 3.11), the meta-regression estimated effectiveness based on differences in the baseline risk of disability progression. The committee noted that, although confidence intervals for cladribine, alemtuzumab, fingolimod and natalizumab compared with placebo were narrower than those for estimates in the network meta-analysis, they overlapped for all treatments in both the rapidly evolving severe and suboptimal treatment subgroups. It also noted that, for the rapidly evolving severe subgroup, the estimated effectiveness of cladribine compared with placebo from the meta-regression was similar to the estimate from the network meta-analysis. However, it was concerned that alemtuzumab compared with placebo appeared substantially less effective in the meta-regression than in the network meta-analysis. The company suggested this could be explained by the differences in baseline risk between trials. The company validated the methodology by comparing the effect sizes predicted by the meta-regression with the effect sizes seen in the relevant trials. The committee agreed with the ERG's concerns that there were differences in effect size not explained by differences in baseline risk, which would make the company's approach invalid. In addition, the committee was aware that the assumptions and issues which the network meta-analysis relied on (see section 3.10) also applied to the meta-regression. The committee acknowledged the company's attempts to address the data limitations, but on balance agreed that the meta-regression approach may be invalid. The committee concluded that, although the meta-regression did provide estimates for effect sizes adjusted for baseline risk, the evidence from the meta-regression was insufficient to show that cladribine had substantially different effectiveness to alemtuzumab, fingolimod and natalizumab.
# Company's economic model
## The model is appropriate for decision making
The committee noted that the company's model was similar to models used in previous NICE technology appraisal guidance, but that the company had removed progression to secondary progressive multiple sclerosis. The company explained that it was difficult to identify the transition to secondary progressive multiple sclerosis in clinical practice, and noted that health-related quality of life is more closely related to EDSS state than to the clinical form of multiple sclerosis. The company suggested that this meant that separating the 2 forms of the disease was unnecessary for economic modelling because all health-related benefits of treatment would be captured by changes in EDSS state. The committee concluded that the company's model was appropriate for decision making.
# Natural history of the disease in subgroup analyses
## Calculating different rates of disability progression in the subgroups is simplistic and potentially inaccurate
The natural history of multiple sclerosis in the company's economic model was based on the British Columbia multiple sclerosis dataset, which was used in previous NICE technology appraisal guidance. The company explained that the British Columbia dataset included a mixture of people with active and highly active multiple sclerosis. The company stated that rapidly evolving severe or suboptimally treated multiple sclerosis is expected to progress faster than active relapsing–remitting multiple sclerosis. Therefore, it adjusted the disease progression rates to allow for a higher probability of progression for EDSS states 0 to 6. This adjustment was based on the difference in 6‑month confirmed disability progression in CLARITY in each subgroup compared with its complement (that is, people not included in that subgroup). The clinical experts and the ERG explained that, although assuming different rates of disease progression for each subgroup was reasonable, the company's approach was simplistic and potentially inaccurate. The committee appreciated that there was no clear alternative data source or method, and was aware that such adjustment had not been used in previous technology appraisals. However, because the adjustment would have a limited effect on the cost effectiveness of cladribine, the committee did not pursue this point any further.
# Treatment effect
## A scenario exploring equal clinical effectiveness should be considered in the economic analysis
Because there was insufficient clinical evidence to show that cladribine had substantially different effectiveness to its comparators (see section 3.12), the ERG provided a scenario assuming that cladribine and its comparators were equally effective in reducing relapses and delaying disability progression. The committee concluded that, based on the evidence, it would take into account this ERG scenario in its decision making.
# Waning of treatment effect
## The waning of the treatment effect should be the same for all comparators
In previous NICE technology appraisal guidance for multiple sclerosis (such as for alemtuzumab and dimethyl fumarate), the committee agreed that most treatments for multiple sclerosis become less effective over time. Therefore, the economic modelling included the assumption that the treatment effect declines by 25% after 2 years and by 50% after 5 years for all therapies. The committee heard that the company had attempted to assess whether there was a declining effect of cladribine by analysing data from the extension of the CLARITY trial. The company used a treatment switching analysis to estimate a hazard ratio for disability progression for cladribine compared with placebo over 4 years. It showed that this hazard ratio was similar to the hazard ratio estimated over 2 years. Therefore, the company suggested that there was no evidence of the treatment effect waning within the first 4 years. The company assumed that the waning effect for cladribine began after 4 years (that is, a 25% decline in treatment effect after 4 years and a 50% decline after 5 years). However, for the comparators, the company used the waning assumptions used in previous appraisals (that is, a 25% decline in treatment effect after 2 years and a 50% decline after 5 years). The committee noted that there was no statistically significant evidence to support different waning effects and that patient numbers used for the analysis in the subgroups were very small. It concluded that the company's evidence was insufficient to justify using a different treatment waning assumption for cladribine.
# Treatment stopping rates
## Applying annualised rates based on clinical trials is likely to overestimate treatment stopping rates
The company used the rates at which patients stop treatment with cladribine or its comparators from the respective clinical trials. The committee understood that, given the method of administration of both cladribine and alemtuzumab (that is, both involve 2 short courses of treatment a year apart), annual discontinuation rates did not apply, and the rate of stopping treatment refers to stopping between the first and second courses. The committee noted that fingolimod and natalizumab were all taken more frequently and for longer, so annual discontinuation rates were relevant. The ERG explained that people are more likely to stop treatment during the first year of treatment than in a subsequent year. Therefore, the company's approach of applying trial-based discontinuation rates to subsequent years would overestimate the number of people stopping treatment. In its exploratory analyses, the ERG assumed that, after the first 2 years of treatment, people only stopped treatment with fingolimod and natalizumab when there was no further clinical benefit (in the company model, until EDSS state 7, which would indicate secondary progressive multiple sclerosis). The committee concluded that the company had likely overestimated treatment stopping rates, but noted that this did not have a substantial effect on the cost-effectiveness analysis.
# Restarting treatment after relapse
## Restarting cladribine treatment should not be included in the economic model
The company included restarting treatment with cladribine and alemtuzumab following relapse in the economic model, which increased the costs but not the clinical effects of each treatment in the model. The ERG explained that there was no published effectiveness evidence on restarting treatment, and that it had removed this from the model in its exploratory analyses. The committee noted that cladribine's marketing authorisation does not refer to restarting treatment, and concluded that it should not be included in the economic model.
# Health-state costs
## Informal care costs should not be included in the model
The committee discussed the annual costs associated with each EDSS health state in the economic model. It noted that the company had used medical costs from Hawton and Green (2016) and non-medical costs from Karampampa et al. (2012), and that these were large compared with the health-state costs accepted in previous NICE technology appraisals. The committee noted that the company had included informal care costs. The ERG argued that these should be excluded to reflect the perspective of the NHS or personal social services on costs, as per the NICE reference case. In its exploratory analyses, the ERG used the UK MS Survey (using 2015/16 unit costs) as its source for EDSS state costs, which had been used in previous appraisals (including for dimethyl fumarate, fingolimod and natalizumab). The committee concluded that it was appropriate to exclude informal care costs and that the UK MS Survey values should be used for decision making.
# Caregiver quality of life
## The effect on the quality of life of carers should be taken into account
The ERG removed the quality-of-life decrement for carers of people with multiple sclerosis from the company's economic modelling because it considered this inconsistent with the NICE reference case. The committee was aware that previous NICE guidance for relapsing–remitting multiple sclerosis included utility values for caregivers. The committee agreed that it was important to recognise the impact that caring for people with multiple sclerosis has on caregivers, and concluded that caregiver quality-of-life decrements should be included in the cost-effectiveness analysis.
# Other factors
## There is no evidence of any additional benefits of cladribine
Cladribine is an oral treatment given in 2 short treatment periods over 2 years. The committee understood that this is significantly less disruptive to daily routines than existing treatments for multiple sclerosis, which need to be given more frequently or by injection. The committee agreed that these benefits would be welcomed by patients, and noted that existing oral treatments are all taken daily. However, the committee was not presented with evidence for the extent of these benefits in practice compared with other treatments. The committee concluded that it had not been presented with any additional evidence of benefits that were not captured in the measurement of quality-adjusted life years (QALYs).
# Cost-effectiveness results and conclusion
## The ERG's changes to the model are appropriate and are considered with the company's results
The committee had concluded that cladribine was clinically effective compared with placebo in the rapidly evolving severe and suboptimal treatment subgroups, but that there was insufficient evidence to determine whether cladribine was any more or less effective than its comparators (see section 3.12). The ERG had provided a scenario in which cladribine and its comparators (that is, alemtuzumab, fingolimod and natalizumab) were equally effective. The committee did not agree with the ERG's change excluding caregiver quality of life from the cost-effectiveness analysis (see section 3.20). The ERG also made other adjustments to the company's model:
assuming equal waning of treatment effectiveness for cladribine and all comparators (see section 3.16)
assuming that after 2 years, trial discontinuation rates for fingolimod and natalizumab did not apply (see section 3.17)
removing restarting treatment with cladribine and alemtuzumab from the model (see section 3.18)
using EDSS health-state costs based on UK MS Survey data (see section 3.19).The committee agreed that these changes were appropriate. It noted that the ERG had not explored the effect of some company assumptions, such as adjusting the natural history of disease progression (see section 3.14). However, it recognised that this was not likely to have a significant effect on cost effectiveness. The committee concluded that, although it did not fully reflect committee preferences, it would consider the ERG's exploratory scenario that assumes equal effectiveness of cladribine and its comparators in addition to the company base-case cost-effectiveness results.
## Cladribine is cost effective for rapidly evolving severe and suboptimally treated relapsing–remitting multiple sclerosis
In the company's base-case cost-effectiveness analysis, cladribine dominated (that is, was more effective and cheaper than) all other treatments. The committee noted that these results were based on effectiveness estimates from the company's meta-regression, which it had concluded was insufficient to show that cladribine had substantially different effectiveness from its comparators (see section 3.12). The committee therefore considered the effect of the ERG's exploratory analyses incorporating most of the committee's preferred assumptions and assuming equal effectiveness of cladribine, and the relevant comparators in both the rapidly evolving severe and suboptimal treatment subgroups. It noted that, in isolation, none of the ERG's changes to the company model changed the company's base-case results, and cladribine continued to dominate all other treatments in both subgroups. After combining the ERG's assumptions, cladribine remained more effective and cheaper than fingolimod and natalizumab in the relevant subgroups. Cladribine was less effective and cheaper than alemtuzumab in the combined scenario analysis in both the rapidly evolving severe and suboptimal treatment subgroups. This resulted in incremental cost-effectiveness ratios (ICERs) of £219,549 gained per QALY lost and £372,802 gained per QALY lost respectively. For interventions that are less costly and less effective than a comparator, an intervention is considered cost effective if the ICER generated is above the level considered acceptable rather than below it. The committee concluded that cladribine was a cost-effective use of NHS resources for rapidly evolving severe relapsing–remitting multiple sclerosis and suboptimally treated relapsing–remitting multiple sclerosis (that is, disease that has responded inadequately to disease-modifying therapy). However, the committee understood from the experts that it was not the number of, but the increase in, MRI lesions that is important to measure response to treatment (see section 3.2). It therefore agreed to refer to MRI evidence of disease activity rather than using the company's definition of suboptimal treatment.
|
{'Recommendations': 'Cladribine is recommended as an option for treating highly active multiple sclerosis in adults, only if the person has:\n\nrapidly evolving severe relapsing–remitting multiple sclerosis, that is with at least:\n\n\n\nrelapses in the previous year and\n\nT1 gadolinium-enhancing lesion at baseline MRI or a significant increase in T2‑lesion load compared with a previous MRI, or\n\n\n\nrelapsing–remitting multiple sclerosis that has responded inadequately to treatment with disease-modifying therapy, defined as 1\xa0relapse in the previous year and MRI evidence of disease activity.\n\nThis recommendation is not intended to affect treatment with cladribine that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nHighly active relapsing–remitting multiple sclerosis is currently treated with alemtuzumab, fingolimod or natalizumab. This appraisal focuses on 2\xa0subgroups of people with highly active relapsing–remitting multiple sclerosis, that is, those with rapidly evolving severe disease and those with suboptimally treated relapsing–remitting multiple sclerosis (disease that has responded inadequately to disease-modifying therapy).\n\nClinical trial results show that cladribine tablets (hereafter referred to as cladribine) reduce relapses and slow the progression of disability compared with placebo for people with relapsing–remitting multiple sclerosis. The effectiveness of cladribine for treating rapidly evolving severe or suboptimally treated relapsing–remitting multiple sclerosis is not proven, but it is likely to be more effective than placebo.\n\nBased on indirect analyses, there is not enough evidence to determine whether cladribine is more or less effective than other treatments for people with rapidly evolving severe and suboptimally treated multiple sclerosis. Because of this, cladribine and alternative treatments are considered equally effective for this appraisal.\n\nThe MRI criteria used by clinicians to define rapidly evolving severe relapsing–remitting multiple sclerosis have changed over time. In addition to the presence of T1\xa0gadolinium-enhancing lesions at baseline, clinicians may now identify patients with rapidly evolving severe relapsing–remitting multiple sclerosis by a significant increase in T2‑lesion load compared with a previous MRI.\n\nCladribine is less costly than other treatments and needs less frequent dosing and monitoring. It is cost effective compared with all other treatments, so can be recommended for rapidly evolving severe and suboptimally treated relapsing–remitting multiple sclerosis.', 'Information about cladribine': "# Marketing authorisation indication\n\nCladribine tablets (Mavenclad, Merck Serono) are 'indicated for the treatment of adult patients with highly active relapsing multiple sclerosis as defined by clinical or imaging features'.\n\n# Dosage in the marketing authorisation\n\nIn the summary of product characteristics, the recommended cumulative dose is 3.5\xa0mg/kg body weight over 2\xa0years, taken as 1\xa0treatment course of 1.75\xa0mg/kg per year. Each treatment course consists of 2\xa0treatment weeks, 1\xa0at the beginning of the first month and 1\xa0at the beginning of the second month of the respective treatment year. Each treatment week consists of 4\xa0days or 5\xa0days on which a patient takes 10\xa0mg or 20\xa0mg (1\xa0or 2\xa0tablets) as a single daily dose, depending on body weight. After completing the 2\xa0treatment courses, no further cladribine treatment is needed in years\xa03 and\xa04.\n\n# Price\n\nThe list price is £2,047.24 per 10\xa0mg tablet (excluding VAT, BNF online, November 2019). Costs may vary in different settings because of negotiated procurement discounts.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Merck Serono and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Clinical need and patient perspective\n\n## Clinicians and patients would value an oral treatment with less frequent dosing and monitoring\n\nRelapsing–remitting multiple sclerosis is a chronic, disabling neurological condition. The patient experts explained that relapses and residual disability between relapses can substantially reduce quality of life. The committee was aware that relapsing–remitting multiple sclerosis can limit people's ability to work, and to engage in social and family life. The patient experts also explained that many of the available treatments need frequent hospital appointments for treatment and monitoring and that this causes significant disruption to patients' lives and careers. The committee heard that an oral treatment taken in 2\xa0short courses over 2\xa0years would be less disruptive.\n\n# Treatment pathway and comparators\n\n## The definitions of multiple sclerosis subgroups are not meaningful in NHS clinical practice\n\nIn the NHS, disease-modifying therapy is used to treat relapsing–remitting multiple sclerosis. The choice of therapy partly depends on the number of relapses and MRI evidence of disease activity, as defined in each treatment's marketing authorisation. Previous NICE technology appraisal guidance has usually defined active disease as at least 2\xa0clinically significant relapses in the previous 2\xa0years. The committee understood that some people with relapsing–remitting multiple sclerosis have highly active disease but that there is no universally accepted definition of highly active disease. The company defined a group of people with 'high disease activity' as having either 1\xa0relapse in the previous year while the person was on disease-modifying therapy and at least 1\xa0T1 gadolinium-enhancing lesion on MRI, or at least 2\xa0relapses (with or without lesions) in the previous year regardless of treatment. The clinical experts explained that this definition was not used in clinical practice and considered it to be very broad. The committee noted that, in previous appraisals, 'highly active disease' has been used to describe a population broadly similar to the population the company referred to as having suboptimally treated multiple sclerosis (see section\xa03.3). It also heard that, in practice, increases in T2‑lesion numbers compared with a previous MRI are an important indicator of disease activity, and may be more important than the absolute number. The committee concluded that the group referred to by the company as having 'high disease activity' may not be meaningful in NHS clinical practice.\n\n## The subgroups in the company submission are appropriate for decision making\n\nPeople with 'high disease activity' relapsing–remitting multiple sclerosis were divided into 2\xa0subgroups:\n\nRapidly evolving severe relapsing–remitting multiple sclerosis: 2\xa0or more relapses in the previous year whether the person was on treatment or not, and at least 1\xa0T1 gadolinium-enhancing lesion.\n\nSuboptimally treated relapsing–remitting multiple sclerosis: at least 1\xa0relapse in the previous year while the person was on disease-modifying therapy, and at least 1\xa0T1 gadolinium-enhancing lesion or 9\xa0T2 lesions.In addition to these subgroups, the 'high disease activity' subgroup also included an undefined group of people, who the committee understood to be those with 2\xa0or more relapses in the previous year without a T1\xa0gadolinium-enhancing lesion. The clinical experts explained that this group was clinically identifiable, but that suboptimal treatment was more difficult to define. The committee considered that the suboptimal treatment subgroup represented people who have highly active disease that had responded inadequately to previous treatment. However, it noted that the criteria used for MRI evidence of disease activity in this group may not be relevant for clinical practice, particularly given the concerns of the clinical experts about using the absolute number of T2\xa0lesions as a criterion (see section\xa03.2). The clinical experts explained that the categorisations in marketing authorisations are difficult to use in clinical practice because there is a spectrum of disease activity rather than rigidly defined stages. However, they explained that the rapidly evolving severe and suboptimal treatment groups were broadly representative of patients at the more active end of the disease spectrum. The committee concluded that the subgroups broadly represent the population who would have cladribine tablets (hereafter referred to as cladribine) in clinical practice, and are appropriate for decision making. However, it also concluded that it would not use the company's definition of suboptimal treatment as the basis of any recommendation.\n\n# Comparators\n\n## The choice of comparator varies by subgroup\n\nThe clinical experts explained that many people with multiple sclerosis do not take disease-modifying therapies, but that people with highly active disease would. The committee understood that, for people with more active disease, clinicians follow NICE guidance, which recommends that people with rapidly evolving severe multiple sclerosis have alemtuzumab or natalizumab. Similarly, in line with NICE guidance, people with suboptimally treated multiple sclerosis (as defined in the company submission) could have alemtuzumab or fingolimod. The committee concluded that it was appropriate to consider the following comparators for cladribine:\n\nalemtuzumab and natalizumab for people with rapidly evolving severe disease\n\nalemtuzumab and fingolimod for people with suboptimally treated disease.\n\n# Direct clinical evidence\n\n## The main clinical evidence for cladribine comes from the CLARITY trial\n\nThe CLARITY trial was a randomised double-blind study of 1,326\xa0people with active relapsing–remitting multiple sclerosis, which compared 2\xa0different doses of cladribine with placebo. In the study, 433\xa0people had the licensed dose (3.5\xa0mg/kg body weight) of cladribine and 437\xa0people had placebo. The primary outcome was annualised relapse rate. An important post-hoc outcome was time to 6‑month confirmed disability progression.\n\n## The relevant subgroups are defined post hoc in CLARITY\n\nThe company provided clinical evidence for the whole (intention-to-treat) population and for a post-hoc high disease activity subgroup from CLARITY. However, it did not provide cost-effectiveness estimates for these groups. The company's main evidence in its cost-effectiveness analysis was based on smaller post-hoc subgroups of the post-hoc high disease activity subgroup. These smaller subgroups were people with rapidly evolving severe and suboptimally treated relapsing–remitting multiple sclerosis. The company explained that it considered the rapidly evolving severe and suboptimal treatment post-hoc groups to broadly reflect the groups in previous NICE appraisals. The committee was concerned that the number of patients who had cladribine in these subgroups was small (50\xa0and 19\xa0patients respectively) meaning that the data based on these subgroups are uncertain. The committee agreed that evidence based on a larger pre-specified subgroup is preferable but appreciated that CLARITY had been planned before the current disease categorisations had emerged.\n\n## Definitions of outcomes in CLARITY differ from other clinical trials and previous appraisals\n\nTo determine disability progression above the Expanded Disability Status Scale (EDSS) state\xa05, a 0.5‑point change in EDSS state was used in CLARITY, whereas other clinical trials used a 1.0‑point change. A clinical expert explained that the difference between EDSS state\xa05 and EDSS state\xa05.5 is more subjective, and that it is less clinically significant than a change from EDSS state\xa05 to EDSS state\xa06, which requires the use of a walking aid. The committee noted that there were also differences in how a relapse was defined, with relapse-related disability specifically based on EDSS state in CLARITY but not in other trials. On balance, the committee considered that the differences in outcomes were unlikely to have a large effect on the comparative effectiveness, and concluded that the outcomes were broadly comparable across trials.\n\n## Cladribine reduces relapses and delays disability compared with placebo in the whole population and the high disease activity subgroup\n\nIn the intention-to-treat analysis and in the high disease activity subgroup, cladribine reduced the annualised relapse rate and delayed disability progression sustained for 6\xa0months compared with placebo (see table\xa01). The committee concluded that, for the overall population of people with relapsing–remitting multiple sclerosis and for the overall high disease activity subgroup, cladribine was more effective than placebo.\n\nOutcome\n\nIntention to treat (433 people having cladribine)\n\nOverall high disease activity (140 people having cladribine)\n\nAnnualised relapse rate\n\n(rate ratio [95% confidence interval])\n\n(0.33 to 0.53)\n\n(0.24 to 0.50)\n\nTime to confirmed 6‑month disability progression\n\n(hazard ratio [95% confidence interval])\n\n(0.36 to 0.78)\n\n(0.08 to 0.44)\n\n## Results for the rapidly evolving severe and suboptimal treatment subgroups are uncertain\n\nIn the rapidly evolving severe subgroup, cladribine reduced relapses and delayed disability progression compared with placebo. However, the effect on disability progression was not statistically significant. In the suboptimal treatment subgroup, the annualised relapse rate was lower with cladribine than with placebo, but the effect was not statistically significant. The effect on disability progression could not be estimated in this group because of small patient numbers. The exact results for the rapidly evolving severe and suboptimal treatment subgroups are commercial in confidence. The committee considered that the lack of statistical significance was partly because of the small patient numbers. It noted that, in the overall high disease activity group, which included both of the smaller subgroups, cladribine was highly effective and the results were statistically significant (see section\xa03.8). The committee concluded that, despite some uncertainty over the effect size, cladribine was likely to be more effective than placebo in both the rapidly evolving severe and suboptimal treatment groups.\n\n# Indirect clinical evidence\n\n## The company network meta-analysis is appropriate\n\nThe company's network meta-analysis compared cladribine with other treatments (including the comparators for this appraisal and other disease-modifying therapies such as beta interferon), in the overall population, and in the high disease activity, rapidly evolving severe and suboptimal treatment subgroups. The committee discussed the company's assumptions in the network meta-analysis:\n\nThe company assumed that the relevant outcomes were comparable between trials, despite the differences in outcome measures in CLARITY compared with clinical trials for other treatments (see section\xa03.7). The ERG explained that it considered this to be a major limitation, but the company suggested that these subtle differences should not have a major impact. The committee agreed that the outcome measures used were broadly similar across trials.\n\nThe company assumed that the subgroups in CLARITY were comparable to those used in other clinical trials. The committee was aware that the definitions of high disease activity, rapidly evolving severe disease and suboptimally treated disease despite previous treatment differed from those used in previous NICE guidance for relapsing–remitting multiple sclerosis (see section 3.2 and\xa0section 3.3). However, the committee considered that the subgroups were defined based on similar radiological and clinical criteria. It accepted that the subgroup populations were comparable between this appraisal and previously published appraisals.The committee concluded that the network meta-analysis was appropriate for this appraisal.\n\n## The network meta-analysis does not provide conclusive evidence for the effectiveness of cladribine compared with current NHS treatments\n\nFor each subgroup, the company used separate evidence networks to estimate the relative effectiveness of cladribine on annualised relapse rate, disability progression sustained for 3\xa0months, and disability progression sustained for 6\xa0months. Comparisons with cladribine were not possible for some of the comparators in each of the subgroups. Notably, results were not available for disability progression in the suboptimal treatment subgroup. Among the comparisons presented, cladribine did not have a statistically significant effect relative to its comparators (that is, alemtuzumab, fingolimod and natalizumab) on any of the outcomes in any of the subgroups. The committee also noted that the confidence intervals were wide and overlapped between treatments. It concluded that there was insufficient evidence from the network meta-analysis to show that cladribine had substantially different effectiveness to alemtuzumab, fingolimod or natalizumab.\n\n## The meta-regression provides a full set of comparisons but may use invalid methods\n\nThe company did a meta-regression for the outcome of disability progression sustained for 6\xa0months for cladribine, alemtuzumab, fingolimod and natalizumab compared with placebo to address the weaknesses of the network meta-analysis, particularly for the suboptimal treatment group. In the absence of data in the network meta-analysis (see section\xa03.11), the meta-regression estimated effectiveness based on differences in the baseline risk of disability progression. The committee noted that, although confidence intervals for cladribine, alemtuzumab, fingolimod and natalizumab compared with placebo were narrower than those for estimates in the network meta-analysis, they overlapped for all treatments in both the rapidly evolving severe and suboptimal treatment subgroups. It also noted that, for the rapidly evolving severe subgroup, the estimated effectiveness of cladribine compared with placebo from the meta-regression was similar to the estimate from the network meta-analysis. However, it was concerned that alemtuzumab compared with placebo appeared substantially less effective in the meta-regression than in the network meta-analysis. The company suggested this could be explained by the differences in baseline risk between trials. The company validated the methodology by comparing the effect sizes predicted by the meta-regression with the effect sizes seen in the relevant trials. The committee agreed with the ERG's concerns that there were differences in effect size not explained by differences in baseline risk, which would make the company's approach invalid. In addition, the committee was aware that the assumptions and issues which the network meta-analysis relied on (see section\xa03.10) also applied to the meta-regression. The committee acknowledged the company's attempts to address the data limitations, but on balance agreed that the meta-regression approach may be invalid. The committee concluded that, although the meta-regression did provide estimates for effect sizes adjusted for baseline risk, the evidence from the meta-regression was insufficient to show that cladribine had substantially different effectiveness to alemtuzumab, fingolimod and natalizumab.\n\n# Company's economic model\n\n## The model is appropriate for decision making\n\nThe committee noted that the company's model was similar to models used in previous NICE technology appraisal guidance, but that the company had removed progression to secondary progressive multiple sclerosis. The company explained that it was difficult to identify the transition to secondary progressive multiple sclerosis in clinical practice, and noted that health-related quality of life is more closely related to EDSS state than to the clinical form of multiple sclerosis. The company suggested that this meant that separating the 2\xa0forms of the disease was unnecessary for economic modelling because all health-related benefits of treatment would be captured by changes in EDSS state. The committee concluded that the company's model was appropriate for decision making.\n\n# Natural history of the disease in subgroup analyses\n\n## Calculating different rates of disability progression in the subgroups is simplistic and potentially inaccurate\n\nThe natural history of multiple sclerosis in the company's economic model was based on the British Columbia multiple sclerosis dataset, which was used in previous NICE technology appraisal guidance. The company explained that the British Columbia dataset included a mixture of people with active and highly active multiple sclerosis. The company stated that rapidly evolving severe or suboptimally treated multiple sclerosis is expected to progress faster than active relapsing–remitting multiple sclerosis. Therefore, it adjusted the disease progression rates to allow for a higher probability of progression for EDSS states 0\xa0to\xa06. This adjustment was based on the difference in 6‑month confirmed disability progression in CLARITY in each subgroup compared with its complement (that is, people not included in that subgroup). The clinical experts and the ERG explained that, although assuming different rates of disease progression for each subgroup was reasonable, the company's approach was simplistic and potentially inaccurate. The committee appreciated that there was no clear alternative data source or method, and was aware that such adjustment had not been used in previous technology appraisals. However, because the adjustment would have a limited effect on the cost effectiveness of cladribine, the committee did not pursue this point any further.\n\n# Treatment effect\n\n## A scenario exploring equal clinical effectiveness should be considered in the economic analysis\n\nBecause there was insufficient clinical evidence to show that cladribine had substantially different effectiveness to its comparators (see section\xa03.12), the ERG provided a scenario assuming that cladribine and its comparators were equally effective in reducing relapses and delaying disability progression. The committee concluded that, based on the evidence, it would take into account this ERG scenario in its decision making.\n\n# Waning of treatment effect\n\n## The waning of the treatment effect should be the same for all comparators\n\nIn previous NICE technology appraisal guidance for multiple sclerosis (such as for alemtuzumab and dimethyl fumarate), the committee agreed that most treatments for multiple sclerosis become less effective over time. Therefore, the economic modelling included the assumption that the treatment effect declines by 25% after 2\xa0years and by 50% after 5\xa0years for all therapies. The committee heard that the company had attempted to assess whether there was a declining effect of cladribine by analysing data from the extension of the CLARITY trial. The company used a treatment switching analysis to estimate a hazard ratio for disability progression for cladribine compared with placebo over 4\xa0years. It showed that this hazard ratio was similar to the hazard ratio estimated over 2\xa0years. Therefore, the company suggested that there was no evidence of the treatment effect waning within the first 4\xa0years. The company assumed that the waning effect for cladribine began after 4\xa0years (that is, a 25% decline in treatment effect after 4\xa0years and a 50% decline after 5\xa0years). However, for the comparators, the company used the waning assumptions used in previous appraisals (that is, a 25% decline in treatment effect after 2\xa0years and a 50% decline after 5\xa0years). The committee noted that there was no statistically significant evidence to support different waning effects and that patient numbers used for the analysis in the subgroups were very small. It concluded that the company's evidence was insufficient to justify using a different treatment waning assumption for cladribine.\n\n# Treatment stopping rates\n\n## Applying annualised rates based on clinical trials is likely to overestimate treatment stopping rates\n\nThe company used the rates at which patients stop treatment with cladribine or its comparators from the respective clinical trials. The committee understood that, given the method of administration of both cladribine and alemtuzumab (that is, both involve 2\xa0short courses of treatment a year apart), annual discontinuation rates did not apply, and the rate of stopping treatment refers to stopping between the first and second courses. The committee noted that fingolimod and natalizumab were all taken more frequently and for longer, so annual discontinuation rates were relevant. The ERG explained that people are more likely to stop treatment during the first year of treatment than in a subsequent year. Therefore, the company's approach of applying trial-based discontinuation rates to subsequent years would overestimate the number of people stopping treatment. In its exploratory analyses, the ERG assumed that, after the first 2\xa0years of treatment, people only stopped treatment with fingolimod and natalizumab when there was no further clinical benefit (in the company model, until EDSS state\xa07, which would indicate secondary progressive multiple sclerosis). The committee concluded that the company had likely overestimated treatment stopping rates, but noted that this did not have a substantial effect on the cost-effectiveness analysis.\n\n# Restarting treatment after relapse\n\n## Restarting cladribine treatment should not be included in the economic model\n\nThe company included restarting treatment with cladribine and alemtuzumab following relapse in the economic model, which increased the costs but not the clinical effects of each treatment in the model. The ERG explained that there was no published effectiveness evidence on restarting treatment, and that it had removed this from the model in its exploratory analyses. The committee noted that cladribine's marketing authorisation does not refer to restarting treatment, and concluded that it should not be included in the economic model.\n\n# Health-state costs\n\n## Informal care costs should not be included in the model\n\nThe committee discussed the annual costs associated with each EDSS health state in the economic model. It noted that the company had used medical costs from Hawton and Green (2016) and non-medical costs from Karampampa et al. (2012), and that these were large compared with the health-state costs accepted in previous NICE technology appraisals. The committee noted that the company had included informal care costs. The ERG argued that these should be excluded to reflect the perspective of the NHS or personal social services on costs, as per the NICE reference case. In its exploratory analyses, the ERG used the UK MS Survey (using 2015/16 unit costs) as its source for EDSS state costs, which had been used in previous appraisals (including for dimethyl fumarate, fingolimod and natalizumab). The committee concluded that it was appropriate to exclude informal care costs and that the UK MS Survey values should be used for decision making.\n\n# Caregiver quality of life\n\n## The effect on the quality of life of carers should be taken into account\n\nThe ERG removed the quality-of-life decrement for carers of people with multiple sclerosis from the company's economic modelling because it considered this inconsistent with the NICE reference case. The committee was aware that previous NICE guidance for relapsing–remitting multiple sclerosis included utility values for caregivers. The committee agreed that it was important to recognise the impact that caring for people with multiple sclerosis has on caregivers, and concluded that caregiver quality-of-life decrements should be included in the cost-effectiveness analysis.\n\n# Other factors\n\n## There is no evidence of any additional benefits of cladribine\n\nCladribine is an oral treatment given in 2\xa0short treatment periods over 2\xa0years. The committee understood that this is significantly less disruptive to daily routines than existing treatments for multiple sclerosis, which need to be given more frequently or by injection. The committee agreed that these benefits would be welcomed by patients, and noted that existing oral treatments are all taken daily. However, the committee was not presented with evidence for the extent of these benefits in practice compared with other treatments. The committee concluded that it had not been presented with any additional evidence of benefits that were not captured in the measurement of quality-adjusted life years (QALYs).\n\n# Cost-effectiveness results and conclusion\n\n## The ERG's changes to the model are appropriate and are considered with the company's results\n\nThe committee had concluded that cladribine was clinically effective compared with placebo in the rapidly evolving severe and suboptimal treatment subgroups, but that there was insufficient evidence to determine whether cladribine was any more or less effective than its comparators (see section\xa03.12). The ERG had provided a scenario in which cladribine and its comparators (that is, alemtuzumab, fingolimod and natalizumab) were equally effective. The committee did not agree with the ERG's change excluding caregiver quality of life from the cost-effectiveness analysis (see section\xa03.20). The ERG also made other adjustments to the company's model:\n\nassuming equal waning of treatment effectiveness for cladribine and all comparators (see section\xa03.16)\n\nassuming that after 2\xa0years, trial discontinuation rates for fingolimod and natalizumab did not apply (see section\xa03.17)\n\nremoving restarting treatment with cladribine and alemtuzumab from the model (see section\xa03.18)\n\nusing EDSS health-state costs based on UK MS Survey data (see section\xa03.19).The committee agreed that these changes were appropriate. It noted that the ERG had not explored the effect of some company assumptions, such as adjusting the natural history of disease progression (see section\xa03.14). However, it recognised that this was not likely to have a significant effect on cost effectiveness. The committee concluded that, although it did not fully reflect committee preferences, it would consider the ERG's exploratory scenario that assumes equal effectiveness of cladribine and its comparators in addition to the company base-case cost-effectiveness results.\n\n## Cladribine is cost effective for rapidly evolving severe and suboptimally treated relapsing–remitting multiple sclerosis\n\nIn the company's base-case cost-effectiveness analysis, cladribine dominated (that is, was more effective and cheaper than) all other treatments. The committee noted that these results were based on effectiveness estimates from the company's meta-regression, which it had concluded was insufficient to show that cladribine had substantially different effectiveness from its comparators (see section\xa03.12). The committee therefore considered the effect of the ERG's exploratory analyses incorporating most of the committee's preferred assumptions and assuming equal effectiveness of cladribine, and the relevant comparators in both the rapidly evolving severe and suboptimal treatment subgroups. It noted that, in isolation, none of the ERG's changes to the company model changed the company's base-case results, and cladribine continued to dominate all other treatments in both subgroups. After combining the ERG's assumptions, cladribine remained more effective and cheaper than fingolimod and natalizumab in the relevant subgroups. Cladribine was less effective and cheaper than alemtuzumab in the combined scenario analysis in both the rapidly evolving severe and suboptimal treatment subgroups. This resulted in incremental cost-effectiveness ratios (ICERs) of £219,549 gained per QALY lost and £372,802 gained per QALY lost respectively. For interventions that are less costly and less effective than a comparator, an intervention is considered cost effective if the ICER generated is above the level considered acceptable rather than below it. The committee concluded that cladribine was a cost-effective use of NHS resources for rapidly evolving severe relapsing–remitting multiple sclerosis and suboptimally treated relapsing–remitting multiple sclerosis (that is, disease that has responded inadequately to disease-modifying therapy). However, the committee understood from the experts that it was not the number of, but the increase in, MRI lesions that is important to measure response to treatment (see section\xa03.2). It therefore agreed to refer to MRI evidence of disease activity rather than using the company's definition of suboptimal treatment."}
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https://www.nice.org.uk/guidance/ta616
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Evidence-based recommendations on cladribine (Mavenclad) for relapsing–remitting multiple sclerosis in adults.
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d25a7189c586308615e8caa46a93ee0cc828a1a2
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nice
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Balloon dilation for chronic eustachian tube dysfunction
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Balloon dilation for chronic eustachian tube dysfunction
Evidence-based recommendations on balloon dilation for chronic eustachian tube dysfunction in adults and children. This involves using a balloon filled with saline to widen the eustachian tube.
# Recommendations
Evidence on the safety and efficacy of balloon dilation for eustachian tube dysfunction is adequate to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.# The condition, current treatments and procedure
# The condition
The eustachian tube is a narrow tube that connects the middle ear with the back of the nose. If it is blocked or does not open properly, there can be symptoms such as muffled hearing, pain, a feeling of fullness in the ear, tinnitus or dizziness. The eustachian tube typically becomes blocked after an upper respiratory tract infection or allergic rhinitis. It is usually a temporary problem that resolves spontaneously, but sometimes symptoms persist and treatment is necessary. Long-term eustachian tube dysfunction is associated with damage to the eardrum and middle-ear transformer mechanism.
# Current treatments
Medical treatments include oral and nasal corticosteroids, decongestants and antihistamines. Autoinflation is a technique that reopens the eustachian tube by raising pressure in the nose. This can be achieved in several ways, including forced exhalation against a closed mouth and nose.
If eustachian tube dysfunction persists, a tympanostomy tube (also known as a ventilation tube or grommet) may be inserted through a small incision in the tympanic membrane. These typically fall out after several months, and repeated tube insertions may be needed. Some tubes are designed to stay in place for longer, but these can become crusted, infected or obstructed. Tympanostomy tubes may result in a small permanent hole in the tympanic membrane; this is more common with long-lasting tubes.
# The procedure
Balloon dilation of the eustachian tube is done using local or general anaesthesia. A balloon catheter is introduced into the eustachian tube via the nose, under transnasal endoscopic vision. Once the balloon is correctly positioned in the eustachian tube, it is filled with saline up to a pressure of about 10 to 12 bars. Pressure is maintained for about 2 minutes. The balloon is then emptied and removed.
The aim of the procedure is to widen the eustachian tube and improve its function.
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{'Recommendations': 'Evidence on the safety and efficacy of balloon dilation for eustachian tube dysfunction is adequate to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.', 'The condition, current treatments and procedure': '# The condition\n\nThe eustachian tube is a narrow tube that connects the middle ear with the back of the nose. If it is blocked or does not open properly, there can be symptoms such as muffled hearing, pain, a feeling of fullness in the ear, tinnitus or dizziness. The eustachian tube typically becomes blocked after an upper respiratory tract infection or allergic rhinitis. It is usually a temporary problem that resolves spontaneously, but sometimes symptoms persist and treatment is necessary. Long-term eustachian tube dysfunction is associated with damage to the eardrum and middle-ear transformer mechanism.\n\n# Current treatments\n\nMedical treatments include oral and nasal corticosteroids, decongestants and antihistamines. Autoinflation is a technique that reopens the eustachian tube by raising pressure in the nose. This can be achieved in several ways, including forced exhalation against a closed mouth and nose.\n\nIf eustachian tube dysfunction persists, a tympanostomy tube (also known as a ventilation tube or grommet) may be inserted through a small incision in the tympanic membrane. These typically fall out after several months, and repeated tube insertions may be needed. Some tubes are designed to stay in place for longer, but these can become crusted, infected or obstructed. Tympanostomy tubes may result in a small permanent hole in the tympanic membrane; this is more common with long-lasting tubes.\n\n# The procedure\n\nBalloon dilation of the eustachian tube is done using local or general anaesthesia. A balloon catheter is introduced into the eustachian tube via the nose, under transnasal endoscopic vision. Once the balloon is correctly positioned in the eustachian tube, it is filled with saline up to a pressure of about 10\xa0to 12\xa0bars. Pressure is maintained for about 2\xa0minutes. The balloon is then emptied and removed.\n\nThe aim of the procedure is to widen the eustachian tube and improve its function.'}
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https://www.nice.org.uk/guidance/ipg665
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Evidence-based recommendations on balloon dilation for chronic eustachian tube dysfunction in adults and children. This involves using a balloon filled with saline to widen the eustachian tube.
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23895d759c6a7203cda2744eb24ffb2d25ccc6f7
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nice
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Acute kidney injury: prevention, detection and management
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Acute kidney injury: prevention, detection and management
This guideline covers preventing, detecting and managing acute kidney injury in children, young people and adults. It aims to improve assessment and detection by non-specialists, and specifies when people should be referred to specialist services. This will improve early recognition and treatment, and reduce the risk of complications in people with acute kidney injury.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Assessing risk of acute kidney injury
## Identifying acute kidney injury in people with acute illness
Investigate for acute kidney injury, by measuring serum creatinine and comparing with baseline, in adults with acute illness if any of the following are likely or present:
chronic kidney disease (adults with an estimated glomerular filtration rate less than 60 ml/min/1.73 m2 are at particular risk)
heart failure
liver disease
diabetes
history of acute kidney injury
-liguria (urine output less than 0.5 ml/kg/hour)
neurological or cognitive impairment or disability, which may mean limited access to fluids because of reliance on a carer
hypovolaemia
use of drugs that can cause or exacerbate kidney injury (such as non‑steroidal anti‑inflammatory drugs , aminoglycosides, angiotensin‑converting enzyme inhibitors, angiotensin II receptor antagonists and diuretics) within the past week, especially if hypovolaemic
use of iodine-based contrast media within the past week
symptoms or history of urological obstruction, or conditions that may lead to obstruction
sepsis
deteriorating early warning scores
age 65 years or over.
Investigate for acute kidney injury, by measuring serum creatinine and comparing with baseline, in children and young people with acute illness if any of the following are likely or present:
chronic kidney disease
heart failure
liver disease
history of acute kidney injury
-liguria (urine output less than 0.5 ml/kg/hour)
young age, neurological or cognitive impairment or disability, which may mean limited access to fluids because of reliance on a parent or carer
hypovolaemia
use of drugs that can cause or exacerbate kidney injury (such as NSAIDs, aminoglycosides, ACE inhibitors, ARBs and diuretics) within the past week, especially if hypovolaemic
symptoms or history of urological obstruction, or conditions that may lead to obstruction
sepsis
a deteriorating paediatric early warning score
severe diarrhoea (children and young people with bloody diarrhoea are at particular risk)
symptoms or signs of nephritis (such as oedema or haematuria)
haematological malignancy
hypotension.
## Identifying acute kidney injury in people with no obvious acute illness
Be aware that in adults, children and young people with chronic kidney disease and no obvious acute illness, a rise in serum creatinine may indicate acute kidney injury rather than a worsening of their chronic disease.
Ensure that acute kidney injury is considered when an adult, child or young person presents with an illness with no clear acute component and has any of the following:
chronic kidney disease, especially stage 3B, 4 or 5 as shown in table1, or urological disease
new onset or significant worsening of urological symptoms
symptoms suggesting complications of acute kidney injury
symptoms or signs of a multi‑system disease affecting the kidneys and other organ systems (for example, signs or symptoms of acute kidney injury, plus a purpuric rash).
## Assessing risk factors in adults having iodine-based contrast media
Before offering iodine-based contrast media to adults for non‑emergency imaging, investigate for chronic kidney disease by measuring eGFR or by checking an eGFR result obtained within the past 3 months.
Before offering iodine-based contrast media to adults, assess their risk of acute kidney injury but do not delay emergency imaging. Be aware that increased risk is associated with:
chronic kidney disease (adults with an eGFR less than 40 ml/min/1.73 m2 are at particular risk)
diabetes but only with chronic kidney disease (adults with an eGFR less than 40 ml/min/1.73 m2 are at particular risk)
heart failure
renal transplant
age 75 years or over
hypovolaemia
increasing volume of contrast agent
intra-arterial administration of contrast medium with first-pass renal exposure.
Include the risks of developing acute kidney injury in the routine discussion of risks and benefits of the imaging procedure. Follow the recommendations in the NICE guideline on shared decision making.
## Assessing risk factors in adults having surgery
Assess the risk of acute kidney injury in adults before surgery. Be aware that increased risk is associated with:
emergency surgery, especially when the person has sepsis or hypovolaemia
intraperitoneal surgery
chronic kidney disease (adults with an eGFR less than 60 ml/min/1.73 m2 are at particular risk)
diabetes
heart failure
age 65 years or over
liver disease
use of drugs that can cause or exacerbate kidney injury in the perioperative period (in particular, NSAIDs after surgery).Use the risk assessment to inform a clinical management plan.
Include the risks of developing acute kidney injury in the routine discussion of risks and benefits of surgery. Follow the recommendations in the NICE guideline on shared decision making.
# Preventing acute kidney injury
## Ongoing assessment of the condition of people in hospital
Follow the recommendations in the NICE guideline on acutely ill adults in hospital on the use of track and trigger systems (early warning scores) to identify adults who are at risk of acute kidney injury because their clinical condition is deteriorating or is at risk of deteriorating.
When adults are at risk of acute kidney injury, ensure that systems are in place to recognise and respond to oliguria (urine output less than 0.5 ml/kg/hour) if the track and trigger system (early warning score) does not monitor urine output.
Consider using a paediatric early warning score to identify children and young people admitted to hospital who are at risk of acute kidney injury because their clinical condition is deteriorating or is at risk of deteriorating.
Record physiological observations at admission and then according to local protocols for given paediatric early warning scores.
Increase the frequency of observations if abnormal physiology is detected.
If using a paediatric early warning score, use one with multiple‑parameter or aggregate weighted scoring systems that allow a graded response and:
define the parameters to be measured and the frequency of observations
include a clear and explicit statement of the parameters, cut‑off points or scores that should trigger a response.
If using a paediatric early warning score, use one with multiple‑parameter or aggregate weighted scoring systems that measure:
heart rate
respiratory rate
systolic blood pressure
level of consciousness
-xygen saturation
temperature
capillary refill time.
When children and young people are at risk of acute kidney injury because of risk factors listed in the recommendation in the section on identifying acute kidney injury in people with acute illness:
measure urine output
record weight twice daily to determine fluid balance
measure urea, creatinine and electrolytes
think about measuring lactate, blood glucose and blood gases.
## Preventing acute kidney injury in adults having iodine-based contrast media
Encourage oral hydration before and after procedures using intravenous iodine-based contrast media in adults at increased risk of contrast-induced acute kidney injury (see the recommendation on increased risk in the section on assessing risk factors in adults having iodine-based contrast media).
For inpatients having iodine-based contrast media, consider intravenous volume expansion with either isotonic sodium bicarbonate or 0.9% sodium chloride if they are at particularly high risk, for example, if:
they have an eGFR less than 30 ml/min/1.73 m2
they have had a renal transplant
a large volume of contrast medium is being used (for example, higher than the standard diagnostic dose or repeat administration within 24 hours)
intra-arterial administration of contrast medium with first-pass renal exposure is being used.For more information on managing intravenous fluid therapy, see the NICE guideline on intravenous fluid therapy in adults in hospital.
Consider temporarily stopping ACE inhibitors and ARBs in adults having iodine-based contrast media if they have chronic kidney disease with an eGFR less than 40 ml/min/1.73 m2.
Discuss the person's care with a nephrology team before offering iodine-based contrast media to adults on renal replacement therapy, including people with a renal transplant, but do not delay emergency imaging for this.
For a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on preventing acute kidney injury in adults having iodine-based contrast media .
Full details of the evidence and the committee's discussion are in evidence review A: preventing contrast-induced acute kidney injury.
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## Monitoring and preventing deterioration in people with or at high risk of acute kidney injury
Consider electronic clinical decision support systems (CDSS) to support clinical decision making and prescribing, but ensure they do not replace clinical judgement.
When acquiring any new CDSS or systems for electronic prescribing, ensure that any systems considered:
can interact with laboratory systems
can recommend drug dosing and frequency
can store and update data on patient history and characteristics, including age, weight and renal replacement therapy
can include alerts that are mandatory for the healthcare professional to acknowledge and review.
Seek advice from a pharmacist about optimising medicines and drug dosing in adults, children and young people with or at risk of acute kidney injury.
Consider temporarily stopping ACE inhibitors and ARBs in adults, children and young people with diarrhoea, vomiting or sepsis until their clinical condition has improved and stabilised.
# Detecting acute kidney injury
Detect acute kidney injury, in line with the (p)RIFLE (paediatric Risk, Injury, Failure, Loss, End stage renal disease), AKIN (Acute Kidney Injury Network) or KDIGO (Kidney Disease: Improving Global Outcomes) definitions, by using any of the following criteria:
a rise in serum creatinine of 26 micromol/litre or greater within 48 hours
a 50% or greater rise in serum creatinine known or presumed to have occurred within the past 7 days (see also an algorithm for early identification of acute kidney injury, endorsed by NHS England)
a fall in urine output to less than 0.5 ml/kg/hour for more than 6 hours in adults and more than 8 hours in children and young people
a 25% or greater fall in eGFR in children and young people within the past 7 days.
Monitor serum creatinine regularly in all adults, children and young people with or at risk of acute kidney injury. Frequency of monitoring should vary according to clinical need, but daily measurement is typical while in hospital.
# Identifying the cause(s) of acute kidney injury
Identify the cause(s) of acute kidney injury and record the details in the person's notes.
## Urinalysis
Perform urine dipstick testing for blood, protein, leucocytes, nitrites and glucose in all people as soon as acute kidney injury is suspected or detected. Document the results and ensure that appropriate action is taken when results are abnormal.
Think about a diagnosis of acute nephritis and referral to the nephrology team when an adult, child or young person with no obvious cause of acute kidney injury has urine dipstick results showing haematuria and proteinuria, without urinary tract infection or trauma due to catheterisation.
## Ultrasound
Do not routinely offer ultrasound of the urinary tract when the cause of the acute kidney injury has been identified.
When pyonephrosis (infected and obstructed kidney) is suspected in adults, children and young people with acute kidney injury, offer immediate ultrasound of the urinary tract (to be performed within 6 hours of assessment).
When adults, children and young people have no identified cause of their acute kidney injury or are at risk of urinary tract obstruction, offer urgent ultrasound of the urinary tract (to be performed within 24 hours of assessment).
# Managing acute kidney injury
## Relieving urological obstruction
Refer all adults, children and young people with upper tract urological obstruction to a urologist. Refer immediately when one or more of the following is present:
pyonephrosis
an obstructed solitary kidney
bilateral upper urinary tract obstruction
complications of acute kidney injury caused by urological obstruction.
When nephrostomy or stenting is used to treat upper tract urological obstruction in adults, children and young people with acute kidney injury, carry it out as soon as possible and within 12 hours of diagnosis.
## Pharmacological management
Do not routinely offer loop diuretics to treat acute kidney injury.
Consider loop diuretics for treating fluid overload or oedema while:
an adult, child or young person is awaiting renal replacement therapy or
renal function is recovering in an adult, child or young person not receiving renal replacement therapy.
Do not offer low-dose dopamine to treat acute kidney injury.
## Referring for renal replacement therapy
Discuss any potential indications for renal replacement therapy with a nephrologist, paediatric nephrologist and/or critical care specialist immediately to ensure that the therapy is started as soon as needed.
When an adult, child or young person has significant comorbidities, discuss with them and/or their parent or carer and within the multidisciplinary team whether renal replacement therapy would offer benefit. Follow the recommendations in the NICE guideline on shared decision making.
Refer adults, children and young people immediately for renal replacement therapy if any of the following are not responding to medical management:
hyperkalaemia
metabolic acidosis
symptoms or complications of uraemia (for example, pericarditis or encephalopathy)
fluid overload
pulmonary oedema.
Base the decision to start renal replacement therapy on the condition of the adult, child or young person as a whole and not on an isolated urea, creatinine or potassium value.
When there are indications for renal replacement therapy, the nephrologist and/or critical care specialist should discuss the treatment with the adult, child or young person and/or their parent or carer as soon as possible and before starting treatment. Follow the recommendations in the NICE guideline on shared decision making.
## Referring to nephrology
Refer adults, children and young people with acute kidney injury to a nephrologist, paediatric nephrologist or critical care specialist immediately if they meet criteria for renal replacement therapy in recommendation 1.5.8.
Do not refer adults, children or young people to a nephrologist or paediatric nephrologist when there is a clear cause for acute kidney injury and the condition is responding promptly to medical management, unless they have a renal transplant.
Consider discussing management with a nephrologist or paediatric nephrologist when an adult, child or young person with severe illness might benefit from treatment, but there is uncertainty as to whether they are nearing the end of their life.
Refer adults, children and young people in intensive care to a nephrology team when there is uncertainty about the cause of acute kidney injury or when specialist management of kidney injury might be needed.
Discuss the management of acute kidney injury with a nephrologist or paediatric nephrologist as soon as possible and within 24 hours of detection when one or more of the following is present:
a possible diagnosis that may need specialist treatment (for example, vasculitis, glomerulonephritis, tubulointerstitial nephritis or myeloma)
acute kidney injury with no clear cause
inadequate response to treatment
complications associated with acute kidney injury
stage 3 acute kidney injury (according to (p)RIFLE, AKIN or KDIGO criteria)
a renal transplant
chronic kidney disease stage 4 or 5 as shown in table 1.
Monitor serum creatinine after an episode of acute kidney injury. Base the frequency of monitoring on the stability and degree of renal function at the time of discharge. Consider referral to a nephrologist or paediatric nephrologist when eGFR is 30 ml/min/1.73 m2 or less in adults, children and young people who have recovered from an acute kidney injury.
Consider referral to a paediatric nephrologist for children and young people who have recovered from an episode of acute kidney injury but have hypertension, impaired renal function or 1+ or greater proteinuria on dipstick testing of an early morning urine sample.
# Information and support for patients and carers
Discuss immediate treatment options, monitoring, prognosis and support options as soon as possible with people with acute kidney injury and/or, if appropriate, their parent or carer. Follow the recommendations on patient views and preferences and shared decision making in the NICE guidelines on patient experience in adult NHS services and shared decision making.
Give information about long‑term treatment options, monitoring, self‑management and support to people who have had acute kidney injury (and/or their parent or carer, if appropriate) in collaboration with a multidisciplinary team appropriate to the person's individual needs.
Give information about future care to people needing renal replacement therapy after discharge following acute kidney injury. This should include information about the frequency and length of dialysis sessions and the preparation needed (such as having a fistula or peritoneal catheter).
Discuss the risk of developing acute kidney injury, particularly the risk associated with conditions leading to dehydration (for example, diarrhoea and vomiting) and drugs that can cause or exacerbate kidney injury (including over‑the‑counter NSAIDs), with people who are at risk of acute kidney injury, particularly those who have:
chronic kidney disease with an eGFR less than 60 ml/min/1.73 m2
neurological or cognitive impairment or disability, which may mean limited access to fluids because of reliance on a carer.Involve parents and carers in the discussion if appropriate.
# Terms used in this guideline
This section defines terms that have been used in a particular way for this guideline. For other definitions see the NICE glossary.
## First-pass renal exposure
First-pass renal exposure is when the contrast medium reaches the renal arteries in a relatively undiluted form, for example, through injection into the left heart, thoracic and suprarenal abdominal aorta, or the renal arteries.
## Stages of chronic kidney disease
Stage
eGFR (ml/min/1.73 m2)
Description
Qualifier
Kidney damage, normal or increased GFR
Kidney damage (presence of structural abnormalities and/or persistent haematuria, proteinuria or microalbuminuria) for ≥3 months
Kidney damage, mildly reduced GFR
Kidney damage (presence of structural abnormalities and/or persistent haematuria, proteinuria or microalbuminuria) for ≥3 months
A
Moderately reduced GFR ± other evidence of kidney damage
GFR <60 ml/min for ≥3 months ± kidney damage
B
Moderately reduced GFR ± other evidence of kidney damage
GFR <60 ml/min for ≥3 months ± kidney damage
Severely reduced GFR ± other evidence of kidney damage
GFR <60 ml/min for ≥3 months ± kidney damage
Established kidney failure
GFR <60 ml/min for ≥3 months ± kidney damage# Recommendations for research
As part of the 2019 update, the guideline committee made 2 new research recommendations (marked ). Research recommendations retained from the 2013 guideline are labelled .
# Key recommendations for research
## Risk stratification for contrast-induced acute kidney injury
Can risk of contrast-induced acute kidney injury be stratified by eGFR thresholds?
For a short explanation of why the committee made the recommendation for research, see the rationale on preventing acute kidney injury in adults having iodine-based contrast media .
Full details of the evidence and the committee's discussion are in evidence review A: preventing contrast-induced acute kidney injury.
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## Different oral fluids and oral fluid regimens
What is the relative effectiveness and cost effectiveness of different oral fluids and different oral fluid regimens, both with and without oral N-acetylcysteine, at preventing contrast-induced acute kidney injury?
For a short explanation of why the committee made the recommendation for research, see the rationale on preventing acute kidney injury in adults having iodine-based contrast media .
Full details of the evidence and the committee's discussion are in evidence review A: preventing contrast-induced acute kidney injury.
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## Long-term outcomes of acute kidney injury
What are the long-term outcomes of acute kidney injury in adults, children and young people?
## Rapid referral to nephrology services for moderate to severe acute kidney injury
What is the clinical and cost effectiveness of rapid referral (within 12 hours) to nephrology services for adults with moderate to severe (stage 2 to 3) acute kidney injury not needing critical care?
## Definition of acute kidney injury – system for staging and detection
Can a simplified definition and staging system, based on Système International (SI) units, be used to predict short- to medium-term outcomes in acute kidney injury?
## Introducing renal replacement therapy
What is the clinical and cost effectiveness of early versus later introduction of renal replacement therapy in patients with acute kidney injury stages 2 and 3, when there is no urgent need for therapy?
## Preventing deterioration
What is the clinical and cost effectiveness of continuing ACE inhibitor or ARB treatment, versus stopping treatment 24 hours before cardiac surgery and resuming 24 hours after, in people with chronic kidney disease and an eGFR of less than 30 ml/min/1.73m2? # Rationale and impact
This section briefly explains why the committee made the recommendations and how they might affect practice. It links to details of the evidence and a full description of the committee's discussion.
# Preventing acute kidney injury in adults having iodine-based contrast media
Recommendations 1.2.7, 1.2.8 and to 1.2.10
## Why the committee made the recommendations
For adults undergoing procedures with intravenous iodine-based contrast media, the evidence showed that oral fluids were as good as intravenous fluids at preventing contrast-induced acute kidney injury. The evidence did not show that any particular type of oral or intravenous fluids is most effective.
The committee agreed that intravenous fluids are not necessary for outpatients who are usually at a lower risk of contrast-induced acute kidney injury. It also agreed that only inpatients at particularly high risk needed intravenous fluids. Most of the risk factors were taken from recommendation 1.1.6 (developed as part of the 2013 guideline) apart from the level of eGFR which was based on the committee's clinical knowledge and experience. The committee also agreed that, based on their experience and expertise, the risk for intra-arterial administration depends on the site of the injection, and is particularly high with first-pass renal exposure because the contrast medium passes into the kidneys relatively undiluted.
For inpatients at particularly high risk of contrast-induced acute kidney injury, economic modelling showed that intravenous volume expansion with a regimen containing intravenous sodium chloride 0.9% and/or intravenous sodium bicarbonate provides best value.
Based on the evidence, the committee decided that intravenous volume expansion should be used only for inpatients at particularly high risk and that oral hydration should be encouraged in all other adults at increased risk of contrast-induced acute kidney injury.
The committee agreed that more research on estimating the risk of contrast-induced acute kidney injury would help to inform future guidance, so made a research recommendation on the use of eGFR thresholds to stratify risk.
Although the committee agreed that oral hydration regimens were non-inferior to intravenous hydration regimens at preventing contrast-induced acute kidney injury, there was not enough comparative data to enable them to be clear about which oral fluid (if any) was most effective. There was some limited evidence that N-acetylcysteine was not beneficial. However, the committee agreed that, in the absence of evidence of harm, this was not sufficient to make a recommendation to restrict its use. Therefore, it made a research recommendation on different oral fluids and different oral fluid regimens, with and without N-acetylcysteine.
The committee did not consider it necessary for all patients being offered iodine-based contrast media to be routinely discussed with a nephrology team, but concluded that this was important for adults on renal replacement therapy, including people with a kidney transplant. The radiology team responsible for administering the contrast medium or the healthcare professional offering the procedure, such as a cardiologist, would usually do this. For people with other contraindications to intravenous fluids, the committee agreed that the decision to give iodine-based contrast media was better made by individual healthcare professionals.
## How the recommendations might affect practice
The recommendations may result in lower resource use for outpatient procedures because people will not need to be admitted to hospital to be given intravenous fluids for volume expansion before they are given a contrast medium.
The recommendation on intravenous volume expansion reflects current practice so there should be no change in practice for inpatients who are at particularly high risk of contrast-induced acute kidney injury. There may be reduced resource use for lower risk inpatients who will not need intravenous fluids.
Full details of the evidence and the committee's discussion are in evidence review A: preventing contrast-induced acute kidney injury.
Return to recommendations# Context
Acute kidney injury, previously known as acute renal failure, encompasses a wide spectrum of injury to the kidneys, not just kidney failure. The definition of acute kidney injury has changed in recent years, and detection is now mostly based on monitoring creatinine levels, with or without urine output. Acute kidney injury is increasingly being seen in primary care in people without any acute illness, and awareness of the condition needs to be raised among primary care health professionals.
Acute kidney injury is seen in 13% to 18% of all people admitted to hospital, with older adults being particularly affected. These people are usually under the care of healthcare professionals practising in specialties other than nephrology, who may not always be familiar with the optimum care of people with acute kidney injury. The number of inpatients affected by acute kidney injury means that it has a major impact on healthcare resources. The costs to the NHS of acute kidney injury (excluding costs in the community) are estimated to be between £434 million and £620 million per year, which is more than the costs associated with breast cancer, or lung and skin cancer combined.
There have been concerns that suboptimal care may contribute to the development of acute kidney injury. In 2009, the National Confidential Enquiry into Patient Outcome and Death (NCEPOD) reported the results of an enquiry into the deaths of a large group of adults with acute kidney injury. This described systemic deficiencies in the care of people who died from acute kidney injury: only 50% of these had received 'good' care. Other deficiencies in the care of people who died of acute kidney injury included failures in acute kidney injury prevention, recognition, therapy and timely access to specialist services. This report led to the Department of Health's request for NICE to develop its first guideline on acute kidney injury in adults and also, importantly, in children and young people.
This guideline emphasises early intervention and stresses the importance of risk assessment and prevention, early recognition and treatment. It is primarily aimed at the non-specialist clinician, who will care for most people with acute kidney injury in a variety of settings. The recommendations aim to address known and unacceptable variations in recognition, assessment, initial treatment and referral for renal replacement therapy. The inpatient mortality of acute kidney injury varies considerably, depending on its severity, setting (intensive care or not), and many other patient-related factors, but in the UK might typically be 25% to 30% or more. In view of its frequency and mortality rate, prevention or amelioration of just 20% of cases of acute kidney injury would prevent a large number of deaths and substantially reduce complications and their associated costs.
New evidence was identified by the NICE surveillance team on preventing contrast-induced acute kidney injury. Topic experts, including those who helped to develop the 2013 guideline, agreed that a significant new study could have an impact on the recommendations. This evidence has been reviewed and the recommendations in this area updated.# Finding more information and resources
You can see everything NICE says on this topic in the NICE Pathway on acute kidney injury.
To find out what NICE has said on topics related to this guideline, see our web page on acute kidney injury.
For full details of the evidence and the guideline committee's discussions, see the evidence reviews. You can also find information about how the guideline was developed, including details of the committee.
NICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting NICE guidelines into practice, see resources to help you put guidance into practice.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Assessing risk of acute kidney injury\n\n## Identifying acute kidney injury in people with acute illness\n\nInvestigate for acute kidney injury, by measuring serum creatinine and comparing with baseline, in adults with acute illness if any of the following are likely or present:\n\nchronic kidney disease (adults with an estimated glomerular filtration rate [eGFR] less than 60\xa0ml/min/1.73\xa0m2 are at particular risk)\n\nheart failure\n\nliver disease\n\ndiabetes\n\nhistory of acute kidney injury\n\noliguria (urine output less than 0.5\xa0ml/kg/hour)\n\nneurological or cognitive impairment or disability, which may mean limited access to fluids because of reliance on a carer\n\nhypovolaemia\n\nuse of drugs that can cause or exacerbate kidney injury (such as non‑steroidal anti‑inflammatory drugs [NSAIDs], aminoglycosides, angiotensin‑converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists [ARBs] and diuretics) within the past week, especially if hypovolaemic\n\nuse of iodine-based contrast media within the past week\n\nsymptoms or history of urological obstruction, or conditions that may lead to obstruction\n\nsepsis\n\ndeteriorating early warning scores\n\nage 65\xa0years or over. \n\nInvestigate for acute kidney injury, by measuring serum creatinine and comparing with baseline, in children and young people with acute illness if any of the following are likely or present:\n\nchronic kidney disease\n\nheart failure\n\nliver disease\n\nhistory of acute kidney injury\n\noliguria (urine output less than 0.5\xa0ml/kg/hour)\n\nyoung age, neurological or cognitive impairment or disability, which may mean limited access to fluids because of reliance on a parent or carer\n\nhypovolaemia\n\nuse of drugs that can cause or exacerbate kidney injury (such as NSAIDs, aminoglycosides, ACE inhibitors, ARBs and diuretics) within the past week, especially if hypovolaemic\n\nsymptoms or history of urological obstruction, or conditions that may lead to obstruction\n\nsepsis\n\na deteriorating paediatric early warning score\n\nsevere diarrhoea (children and young people with bloody diarrhoea are at particular risk)\n\nsymptoms or signs of nephritis (such as oedema or haematuria)\n\nhaematological malignancy\n\nhypotension. \n\n## Identifying acute kidney injury in people with no obvious acute illness\n\nBe aware that in adults, children and young people with chronic kidney disease and no obvious acute illness, a rise in serum creatinine may indicate acute kidney injury rather than a worsening of their chronic disease. \n\nEnsure that acute kidney injury is considered when an adult, child or young person presents with an illness with no clear acute component and has any of the following:\n\nchronic kidney disease, especially stage 3B, 4 or 5 as shown in table1, or urological disease\n\nnew onset or significant worsening of urological symptoms\n\nsymptoms suggesting complications of acute kidney injury\n\nsymptoms or signs of a multi‑system disease affecting the kidneys and other organ systems (for example, signs or symptoms of acute kidney injury, plus a purpuric rash). \n\n## Assessing risk factors in adults having iodine-based contrast media\n\nBefore offering iodine-based contrast media to adults for non‑emergency imaging, investigate for chronic kidney disease by measuring eGFR or by checking an eGFR result obtained within the past 3\xa0months. \n\nBefore offering iodine-based contrast media to adults, assess their risk of acute kidney injury but do not delay emergency imaging. Be aware that increased risk is associated with:\n\nchronic kidney disease (adults with an eGFR less than 40\xa0ml/min/1.73\xa0m2 are at particular risk)\n\ndiabetes but only with chronic kidney disease (adults with an eGFR less than 40\xa0ml/min/1.73\xa0m2 are at particular risk)\n\nheart failure\n\nrenal transplant\n\nage 75\xa0years or over\n\nhypovolaemia\n\nincreasing volume of contrast agent\n\nintra-arterial administration of contrast medium with first-pass renal exposure. \n\nInclude the risks of developing acute kidney injury in the routine discussion of risks and benefits of the imaging procedure. Follow the recommendations in the NICE guideline on shared decision making. \n\n## Assessing risk factors in adults having surgery\n\nAssess the risk of acute kidney injury in adults before surgery. Be aware that increased risk is associated with:\n\nemergency surgery, especially when the person has sepsis or hypovolaemia\n\nintraperitoneal surgery\n\nchronic kidney disease (adults with an eGFR less than 60\xa0ml/min/1.73\xa0m2 are at particular risk)\n\ndiabetes\n\nheart failure\n\nage 65\xa0years or over\n\nliver disease\n\nuse of drugs that can cause or exacerbate kidney injury in the perioperative period (in particular, NSAIDs after surgery).Use the risk assessment to inform a clinical management plan. \n\nInclude the risks of developing acute kidney injury in the routine discussion of risks and benefits of surgery. Follow the recommendations in the NICE guideline on shared decision making. \n\n# Preventing acute kidney injury\n\n## Ongoing assessment of the condition of people in hospital\n\nFollow the recommendations in the NICE guideline on acutely ill adults in hospital on the use of track and trigger systems (early warning scores) to identify adults who are at risk of acute kidney injury because their clinical condition is deteriorating or is at risk of deteriorating. \n\nWhen adults are at risk of acute kidney injury, ensure that systems are in place to recognise and respond to oliguria (urine output less than 0.5\xa0ml/kg/hour) if the track and trigger system (early warning score) does not monitor urine output. \n\nConsider using a paediatric early warning score to identify children and young people admitted to hospital who are at risk of acute kidney injury because their clinical condition is deteriorating or is at risk of deteriorating.\n\nRecord physiological observations at admission and then according to local protocols for given paediatric early warning scores.\n\nIncrease the frequency of observations if abnormal physiology is detected. \n\nIf using a paediatric early warning score, use one with multiple‑parameter or aggregate weighted scoring systems that allow a graded response and:\n\ndefine the parameters to be measured and the frequency of observations\n\ninclude a clear and explicit statement of the parameters, cut‑off points or scores that should trigger a response. \n\nIf using a paediatric early warning score, use one with multiple‑parameter or aggregate weighted scoring systems that measure:\n\nheart rate\n\nrespiratory rate\n\nsystolic blood pressure\n\nlevel of consciousness\n\noxygen saturation\n\ntemperature\n\ncapillary refill time. \n\nWhen children and young people are at risk of acute kidney injury because of risk factors listed in the recommendation in the section on identifying acute kidney injury in people with acute illness:\n\nmeasure urine output\n\nrecord weight twice daily to determine fluid balance\n\nmeasure urea, creatinine and electrolytes\n\nthink about measuring lactate, blood glucose and blood gases. \n\n## Preventing acute kidney injury in adults having iodine-based contrast media\n\nEncourage oral hydration before and after procedures using intravenous iodine-based contrast media in adults at increased risk of contrast-induced acute kidney injury (see the recommendation on increased risk in the section on assessing risk factors in adults having iodine-based contrast media). \n\nFor inpatients having iodine-based contrast media, consider intravenous volume expansion with either isotonic sodium bicarbonate or 0.9% sodium chloride if they are at particularly high risk, for example, if:\n\nthey have an eGFR less than 30\xa0ml/min/1.73\xa0m2\n\nthey have had a renal transplant\n\na large volume of contrast medium is being used (for example, higher than the standard diagnostic dose or repeat administration within 24\xa0hours)\n\nintra-arterial administration of contrast medium with first-pass renal exposure is being used.For more information on managing intravenous fluid therapy, see the NICE guideline on intravenous fluid therapy in adults in hospital. \n\nConsider temporarily stopping ACE inhibitors and ARBs in adults having iodine-based contrast media if they have chronic kidney disease with an eGFR less than 40\xa0ml/min/1.73\xa0m2. \n\nDiscuss the person's care with a nephrology team before offering iodine-based contrast media to adults on renal replacement therapy, including people with a renal transplant, but do not delay emergency imaging for this. \n\nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on preventing acute kidney injury in adults having iodine-based contrast media\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: preventing contrast-induced acute kidney injury.\n\nLoading. Please wait.\n\n## Monitoring and preventing deterioration in people with or at high risk of acute kidney injury\n\nConsider electronic clinical decision support systems (CDSS) to support clinical decision making and prescribing, but ensure they do not replace clinical judgement. \n\nWhen acquiring any new CDSS or systems for electronic prescribing, ensure that any systems considered:\n\ncan interact with laboratory systems\n\ncan recommend drug dosing and frequency\n\ncan store and update data on patient history and characteristics, including age, weight and renal replacement therapy\n\ncan include alerts that are mandatory for the healthcare professional to acknowledge and review. \n\nSeek advice from a pharmacist about optimising medicines and drug dosing in adults, children and young people with or at risk of acute kidney injury. \n\nConsider temporarily stopping ACE inhibitors and ARBs in adults, children and young people with diarrhoea, vomiting or sepsis until their clinical condition has improved and stabilised. \n\n# Detecting acute kidney injury\n\nDetect acute kidney injury, in line with the (p)RIFLE (paediatric Risk, Injury, Failure, Loss, End stage renal disease), AKIN (Acute Kidney Injury Network) or KDIGO (Kidney Disease: Improving Global Outcomes) definitions, by using any of the following criteria:\n\na rise in serum creatinine of 26\xa0micromol/litre or greater within 48\xa0hours\n\na 50% or greater rise in serum creatinine known or presumed to have occurred within the past 7\xa0days (see also an algorithm for early identification of acute kidney injury, endorsed by NHS England)\n\na fall in urine output to less than 0.5\xa0ml/kg/hour for more than 6\xa0hours in adults and more than 8\xa0hours in children and young people\n\na 25% or greater fall in eGFR in children and young people within the past 7\xa0days. \n\nMonitor serum creatinine regularly in all adults, children and young people with or at risk of acute kidney injury. Frequency of monitoring should vary according to clinical need, but daily measurement is typical while in hospital. \n\n# Identifying the cause(s) of acute kidney injury\n\nIdentify the cause(s) of acute kidney injury and record the details in the person's notes. \n\n## Urinalysis\n\nPerform urine dipstick testing for blood, protein, leucocytes, nitrites and glucose in all people as soon as acute kidney injury is suspected or detected. Document the results and ensure that appropriate action is taken when results are abnormal. \n\nThink about a diagnosis of acute nephritis and referral to the nephrology team when an adult, child or young person with no obvious cause of acute kidney injury has urine dipstick results showing haematuria and proteinuria, without urinary tract infection or trauma due to catheterisation. \n\n## Ultrasound\n\nDo not routinely offer ultrasound of the urinary tract when the cause of the acute kidney injury has been identified. \n\nWhen pyonephrosis (infected and obstructed kidney[s]) is suspected in adults, children and young people with acute kidney injury, offer immediate ultrasound of the urinary tract (to be performed within 6\xa0hours of assessment). \n\nWhen adults, children and young people have no identified cause of their acute kidney injury or are at risk of urinary tract obstruction, offer urgent ultrasound of the urinary tract (to be performed within 24\xa0hours of assessment). \n\n# Managing acute kidney injury\n\n## Relieving urological obstruction\n\nRefer all adults, children and young people with upper tract urological obstruction to a urologist. Refer immediately when one or more of the following is present:\n\npyonephrosis\n\nan obstructed solitary kidney\n\nbilateral upper urinary tract obstruction\n\ncomplications of acute kidney injury caused by urological obstruction. \n\nWhen nephrostomy or stenting is used to treat upper tract urological obstruction in adults, children and young people with acute kidney injury, carry it out as soon as possible and within 12\xa0hours of diagnosis. \n\n## Pharmacological management\n\nDo not routinely offer loop diuretics to treat acute kidney injury. \n\nConsider loop diuretics for treating fluid overload or oedema while:\n\nan adult, child or young person is awaiting renal replacement therapy or\n\nrenal function is recovering in an adult, child or young person not receiving renal replacement therapy. \n\nDo not offer low-dose dopamine to treat acute kidney injury. \n\n## Referring for renal replacement therapy\n\nDiscuss any potential indications for renal replacement therapy with a nephrologist, paediatric nephrologist and/or critical care specialist immediately to ensure that the therapy is started as soon as needed. \n\nWhen an adult, child or young person has significant comorbidities, discuss with them and/or their parent or carer and within the multidisciplinary team whether renal replacement therapy would offer benefit. Follow the recommendations in the NICE guideline on shared decision making. \n\nRefer adults, children and young people immediately for renal replacement therapy if any of the following are not responding to medical management:\n\nhyperkalaemia\n\nmetabolic acidosis\n\nsymptoms or complications of uraemia (for example, pericarditis or encephalopathy)\n\nfluid overload\n\npulmonary oedema. \n\nBase the decision to start renal replacement therapy on the condition of the adult, child or young person as a whole and not on an isolated urea, creatinine or potassium value. \n\nWhen there are indications for renal replacement therapy, the nephrologist and/or critical care specialist should discuss the treatment with the adult, child or young person and/or their parent or carer as soon as possible and before starting treatment. Follow the recommendations in the NICE guideline on shared decision making. \n\n## Referring to nephrology\n\nRefer adults, children and young people with acute kidney injury to a nephrologist, paediatric nephrologist or critical care specialist immediately if they meet criteria for renal replacement therapy in recommendation 1.5.8. \n\nDo not refer adults, children or young people to a nephrologist or paediatric nephrologist when there is a clear cause for acute kidney injury and the condition is responding promptly to medical management, unless they have a renal transplant. \n\nConsider discussing management with a nephrologist or paediatric nephrologist when an adult, child or young person with severe illness might benefit from treatment, but there is uncertainty as to whether they are nearing the end of their life. \n\nRefer adults, children and young people in intensive care to a nephrology team when there is uncertainty about the cause of acute kidney injury or when specialist management of kidney injury might be needed. \n\nDiscuss the management of acute kidney injury with a nephrologist or paediatric nephrologist as soon as possible and within 24\xa0hours of detection when one or more of the following is present:\n\na possible diagnosis that may need specialist treatment (for example, vasculitis, glomerulonephritis, tubulointerstitial nephritis or myeloma)\n\nacute kidney injury with no clear cause\n\ninadequate response to treatment\n\ncomplications associated with acute kidney injury\n\nstage 3 acute kidney injury (according to (p)RIFLE, AKIN or KDIGO criteria)\n\na renal transplant\n\nchronic kidney disease stage 4 or 5 as shown in table 1. \n\nMonitor serum creatinine after an episode of acute kidney injury. Base the frequency of monitoring on the stability and degree of renal function at the time of discharge. Consider referral to a nephrologist or paediatric nephrologist when eGFR is 30\xa0ml/min/1.73\xa0m2 or less in adults, children and young people who have recovered from an acute kidney injury. \n\nConsider referral to a paediatric nephrologist for children and young people who have recovered from an episode of acute kidney injury but have hypertension, impaired renal function or 1+ or greater proteinuria on dipstick testing of an early morning urine sample. \n\n# Information and support for patients and carers\n\nDiscuss immediate treatment options, monitoring, prognosis and support options as soon as possible with people with acute kidney injury and/or, if appropriate, their parent or carer. Follow the recommendations on patient views and preferences and shared decision making in the NICE guidelines on patient experience in adult NHS services and shared decision making. \n\nGive information about long‑term treatment options, monitoring, self‑management and support to people who have had acute kidney injury (and/or their parent or carer, if appropriate) in collaboration with a multidisciplinary team appropriate to the person's individual needs. \n\nGive information about future care to people needing renal replacement therapy after discharge following acute kidney injury. This should include information about the frequency and length of dialysis sessions and the preparation needed (such as having a fistula or peritoneal catheter). \n\nDiscuss the risk of developing acute kidney injury, particularly the risk associated with conditions leading to dehydration (for example, diarrhoea and vomiting) and drugs that can cause or exacerbate kidney injury (including over‑the‑counter NSAIDs), with people who are at risk of acute kidney injury, particularly those who have:\n\nchronic kidney disease with an eGFR less than 60\xa0ml/min/1.73\xa0m2\n\nneurological or cognitive impairment or disability, which may mean limited access to fluids because of reliance on a carer.Involve parents and carers in the discussion if appropriate. \n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a particular way for this guideline. For other definitions see the NICE glossary.\n\n## First-pass renal exposure\n\nFirst-pass renal exposure is when the contrast medium reaches the renal arteries in a relatively undiluted form, for example, through injection into the left heart, thoracic and suprarenal abdominal aorta, or the renal arteries.\n\n## Stages of chronic kidney disease\n\nStage\n\neGFR (ml/min/1.73\xa0m2)\n\nDescription\n\nQualifier\n\n\n\n≥90\n\nKidney damage, normal or increased GFR\n\nKidney damage (presence of structural abnormalities and/or persistent haematuria, proteinuria or microalbuminuria) for ≥3 months\n\n\n\n–89\n\nKidney damage, mildly reduced GFR\n\nKidney damage (presence of structural abnormalities and/or persistent haematuria, proteinuria or microalbuminuria) for ≥3 months\n\nA\n\n–59\n\nModerately reduced GFR ± other evidence of kidney damage\n\nGFR <60 ml/min for ≥3 months ± kidney damage\n\nB\n\n–44\n\nModerately reduced GFR ± other evidence of kidney damage\n\nGFR <60 ml/min for ≥3 months ± kidney damage\n\n\n\n–29\n\nSeverely reduced GFR ± other evidence of kidney damage\n\nGFR <60 ml/min for ≥3 months ± kidney damage\n\n\n\n<15\n\nEstablished kidney failure\n\nGFR <60 ml/min for ≥3 months ± kidney damage", 'Recommendations for research': "As part of the 2019 update, the guideline committee made 2 new research recommendations (marked ). Research recommendations retained from the 2013 guideline are labelled .\n\n# Key recommendations for research\n\n## Risk stratification for contrast-induced acute kidney injury\n\nCan risk of contrast-induced acute kidney injury be stratified by eGFR thresholds? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on preventing acute kidney injury in adults having iodine-based contrast media\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: preventing contrast-induced acute kidney injury.\n\nLoading. Please wait.\n\n## Different oral fluids and oral fluid regimens\n\nWhat is the relative effectiveness and cost effectiveness of different oral fluids and different oral fluid regimens, both with and without oral N-acetylcysteine, at preventing contrast-induced acute kidney injury? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on preventing acute kidney injury in adults having iodine-based contrast media\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: preventing contrast-induced acute kidney injury.\n\nLoading. Please wait.\n\n## Long-term outcomes of acute kidney injury\n\nWhat are the long-term outcomes of acute kidney injury in adults, children and young people? \n\n## Rapid referral to nephrology services for moderate to severe acute kidney injury\n\nWhat is the clinical and cost effectiveness of rapid referral (within 12 hours) to nephrology services for adults with moderate to severe (stage 2 to 3) acute kidney injury not needing critical care? \n\n## Definition of acute kidney injury – system for staging and detection\n\nCan a simplified definition and staging system, based on Système International (SI) units, be used to predict short- to medium-term outcomes in acute kidney injury? \n\n## Introducing renal replacement therapy\n\nWhat is the clinical and cost effectiveness of early versus later introduction of renal replacement therapy in patients with acute kidney injury stages 2 and 3, when there is no urgent need for therapy? \n\n## Preventing deterioration\n\nWhat is the clinical and cost effectiveness of continuing ACE inhibitor or ARB treatment, versus stopping treatment 24 hours before cardiac surgery and resuming 24 hours after, in people with chronic kidney disease and an eGFR of less than 30 ml/min/1.73m2? ", 'Rationale and impact': "This section briefly explains why the committee made the recommendations and how they might affect practice. It links to details of the evidence and a full description of the committee's discussion.\n\n# Preventing acute kidney injury in adults having iodine-based contrast media\n\nRecommendations 1.2.7, 1.2.8 and to 1.2.10\n\n## Why the committee made the recommendations\n\nFor adults undergoing procedures with intravenous iodine-based contrast media, the evidence showed that oral fluids were as good as intravenous fluids at preventing contrast-induced acute kidney injury. The evidence did not show that any particular type of oral or intravenous fluids is most effective.\n\nThe committee agreed that intravenous fluids are not necessary for outpatients who are usually at a lower risk of contrast-induced acute kidney injury. It also agreed that only inpatients at particularly high risk needed intravenous fluids. Most of the risk factors were taken from recommendation 1.1.6 (developed as part of the 2013 guideline) apart from the level of eGFR which was based on the committee's clinical knowledge and experience. The committee also agreed that, based on their experience and expertise, the risk for intra-arterial administration depends on the site of the injection, and is particularly high with first-pass renal exposure because the contrast medium passes into the kidneys relatively undiluted.\n\nFor inpatients at particularly high risk of contrast-induced acute kidney injury, economic modelling showed that intravenous volume expansion with a regimen containing intravenous sodium chloride 0.9% and/or intravenous sodium bicarbonate provides best value.\n\nBased on the evidence, the committee decided that intravenous volume expansion should be used only for inpatients at particularly high risk and that oral hydration should be encouraged in all other adults at increased risk of contrast-induced acute kidney injury.\n\nThe committee agreed that more research on estimating the risk of contrast-induced acute kidney injury would help to inform future guidance, so made a research recommendation on the use of eGFR thresholds to stratify risk.\n\nAlthough the committee agreed that oral hydration regimens were non-inferior to intravenous hydration regimens at preventing contrast-induced acute kidney injury, there was not enough comparative data to enable them to be clear about which oral fluid (if any) was most effective. There was some limited evidence that N-acetylcysteine was not beneficial. However, the committee agreed that, in the absence of evidence of harm, this was not sufficient to make a recommendation to restrict its use. Therefore, it made a research recommendation on different oral fluids and different oral fluid regimens, with and without N-acetylcysteine.\n\nThe committee did not consider it necessary for all patients being offered iodine-based contrast media to be routinely discussed with a nephrology team, but concluded that this was important for adults on renal replacement therapy, including people with a kidney transplant. The radiology team responsible for administering the contrast medium or the healthcare professional offering the procedure, such as a cardiologist, would usually do this. For people with other contraindications to intravenous fluids, the committee agreed that the decision to give iodine-based contrast media was better made by individual healthcare professionals.\n\n## How the recommendations might affect practice\n\nThe recommendations may result in lower resource use for outpatient procedures because people will not need to be admitted to hospital to be given intravenous fluids for volume expansion before they are given a contrast medium.\n\nThe recommendation on intravenous volume expansion reflects current practice so there should be no change in practice for inpatients who are at particularly high risk of contrast-induced acute kidney injury. There may be reduced resource use for lower risk inpatients who will not need intravenous fluids.\n\nFull details of the evidence and the committee's discussion are in evidence review A: preventing contrast-induced acute kidney injury.\n\nReturn to recommendations", 'Context': "Acute kidney injury, previously known as acute renal failure, encompasses a wide spectrum of injury to the kidneys, not just kidney failure. The definition of acute kidney injury has changed in recent years, and detection is now mostly based on monitoring creatinine levels, with or without urine output. Acute kidney injury is increasingly being seen in primary care in people without any acute illness, and awareness of the condition needs to be raised among primary care health professionals.\n\nAcute kidney injury is seen in 13% to 18% of all people admitted to hospital, with older adults being particularly affected. These people are usually under the care of healthcare professionals practising in specialties other than nephrology, who may not always be familiar with the optimum care of people with acute kidney injury. The number of inpatients affected by acute kidney injury means that it has a major impact on healthcare resources. The costs to the NHS of acute kidney injury (excluding costs in the community) are estimated to be between £434 million and £620 million per year, which is more than the costs associated with breast cancer, or lung and skin cancer combined.\n\nThere have been concerns that suboptimal care may contribute to the development of acute kidney injury. In 2009, the National Confidential Enquiry into Patient Outcome and Death (NCEPOD) reported the results of an enquiry into the deaths of a large group of adults with acute kidney injury. This described systemic deficiencies in the care of people who died from acute kidney injury: only 50% of these had received 'good' care. Other deficiencies in the care of people who died of acute kidney injury included failures in acute kidney injury prevention, recognition, therapy and timely access to specialist services. This report led to the Department of Health's request for NICE to develop its first guideline on acute kidney injury in adults and also, importantly, in children and young people.\n\nThis guideline emphasises early intervention and stresses the importance of risk assessment and prevention, early recognition and treatment. It is primarily aimed at the non-specialist clinician, who will care for most people with acute kidney injury in a variety of settings. The recommendations aim to address known and unacceptable variations in recognition, assessment, initial treatment and referral for renal replacement therapy. The inpatient mortality of acute kidney injury varies considerably, depending on its severity, setting (intensive care or not), and many other patient-related factors, but in the UK might typically be 25% to 30% or more. In view of its frequency and mortality rate, prevention or amelioration of just 20% of cases of acute kidney injury would prevent a large number of deaths and substantially reduce complications and their associated costs.\n\nNew evidence was identified by the NICE surveillance team on preventing contrast-induced acute kidney injury. Topic experts, including those who helped to develop the 2013 guideline, agreed that a significant new study could have an impact on the recommendations. This evidence has been reviewed and the recommendations in this area updated.", 'Finding more information and resources': "You can see everything NICE says on this topic in the NICE Pathway on acute kidney injury.\n\nTo find out what NICE has said on topics related to this guideline, see our web page on acute kidney injury.\n\nFor full details of the evidence and the guideline committee's discussions, see the evidence reviews. You can also find information about how the guideline was developed, including details of the committee.\n\nNICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting NICE guidelines into practice, see resources to help you put guidance into practice."}
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https://www.nice.org.uk/guidance/ng148
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This guideline covers preventing, detecting and managing acute kidney injury in children, young people and adults. It aims to improve assessment and detection by non-specialists, and specifies when people should be referred to specialist services. This will improve early recognition and treatment, and reduce the risk of complications in people with acute kidney injury.
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